Non-Hodgkin lymphoma is a disease in which malignant (cancer) cells form in the lymph system.

Non-Hodgkin lymphoma is a type of cancer that forms in the lymph system. The lymph system is part of the immune system. It helps protect the body from infection and disease.

The lymph system is made up of the following:

• Lymph: Colorless, watery fluid that travels through the lymph vessels and carries lymphocytes (white blood cells). There are three types of lymphocytes:
  • B lymphocytes that make antibodies to help fight infection. Also called B cells. Most types of non-Hodgkin lymphoma begin in B lymphocytes.
  • T lymphocytes that help B lymphocytes make the antibodies that help fight infection. Also called T cells.
  • Natural killer cells that attack cancer cells and viruses. Also called NK cells.
• Lymph vessels: A network of thin tubes that collect lymph from different parts of the body and return it to the bloodstream.
• Lymph nodes: Small, bean-shaped structures that filter lymph and store white blood cells that help fight infection and disease. Lymph nodes are found along a network of lymph vessels throughout the body. Groups of lymph nodes are found in the neck, underarm, mediastinum, abdomen, pelvis, and groin.
• Spleen: An organ that makes lymphocytes, stores red blood cells and lymphocytes, filters the blood, and destroys old blood cells. The spleen is on the left side of the abdomen near the stomach.
• Thymus: An organ in which T lymphocytes mature and multiply. The thymus is in the chest behind the breastbone.
• Tonsils: Two small masses of lymph tissue at the back of the throat. There is one tonsil on each side of the throat.
• Bone marrow: The soft, spongy tissue in the center of certain bones, such as the hip bone and breastbone. White blood cells, red blood cells, and platelets are made in the bone marrow.

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Lymph tissue is also found in other parts of the body such as the lining of the digestive tract, bronchus, and skin.

There are two general types of lymphomas: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of non-Hodgkin lymphoma in adults, including during pregnancy.

Non-Hodgkin lymphoma can be indolent or aggressive.

Non-Hodgkin lymphoma grows and spreads at different rates and can be indolent or aggressive. Indolent lymphoma tends to grow and spread slowly, and has few signs and symptoms. Aggressive lymphoma grows and spreads quickly, and has signs and symptoms that can be severe. The treatments for indolent and aggressive lymphoma are different.

This summary is about the following types of non-Hodgkin lymphoma:

Indolent non-Hodgkin lymphomas

• Follicular lymphoma. Follicular lymphoma is the most common type of indolent non-Hodgkin lymphoma. It is a very slow-growing type of non-Hodgkin lymphoma that begins in B lymphocytes. It affects the lymph nodes and may spread to the bone marrow or spleen. Most patients with follicular lymphoma are age 50 years and older when they are diagnosed. Follicular lymphoma may go away without treatment. The patient is closely watched for signs or symptoms that the disease has come back. Treatment is needed if signs or symptoms occur after the cancer disappeared or after initial cancer treatment. Sometimes follicular lymphoma can become a more aggressive type of lymphoma, such as diffuse large B-cell lymphoma.
• Lymphoplasmacytic lymphoma. In most cases of lymphoplasmacytic lymphoma, B lymphocytes that are turning into plasma cells make large amounts of a protein called monoclonal immunoglobulin M (IgM) antibody. High levels of IgM antibody in the blood cause the blood plasma to thicken. This may cause signs or symptoms such as trouble seeing or hearing, heart problems, shortness of breath, headache, dizziness, and numbness or tingling of the hands and feet. Sometimes there are no signs or symptoms of lymphoplasmacytic lymphoma. It may be found when a blood test is done for another reason. Lymphoplasmacytic lymphoma often spreads to the bone marrow, lymph nodes, and spleen. Patients with lymphoplasmacytic lymphoma should be checked for hepatitis C virus infection. It is also called Waldenström macroglobulinemia.
• Marginal zone lymphoma. This type of non-Hodgkin lymphoma begins in B lymphocytes in a part of lymph tissue called the marginal zone. The prognosis may be worse for patients aged 70 years or older, those with stage III or stage IV disease, and those with high lactate dehydrogenase (LDH) levels. There are five different types of marginal zone lymphoma. They are grouped by the type of tissue where the lymphoma formed:
  • Nodal marginal zone lymphoma. Nodal marginal zone lymphoma forms in lymph nodes. This type of non-Hodgkin lymphoma is rare. It is also called monocytoid B-cell lymphoma.
  • Gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Gastric MALT lymphoma usually begins in the stomach. This type of marginal zone lymphoma forms in cells in the mucosa that help make antibodies. Patients with gastric MALT lymphoma may also have Helicobacter gastritis or an autoimmune disease, such as Hashimoto thyroiditis or Sjögren syndrome.
  • Extragastric MALT lymphoma. Extragastric MALT lymphoma begins outside of the stomach in almost every part of the body including other parts of the gastrointestinal tract, salivary glands, thyroid, lung, skin, and around the eye. This type of marginal zone lymphoma forms in cells in the mucosa that help make antibodies. Extragastric MALT lymphoma may come back many years after treatment.
  • Mediterranean abdominal lymphoma. This is a type of MALT lymphoma that occurs in young adults in eastern Mediterranean countries. It often forms in the abdomen and patients may also be infected with bacteria called Campylobacter jejuni. This type of lymphoma is also called immunoproliferative small intestinal disease.
  • Splenic marginal zone lymphoma. This type of marginal zone lymphoma begins in the spleen and may spread to the peripheral blood and bone marrow. The most common sign of this type of splenic marginal zone lymphoma is a spleen that is larger than normal.
• Primary cutaneous anaplastic large cell lymphoma. This type of non-Hodgkin lymphoma is in the skin only. It can be a benign (not cancer) nodule that may go away on its own or it can spread to many places on the skin and need treatment.

Aggressive non-Hodgkin lymphomas

• Diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. It grows quickly in the lymph nodes and often the spleen, liver, bone marrow, or other organs are also affected. Signs and symptoms of diffuse large B-cell lymphoma may include fever, drenching night sweats, and weight loss. These are also called B symptoms.
• Primary mediastinal large B-cell lymphoma. This type of non-Hodgkin lymphoma is marked by the overgrowth of fibrous (scar-like) lymph tissue. A tumor most often forms behind the breastbone. It may press on the airways and cause coughing and trouble breathing. Most patients with primary mediastinal large B-cell lymphoma are women who are age 30 to 40 years.
• Follicular large cell lymphoma, stage III. Follicular large cell lymphoma, stage III, is a very rare type of non-Hodgkin lymphoma. Treatment of this type of follicular lymphoma is more like treatment of aggressive NHL than of indolent NHL.
• Anaplastic large cell lymphoma. Anaplastic large cell lymphoma is a type of non-Hodgkin lymphoma that usually begins in T lymphocytes. The cancer cells also have a marker called CD30 on the surface of the cell.

  There are two types of anaplastic large cell lymphoma:

  • Cutaneous anaplastic large cell lymphoma. This type of anaplastic large cell lymphoma mostly affects the skin, but other parts of the body may also be affected. Signs of cutaneous anaplastic large cell lymphoma include one or more bumps or ulcers on the skin. This type of lymphoma is rare and indolent.
  • Systemic anaplastic large cell lymphoma. This type of anaplastic large cell lymphoma begins in the lymph nodes and may affect other parts of the body. This type of lymphoma is more aggressive. Patients may have a lot of anaplastic lymphoma kinase (ALK) protein inside the lymphoma cells. These patients have a better prognosis than patients who do not have extra ALK protein. Systemic anaplastic large cell lymphoma is more common in children than adults. For more information, see Childhood Non-Hodgkin Lymphoma Treatment.
• Extranodal NK-/T-cell lymphoma. Extranodal NK-/T-cell lymphoma usually begins in the area around the nose. It may also affect the paranasal sinus (hollow spaces in the bones around the nose), roof of the mouth, trachea, skin, stomach, and intestines. Most cases of extranodal NK-/T-cell lymphoma have Epstein-Barr virus in the tumor cells. Sometimes hemophagocytic syndrome occurs (a serious condition in which there are too many active histiocytes and T cells that cause severe inflammation in the body). Treatment to suppress the immune system is needed. This type of non-Hodgkin lymphoma is not common in the United States.
• Lymphomatoid granulomatosis. Lymphomatoid granulomatosis mostly affects the lungs. It may also affect the paranasal sinuses (hollow spaces in the bones around the nose), skin, kidneys, and central nervous system. In lymphomatoid granulomatosis, cancer invades the blood vessels and kills tissue. Because the cancer may spread to the brain, intrathecal chemotherapy or radiation therapy to the brain is given.
• Angioimmunoblastic T-cell lymphoma. This type of non-Hodgkin lymphoma begins in T cells. Swollen lymph nodes are a common sign. Other signs may include a skin rash, fever, weight loss, or drenching night sweats. There may also be high levels of gamma globulin (antibodies) in the blood. Patients may also have opportunistic infections because their immune systems are weakened.
• Peripheral T-cell lymphoma. Peripheral T-cell lymphoma begins in mature T lymphocytes. This type of T lymphocyte matures in the thymus gland and travels to other lymphatic sites in the body such as the lymph nodes, bone marrow, and spleen. There are three subtypes of peripheral T-cell lymphoma:
  • Hepatosplenic T-cell lymphoma. This is an uncommon type of peripheral T-cell lymphoma that occurs mostly in young men. It begins in the liver and spleen and the cancer cells also have a T-cell receptor called gamma/delta on the surface of the cell.
  • Subcutaneous panniculitis-like T-cell lymphoma. Subcutaneous panniculitis-like T-cell lymphoma begins in the skin or mucosa. It may occur with hemophagocytic syndrome (a serious condition in which there are too many active histiocytes and T cells that cause severe inflammation in the body). Treatment to suppress the immune system is needed.
  • Enteropathy-type intestinal T-cell lymphoma. This type of peripheral T-cell lymphoma occurs in the small bowel of patients with untreated celiac disease (an immune response to gluten that causes malnutrition). Patients who are diagnosed with celiac disease in childhood and stay on a gluten-free diet rarely develop enteropathy-type intestinal T-cell lymphoma.
• Intravascular large B-cell lymphoma. This type of non-Hodgkin lymphoma affects blood vessels, especially the small blood vessels in the brain, kidney, lung, and skin. Signs and symptoms of intravascular large B-cell lymphoma are caused by blocked blood vessels. It is also called intravascular lymphomatosis.
• Burkitt lymphoma. Burkitt lymphoma is a type of B-cell non-Hodgkin lymphoma that grows and spreads very quickly. It may affect the jaw, bones of the face, bowel, kidneys, ovaries, or other organs. There are three main types of Burkitt lymphoma (endemic, sporadic, and immunodeficiency related). Endemic Burkitt lymphoma commonly occurs in Africa and is linked to the Epstein-Barr virus, and sporadic Burkitt lymphoma occurs throughout the world. Immunodeficiency-related Burkitt lymphoma is most often seen in patients who have AIDS. Burkitt lymphoma may spread to the brain and spinal cord and treatment to prevent its spread may be given. Burkitt lymphoma occurs most often in children and young adults. For more information, see Childhood Non-Hodgkin Lymphoma Treatment. Burkitt lymphoma is also called diffuse small noncleaved-cell lymphoma.
• Lymphoblastic lymphoma. Lymphoblastic lymphoma may begin in T cells or B cells, but it usually begins in T cells. In this type of non-Hodgkin lymphoma, there are too many lymphoblasts (immature white blood cells) in the lymph nodes and the thymus gland. These lymphoblasts may spread to other places in the body, such as the bone marrow, brain, and spinal cord. Lymphoblastic lymphoma is most common in teenagers and young adults. It is a lot like acute lymphoblastic leukemia (lymphoblasts are mostly found in the bone marrow and blood). For more information, see Acute Lymphoblastic Leukemia Treatment.
• T-cell leukemia/lymphoma. T-cell leukemia/lymphoma is caused by the human T-cell leukemia virus type 1 (HTLV-1). Signs include bone and skin lesions, high blood calcium levels, and lymph nodes, spleen, and liver that are larger than normal.
• Mantle cell lymphoma. Mantle cell lymphoma is a type of B-cell non-Hodgkin lymphoma that usually occurs in middle-aged or older adults. It begins in the lymph nodes and spreads to the spleen, bone marrow, blood, and sometimes the esophagus, stomach, and intestines. Patients with mantle cell lymphoma have too much of a protein called cyclin-D1 or a certain gene change in the lymphoma cells. In some patients who do not have signs or symptoms of lymphoma, delaying the start of treatment does not affect the prognosis.
• Posttransplantation lymphoproliferative disorder. This disease occurs in patients who have had a heart, lung, liver, kidney, or pancreas transplant and need lifelong immunosuppressive therapy. Most posttransplant lymphoproliferative disorders affect the B cells and have Epstein-Barr virus in the cells. Lymphoproliferative disorders are often treated like cancer.
• True histiocytic lymphoma. This is a rare, very aggressive type of lymphoma. It is not known whether it begins in B cells or T cells. It does not respond well to treatment with standard chemotherapy.
• Primary effusion lymphoma. Primary effusion lymphoma begins in B cells that are found in an area where there is a large build-up of fluid, such as the areas between the lining of the lung and chest wall (pleural effusion), the sac around the heart and the heart (pericardial effusion), or in the abdominal cavity. There is usually no tumor that can be seen. This type of lymphoma often occurs in patients who are infected with HIV.
• Plasmablastic lymphoma. Plasmablastic lymphoma is a type of large B-cell non-Hodgkin lymphoma that is very aggressive. It is most often seen in patients with HIV infection.

Older age, being male, and having a weakened immune system can increase the risk of non-Hodgkin lymphoma.

Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop non-Hodgkin lymphoma, and it can develop in people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk.

These and other risk factors may increase the risk of certain types of non-Hodgkin lymphoma:

• Being older, male, or White.
• Having one of the following medical conditions that weakens the immune system:
  • An inherited immune disorder (such as hypogammaglobulinemia or Wiskott-Aldrich syndrome).
  • An autoimmune disease (such as rheumatoid arthritis, psoriasis, or Sjögren syndrome).
  • HIV/AIDS.
  • Human T-lymphotrophic virus type I or Epstein-Barr virus infection.
  • Helicobacter pylori infection.
• Taking immunosuppressant drugs after an organ transplant.

Signs and symptoms of non-Hodgkin lymphoma include swollen lymph nodes, fever, drenching night sweats, weight loss, and fatigue.

These signs and symptoms may be caused by non-Hodgkin lymphoma or by other conditions. Check with your doctor if you have any of the following:

• Swelling in the lymph nodes in the neck, underarm, groin, or stomach.
• Fever for no known reason.
• Drenching night sweats.
• Feeling very tired.
• Weight loss for no known reason.
• Skin rash or itchy skin.
• Pain in the chest, abdomen, or bones for no known reason.

When fever, drenching night sweats, and weight loss occur together, this group of symptoms is called B symptoms.

Other signs and symptoms of non-Hodgkin lymphoma may occur and depend on the following:

• Where the cancer forms in the body.
• The size of the tumor.
• How fast the tumor grows.

Tests that examine the lymph system and other parts of the body are used to diagnose and stage non-Hodgkin lymphoma.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

• Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
  • The number of red blood cells, white blood cells, and platelets.
  • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
  • The portion of the sample made up of red blood cells.

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• Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
• LDH test: A procedure in which a blood sample is checked to measure the amount of lactic dehydrogenase. An increased amount of LDH in the blood may be a sign of tissue damage, lymphoma, or other diseases.
• Hepatitis B and hepatitis C test: A procedure in which a sample of blood is checked to measure the amounts of hepatitis B virus-specific antigens and/or antibodies and the amounts of hepatitis C virus-specific antibodies. These antigens or antibodies are called markers. Different markers or combinations of markers are used to determine whether a patient has a hepatitis B or C infection, has had a prior infection or vaccination, or is susceptible to infection. Patients who have been treated for hepatitis B virus in the past need continued monitoring to check if it has reactivated. Knowing whether a person has hepatitis B or C may help plan treatment.
• HIV test: A test to measure the level of HIV antibodies in a sample of blood. Antibodies are made by the body when it is invaded by a foreign substance. A high level of HIV antibodies may mean the body has been infected with HIV.
• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the neck, chest, abdomen, pelvis, and lymph nodes, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
• PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
• Bone marrow aspiration and biopsy: The removal of bone marrow and a small piece of bone by inserting a needle into the hipbone or breastbone. A pathologist views the bone marrow and bone under a microscope to look for signs of cancer.
  

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• Lymph node biopsy: The removal of all or part of a lymph node. A pathologist views the tissue under a microscope to check for cancer cells. One of the following types of biopsies may be done:
  • Excisional biopsy: The removal of an entire lymph node.
  • Incisional biopsy: The removal of part of a lymph node.
  • Core biopsy: The removal of part of a lymph node using a wide needle.

If cancer is found, the following tests may be done to study the cancer cells:

• Immunohistochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.
• Cytogenetic analysis: A laboratory test in which the chromosomes of cells in a sample of blood or bone marrow are counted and checked for any changes, such as broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes may be a sign of cancer. Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working.
• Immunophenotyping: A laboratory test that uses antibodies to identify cancer cells based on the types of antigens or markers on the surface of the cells. This test is used to help diagnose specific types of lymphoma.
• FISH (fluorescence in situ hybridization): A laboratory test used to look at and count genes or chromosomes in cells and tissues. Pieces of DNA that contain fluorescent dyes are made in the laboratory and added to a sample of a patient’s cells or tissues. When these dyed pieces of DNA attach to certain genes or areas of chromosomes in the sample, they light up when viewed under a fluorescent microscope. The FISH test is used to help diagnose cancer and help plan treatment.

Other tests and procedures may be done depending on the signs and symptoms seen and where the cancer forms in the body.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on the following:

• The patient’s signs and symptoms, including whether or not they have B symptoms (fever for no known reason, weight loss for no known reason, or drenching night sweats).
• The stage of the cancer (the size of the cancer tumors and whether the cancer has spread to other parts of the body or lymph nodes).
• The type of non-Hodgkin lymphoma.
• The amount of lactate dehydrogenase (LDH) in the blood.
• Whether there are certain changes in the genes.
• The patient’s age, sex, and general health.
• Whether the lymphoma is newly diagnosed, continues to grow during treatment, or has recurred (come back).

For non-Hodgkin lymphoma during pregnancy, treatment options also depend on:

• The wishes of the patient.
• Which trimester of pregnancy the patient is in.
• Whether the baby can be delivered early.

Some types of non-Hodgkin lymphoma spread more quickly than others do. Most non-Hodgkin lymphomas that occur during pregnancy are aggressive. Delaying treatment of aggressive lymphoma until after the baby is born may lessen the mother’s chance of survival. Immediate treatment is often recommended, even during pregnancy.

After non-Hodgkin lymphoma has been diagnosed, tests are done to find out whether cancer cells have spread within the lymph system or to other parts of the body.

The process used to find out the type of cancer and if cancer cells have spread within the lymph system or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage of the disease in order to plan treatment. The results of the tests and procedures done to diagnose non-Hodgkin lymphoma are used to help make decisions about treatment.

The following tests and procedures may also be used in the staging process:

• MRI (magnetic resonance imaging) with gadolinium: A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the brain and spinal cord. A substance called gadolinium is injected into the patient through a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
• Lumbar puncture: A procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the CSF around the spinal cord and removing a sample of the fluid. The sample of CSF is checked under a microscope for signs that the cancer has spread to the brain and spinal cord. This procedure is also called an LP or spinal tap.
  

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For pregnant women with non-Hodgkin lymphoma, staging tests and procedures that protect the fetus from the harms of radiation are used. These tests and procedures include MRI (without contrast), lumbar puncture, and ultrasound.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

• Tissue. The cancer spreads from where it began by growing into nearby areas.
• Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
• Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

The following stages are used for non-Hodgkin lymphoma:

Stage I

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Stage I non-Hodgkin lymphoma is divided into stages I and IE.

In stage I, cancer is found in one of the following places in the lymph system:

• One or more lymph nodes in a group of lymph nodes.
• Waldeyer’s ring.
• Thymus.
• Spleen.

In stage IE, cancer is found in one area outside the lymph system.

Stage II

Stage II non-Hodgkin lymphoma is divided into stages II and IIE.

• In stage II, cancer is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm.
  

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• In stage IIE, cancer has spread from a group of lymph nodes to a nearby area that is outside the lymph system. Cancer may have spread to other lymph node groups on the same side of the diaphragm.
  

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In stage II, the term bulky disease refers to a larger tumor mass. The size of the tumor mass that is referred to as bulky disease varies based on the type of lymphoma.

Stage III

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In stage III non-Hodgkin lymphoma, cancer is found:

• in groups of lymph nodes both above and below the diaphragm; or
• in lymph nodes above the diaphragm and in the spleen.

Stage IV

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In stage IV non-Hodgkin lymphoma, cancer:

• has spread throughout one or more organs outside the lymph system; or
• is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm and in one organ that is outside the lymph system and not near the affected lymph nodes; or
• is found in groups of lymph nodes both above and below the diaphragm and in any organ that is outside the lymph system; or
• is found in the liver, bone marrow, more than one place in the lung, or cerebrospinal fluid (CSF). The cancer has not spread directly into the liver, bone marrow, lung, or CSF from nearby lymph nodes.

Non-Hodgkin lymphomas may be grouped for treatment according to whether the cancer is indolent or aggressive, whether affected lymph nodes are next to each other in the body, and whether the cancer is newly diagnosed or recurrent.

For more information on the types of indolent (slow-growing) and aggressive (fast-growing) non-Hodgkin lymphoma, see the General Information section.

Non-Hodgkin lymphoma can also be described as contiguous or noncontiguous:

• Contiguous lymphomas: Lymphomas in which the lymph nodes with cancer are next to each other.
• Noncontiguous lymphomas: Lymphomas in which the lymph nodes with cancer are not next to each other, but are on the same side of the diaphragm.

Non-Hodgkin lymphoma can recur (come back) after it has been treated.

The lymphoma may come back in the lymph system or in other parts of the body. Indolent lymphoma may come back as aggressive lymphoma. Aggressive lymphoma may come back as indolent lymphoma.

There are different types of treatment for patients with non-Hodgkin lymphoma.

Different types of treatment are available for patients with non-Hodgkin lymphoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

For pregnant women with non-Hodgkin lymphoma, treatment is carefully chosen to protect the fetus. Treatment decisions are based on the mother’s wishes, the stage of the non-Hodgkin lymphoma, and the trimester of the pregnancy. The treatment plan may change as the signs and symptoms, cancer, and pregnancy change. Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.

Patients with non-Hodgkin lymphoma should have their treatment planned by a team of health care providers who are experts in treating lymphomas.

Treatment will be overseen by a medical oncologist, a doctor who specializes in treating cancer, or a hematologist, a doctor who specializes in treating blood cancers. The medical oncologist may refer you to other health care providers who have experience and are experts in treating non-Hodgkin lymphoma and who specialize in certain areas of medicine. These may include the following specialists:

• Neurosurgeon.
• Neurologist.
• Radiation oncologist.
• Endocrinologist.
• Rehabilitation specialist.
• Fertility specialist.
• Other oncology specialists.

Treatment for non-Hodgkin lymphoma may cause side effects.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Side effects from cancer treatment that begin after treatment and continue for months or years are called late effects. Treatment with chemotherapy, radiation therapy, or stem cell transplant for non-Hodgkin lymphoma may increase the risk of late effects.

Late effects of cancer treatment may include the following:

• Heart problems.
• Infertility (inability to have children).
• Loss of bone density.
• Neuropathy (nerve damage that causes numbness or trouble walking).
• A second cancer, such as:
  • Lung cancer.
  • Brain cancer.
  • Kidney cancer.
  • Bladder cancer.
  • Melanoma.
  • Hodgkin lymphoma.
  • Myelodysplastic syndrome.
  • Acute myeloid leukemia.

Some late effects may be treated or controlled. It is important to talk with your doctor about the effects cancer treatment can have on you. Regular follow-up to check for late effects is important.

The following types of treatment are used:

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing.

External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Sometimes total-body irradiation is given before a stem cell transplant.

Proton beam radiation therapy is a type of high-energy, external radiation therapy that uses streams of protons (tiny particles with a positive charge) to kill tumor cells. This type of treatment can lower the amount of radiation damage to healthy tissue near a tumor such as the heart or breast.

External radiation therapy is used to treat non-Hodgkin lymphoma, and may also be used as palliative therapy to relieve symptoms and improve quality of life.

For a pregnant woman with non-Hodgkin lymphoma, radiation therapy should be given after delivery, if possible, to avoid any risk to the fetus. If treatment is needed right away, the woman may decide to continue the pregnancy and receive radiation therapy. A lead shield is used to cover the pregnant woman’s abdomen to help protect the fetus from radiation as much as possible.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid (intrathecal chemotherapy), an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Combination chemotherapy is treatment using two or more anticancer drugs. Steroid drugs may be added, to lessen inflammation and lower the body’s immune response.

Systemic combination chemotherapy is used for the treatment of non-Hodgkin lymphoma.

Intrathecal chemotherapy may also be used in the treatment of lymphoma that first forms in the testicles or sinuses (hollow areas) around the nose, diffuse large B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, and some aggressive T-cell lymphomas. It is given to lessen the chance that lymphoma cells will spread to the brain and spinal cord. This is called CNS prophylaxis.

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When a pregnant woman is treated with chemotherapy for non-Hodgkin lymphoma, the fetus cannot be protected from being exposed to chemotherapy. Some chemotherapy regimens may cause birth defects if given in the first trimester.

For more information, see Drugs Approved for Non-Hodgkin Lymphoma.

Immunotherapy

Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer.

• Immunomodulators: Lenalidomide is an immunomodulator used to treat non-Hodgkin lymphoma.
• CAR T-cell therapy: The patient’s T cells (a type of immune system cell) are changed so they will attack certain proteins on the surface of cancer cells. T cells are taken from the patient and special receptors are added to their surface in the laboratory. The changed cells are called chimeric antigen receptor (CAR) T cells. The CAR T cells are grown in the laboratory and given to the patient by infusion. The CAR T cells multiply in the patient’s blood and attack cancer cells. CAR T-cell therapy (such as axicabtagene ciloleucel or tisagenlecleucel) is used to treat large B-cell lymphoma that has not responded to treatment. CAR T-cell therapy is being studied to treat mantle cell lymphoma that has relapsed or not responded to treatment.

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For more information, see Drugs Approved for Non-Hodgkin Lymphoma.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Monoclonal antibody therapy, proteasome inhibitor therapy, and kinase inhibitor therapy are types of targeted therapy used to treat non-Hodgkin lymphoma.

• Monoclonal antibody therapy: Monoclonal antibodies are immune system proteins made in the laboratory to treat many diseases, including cancer. As a cancer treatment, these antibodies can attach to a specific target on cancer cells or other cells that may help cancer cells grow. The antibodies are able to then kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.

  Types of monoclonal antibodies include:

  • Rituximab, used to treat many types of non-Hodgkin lymphoma.
  • Obinutuzumab, used to treat follicular lymphoma.
  • Mogamulizumab, used to treat certain types of relapsed or refractory T-cell lymphoma.
  • Tafasitamab combined with lenalidomide to treat relapsed or refractory diffuse large B-cell lymphoma.
  • Pembrolizumab to treat primary mediastinal large B-cell lymphoma.
  • Polatuzumab vedotin, combined with bendamustine and rituximab to treat relapsed or refractory diffuse large B-cell lymphoma.
  • Brentuximab vedotin, which contains a monoclonal antibody that binds to a protein called CD30 that is found on some lymphoma cells. It also contains an anticancer drug that may help kill cancer cells.
  • Yttrium Y 90-ibritumomab tiuxetan, an example of a radiolabeled monoclonal antibody.
  • Mosunetuzumab, which is a bispecific monoclonal antibody that helps the body’s immune system recognize and kill cancer cells. It is used to treat relapsed or refractory follicular lymphoma.

• Proteasome inhibitor therapy: This treatment blocks the action of proteasomes in cancer cells. Proteasomes remove proteins no longer needed by the cell. When the proteasomes are blocked, the proteins build up in the cell and may cause the cancer cell to die. Bortezomib or ixazomib is used to decrease how much immunoglobulin M is in the blood after cancer treatment for lymphoplasmacytic lymphoma (Waldenström macroglobulinemia). It is also being studied to treat relapsed mantle cell lymphoma.
• Kinase inhibitor therapy: This treatment blocks certain proteins, which may help keep lymphoma cells from growing and may kill them. Kinase inhibitor therapies include:
  • Ibrutinib, acalabrutinib, and zanubrutinib, which are types of Bruton tyrosine kinase inhibitor therapy. They are used to treat mantle cell lymphoma. Ibrutinib and acalabrutinib are also used to treat lymphoplasmacytic lymphoma, and zanubrutinib is being studied to treat it.
• Histone methyltransferase inhibitor therapy: Tazemetostat is used to treat follicular lymphoma that has come back or has not gotten better with other treatment. It is used in adults whose cancer has a certain mutation (change) in the EZH2 gene that has already been treated with at least two other anticancer therapies.
• B-cell lymphoma-2 (BCL-2) inhibitor therapy: Venetoclax may be used to treat mantle cell lymphoma. It blocks the action of a protein called BCL-2 and may help kill cancer cells.

For more information, see Drugs Approved for Non-Hodgkin Lymphoma.

Plasmapheresis

If the blood becomes thick with extra antibody proteins and affects circulation, plasmapheresis is done to remove extra plasma and antibody proteins from the blood. In this procedure, blood is removed from the patient and sent through a machine that separates the plasma (the liquid part of the blood) from the blood cells. The patient’s plasma contains the unneeded antibodies and is not returned to the patient. The normal blood cells are returned to the bloodstream along with donated plasma or a plasma replacement. Plasmapheresis does not keep new antibodies from forming.

Watchful waiting

Watchful waiting is closely monitoring a patient’s condition without giving any treatment until signs or symptoms appear or change.

Antibiotic therapy

Antibiotic therapy is a treatment that uses drugs to treat infections and cancer caused by bacteria and other microorganisms.

Surgery

Surgery may be used to remove the lymphoma in certain patients with indolent or aggressive non-Hodgkin lymphoma.

The type of surgery used depends on where the lymphoma formed in the body:

• Local excision for certain patients with mucosa-associated lymphoid tissue (MALT) lymphoma, PTLD, and small bowel T-cell lymphoma.
• Splenectomy for patients with marginal zone lymphoma of the spleen.

Patients who have a heart, lung, liver, kidney, or pancreas transplant usually need to take drugs to suppress their immune system for the rest of their lives. Long-term immunosuppression after an organ transplant can cause a certain type of non-Hodgkin lymphoma called posttransplant lymphoproliferative disorder (PLTD).

Small bowel surgery is often needed to diagnose celiac disease in adults who develop a type of T-cell lymphoma.

Stem cell transplant

Stem cell transplant is a method of giving high doses of chemotherapy and/or total-body irradiation and then replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient (autologous transplant) or a donor (allogeneic transplant) and are frozen and stored. After the chemotherapy and/or radiation therapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

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New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI website.

Vaccine therapy

Vaccine therapy is a cancer treatment that uses a substance or group of substances to stimulate the immune system to find the tumor and kill it.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of indolent stage I and indolent, contiguous stage II non-Hodgkin lymphoma may include the following:

If the tumor is too large to be treated with radiation therapy, the treatment options for indolent, noncontiguous stage II, III, or IV non-Hodgkin lymphoma will be used.

Treatment of indolent, noncontiguous stage II, III, or IV non-Hodgkin lymphoma may include the following:

Other treatments for indolent non-Hodgkin lymphoma depend on the type of non-Hodgkin lymphoma. Treatment may include the following:

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of aggressive stage I and aggressive, contiguous stage II non-Hodgkin lymphoma may include the following:

Treatment of aggressive, noncontiguous stage II, III, or IV non-Hodgkin lymphoma may include the following:

Other treatments depend on the type of aggressive non-Hodgkin lymphoma. Treatment may include the following:

For information on the treatment of lymphoblastic lymphoma, see Treatment Options for Lymphoblastic Lymphoma and for information on the treatment of Burkitt lymphoma, see Treatment Options for Burkitt Lymphoma.

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of lymphoblastic lymphoma may include the following:

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of Burkitt lymphoma may include the following:

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of indolent, recurrent non-Hodgkin lymphoma may include the following:

Treatment of aggressive, recurrent non-Hodgkin lymphoma may include the following:

Treatment of indolent lymphoma that comes back as aggressive lymphoma depends on the type of non-Hodgkin lymphoma and may include radiation therapy as palliative therapy to relieve symptoms and improve quality of life. Treatment of aggressive lymphoma that comes back as indolent lymphoma may include chemotherapy.

For information about the treatments listed below, see the Treatment Option Overview section.

Indolent Non-Hodgkin Lymphoma During Pregnancy

Women who have indolent (slow-growing) non-Hodgkin lymphoma during pregnancy may be treated with watchful waiting until after they give birth. (See the Treatment Options for Indolent Non-Hodgkin Lymphoma section for more information.)

Aggressive Non-Hodgkin Lymphoma During Pregnancy

Treatment of aggressive non-Hodgkin lymphoma during pregnancy may include the following:

• Treatment given right away based on the type of non-Hodgkin lymphoma to increase the mother’s chance of survival. Treatment may include combination chemotherapy and rituximab.
• Early delivery of the baby followed by treatment based on the type of non-Hodgkin lymphoma.
• If in the first trimester of pregnancy, medical oncologists may advise ending the pregnancy so that treatment may begin. Treatment depends on the type of non-Hodgkin lymphoma.

For more information from the National Cancer Institute about non-Hodgkin lymphoma, see the following:

For general cancer information and other resources from the National Cancer Institute, visit:

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of adult non-Hodgkin lymphoma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/patient/adult-nhl-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389337]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Acute lymphoblastic leukemia (ALL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).

Acute lymphoblastic leukemia (ALL; also called acute lymphocytic leukemia) is a cancer of the blood and bone marrow. This type of cancer usually gets worse quickly if it is not treated.

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Leukemia may affect red blood cells, white blood cells, and platelets.

The bone marrow makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A lymphoid stem cell becomes a lymphoblast and then one of three types of lymphocytes (white blood cells):

• B lymphocytes that make antibodies to help fight infection
• T lymphocytes that help B lymphocytes make the antibodies that help fight infection
• natural killer cells that attack cancer cells and viruses

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In ALL, too many stem cells become lymphoblasts, B lymphocytes, or T lymphocytes. These cells are also called leukemia cells. Leukemia cells are not able to fight infection very well. Also, as the number of leukemia cells increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding. The cancer can also spread to the central nervous system (brain and spinal cord), lymph nodes, spleen, liver, testicles, and other organs.

Previous chemotherapy and exposure to radiation may increase the risk of developing ALL.

ALL is caused by certain changes to the way blood stem cells function, especially how they grow and divide into new cells. A risk factor is anything that increases the chance of getting a disease. Some risk factors for cancer, like smoking, can be changed. However, risk factors also include things people cannot change, like their genetics, getting older, and their health history.

There are many risk factors for ALL, but many do not directly cause cancer. Instead, they increase the chance of DNA damage in cells that may lead to ALL. Learn more about how cancer develops at What Is Cancer?

Having one or more of these risk factors does not mean that you will get ALL. Many people with risk factors never develop ALL, while others with no known risk factors do.

Possible risk factors for ALL include:

• being male
• being White
• being older than 70
• past treatment with chemotherapy or radiation therapy
• being exposed to high levels of radiation in the environment (such as nuclear radiation)
• having certain genetic disorders, such as Down syndrome

Talk with your doctor if you think you may be at risk.

Signs and symptoms of ALL include fatigue, fever, and easy bruising or bleeding.

The early signs and symptoms of ALL may be like the flu or other common diseases. Check with your doctor if you have:

• weakness or fatigue
• fever or drenching night sweats
• easy bruising or bleeding
• petechiae (flat, pinpoint spots under the skin, caused by bleeding)
• shortness of breath
• weight loss or loss of appetite
• pain in the bones or stomach
• pain or feeling of fullness below the ribs
• painless lumps in the neck, underarm, stomach, or groin
• frequent infections

These and other signs and symptoms may be caused by ALL or by other conditions.

Tests that examine the blood and bone marrow are used to diagnose ALL.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

• Complete blood count (CBC) with differential checks a sample of blood for:
  • the number of red blood cells and platelets
  • the number and type of white blood cells
  • the amount of hemoglobin (the protein that carries oxygen) in the red blood cells
  • the amount of hematocrit (whole blood that is made up of red blood cells)

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• Blood chemistry study uses a blood sample to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease.
• Peripheral blood smear checks a sample of blood for blast cells, the number and kinds of white blood cells, the number of platelets, and changes in the shape of blood cells.
• Bone marrow aspiration and biopsy is the removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for abnormal cells.
  

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  The following tests may be done on the samples of blood or bone marrow tissue that are removed:

  • Cytogenetic analysis checks the chromosomes of cells in a blood or bone marrow sample for changes, such as broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes may be a sign of cancer. For example, in Philadelphia chromosome–positive ALL, part of one chromosome switches places with part of another chromosome. This is called the “Philadelphia chromosome.” Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working.
    

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  • Immunophenotyping uses antibodies to identify cancer cells based on the types of antigens or markers on the surface of the cells. This test is used to help diagnose specific types of leukemia. For example, a cytochemistry study may test the cells in a sample of tissue using chemicals (dyes) to look for certain changes in the sample. A chemical may cause a color change in one type of leukemia cell but not in another type of leukemia cell.

After ALL has been diagnosed, tests are done to find out if the cancer has spread to the central nervous system (brain and spinal cord) or to other parts of the body.

The following tests and procedures may be used to find out if the leukemia has spread outside the blood and bone marrow:

• Chest x-ray is a type of radiation that can go through the body and make pictures of the organs and bones inside the chest.
• Lumbar puncture is a procedure used to collect a sample of cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the lining around the spinal cord to remove a sample of CSF. The sample of CSF is checked under a microscope for signs that leukemia cells have spread to the brain and spinal cord. This procedure is also called an LP or spinal tap.
  

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• CT scan (CAT scan) uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body, such as the abdomen. The pictures are taken from different angles and are used to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer.
• MRI (magnetic resonance imaging) uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).

Some people decide to get a second opinion.

You may want to get a second opinion to confirm your ALL diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. They may agree with the first doctor, suggest changes or another treatment approach, or provide more information about your cancer.

To learn more about choosing a doctor and getting a second opinion, visit Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor, hospital, or getting a second opinion. For questions you might want to ask at your appointments, visit Questions to Ask Your Doctor About Cancer.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options for ALL depend on:

• the person’s age
• whether the cancer has spread to the brain or spinal cord
• whether there are certain changes in the genes, including the Philadelphia chromosome
• whether the cancer has been treated before or has recurred (come back)

There is no standard staging system for acute lymphoblastic leukemia (ALL).

The extent or spread of cancer is usually described as stages. Instead of stages, ALL treatment is based on whether the cancer is untreated, in remission, or recurrent.

Untreated ALL

In untreated ALL, the disease is newly diagnosed. It has not been treated, except to relieve signs and symptoms caused by the cancer, such as fever, bleeding, or pain, and the following are true:

• The complete blood count (CBC) is abnormal.
• More than 5% of the cells in the bone marrow are blasts (leukemia cells).
• There are signs and symptoms of leukemia.

ALL in remission

In ALL in remission, the disease has been treated, and the following are true:

• The CBC is normal.
• 5% or fewer of the cells in the bone marrow are blasts (leukemia cells).
• There are no signs or symptoms of leukemia other than in the bone marrow.

Recurrent ALL

Recurrent ALL is cancer that has recurred (come back) after going into remission. ALL may come back in the blood, bone marrow, or other parts of the body.

Learn more in Recurrent Cancer: When Cancer Comes Back.

There are different types of treatment for patients with acute lymphoblastic leukemia (ALL).

Different types of treatment are available for people with ALL. You and your cancer care team will work together to decide your treatment plan, which may include more than one type of treatment. Many factors will be considered, such as whether the ALL is untreated, in remission, or recurrent, and your overall health and preferences. Your plan will include information about your cancer, the goals of treatment, your treatment options and the possible side effects, and the expected length of treatment. 

Talking with your cancer care team before treatment begins about what to expect will be helpful. You’ll want to learn what you need to do before treatment begins, how you’ll feel while going through it, and what kind of help you will need. Learn more at Questions to Ask Your Doctor About Treatment.

The treatment of ALL usually has two phases.

There are two treatment phases of ALL:

• Remission induction therapy is the first phase of treatment. The goal is to kill the leukemia cells in the blood and bone marrow. This puts the leukemia into remission.
• Consolidation therapy is the second phase of treatment. It begins once the leukemia is in remission. The goal of consolidation therapy is to kill any remaining leukemia cells that may not be active but could begin to regrow and cause a relapse. This phase is also called remission continuation therapy.

Treatment called central nervous system (CNS) prophylaxis is usually given during each phase of therapy. Because standard doses of chemotherapy may not reach leukemia cells in the CNS (brain and spinal cord), the leukemia cells are able to hide in the CNS. Systemic chemotherapy given in high doses, intrathecal chemotherapy, and radiation therapy to the brain are able to reach leukemia cells in the CNS. These treatments are given to kill the leukemia cells and lessen the chance the leukemia will recur (come back).

The following types of treatment are used:

Chemotherapy

Chemotherapy (also called chemo) uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. The way the chemotherapy is given depends on whether the leukemia cells have spread to the central nervous system (CNS; brain and spinal cord).

Systemic chemotherapy is when chemotherapy drugs are taken by mouth or injected into a vein or muscle. When given this way, the drugs enter the bloodstream and can reach cancer cells throughout the body.

Intrathecal chemotherapy may be used to treat ALL that has spread, or may spread, to the brain and spinal cord. Intrathecal chemotherapy is a method of placing chemotherapy directly into the cerebrospinal fluid, which is the fluid that surrounds the brain and spinal cord. When used to lessen the chance leukemia cells will spread to the brain and spinal cord, it is called CNS prophylaxis.

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Learn more about Drugs Approved for Acute Lymphoblastic Leukemia.

Learn more about how chemotherapy works, how it is given, common side effects, and more at Chemotherapy to Treat Cancer and Chemotherapy and You: Support for People with Cancer.

Radiation therapy

Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.

External radiation therapy may be used to treat ALL that has spread, or may spread, to the brain and spinal cord. When used this way, it is called central nervous system (CNS) sanctuary therapy or CNS prophylaxis. Total-body irradiation may be used to send radiation toward the whole body when preparing for a stem cell transplant. External radiation therapy may also be used as palliative therapy to relieve symptoms and improve quality of life.

Learn more about External Beam Radiation Therapy for Cancer and Radiation Therapy Side Effects.

Chemotherapy with stem cell transplant

Chemotherapy is given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy or total-body radiation therapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

Learn more about Stem Cell Transplants in Cancer Treatment.

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Targeted therapy

Targeted therapy uses drugs or other substances to identify and attack specific cancer cells. Your doctor may suggest biomarker tests to help predict your response to certain targeted therapy drugs. Learn more about Biomarker Testing for Cancer Treatment.

Targeted therapies used to treat ALL include:

• dasatinib
• imatinib mesylate
• inotuzumab ozogamicin
• nilotinib
• revumenib

Learn more about Targeted Therapy to Treat Cancer. 

Immunotherapy

Immunotherapy helps a person’s immune system fight cancer. Your doctor may suggest biomarker tests to help predict your response to certain immunotherapy drugs. Learn more about Biomarker Testing for Cancer Treatment.

Immunotherapies used to treat ALL include:

• blinatumomab
• inotuzumab ozogamicin
• CAR T-cell therapy with brexucabtagene autoleucel or tisagenlecleucel

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Learn more about Immunotherapy to Treat Cancer.

New types of treatment are being tested in clinical trials.

For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.

You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Learn more about clinical trials, including how to find and join one, at Clinical Trials Information for Patients and Caregivers.

Treatment for ALL may cause side effects.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Side effects from cancer treatment that begin after treatment and continue for months or years are called late effects. Late effects of treatment for ALL may include the risk of second cancers (new types of cancer). Regular follow-up exams are very important for long-term survivors.

Follow-up care may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

Treatment of ALL during the remission induction phase includes:

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of ALL during the post-remission phase includes:

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of recurrent ALL may include:

Some of the treatments being studied in clinical trials for recurrent ALL include stem cell transplant using the patient’s stem cells.

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For more information from the National Cancer Institute about ALL, visit the Leukemia Home Page.

For general cancer information and other resources from the National Cancer Institute, visit:

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of acute lymphoblastic leukemia. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/leukemia/patient/adult-all-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389283]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

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Because of the intensity of therapy associated with the transplant process, the pretransplant clinical status of recipients (e.g., age, presence of infections or organ dysfunction, and functional status) is associated with a risk of transplant-related mortality.

The best tool to assess the impact of pretransplant comorbidities on outcomes after transplant was developed by adapting an existing comorbidity scale, the Charlson Comorbidity Index (CCI). Investigators at the Fred Hutchinson Cancer Research Center systematically defined which of the CCI elements were correlated with transplant-related mortality in adult and pediatric patients. They also determined several additional comorbidities that have predictive power specific to transplant patients.

Successful validation defined what is now termed the hematopoietic cell transplant–specific comorbidity index (HCT-CI).[1,2] The rate of transplant-related mortality increases with the presence of cardiac, hepatic, pulmonary, gastrointestinal, infectious, and autoimmune comorbidities, or a history of previous solid tumors (see Table 1).

Table 1. Definitions of Comorbidities Included in the Hematopoietic Cell Transplant–Specific Comorbidity Index (HCT-CI)a

HCT-CI Score
1	2	3
AST/ALT = aspartate aminotransferase/alanine aminotransferase; DLCO = diffusion capacity of carbon monoxide; FEV1 = forced expiratory volume in one second; ULN = upper limit of normal.
aAdapted from Sorror et al.[1]
bOne-or-more–vessel coronary artery stenosis requiring medical treatment, stent, or bypass graft.
Arrhythmia: Atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmias	Moderate pulmonary: DLCO and/or FEV1 66%–80% or dyspnea on slight activity	Heart valve disease: Excluding mitral valve prolapse
Cardiac: Coronary artery disease,b congestive heart failure, myocardial infarction, or ejection fraction ≤50%	Moderate/severe renal: Serum creatinine >2 mg/dL, on dialysis, or prior renal transplant	Moderate/severe hepatic: Liver cirrhosis, bilirubin >1.5 × ULN, or AST/ALT >2.5 × ULN
Cerebrovascular disease: Transient ischemic attack or cerebrovascular accident	Peptic ulcer: Requiring treatment	Prior solid tumor: Treated at any time in the patient’s history, excluding nonmelanoma skin cancer
Diabetes: Requiring treatment with insulin or oral hypoglycemic agents but not diet alone	Rheumatologic: Systemic lupus erythematosus, rheumatoid arthritis, polymyositis, mixed connective tissue disease, or polymyalgia rheumatica	Severe pulmonary: DLCO and/or FEV1 <65% or dyspnea at rest or requiring oxygen
Hepatic, mild: Chronic hepatitis, bilirubin >ULN or AST/ALT >ULN to 2.5 × ULN
Infection: Requiring continuation of antimicrobial treatment after day 0
Inflammatory bowel disease: Crohn disease or ulcerative colitis
Obesity: Body mass index >35 kg/m2
Psychiatric disturbance: Depression or anxiety requiring psychiatric consult or treatment

The predictive power of this index for both transplant-related mortality and overall survival (OS) is strong, with a hazard ratio of 3.54 (95% confidence interval [CI], 2.0–6.3) for nonrelapse mortality and 2.69 (95% CI, 1.8–4.1) for survival in patients with a score of 3 or higher, compared with those who have a score of 0. Although the original studies were performed with patients who received intense myeloablative approaches, the HCT-CI has also been shown to predict outcomes for patients receiving reduced-intensity and nonmyeloablative regimens.[3] It has also been combined with disease status [4] and Karnofsky score,[5] leading to even better prediction of survival outcomes. In addition, high HCT-CI scores (>3) have been associated with a higher risk of grades III to IV acute graft-versus-host disease.[6]

Most patients assessed in the HCT-CI studies have been adults, and the comorbidities listed are skewed toward adult diseases. Several studies have explored the relevance of this scale for pediatric and young adult recipients of hematopoietic stem cell transplant (HSCT).

Evidence (use of HCT-CI score in pediatrics):

Most of the reported comorbidities in these studies were respiratory or hepatic conditions and infections.[7,8] In the adolescent and young adult study, patients with pre-HSCT pulmonary dysfunction were at particularly higher risk of poor outcomes, with a 2-year OS rate of 29%, compared with 61% in those with normal lung function before HSCT.[8]

References

1. Sorror ML, Maris MB, Storb R, et al.: Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106 (8): 2912-9, 2005. [PUBMED Abstract]
2. ElSawy M, Storer BE, Pulsipher MA, et al.: Multi-centre validation of the prognostic value of the haematopoietic cell transplantation- specific comorbidity index among recipient of allogeneic haematopoietic cell transplantation. Br J Haematol 170 (4): 574-83, 2015. [PUBMED Abstract]
3. Sorror ML, Storer BE, Maloney DG, et al.: Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood 111 (1): 446-52, 2008. [PUBMED Abstract]
4. Sorror ML, Sandmaier BM, Storer BE, et al.: Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 25 (27): 4246-54, 2007. [PUBMED Abstract]
5. Sorror M, Storer B, Sandmaier BM, et al.: Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer 112 (9): 1992-2001, 2008. [PUBMED Abstract]
6. Sorror ML, Martin PJ, Storb RF, et al.: Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. Blood 124 (2): 287-95, 2014. [PUBMED Abstract]
7. Smith AR, Majhail NS, MacMillan ML, et al.: Hematopoietic cell transplantation comorbidity index predicts transplantation outcomes in pediatric patients. Blood 117 (9): 2728-34, 2011. [PUBMED Abstract]
8. Wood W, Deal A, Whitley J, et al.: Usefulness of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) in predicting outcomes for adolescents and young adults with hematologic malignancies undergoing allogeneic stem cell transplant. Pediatr Blood Cancer 57 (3): 499-505, 2011. [PUBMED Abstract]
9. Sorror ML, Logan BR, Zhu X, et al.: Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant 21 (8): 1479-87, 2015. [PUBMED Abstract]

Infectious Risks and Immune Recovery After Transplant

Defective immune reconstitution is a major barrier to successful HSCT, regardless of graft source.[1,2] Serious infections have accounted for a significant percentage (4%–20%) of late deaths after HSCT.[3]

Factors that can significantly slow immune recovery include the following:[4]

• Graft manipulation (removal of T cells).
• Stem cell source (slow recovery with cord blood).
• Chronic graft-versus-host disease (GVHD).

Figure 1 illustrates the immune defects, contributing transplant-related factors, and types and timing of infections that occur after allogeneic transplant.[5]

Enlarge

Bacterial infections tend to occur in the first few weeks after transplant during the neutropenic phase, when mucosal barriers are damaged from the conditioning regimen. There is significant ongoing research into the role of prophylactic antibacterial medications during the neutropenic phase.[6]

A joint effort between the Centers for Disease Control and Prevention, the Infectious Disease Society of America, and the American Society of Transplantation and Cellular Therapy established guidelines for the prevention of infections after HSCT.[7] Approaches include preventive or prophylactic antivirals, antifungals, and antibiotics; escalation to heightened empiric therapy for signs of infection; and continued careful monitoring through the full duration of the immunocompromised period after HSCT.

Prophylaxis against fungal infections is standard during the first several months after transplant and may be considered for patients with chronic GVHD who are at high risk of fungal infection. Antifungal prophylaxis must be tailored to the patient’s underlying immune status. Pneumocystis infections can occur in all patients after bone marrow transplants, and prophylaxis is mandatory.[6]; [8][Level of evidence C1]

After HSCT, viral infections can be a major source of mortality, especially after T-cell–depleted or cord blood procedures. Types of viral infections include the following:

• Cytomegalovirus (CMV). CMV infection has been a major cause of mortality in the past, but today, effective drugs to treat CMV are available. In addition, preventive strategies, including quantitative polymerase chain reaction (PCR) monitoring followed by preemptive therapy with ganciclovir, have been developed. In addition, the U.S. Food and Drug Administration (FDA) approved letermovir for CMV prophylaxis in adults. There is solid experience using letermovir in children aged 12 years and older and emerging experience in children younger than 12 years.[9,10]
• Epstein-Barr virus (EBV). EBV rarely causes lymphoproliferative disease and is generally associated with intensive, multidrug GVHD therapy or T-cell–depleted HSCT.
• Adenovirus. Adenovirus infection is a major issue in T-cell–depleted transplant, and monitoring by quantitative blood PCR followed by therapy with cidofovir or brincidofovir (available through a compassionate-use protocol) has led to a major decrease in morbidity.[11]
• Other. Other viruses have been implicated in hemorrhagic cystitis (BK virus), encephalitis and poor count recovery (human herpes virus 6), and other clinical issues.[6] One study suggested that high BK viral loads early after transplant (4–7 weeks) may be associated with long-term decreases in glomerular filtration rate.[12]

Careful viral monitoring is essential during high-risk allogeneic procedures.

Late bacterial infections can occur in patients who have central lines or patients with significant chronic GVHD. These patients are susceptible to infection with encapsulated organisms, particularly pneumococcus. Despite reimmunization, these patients can sometimes develop significant infections, and continued prophylaxis is recommended until a serological response to immunizations has been documented. Occasionally, postallogeneic HSCT patients can become functionally asplenic, and antibiotic prophylaxis is recommended. Patients should remain on infection prophylaxis (e.g., Pneumocystis jirovecii pneumonia prophylaxis) until immune recovery. Time to immune recovery varies but ranges from 3 months to 9 months after autologous HSCT, and 9 months to 24 months after allogeneic HSCT without GVHD. Patients with active chronic GVHD may have persistent immunosuppression for years. Many centers monitor T-cell subset recovery after bone marrow transplants as a guide to infection risk.[6]

Vaccination after transplant

International transplant and infectious disease groups have developed specific guidelines for the administration of vaccines after autologous and allogeneic transplants.[6,13–15] Comparative studies aimed at defining ideal timing of vaccination after transplant have not been performed, but the vaccine guidelines outlined in Table 2 result in protective titers in most patients who receive vaccinations. These guidelines recommend that autologous transplant recipients receive immunizations beginning at 6 months after stem cell infusion and receive live vaccines 24 months after the transplant. Patients undergoing allogeneic procedures can begin immunizations as soon as 6 months after transplant. However, many groups prefer to wait either until 12 months after the procedure for patients who continue to receive immunosuppressive drugs or until patients are no longer receiving immunosuppressants.

Vaccination recommendations should be reconsidered at times of local endemic or epidemic disease outbreaks. In those settings, earlier vaccination with killed vaccines may be implemented, acknowledging limited host responses. SARS-CoV-2 vaccination recommendations have been included in a recently updated consensus guideline on vaccines after HSCT.[15] Efficacy in gaining protective immunity has been noted with early studies, but given the way the virus has changed over time, the approach to vaccination for SARS-CoV-2 is an ongoing area of study.[16]

Table 2. Vaccination Schedule for Hematopoietic Stem Cell Transplant (HSCT) Recipientsa

Autologous HSCT	6 Mob	8 Mob	12 Mob	24 Mob
Allogeneic HSCT (if not immunized before 12 mo post-HSCT; start regardless of GVHD status or immunosuppression)	12 mob (sooner if off immunosuppression)	14 mob (or 2 mo after first dose)	18 mob (or 6 mo after first dose)	24 mob
GVHD = graft-versus-host disease; IM = intramuscular; PO = orally.
aAdapted from Tomblyn et al.,[6] Centers for Disease Control and Prevention,[7] and Kumar et al.[17]
bTimes indicated are times posttransplant (day 0).
cUse of Tdap is acceptable if DTap is not available.
dTiters may be considered for pediatric patients and patients with GVHD who received immunizations while on immune suppression (minimum 6–8 weeks after last vaccination).
eMay start as soon as 4 months post-HSCT or sooner for patients with CD4 counts >200/mcL or at any time during an epidemic. If given <6 months after HSCT, may require second dose. Children younger than 9 years require second dose, separated by 1 month.
fConsider pre- or postvaccine (at least 6–8 weeks after) titers.
gPCV 7 at 24 months only for patients with GVHD; all other patients can get PPV 23.
hPediatric patients should receive two doses at least 1 month apart.
Inactivated Vaccines
Diphtheria, tetanus, acellular pertussis (DTap)	Xc	Xc	Xc,d
Haemophilus influenzae (Hib)	X	X	Xd
Hepatitis B (HepB)	X	X	Xd
Inactive polio (IPV)	X	X	Xd
Influenza—seasonal injection (IM)	Xe
Pneumococcal conjugate (PCV 7, PCV 13)	Xf	X	Xd,f,g
Pneumococcal polysaccharide (PPV 23)			Xd,f,g
Live Attenuated Vaccines (contraindicated in patients with active GVHD or on immunosuppression)
Measles, mumps, rubella				Xd,h
Optional Inactivated Vaccines
Hepatitis A			Optional
Meningococcal			Xd (for high-risk patients)
Optional Live Vaccines (contraindicated in patients with active GVHD or on immunosuppression)
Chicken pox (varicella vaccine)				Optional
Rabies			May be considered at 12–24 mo if exposed
Yellow fever, tick-borne encephalitis (TBE), Japanese B encephalitis				For travel in endemic areas
Contraindicated Vaccines
Intranasal influenza (trivalent live-attenuated influenza vaccine)—household contacts and caregivers should not receive within 2 weeks before contact with HSCT recipient; shingles; bacillus Calmette-Guerin (BCG); oral polio vaccine (OPV); cholera; typhoid vaccine (PO, IM); rotavirus.

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease (SOS/VOD)

Pathologically, SOS/VOD of the liver is the result of damage to the hepatic sinusoids, resulting in biliary obstruction. This syndrome has been estimated to occur in 15% to 40% of pediatric patients who undergo myeloablative transplants.[18,19]

Risk factors for SOS/VOD include the following:[18,19]

• Use of busulfan (especially before therapeutic pharmacokinetic monitoring).
• Total-body irradiation.
• Serious infection.
• GVHD.
• Preexisting liver dysfunction caused by hepatitis or iron overload.

SOS/VOD is defined clinically by the following:

• Right upper quadrant pain with hepatomegaly.
• Fluid retention (weight gain and ascites).
• Hyperbilirubinemia.

Life-threatening SOS/VOD generally occurs soon after transplant and is characterized by multiorgan system failure.[20] Milder, reversible forms can occur, with full recovery expected. Pediatric patients who have severe SOS/VOD without increased bilirubin have been reported.[21] Therefore, it is important to be vigilant about monitoring patients who have other symptoms without increased bilirubin.

Diagnosis of SOS/VOD

Older definitions of SOS/VOD include the modified Seattle criteria or the Baltimore criteria.

• In the Seattle criteria, at least two of the following must be present by day 20 post HSCT:[22]
  • Bilirubin level higher than 2 mg/dL.
  • Hepatomegaly or right upper quadrant pain.
  • Weight gain (>2%).
• In the Baltimore criteria, a bilirubin level of 2 mg/dL or higher and at least two of the following must be present by day 21 post HSCT:[23]
  • Painful hepatomegaly.
  • Weight gain (>5%).
  • Ascites.

These definitions are inadequate, especially in pediatric practice, as they do not recognize late-onset SOS/VOD or VOD with normal bilirubin levels.

The European Society for Blood and Marrow Transplantation (EBMT) have published revised criteria that are now broadly in use.[24] These criteria recognize late-onset SOS/VOD if proved histologically or have hemodynamic and/or ultrasound evidence of SOS/VOD (hepatomegaly, ascites, and decrease in velocity or reversal of portal flow). They have also included a modification for pediatric patients,[25] with no time limitation for SOS/VOD onset and the presence of two or more of the following:

• Unexplained consumptive and transfusion-refractory thrombocytopenia.
• Otherwise unexplained weight gain on three consecutive days, despite the use of diuretics, or weight gain greater than 5% above baseline value.
• Hepatomegaly above baseline value (best if confirmed by imaging).
• Ascites above baseline value (best if confirmed by imaging).
• Rising bilirubin level from a baseline value on three consecutive days or bilirubin level of 2 mg/dL or higher within 72 hours.

An additional modification of the diagnostic algorithm (Cairo/Cooke criteria) has been proposed, which allows for flexibility with symptoms in unusual situations.[26] The EBMT and Cairo/Cooke criteria have not been prospectively validated in clinical trials.

Prevention and treatment of SOS/VOD

Approaches to both prevention and treatment with agents such as heparin, protein C, and antithrombin III have been studied, with mixed results.[27] One small, retrospective, single-center study showed a benefit from corticosteroid therapy, but further validation is needed.[28]

Another agent with demonstrated activity is defibrotide, a mixture of oligonucleotides with antithrombotic and fibrinolytic effects on microvascular endothelium. Studies of defibrotide have shown the following:

• Decreased mortality in patients who were treated with defibrotide for severe SOS/VOD, compared with historical controls.[29–32]; [33][Level of evidence C1]
• Decreased SOS/VOD mortality associated with the early initiation of defibrotide treatment soon after diagnostic criteria for SOS/VOD were met.[34][Level of evidence B4]
• Efficacy in decreasing SOS/VOD incidence when used prophylactically.[35][Level of evidence A1] However, a second study was closed due to a lack of efficacy, questioning the validity of prophylactic defibrotide use.[36]

The FDA approved defibrotide for the treatment of patients who have hepatic SOS/VOD with renal or pulmonary dysfunction after HSCT.

The British Society for Blood and Marrow Transplantation (BSBMT) published evidence-guided recommendations for the diagnosis and management of SOS/VOD.[32] They recommend that biopsy be reserved for difficult cases and be performed using the transjugular approach. The BSBMT supports the use of defibrotide for the prevention of SOS/VOD (defibrotide prophylaxis is not currently part of the FDA indication) but maintains there is insufficient data to support the use of prostaglandin E1, pentoxifylline, or antithrombin. For treatment of SOS/VOD, they recommend aggressive fluid balance management, early involvement of critical care and gastroenterology specialists, and the use of defibrotide and possibly methylprednisolone. However, they concluded there is insufficient evidence to support the use of tissue plasminogen activator or N-acetylcysteine.[32,37] The Pediatric Transplantation and Cellular Therapy Consortium, which worked with the Pediatric Acute Lung Injury and Sepsis Investigators, published more detailed consensus recommendations for the diagnosis and management of SOS/VOD in children after HSCT.[38–40]

Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

Although TA-TMA clinically mirrors hemolytic uremic syndrome, its causes and clinical course differ from those of other hemolytic uremic syndrome–like diseases. Studies have linked this syndrome with dysregulation of complement pathways.[41] TA-TMA has most frequently been associated with the use of the calcineurin inhibitors tacrolimus and cyclosporine, and it has been noted to occur more frequently when either of these medications is used in combination with sirolimus.[42]

Diagnostic criteria for this syndrome have been updated based on expert consensus opinion and are a modification of criteria published in 2014 (see Table 3).[43,44]

Table 3. TMA Harmonization Panel Consensus Recommended Diagnostic Criteria, Modified Jodele Criteriaa

Biopsy-proven disease (kidney or GI) OR
Clinical criteria: Must meet ≥4 of the following 7 criteria within 14 days at 2 consecutive time points
AIHA = autoimmune hemolytic anemia; BP = blood pressure; GI = gastrointestinal; LDH = lactate dehydrogenase; pRBCs = packed red blood cells; PRCA = pure red cell aplasia; rUPCR = random urine protein to creatinine ratio; ULN = upper limit of normal.
aReprinted with permission from Schoettler et al., which is available under the Creative Commons CC-BY-NC-ND license.[43]
bIndicates clarification from published Jodele et al. criteria.[45]
Anemiab	Defined as one of the following:
	1. Failure to achieve transfusion independence for pRBCs despite evidence of neutrophil engraftment
	2. Hemoglobin decline from patient’s baseline by 1 g/dL
	3. New onset of transfusion dependence
	Rule out other causes of anemia, such as AIHA and PRCA
Thrombocytopeniab	Defined as one of the following:
	1. Failure to achieve platelet engraftment
	2. Higher than expected platelet transfusion needs
	3. Refractoriness to platelet transfusion
	4. 50% reduction or greater in baseline platelet count after full platelet engraftment
Elevated LDH	>ULN for age
Schistocytes	Present
Hypertension	>99th percentile for age (<18 y), or systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg (≥18 y)
Elevated sC5b-9	≥ULN
Proteinuria	≥1 mg/mg rUPCR

Evidence (impact of TA-TMA on HSCT outcomes):

1. A multicenter study of TA-TMA in pediatric patients used the following definition of TA-TMA:[46]
   1. Histological evidence of TA-TMA, or
   2. Presence of at least four of the following laboratory and clinical markers diagnostic for TA-TMA:
      • Lactate dehydrogenase (LDH) levels above reference value for age.
      • Schistocytes on peripheral blood smear.
      • De novo thrombocytopenia or requirement for platelet transfusions.
      • De novo anemia or requirement for red blood cell transfusions.
      • Hypertension greater than 99% for age (aged <18 years) or 140/90 mm Hg (aged ≥18 years) requiring ≥2 antihypertensive agents.
      • Proteinuria ≥30 mg/dL on random urine analysis twice or random urine protein to creatinine ratio >1 mg/mg.
      • Terminal complement activation: Elevated plasma sC5b-9 above normal limit (≥244 ng/mL).
   3. This study demonstrated the following results:
      • In 614 sequential patients who underwent allogeneic or autologous HSCT, 19% of allogeneic recipients and 10% of autologous recipients developed TA-TMA.
      • Patients who developed TA-TMA had increased rates of acute GVHD and steroid-refractory GVHD, intensive care unit admission, invasive ventilation, pericardial effusions, pulmonary hypertension, dialysis or continuous renal replacement therapy, acute kidney injury, and VOD.
      • In patients who underwent allogeneic HSCT, treatment-related mortality during the first 6 months was significantly higher in patients with TA-TMA than in those without TA-TMA (20% vs. 3%; P ≤ .0001).
      • In patients who underwent autologous HSCT, the overall survival (OS) rate during the first 6 months was significantly lower in patients with TA-TMA than in those without TA-TMA (79% vs. 98%; P = .001).

Treatment of TA-TMA

Treatment for TA-TMA includes the following:

• Cessation of the calcineurin inhibitor and substitution with other immune suppressants, if necessary.
• Careful management of hypertension and renal damage by dialysis, if necessary.

Prognosis for normal kidney function when disease is caused by calcineurin inhibitors alone is generally poor. However, most TA-TMA that is associated with the combination of a calcineurin inhibitor and sirolimus has been reversed after sirolimus is discontinued, and in some cases, after both medications are stopped.[42]

Some evidence suggests a role for complement modulation (c5, eculizumab therapy) in preserving renal function. Further assessment of the role of this medication in treating this complication is ongoing.[47–49] Although there are no randomized trials that used eculizumab to treat TA-TMA, there are published data from retrospective institutional and multicenter studies and one prospective trial. Historically, the 1-year survival rate for untreated patients with high-risk TA-TMA was about 20%.[50] Two retrospective studies that examined the use of eculizumab showed survival that was better than historical controls. A single-center study showed a 1-year OS rate of 66%,[50] and a multicenter study reported a 6-month OS rate of 47% with eculizumab treatment.[51] Another retrospective multicenter study that examined the use of eculizumab demonstrated a 6-month response rate of 62% and a 1-year OS rate of 55%.[52]

Evidence (treatment of high-risk TA-TMA with eculizumab):

A prospective multicenter trial enrolled 21 patients with high-risk TA-TMA and multisystem organ dysfunction. The eculizumab dosing regimen included intensive loading, induction, and maintenance phases for up to 24 weeks of therapy.[44]

• The primary outcome was met, with an OS rate of 71% at 6 months after HSCT (vs. 18% for untreated historical controls; P < .0001).
• Eleven of fifteen survivors (73%) had fully recovered organ function at the time of reporting.

Idiopathic Pneumonia Syndrome (IPS)

IPS is characterized by diffuse, noninfectious lung injury that occurs between 14 and 90 days after the infusion of donor cells. Possible etiologies include direct toxic effects of conditioning regimens and occult infection leading to secretion of high levels of inflammatory cytokines into the alveoli.[53]

The incidence of IPS appears to be decreasing, possibly because of less intensive preparative regimens, better HLA matching, and better definition of occult infections through PCR testing of blood and bronchioalveolar specimens. Mortality rates of 50% to 70% have been reported.[53] However, these estimates are from the mid-1990s, and outcomes may have improved.

Diagnostic criteria include the following signs and symptoms in the absence of documented infectious organisms:[54]

• Pneumonia.
• Evidence of nonlobar radiographic infiltrates.
• Abnormal pulmonary function.

Early assessment by bronchioalveolar lavage to rule out infection is important.

Treatment of IPS

The traditional therapy for IPS has been high-dose methylprednisolone and pulmonary support.

Etanercept is a soluble fusion protein that joins the extracellular ligand-binding domain of the tumor necrosis factor (TNF)–alpha receptor to the Fc region of the immunoglobulin G1 antibody. It acts by blocking TNF-alpha signaling. The addition of etanercept to steroid therapies has shown promising short-term outcomes (extubation, improved short-term survival) in single-center studies.[55] A large phase II trial of this approach in pediatric patients showed promising results, with OS rates of 89% at 1 month and 63% at 12 months.[56]

Autoimmune Cytopenias (AIC)

AIC after allogeneic HSCT can be restricted to one cell lineage (e.g., autoimmune hemolytic anemia), two cell lineages, or three cell lineages. Most data about AIC in pediatric patients after HSCT are reported from single-center experiences, with the number of cases ranging from 20 to 30 over a 10- to 20-year period.[57–59] The incidence of AIC is about 5% after allogeneic HSCT. Risk factors for developing AIC seem to be age younger than 10 years and having a nonmalignant disease as an HSCT indication. At least one study has identified use of serotherapy, use of cord blood as the donor source, and severe GVHD as risk factors, but this finding has not been confirmed in other studies. One study demonstrated that patients who develop AIC have inferior outcomes compared with patients who did not develop AIC.[59] However, other studies did not demonstrate an inferior outcome.[57,58]

The National Institutes of Health task force on chronic GVHD has recognized AIC as a possible atypical feature of chronic GVHD (although they may be distinct pathologically).[60] This group has created standardized diagnostic criteria and a proposed prospective study of this complication.

Treatment of AIC

The most common first-line therapy for AIC has been corticosteroids.[57–59] Additional immunosuppression or B-cell targeting monoclonal antibodies have been used and produced good responses. Intravenous immunoglobulin is used frequently as adjunct treatment for AIC and/or immunoglobulin replacement.[61] Some clinicians have used bortezomib or daratumumab as third-line agents, with responses noted.[62]

Epstein-Barr Virus (EBV)–Associated Lymphoproliferative Disorder

After HSCT, EBV infection incidence increases through childhood, from approximately 40% in children aged 4 years to more than 80% in teenagers. Patients with a history of previous EBV infection are at risk of EBV reactivation when undergoing HSCT procedures that result in intense, prolonged lymphopenia (T-cell–depleted procedures, use of antithymocyte globulin [ATG] or alemtuzumab, and, to a lesser degree, use of cord blood).[63–65]

Features of EBV reactivation can vary, from an isolated increase in EBV titers in the bloodstream as measured by PCR to an aggressive monoclonal disease with marked lymphadenopathy presenting as lymphoma (lymphoproliferative disorder).

Treatment of EBV-associated lymphoproliferative disorder

Isolated bloodstream reactivation of EBV can improve in some cases without therapy as immune function improves. However, lymphoproliferative disorder requires more aggressive therapy.

Treatment of EBV-associated lymphoproliferative disorder involves decreasing immune suppression and treatment with chemotherapy agents such as cyclophosphamide. CD20-positive EBV-associated lymphoproliferative disorder and EBV reactivation have been shown to respond to therapy with the CD20 monoclonal antibody therapy rituximab.[66–68] In addition, some centers have shown efficacy in treating or preventing this complication with therapeutic or prophylactic EBV-specific cytotoxic T cells.[69–71]

Improved understanding of the risk of EBV reactivation, early monitoring, and aggressive therapy have significantly decreased the risk of mortality from this challenging complication.

Acute GVHD

GVHD is the result of immunologic activation of donor lymphocytes targeting major or minor HLA disparities in the tissues of a recipient.[72] Acute GVHD usually occurs within the first 3 months posttransplant, although delayed acute GVHD has been noted with reduced-intensity conditioning and nonmyeloablative approaches, where achieving a high level of full donor chimerism is sometimes delayed.

Typically, acute GVHD presents with at least one of the following:

• Skin rash.
• Hyperbilirubinemia.
• Secretory diarrhea.

Acute GVHD is classified by staging the severity of skin, liver, and gastrointestinal involvement, and further combining the individual staging of these three areas into an overall grade that is prognostically significant (see Tables 4 and 5).[73] Patients with grade III or grade IV acute GVHD are at higher risk of mortality, generally resulting from organ system damage caused by infections or progressive acute GVHD that is sometimes resistant to therapy.

Table 4. Staging of Acute Graft-Versus-Host Disease (GVHD)a

Stage	Skin	Liver (bilirubin)b	GI/Gut (stool output per day)c
			Adult	Child
BSA = body surface area; GI = gastrointestinal.
aAdapted from Harris et al.[74]
bThere is no modification of liver staging for other causes of hyperbilirubinemia.
cFor GI staging: The adult stool output values should be used for patients weighing >50 kg. Use 3-day averages for GI staging based on stool output. If stool and urine are mixed, stool output is presumed to be 50% of total stool/urine mix.
dIf results of colon or rectal biopsy are positive but stool output is <500 mL/day (<10 mL/kg/day), then consider as GI stage 0.
eFor stage 4 GI: the term severe abdominal pain will be defined as having both (a) pain control requiring treatment with opioids or an increased dose in ongoing opioid use and (b) pain that significantly impacts performance status, as determined by the treating physician.
0	No GVHD rash	<2 mg/dL	<500 mL or <3 episodes/day	<10 mL/kg or <4 episodes/day
1	Maculopapular rash <25% BSA	2–3 mg/dL	500–999 mLd or 3–4 episodes/day	10–19.9 mL/kg or 4–6 episodes/day; persistent nausea, vomiting, or anorexia, with a positive result from upper GI biopsy
2	Maculopapular rash 25%–50% BSA	3.1–6 mg/dL	1,000–1,500 mL or 5–7 episodes/day	20–30 mL/kg or 7–10 episodes/day
3	Maculopapular rash >50% BSA	6.1–15 mg/dL	>1,500 mL or >7 episodes/day	>30 mL/kg or >10 episodes/day
4	Generalized erythroderma plus bullous formation and desquamation >5% BSA	>15 mg/dL	Severe abdominal paine with or without ileus, or grossly bloody stool (regardless of stool volume)	Severe abdominal paine with or without ileus, or grossly bloody stool (regardless of stool volume)

Table 5. Overall Clinical Grade (Based on the Highest Stage Obtained)

GI = gastrointestinal.
Grade 0:	No stage 1–4 of any organ
Grade I:	Stage 1–2 skin and no liver or gut involvement
Grade II:	Stage 3 skin and/or stage 1 liver involvement and/or stage 1 GI
Grade III:	Stage 0–3 skin, with stage 2–3 liver and/or stage 2–3 GI
Grade IV:	Stage 4 skin, liver, or GI involvement

Because the outcomes of patients with different grades of acute GVHD vary, investigators have sought to more precisely define acute GVHD risk based on serum biomarkers. A study that included both adults and children used a score calculated based on the levels of a combination of three biomarkers (tumor necrosis factor receptor 1 [TNFR1], suppression of tumorigenicity 2 [ST2], and regenerating islet-derived 3-alpha [REG3-alpha]), measured at the onset of acute GVHD. Investigators were able to define patients with low (8%), intermediate (27%), and high (46%, P < .0001) risk of 6-month mortality. The biomarker score was more sensitive and specific for predicting survival than clinical staging.[75] Additional refining of the prediction algorithm showed that measurement of only two biomarkers (ST2 and REG3-alpha) reliably predicted outcome. In addition, after 4 weeks of therapy, changes in the biomarker score were able to further refine prediction of survival outcomes.[76] These findings have led to several studies targeting biomarker high-risk or low-risk subsets of patients with acute GVHD and are influencing clinicians regarding the timing and intensity of acute GVHD therapies.

Prevention and treatment of acute GVHD

Morbidity and mortality from acute GVHD can be reduced through immune suppressive medications given prophylactically or T-cell depletion of grafts, either ex vivo by actual removal of cells from a graft or in vivo with anti–T-lymphocyte antibodies (ATG or anti-CD52 [alemtuzumab]). A newer approach includes administering posttransplant cyclophosphamide on days 3 and 4 after HSCT.[77] While it does not affect stem cells in the graft, cyclophosphamide eliminates or reduces the function or proliferation of alloreactive T cells,[78] markedly decreasing rates of both acute and chronic GVHD.

Complete elimination of acute GVHD with intense T-cell depletion has generally resulted in increased relapse, more infectious morbidity, and increased EBV-associated lymphoproliferative disorder. Because of this issue, most HSCT GVHD prophylaxis approaches try to balance risk by giving sufficient immune suppression to prevent severe acute and/or chronic GVHD but not completely remove GVHD risk.

GVHD prophylaxis approaches

GVHD prophylaxis has evolved, from one approach for all donor types to specific and varied approaches tailored to the following factors:

• Stem cell sources. For example, using higher intensity prophylaxis for mismatched bone marrow/peripheral blood stem cell (PBSC) HSCT, compared with low intensity/early immune tapering for matched-sibling bone marrow HSCT.[79]
• Clinical situations. For example, using planned early tapering of prophylaxis for high-risk disease to stimulate the graft-versus-leukemia (GVL) effect.[79]
• Intensity of the HSCT procedure. For example, using less intense prophylaxis for reduced-intensity regimens to increase the GVL effect because of the absence of myeloablation for disease control.

Because of these factors, it is best to consider the combination of preparative regimen, GVHD prophylaxis, and stem cell source as a unit because survival and toxicity outcomes vary if any of these three elements change.

GVHD prophylaxis for matched-sibling HSCT

The most commonly used GVHD prophylaxis approaches in pediatrics for matched-sibling HSCT consist of a calcineurin inhibitor (cyclosporine or tacrolimus), either as a single agent or in combination with methotrexate.[80,81] Doses of methotrexate are often lower for matched-sibling HSCT than for unrelated-donor HSCT. Many centers choose to give prophylaxis on three, rather than four, days after HSCT (days 1, 3, 6, and maybe 11). A large Children’s Oncology Group study had good results tapering the calcineurin inhibitor on day 42 and discontinuing it by day 96 when using matched-sibling HSCT,[82] but the traditional taper starts on day 100 posttransplant and continues over 3 months when using unrelated bone marrow/PBSC and cord blood HSCT.

A calcineurin inhibitor in combination with mycophenolate mofetil has also been used with matched-sibling HSCT, especially when reduced-intensity conditioning approaches are used.[83] Posttransplant cyclophosphamide is effective in adult matched-sibling HSCT,[84] but has generally been given with PBSCs in combination with reduced-intensity conditioning approaches. Limited data address the use of posttransplant cyclophosphamide in children undergoing matched-sibling HSCT using bone marrow as a stem cell source,[85] but outcomes appear similar to standard approaches.

GVHD prophylaxis for matched unrelated-donor HSCT

A calcineurin inhibitor in combination with methotrexate (10 mg/m2 for four doses) has been a standard approach that leads to excellent outcomes.[82] However, more recent studies have also shown excellent outcomes with posttransplant cyclophosphamide.[86–88]

A number of studies have assessed the role of ATG or alemtuzumab (both considered serotherapy, antibodies that deplete T cells) in improving outcomes after unrelated-donor bone marrow transplant.[89–91] Serotherapy includes anti–T-cell approaches (equine ATG and rabbit ATG [rATG] against either a human T-cell leukemia line [ATG-Fresenius] or human thymocytes [thymoglobulin]) and anti-CD52 antibodies (alemtuzumab). Most centers use serotherapy after HSCT for nonmalignant diseases where GVL is not as important, but the results have varied when treating malignancies. Reasonable evidence suggests that when unrelated-donor PBSCs are used, serotherapy may be beneficial. Studies in children who received unrelated-donor bone marrow HSCT have shown that targeting rATG in a pharmacokinetic-dependent model leads to faster immune recovery and better outcomes.[92,93]

A combined adult and pediatric study compared abatacept (T-cell costimulatory blocker) plus a calcineurin inhibitor/methotrexate with placebo plus a calcineurin inhibitor/methotrexate. Patients who received abatacept had improved rates of grades 2 to 4 acute GVHD and severe GVHD-free survival.[94]

GVHD prophylaxis for mismatched unrelated-donor HSCT

Use of a calcineurin inhibitor/methotrexate for mismatched unrelated-donor HSCT has led to higher rates of severe GVHD and lower rates of survival. This outcome is partially mitigated by the use of serotherapy in combination with a calcineurin inhibitor/methotrexate. Using this combined approach, the International BFM Study Group has considered the use of a single-antigen mismatched donor (7/8 or 9/10) to be a well-matched donor, with outcomes similar to those with matched unrelated donors.[95]

A prospective trial in mismatched unrelated-donor recipients added abatacept to a calcineurin inhibitor/methotrexate regimen. The study showed a marked improvement in severe acute GVHD and OS, compared with a Center for International Blood and Marrow Transplant Research (CIBMTR) control trial that used a calcineurin inhibitor/methotrexate alone.[94] An analysis of the CIBMTR registry showed similar relapse-free survival for mismatched unrelated-donor recipients using abatacept or posttransplant cyclophosphamide.[96] Posttransplant cyclophosphamide approaches have also led to improvements in outcomes when mismatched unrelated-donor HSCT have been used. A key trial run by the National Marrow Donor Program tested posttransplant cyclophosphamide using single and multiply mismatched unrelated donors. The results showed impressive decreases in acute and chronic GVHD and improved event-free survival and OS.[97] While these new approaches have revived interest in mismatched unrelated-donor use, prospective trials comparing mismatched unrelated donors using these new approaches with unrelated cord blood or haploidentical stem cell sources have not been performed.

GVHD prophylaxis for unrelated-donor cord blood HSCT

A calcineurin inhibitor/methotrexate and cyclosporine/prednisone regimen has been used as GVHD prophylaxis in cord blood HSCT. However, a number of studies in pediatric patients have documented better survival and GVHD outcomes using a calcineurin inhibitor/mycophenolate mofetil combination.[97–99] Although serotherapy has often been used for cord blood HSCT, especially in the context of nonmalignant indications, there is good evidence of improved outcomes and faster immune reconstitution without serotherapy.[100,101] Targeted dosing of serotherapy shows improved outcomes when used during cord blood HSCT,[102] but a comparison of targeted serotherapy with no serotherapy has not been performed.

GVHD prophylaxis for haploidentical-donor HSCT

Early approaches using various intensities of GVHD prophylaxis and different types of T-cell depletion led to relatively poor rates of survival and high rates of GVHD when haploidentical donors were used.[103] The approach has changed dramatically with the use of posttransplant cyclophosphamide, both for bone marrow and PBSCs, leading to outcomes comparable to those for fully matched unrelated donors.[86]

The other widely used approach to haploidentical HSCT in pediatrics is T-cell receptor (TCR) alpha beta/CD19 depletion. Using this process, several pediatric groups have demonstrated outcomes similar to those for fully matched stem cell sources, with low rates of GVHD.[104–106] Studies that compare this method with posttransplant cyclophosphamide or other stem cell sources have not been performed. Other approaches to T-cell depletion (e.g., CD34+ isolation,[107] CD45RA depletion [108]) are used by some centers, but comparative studies with other approaches are not available.

Similar to unrelated-donor bone marrow and cord blood HSCT, outcomes improved after TCR alpha beta/CD19 depletion when rATG was targeted to specific pre- and post-HSCT exposures.[109]

Nutritional approaches to prevent GVHD

Other nonimmune approaches to prevent GVHD are emerging. In a double-blind randomized study, patients with low vitamin A levels received either one pretransplant dose of vitamin A or a placebo. Patients who received vitamin A had statistically less acute GVHD (grades II to IV), acute gastrointestinal GVHD, and chronic GVHD.[110]

Steroid-refractory acute GVHD

When significant acute GVHD occurs, first-line therapy is generally methylprednisolone.[111] Patients with acute GVHD who are resistant to this therapy have a poor prognosis. However, many patients respond to second-line agents (e.g., mycophenolate mofetil, infliximab, pentostatin, sirolimus, or extracorporeal photopheresis).[112] Ruxolitinib was approved in 2019 for the treatment of children aged 12 years and older with steroid-refractory acute GVHD, with an overall response rate of 55% and a complete response rate of 27% at day 28 after initiation of therapy. Comparative trials of these agents have not been performed, so a best option for steroid-refractory GVHD has not been identified.[113–115]

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77. Luznik L, O’Donnell PV, Fuchs EJ: Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol 39 (6): 683-93, 2012. [PUBMED Abstract]
78. Nunes NS, Kanakry CG: Mechanisms of Graft-versus-Host Disease Prevention by Post-transplantation Cyclophosphamide: An Evolving Understanding. Front Immunol 10: 2668, 2019. [PUBMED Abstract]
79. Watkins B, Williams KM: Controversies and expectations for the prevention of GVHD: A biological and clinical perspective. Front Immunol 13: 1057694, 2022. [PUBMED Abstract]
80. Locatelli F, Zecca M, Rondelli R, et al.: Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial. Blood 95 (5): 1572-9, 2000. [PUBMED Abstract]
81. Storb R, Deeg HJ, Pepe M, et al.: Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood 73 (6): 1729-34, 1989. [PUBMED Abstract]
82. Pulsipher MA, Langholz B, Wall DA, et al.: The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children’s Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood 123 (13): 2017-25, 2014. [PUBMED Abstract]
83. Ueda Oshima M, Storer BE, Qiu H, et al.: Long-term Outcomes with Nonmyeloablative HLA-Identical Related Hematopoietic Cell Transplantation Using Tacrolimus and Mycophenolate Mofetil for Graft-versus-Host Disease Prophylaxis. Transplant Cell Ther 27 (2): 163.e1-163.e7, 2021. [PUBMED Abstract]
84. Mehta RS, Saliba RM, Rondon G, et al.: Post-Transplantation Cyclophosphamide Versus Tacrolimus and Methotrexate Graft-Versus-Host Disease Prophylaxis for HLA-Matched Donor Transplantation. Transplant Cell Ther 28 (10): 695.e1-695.e10, 2022. [PUBMED Abstract]
85. Borovkova AS, Paina OV, Semenova EV, et al.: Post-transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia. Clin Transplant 38 (1): e15181, 2024. [PUBMED Abstract]
86. Fierro-Pineda JC, Tsai HL, Blackford A, et al.: Prospective PTCTC trial of myeloablative haplo-BMT with posttransplant cyclophosphamide for pediatric acute leukemias. Blood Adv 7 (18): 5639-5648, 2023. [PUBMED Abstract]
87. McCurdy SR, Kanakry CG, Tsai HL, et al.: Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide. Biol Blood Marrow Transplant 25 (6): 1128-1135, 2019. [PUBMED Abstract]
88. Kanakry CG, O’Donnell PV, Furlong T, et al.: Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol 32 (31): 3497-505, 2014. [PUBMED Abstract]
89. Soiffer RJ, Kim HT, McGuirk J, et al.: Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation. J Clin Oncol 35 (36): 4003-4011, 2017. [PUBMED Abstract]
90. Socié G, Schmoor C, Bethge WA, et al.: Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood 117 (23): 6375-82, 2011. [PUBMED Abstract]
91. Kröger N, Solano C, Wolschke C, et al.: Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. N Engl J Med 374 (1): 43-53, 2016. [PUBMED Abstract]
92. Admiraal R, Nierkens S, Bierings MB, et al.: Individualised dosing of anti-thymocyte globulin in paediatric unrelated allogeneic haematopoietic stem-cell transplantation (PARACHUTE): a single-arm, phase 2 clinical trial. Lancet Haematol 9 (2): e111-e120, 2022. [PUBMED Abstract]
93. Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al.: Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol 2 (5): e194-203, 2015. [PUBMED Abstract]
94. Watkins B, Qayed M, McCracken C, et al.: Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD. J Clin Oncol 39 (17): 1865-1877, 2021. [PUBMED Abstract]
95. Peters C, Schrappe M, von Stackelberg A, et al.: Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol 33 (11): 1265-74, 2015. [PUBMED Abstract]
96. Kean LS, Burns LJ, Kou TD, et al.: Abatacept for acute graft-versus-host disease prophylaxis after unrelated donor hematopoietic cell transplantation. Blood 144 (17): 1834-1845, 2024. [PUBMED Abstract]
97. Shaw BE, Jimenez-Jimenez AM, Burns LJ, et al.: National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide. J Clin Oncol 39 (18): 1971-1982, 2021. [PUBMED Abstract]
98. Wagner JE, Eapen M, Carter S, et al.: One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med 371 (18): 1685-94, 2014. [PUBMED Abstract]
99. Eapen M, Kurtzberg J, Zhang MJ, et al.: Umbilical Cord Blood Transplantation in Children with Acute Leukemia: Impact of Conditioning on Transplantation Outcomes. Biol Blood Marrow Transplant 23 (10): 1714-1721, 2017. [PUBMED Abstract]
100. Lindemans CA, Chiesa R, Amrolia PJ, et al.: Impact of thymoglobulin prior to pediatric unrelated umbilical cord blood transplantation on immune reconstitution and clinical outcome. Blood 123 (1): 126-32, 2014. [PUBMED Abstract]
101. Admiraal R, Lindemans CA, van Kesteren C, et al.: Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation. Blood 128 (23): 2734-2741, 2016. [PUBMED Abstract]
102. Admiraal R, Versluijs AB, Huitema ADR, et al.: High-dose individualized antithymocyte globulin with therapeutic drug monitoring in high-risk cord blood transplant. Cytotherapy 26 (6): 599-605, 2024. [PUBMED Abstract]
103. Pulsipher MA: Haplo is the new black. Blood 124 (5): 675-6, 2014. [PUBMED Abstract]
104. Pulsipher MA, Ahn KW, Bunin NJ, et al.: KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial. Blood 140 (24): 2556-2572, 2022. [PUBMED Abstract]
105. Bertaina A, Zecca M, Buldini B, et al.: Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood 132 (24): 2594-2607, 2018. [PUBMED Abstract]
106. Merli P, Algeri M, Galaverna F, et al.: TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. Blood 143 (3): 279-289, 2024. [PUBMED Abstract]
107. Mehta PA, Davies SM, Leemhuis T, et al.: Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 129 (16): 2308-2315, 2017. [PUBMED Abstract]
108. Bleakley M, Heimfeld S, Loeb KR, et al.: Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest 125 (7): 2677-89, 2015. [PUBMED Abstract]
109. Dvorak CC, Long-Boyle JR, Holbrook-Brown L, et al.: Effect of rabbit ATG PK on outcomes after TCR-αβ/CD19-depleted pediatric haploidentical HCT for hematologic malignancy. Blood Adv 8 (23): 6003-6014, 2024. [PUBMED Abstract]
110. Khandelwal P, Langenberg L, Luebbering N, et al.: A randomized phase 2 trial of oral vitamin A for graft-versus-host disease in children and young adults. Blood 143 (12): 1181-1192, 2024. [PUBMED Abstract]
111. Jacobsohn DA: Acute graft-versus-host disease in children. Bone Marrow Transplant 41 (2): 215-21, 2008. [PUBMED Abstract]
112. Deeg HJ: How I treat refractory acute GVHD. Blood 109 (10): 4119-26, 2007. [PUBMED Abstract]
113. Jagasia M, Perales MA, Schroeder MA, et al.: Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood 135 (20): 1739-1749, 2020. [PUBMED Abstract]
114. Laisne L, Neven B, Dalle JH, et al.: Ruxolitinib in children with steroid-refractory acute graft-versus-host disease: A retrospective multicenter study of the pediatric group of SFGM-TC. Pediatr Blood Cancer 67 (9): e28233, 2020. [PUBMED Abstract]
115. Locatelli F, Kang HJ, Bruno B, et al.: Ruxolitinib for pediatric patients with treatment-naïve and steroid-refractory acute graft-versus-host disease: the REACH4 study. Blood 144 (20): 2095-2106, 2024. [PUBMED Abstract]

Chronic GVHD is a syndrome that can involve a single organ system or several organ systems, with clinical features resembling an autoimmune disease.[1,2] Chronic GVHD is usually first noted 2 to 12 months after hematopoietic stem cell transplant (HSCT). Traditionally, symptoms occurring more than 100 days after HSCT were considered chronic GVHD, and symptoms occurring sooner than 100 days after HSCT were considered acute GVHD. Because some approaches to HSCT can lead to late-onset acute GVHD, and manifestations that are diagnostic for chronic GVHD can occur sooner than 100 days post-HSCT, the following three distinct types of chronic GVHD have been described:

Organ Manifestations of Chronic GVHD

The diagnosis of chronic GVHD is based on clinical features (at least one diagnostic clinical sign, e.g., poikiloderma) or distinctive manifestations complemented by relevant tests (e.g., dry eye with positive results of a Schirmer test).[3]

Commonly involved tissues include the skin, eyes, mouth, hair, joints, liver, and gastrointestinal tract. Other tissues such as lungs, nails, muscles, urogenital system, and nervous system may also be involved. Tables 6 to 10 list organ manifestations of chronic GVHD, including a description of findings that are sufficient to establish the diagnosis of chronic GVHD. Biopsies of affected sites may be needed to confirm the diagnosis.[4]

Common skin manifestations include alterations in pigmentation, texture, elasticity, and thickness, with papules, plaques, or follicular changes. Patient-reported symptoms include dry skin, itching, limited mobility, rash, sores, or changes in coloring or texture. Generalized scleroderma may lead to severe joint contractures and debility. Associated hair loss and nail changes are common. Other important symptoms that should be assessed include dry eyes and oral changes such as atrophy, ulcers, and lichen planus. In addition, joint stiffness along with restricted range of motion, weight loss, nausea, difficulty swallowing, and diarrhea should be noted.

Table 6. Chronic Graft-Versus-Host Disease (GVHD) Symptoms in the Skin, Nails, Scalp, and Body Haira

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (Seen With Both Acute and Chronic GVHD)
aReprinted from Biology of Blood and Marrow Transplantation, Volume 11 (Issue 12), Alexandra H. Filipovich, Daniel Weisdorf, Steven Pavletic, Gerard Socie, John R. Wingard, Stephanie J. Lee, Paul Martin, Jason Chien, Donna Przepiorka, Daniel Couriel, Edward W. Cowen, Patricia Dinndorf, Ann Farrell, Robert Hartzman, Jean Henslee-Downey, David Jacobsohn, George McDonald, Barbara Mittleman, J. Douglas Rizzo, Michael Robinson, Mark Schubert, Kirk Schultz, Howard Shulman, Maria Turner, Georgia Vogelsang, Mary E.D. Flowers, National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report, Pages 945-956, Copyright 2005, with permission from American Society for Blood and Marrow Transplantation and Elsevier.[3]
bSufficient to establish a diagnosis of chronic GVHD.
cSeen in chronic GVHD but insufficient alone to establish a diagnosis of chronic GVHD.
dCan be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is confirmed.
eIn all cases, infection, drug effects, malignancy, or other causes must be excluded.
fDiagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes).
Skin	Poikiloderma	Depigmentation	Sweat impairment	Pruritus
	Lichen planus–like features		Ichthyosis	Erythema
	Sclerotic features		Keratosis pilaris	Maculopapular rash
	Morphea-like features		Hypopigmentation
	Lichen sclerosus–like features		Hyperpigmentation
Nails		Dystrophy
		Longitudinal ridging, splitting, or brittle features
		Onycholysis
		Pterygium unguis
		Nail loss (usually symmetric; affects most nails)e
Scalp and body hair		New onset of scarring or nonscarring scalp alopecia (after recovery from chemoradiotherapy)	Thinning scalp hair, typically patchy, coarse, or dull (not explained by endocrine or other causes)
		Scaling, papulosquamous lesions	Premature gray hair

Table 7. Chronic Graft-Versus-Host Disease (GVHD) Symptoms in the Mouth and GI Tracta

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (Seen With Both Acute and Chronic GVHD)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal; ULN = upper limit of normal.
a–eSee definitions in Table 6.
Mouth	Lichen-type features	Xerostomia		Gingivitis
	Hyperkeratotic plaques	Mucocele		Mucositis
	Restriction of mouth opening from sclerosis	Pseudomembranese		Erythema
		Mucosal atrophy		Pain
		Ulcerse
GI Tract	Esophageal web		Exocrine pancreatic insufficiency	Anorexia
	Strictures or stenosis in the upper to mid third of the esophaguse			Nausea
				Vomiting
				Diarrhea
				Weight loss
				Failure to thrive (infants and children)
				Total bilirubin, alkaline phosphatase >2 × ULNe
				ALT or AST >2 × ULNe

Table 8. Chronic Graft-Versus-Host Disease (GVHD) Symptoms in the Eyesa

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (Seen With Both Acute and Chronic GVHD)
a–fSee definitions in Table 6.
Eyes		New onset dry, gritty, or painful eyesf	Blepharitis (erythema of the eyelids with edema)
		Cicatricial conjunctivitis
		Keratoconjunctivitis siccaf	Photophobia
		Confluent areas of punctate keratopathy	Periorbital hyperpigmentation

Table 9. Chronic Graft-Versus-Host Disease (GVHD) Symptoms in the Genitaliaa

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (Seen With Both Acute and Chronic GVHD)
a–eSee definitions in Table 6.
Genitalia	Lichen planus–like features	Erosionse
	Vaginal scarring or stenosis	Fissurese
		Ulcerse

Table 10. Chronic Graft-Versus-Host Disease (GVHD) Symptoms in the Lung, Muscles, Fascia, Joints, Hematopoietic and Immune Systems, and Other Symptomsa

Organ or Site	Diagnosticb	Distinctivec	Other Featuresd	Common (Seen With Both Acute and Chronic GVHD)
AIHA = autoimmune hemolytic anemia; BOOP = bronchiolitis obliterans–organizing pneumonia; ITP = idiopathic thrombocytopenic purpura; PFTs = pulmonary function tests.
a–fSee definitions in Table 6.
Lung	Bronchiolitis obliterans diagnosed with lung biopsy	Bronchiolitis obliterans diagnosed with PFTs and radiologyf		BOOP
Muscles, fascia, joints	Fasciitis	Myositis or polymyositisf	Edema
			Muscle cramps
			Arthralgia or arthritis
Hematopoietic and immune			Thrombocytopenia
			Eosinophilia
			Lymphopenia
			Hypo- or hypergammaglobulinemia
			Autoantibodies (AIHA and ITP)
Other			Pericardial or pleural effusions
			Ascites
			Peripheral neuropathy
			Nephrotic syndrome
			Myasthenia gravis
			Cardiac conduction abnormality or cardiomyopathy

Risk Factors for Chronic GVHD

Chronic GVHD occurs in approximately 15% to 30% of children after sibling-donor HSCT [5] and in 20% to 45% of children after unrelated-donor HSCT. There is a higher risk of chronic GVHD with peripheral blood stem cells (PBSCs) and a lower risk with cord blood and selected approaches to haploidentical HSCT.[6–8]

Risk factors for the development of chronic GVHD include the following:[5,9,10]

• Patient’s age (older than 10 years).
• Type of donor (unrelated and mismatched donors).
• Use of PBSCs.
• History of acute GVHD.
• Conditioning regimen (myeloablative and total-body irradiation (TBI)–based regimens).

Several factors have been associated with increased risk of nonrelapse mortality in children who develop significant chronic GVHD. Children who received HLA-mismatched grafts, received PBSCs, were older than 10 years, or had platelet counts lower than 100,000/µL at diagnosis of chronic GVHD have an increased risk of nonrelapse mortality.

The nonrelapse mortality rates were 17% at 1 year, 22% at 3 years, and 24% at 5 years after diagnosis of chronic GVHD. Many of these children required long-term immune suppression. By 3 years after diagnosis of chronic GVHD, about a third of children had died of either relapse or nonrelapse mortality, a third were off immune suppression, and a third still required some form of immune suppressive therapy.[11]

Older literature describes chronic GVHD as either limited or extensive. A National Institutes of Health (NIH) Consensus Workshop in 2006 broadened the description of chronic GVHD to three categories to better predict long-term outcomes.[12] The three NIH grading categories are as follows:[3]

• Mild disease: Involving only one or two sites, with no significant functional impairment (maximum severity score of 1 on a scale of 0 to 3).
• Moderate disease: Either involving more sites (>2) or associated with higher severity score (maximum score of 2 in any site).
• Severe disease: Indicating major disability (a score of 3 in any site or a lung score of 2).

Thus, high-risk patients include those with severe disease of any site or extensive involvement of multiple sites, especially those with the following:

• Symptomatic lung involvement.
• Skin involvement greater than 50%.
• Platelet count lower than 100,000/µL.
• Poor performance score (<60%).
• Weight loss of more than 15%.
• Chronic diarrhea.
• Progressive-onset chronic GVHD.
• History of steroid treatment with more than 0.5 mg/kg of prednisone per day for acute GVHD.

One study demonstrated a much higher chance of long-term GVHD-free survival and lower treatment-related mortality in children with mild and moderate chronic GVHD than in children with severe chronic GVHD. At 8 years, the probability of continued chronic GVHD was 4% for children with mild chronic GVHD, 11% for children with moderate chronic GVHD, and 36% for children with severe chronic GVHD.[13] In another large prospective trial with central review that used the NIH consensus criteria, about 28% of patients were misclassified as having chronic GVHD when they actually had late-acute GVHD. Additionally, there were significant challenges when using the NIH consensus criteria for bronchiolitis obliterans in children.[14]

Treatment of Chronic GVHD

Steroids remain the cornerstone of chronic GVHD therapy. However, many approaches have been developed to minimize steroid dosing, including the use of calcineurin inhibitors.[15] Topical therapy to affected areas is preferred for patients with limited disease.[16] The following agents have been tested with some success:

• Mycophenolate mofetil.[17]
• Pentostatin.[18]
• Sirolimus.[19]
• Rituximab.[20]
• Ibrutinib.[21]
• Ruxolitinib.[22]
• Belumosudil.[23]

Other approaches, including extracorporeal photopheresis, have been evaluated and show some efficacy in some patients.[24]

A series of drugs have been approved for the treatment of chronic GVHD in children.

Evidence (treatment of chronic GVHD in children):

1. Ibrutinib is indicated for pediatric patients aged 1 year or older with chronic GVHD after failure of one or more lines of systemic therapy. Efficacy of ibrutinib was evaluated in an open-label multicenter trial of pediatric and young adult patients with moderate or severe chronic GVHD. The study included 47 patients who had one or more lines of therapy fail. The median age was 13 years (range, 1–19 years).[25]
   • The overall response rate was 60% (95% confidence interval [CI], 44%–74%) by week 25.
   • The median duration of response was 5.3 months (95% CI, 2.8–8.8).
   • The median time from first response to death or new systemic therapies for chronic GVHD was 14.8 months.
2. The U.S. Food and Drug Administration (FDA) approved ruxolitinib for the treatment of chronic GVHD in adults and children older than 12 years after failure of one or two lines of systemic therapy. The approval was based on one study that randomly assigned 329 patients to receive either ruxolitinib or best available therapy.[22]
   • The overall response rate was 70% (95% CI, 63%–77%) for patients in the ruxolitinib arm and 57% (95% CI, 49%–65%) for patients in the best available therapy arm.
3. Belumosudil, a kinase inhibitor, was approved to treat chronic GVHD in adult and pediatric patients aged 12 years and older after failure of at least two prior lines of systemic therapy. The approval was based on a study of 65 patients with chronic GVHD that was refractory to multiple lines of therapy.[23]
   • The overall response rate was 74% (95% CI, 62%–84%) for patients who received 200 mg of belumosudil once per day and 77% (95% CI, 65%–87%) for patients who received 200 mg of belumosudil twice per day. High response rates were observed in all subgroups of patients.
   • All affected organs demonstrated complete responses.

No comparative studies have been performed with these three agents. Therefore, the best drug for specific types of chronic GVHD in children has yet to be determined.

Besides significantly affecting organ function, quality of life, and functional status, infection is the major cause of chronic GVHD–related death. Therefore, all patients with chronic GVHD receive prophylaxis against Pneumocystis jirovecii pneumonia, common encapsulated organisms, and varicella by using agents such as trimethoprim/sulfamethoxazole, penicillin, and acyclovir.

Transplant-related complications account for 70% of the deaths in patients with chronic GVHD.[5] Guidelines concerning ancillary therapy and supportive care of patients with chronic GVHD have been published.[16,26]

References

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25. Carpenter PA, Kang HJ, Yoo KH, et al.: Ibrutinib Treatment of Pediatric Chronic Graft-versus-Host Disease: Primary Results from the Phase 1/2 iMAGINE Study. Transplant Cell Ther 28 (11): 771.e1-771.e10, 2022. [PUBMED Abstract]
26. Carpenter PA, Kitko CL, Elad S, et al.: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 21 (7): 1167-87, 2015. [PUBMED Abstract]

The highest incidence of mortality after HSCT occurs in the first 2 years and is mostly caused by relapse. A study of late mortality (≥2 years posttransplant) in children with malignancies who underwent HSCT showed that approximately 20% of the 479 patients who were alive at 2 years had a late death. The late mortality rate was 15% in the allogeneic HSCT group (median follow-up, 10.0 years [2.0–25.6]), mainly caused by relapse (65%). A total of 26% of patients had a late death after autologous HSCT (median follow-up, 6.7 years [2.0–22.2]),[1] and recurrence of the primary malignancy accounted for 88% of these deaths. Nonrelapse mortality, death caused by chronic graft-versus-host disease (GVHD), and secondary malignancies are less common in children.

Another study reviewed the causes of late mortality after a second allogeneic transplant.[2] Of the children who were alive and relapse free 1 year after a second HSCT, 55% remained alive at 10 years. The most common cause of mortality between 1 and 10 years after HSCT in this group was relapse (77% of deaths), generally occurring in the first 3 years after transplant. The cumulative incidence of nonrelapse mortality at 10 years was 10% for this cohort. Chronic GVHD occurred in 43% of children in this study and was the leading cause of nonrelapse mortality.

One study focused on late mortality in children after autologous HSCT. The study showed that mortality rates of children who underwent transplant remained elevated compared with those of the general population more than 10 years after the procedure. However, their mortality rates approached the rates of the general population at 15 years. The study also showed a decrease in late mortality in the more current treatment eras (before 1990, 35.1%; 1990–1999, 25.6%; 2000–2010, 21.8%; P = .05).[3]

References

1. Schechter T, Pole JD, Darmawikarta D, et al.: Late mortality after hematopoietic SCT for a childhood malignancy. Bone Marrow Transplant 48 (10): 1291-5, 2013. [PUBMED Abstract]
2. Duncan CN, Majhail NS, Brazauskas R, et al.: Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant 21 (1): 151-8, 2015. [PUBMED Abstract]
3. Holmqvist AS, Chen Y, Wu J, et al.: Late mortality after autologous blood or marrow transplantation in childhood: a Blood or Marrow Transplant Survivor Study-2 report. Blood 131 (24): 2720-2729, 2018. [PUBMED Abstract]

Data from studies of child and adult survivors of HSCT have shown that treatment-related exposures have a significant impact on survival and quality of life.[1] In one study of patients who were alive 2 years after undergoing HSCT, survivors had a 9.9-fold increased risk of premature death compared with age- and sex-matched controls in the U.S. general population.[2] Another multicenter study showed that more than one-half of adult survivors who underwent HSCT during childhood would have a grade 3 or 4 chronic health issue. Survivors had an odds ratio (OR) of 15.1 compared with siblings.[3]

Methodological Challenges in the Study of Late Effects After HSCT

Although the main cause of death in patients who have undergone HSCT is from relapse of the primary disease, many of these patients die from infections related to graft-versus-host disease (GVHD), second malignancies, or cardiac or pulmonary issues.[2,4–6] In addition, other studies have revealed that up to 40% of HSCT survivors experience severe, disabling, and/or life-threatening events or die because of an adverse event associated with primary or previous cancer treatment.[7,8]

Before studies aimed at decreasing the incidence and severity of these effects are initiated, it is important to understand what leads to the development of these complications:

• Pretransplant therapy: Pretransplant therapy plays an important role, but the details of significant exposures associated with pre-HSCT therapy are not included in many studies.[9]
• Preparative regimen: The transplant preparative regimen itself, including total-body irradiation (TBI) and high-dose chemotherapy, has often been studied, but this intense therapy is only a small part of a long course of therapy filled with potential causes of late effects.
• Allogenicity: The effect of allogenicity—differences in major and minor HLA antigens that lead to GVHD, autoimmunity, chronic inflammation, and, sometimes, undetected organ damage—also contributes to these late effects.
• Extended exposure to nonchemotherapeutic agents: Patients who undergo transplants may receive immunosuppressants that have significant toxicity for an extended period of time (e.g., cyclosporine or tacrolimus, which can cause hypertension and kidney damage). In addition, it is routine for patients to receive extended courses of supportive medications or antimicrobials that can be associated with organ damage (e.g., liposomal amphotericin B). These medications should be considered when assessing the risk of late effects.

Individuals differ in their susceptibility to specific organ damage from chemotherapy or in their risk of GVHD based on genetic differences in both the donor and recipient.[9–11]

Cardiovascular System Late Effects

Although cardiac dysfunction has been studied extensively in non-HSCT settings, less is known about the incidence and predictors of congestive heart failure following HSCT in childhood. Potentially cardiotoxic exposures unique to HSCT include the following:[12]

• Conditioning with high-dose chemotherapy, especially cyclophosphamide.
• TBI.

HSCT survivors are at increased risk of developing cardiovascular risk factors such as hypertension and diabetes, partly as a result of exposure to TBI and prolonged immunosuppressive therapy after allogeneic HSCT or related to other health conditions (e.g., hypothyroidism or growth hormone deficiency).[8,12] In a study of 661 pediatric patients who survived at least 2 years after allogeneic HSCT, 52% of patients had obesity or were overweight at their most recent examination, 18% of patients had dyslipidemia (associated with pre-HSCT anthracycline or cranial or chest irradiation), and 7% of patients were diagnosed with diabetes.[13]

Rates of cardiovascular outcomes were examined among nearly 1,500 transplant survivors (surviving ≥2 years) who were treated in Seattle from 1985 to 2006. The survivors and a population-based comparison group were matched by age, year, and sex.[14] Survivors experienced increased rates of cardiovascular death (adjusted incidence rate difference, 3.6 per 1,000 person-years [95% confidence interval, 1.7–5.5]). Survivors also had an increased cumulative incidence of the following:

• Ischemic heart disease.
• Cardiomyopathy/heart failure.
• Stroke.
• Vascular diseases.
• Rhythm disorders.

Survivors also had an increased cumulative incidence of related conditions that increased their risk of developing more serious cardiovascular disease (i.e., hypertension, renal disease, dyslipidemia, and diabetes).[14]

In addition, cardiac function and pre-HSCT exposures to chemotherapy and radiation therapy have been shown to significantly impact post-HSCT cardiac function. In evaluating post-HSCT patients for long-term issues, it is important to consider levels of pre-HSCT anthracycline and chest irradiation.[15] Although more specific studies are needed to verify this approach, current evidence suggests that the risk of late-occurring cardiovascular complications after HSCT may largely result from pre-HSCT therapeutic exposures, with little additional risk from conditioning-related exposures or GVHD.[16,17]

For more information, see the Late Effects of the Cardiovascular System section in Late Effects of Treatment for Childhood Cancer.

Neurocognitive Late Effects

Many studies report normal neurodevelopment after HSCT, with no evidence of decline.[18–25]

Researchers from St. Jude Children’s Research Hospital have reported on the largest longitudinal cohort to date, describing remarkable stability in global cognitive function and academic achievement during 5 years of posttransplant follow-up.[21–23] This research group reported poorer outcomes in patients who underwent unrelated-donor transplant when the patients received TBI and when they experienced GVHD. But these effects on outcomes were small compared with the much larger effects of socioeconomic status on cognitive function.[22] Most published studies report similar outcomes. Normal cognitive function and academic achievement were reported in a cohort of 47 patients monitored prospectively through 2 years post-HSCT.[25] Stable cognitive function was also noted in a large cohort monitored from pretransplant to 2 years post-HSCT.[20] A smaller study reported similar normal functioning and the absence of declines over time in HSCT survivors.[18] HSCT survivors did not differ from their siblings in cognitive and academic function, with the exception that survivors performed better than siblings on measures of perceptual organization.[19] Based on findings to date, it appears that HSCT poses low-to-minimal risk of late cognitive and academic deficits in survivors.

Several studies, however, have reported some decline in cognitive function after HSCT.[26–32] These studies tended to include samples with a high percentage of very young children. One study reported a significant decline in IQ in their cohort at 1 year post-HSCT, deficits that were maintained at 3 years post-HSCT.[27,28] Similarly, studies from Sweden have reported deficits in visual-spatial domains and executive functioning in very young children who underwent transplant with TBI.[30,31] Another study from St. Jude Children’s Research Hospital reported that while all children younger than 3 years had a decline in IQ at 1 year after transplant, patients who did not receive TBI during conditioning recovered later. Patients who received TBI had a significantly lower IQ at 5 years (P = .05) than did those who did not receive TBI.[32]

For more information, see the Hematopoietic stem cell transplant (HSCT) section in Late Effects of Treatment for Childhood Cancer.

Digestive System Late Effects

Gastrointestinal, biliary, and pancreatic dysfunction

Most gastrointestinal late effects are related to protracted acute GVHD and chronic GVHD (see Table 11). For more information, see the Hepatobiliary section in Late Effects of Treatment for Childhood Cancer.

As GVHD is controlled and tolerance is developed, most symptoms resolve. Major hepatobiliary concerns include the consequences of viral hepatitis acquired before or during the transplant, biliary stone disease, and focal liver lesions.[33] Viral serology and polymerase chain reaction should be performed to differentiate these from GVHD presenting with hepatocellular injury.[34]

Table 11. Causes of Gastrointestinal (GI), Hepatobiliary, and Pancreatic Problems in Long-Term Transplant Survivorsa

Problem Areas	Common Causes	Less Common Causes
ALT = alanine transaminase; AP = alkaline phosphatase; CMV = cytomegalovirus; GGT = gamma glutamyl transpeptidase; GVHD = graft-versus-host disease; HSV = herpes simplex virus; Mg++ = magnesium; VZV = varicella zoster virus.
aReprinted from Biology of Blood and Marrow Transplantation, Volume 17 (Issue 11), Michael L. Nieder, George B. McDonald, Aiko Kida, Sangeeta Hingorani, Saro H. Armenian, Kenneth R. Cooke, Michael A. Pulsipher, K. Scott Baker, National Cancer Institute–National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on Late Effects After Pediatric Hematopoietic Cell Transplantation: Long-Term Organ Damage and Dysfunction, Pages 1573–1584, Copyright 2011, with permission from American Society for Blood and Marrow Transplantation and Elsevier.[34]
Esophageal symptoms: heartburn, dysphagia, painful swallowing [35–40]	Oral chronic GVHD (mucosal changes, poor dentition, xerostomia)	Chronic GVHD of the esophagus (webs, rings, submucosal fibrosis and strictures, aperistalsis)
	Reflux of gastric fluid	Hypopharyngeal dysmotility (myasthenia gravis, cricopharyngeal incoordination)
		Squamous > adenocarcinoma
		Pill esophagitis
		Infection (fungal, viral)
Upper gut symptoms: anorexia, nausea, vomiting [41–45]	Protracted acute GI GVHD	Secondary adrenal insufficiency
	Activation of latent infection (CMV, HSV, VZV)	Acquisition of infection (enteric viruses, Giardia, cryptosporidia, Haemophilus pylori)
	Medication adverse effects	Gut dysmotility
Mid gut and colonic symptoms: diarrhea and abdominal pain [46,47]	Protracted acute GI GVHD	Acquisition of infection (enteric viruses, bacteria, parasites)
	Activation of latent CMV, VZV	Pancreatic insufficiency
	Drugs (mycophenolate mofetil, Mg++, antibiotics)	Clostridium difficile colitis
		Collagen-encased bowel (GVHD)
		Rare: inflammatory bowel disease, sprue;[47] bile salt malabsorption; disaccharide malabsorption
Liver problems [33,48–57]	Cholestatic GVHD	Hepatitic GVHD
	Chronic viral hepatitis (B and C)	VZV or HSV hepatitis
	Cirrhosis	Fungal abscess
	Focal nodular hyperplasia	Nodular regenerative hyperplasia
	Nonspecific elevation of liver enzymes in serum (AP, ALT, GGT)	Biliary obstruction
		Drug-induced liver injury
Biliary and pancreatic problems [58–61]	Cholecystitis	Pancreatic atrophy/insufficiency
	Common duct stones/sludge	Pancreatitis/edema, stone or sludge related
	Gall bladder sludge (calcium bilirubinate)	Pancreatitis, tacrolimus related
	Gallstones

Iron overload

Iron overload occurs in almost all patients who undergo HSCT, especially if the procedure is for a condition associated with transfusion dependence before HSCT (e.g., thalassemia, bone marrow failure syndromes) or pre-HSCT treatments requiring transfusions after myelotoxic chemotherapy (e.g., acute leukemias). Inflammatory conditions such as GVHD also increase gastrointestinal iron absorption. Non-HSCT conditions leading to iron overload can lead to cardiac dysfunction, endocrine disorders (e.g., pituitary insufficiency, hypothyroidism), diabetes, neurocognitive effects, and second malignancies.[34]

The effects of iron overload on morbidity post-HSCT have not been well studied. However, reducing iron levels after HSCT for thalassemia has been shown to improve cardiac function.[62]

Data supporting iron reduction therapies (such as phlebotomy or chelation after HSCT) have not identified specific levels at which iron reduction should be performed. However, higher levels of ferritin and/or evidence of significant iron overload by liver biopsy or T2-weighted magnetic resonance imaging (MRI) [63] should be addressed by iron reduction therapy.[64]

Endocrine System Late Effects

Thyroid dysfunction

Studies show that rates of thyroid dysfunction in children after myeloablative HSCT vary, with larger series reporting an average incidence of about 30%.[65–75] A lower incidence in adults (on average, 15%) and a notable increase in incidence in children younger than 10 years who underwent HSCT suggest that a developing thyroid gland may be more susceptible to damage.[65,67,71,75]

Pretransplant local thyroid radiation contributes to high rates of thyroid dysfunction in patients with Hodgkin lymphoma.[65] Early studies showed very high rates of thyroid dysfunction after high single-dose fractions of TBI,[76] but traditional fractionated TBI/cyclophosphamide compared with busulfan/cyclophosphamide showed similar rates of thyroid dysfunction, suggesting a role for high-dose chemotherapy in thyroid damage.[68–70] Notably, one large study showed that patients treated with either TBI or busulfan had similar high rates of thyroid dysfunction, while patients treated with treosulfan or reduced-intensity, chemotherapy-based regimens had low rates of thyroid disease.[75] For more information, see the Posttransplant thyroid dysfunction section in Late Effects of Treatment for Childhood Cancer.

Higher rates of thyroid dysfunction occur with single-drug prophylaxis than with three-drug GVHD prophylaxis.[77] Increased rates of thyroid dysfunction occur after unrelated-donor HSCT than after related-donor HSCT (36% vs. 9%),[66] suggesting a role for alloimmune damage in causing thyroid dysfunction.[70,78]

Growth impairment

Growth impairment is generally multifactorial. Factors that play a role in failure to achieve expected adult height in young children who have undergone HSCT include the following:

• Diminished growth hormone level.
• Thyroid dysfunction.
• Disruption of pubertal sex hormone production.
• Steroid therapy.
• Poor nutritional status.

The incidence of growth impairment varies from 20% to 80%, depending on age, risk factors, and the definition of growth impairment used by reporting groups.[72,73,79–82] Risk factors include the following:[68,69,80,83]

• TBI.
• Cranial irradiation.
• Younger age.
• HSCT for acute lymphoblastic leukemia.
• HSCT occurring during a pubertal growth spurt.[84]

Patients younger than 10 years at the time of HSCT are at the highest risk of growth impairment, but they also respond best to growth hormone replacement therapy. Early screening and referral of patients with signs of growth impairment to endocrinology specialists can result in significant restoration of height in younger children.[82]

For more information, see the Growth hormone deficiency section in Late Effects of Treatment for Childhood Cancer.

Abnormal body composition and metabolic syndrome

After HSCT, adult survivors have a 2.3-fold higher risk of premature cardiovascular-related death compared with the general population.[85,86] The exact etiology of cardiovascular risk and subsequent death is largely unknown. However, the development of metabolic syndrome (a constellation of central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension), especially insulin resistance, as a consequence of HSCT has been suggested.[87–89]

In studies of conventionally treated leukemia survivors compared with those who underwent HSCT, transplant survivors are significantly more likely to manifest metabolic syndrome or multiple adverse cardiac risk factors, including central adiposity, hypertension, insulin resistance, and dyslipidemia.[34,90,91] The concern over time is that survivors who develop metabolic syndrome after HSCT will be at higher risk of significant cardiovascular-related events and/or premature death from cardiovascular-related causes.

For more information, see the Metabolic Syndrome section in Late Effects of Treatment for Childhood Cancer.

Sarcopenic obesity

The association of obesity with diabetes and cardiovascular disease risk in the general population is well established, but obesity as determined by body mass index (BMI) is uncommon in long-term survivors after HSCT.[91] However, despite having a normal BMI, HSCT survivors develop significantly altered body composition that results in both an increase in total percent fat mass and a reduction in lean body mass. This finding, called sarcopenic obesity, results in a loss of myocyte insulin receptors and an increase in adipocyte insulin receptors; the latter are less efficient in binding insulin and clearing glucose, ultimately contributing to insulin resistance.[92–94]

Preliminary data from 119 children and young adult survivors and 81 healthy sibling controls found that HSCT survivors had significantly lower weight but no differences in BMI or waist circumference when compared with siblings.[95] HSCT survivors had a significantly higher percent fat mass and lower lean body mass than did controls. HSCT survivors were significantly more insulin resistant than were controls, and they also had a higher incidence of other cardiovascular risk factors, such as elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides. These differences were found only in patients who had received TBI as part of their transplant conditioning regimen.

Musculoskeletal System Late Effects

Low bone mineral density

Few studies have addressed low bone mineral density after HSCT in children.[96–102] A significant portion of children experienced reduction in total-body bone mineral density or lumbar Z-scores showing osteopenia (18%–33%) or osteoporosis (6%–21%). Although general risk factors have been described (female sex, inactivity, poor nutritional status, White or Asian ethnicity, family history, TBI, craniospinal irradiation, corticosteroid therapy, GVHD, cyclosporine, and endocrine deficiencies [e.g., growth hormone deficiency, hypogonadism]), most reported populations have been too small for multivariate analysis to test the relative importance of each factor.[103–113]

Some studies in adults have shown improvement over time in low bone mineral density after HSCT.[101,114,115] However, this finding has yet to be shown in children.

Treatment for children has generally included a multifactorial approach, with vitamin D and calcium supplementation, minimization of corticosteroid therapy, participation in weight-bearing exercise, and resolution of other endocrine problems. The role of bisphosphonate therapy in children with this condition is unclear.

For more information, see the Osteoporosis and Fractures section in Late Effects of Treatment for Childhood Cancer.

Osteonecrosis

Reported incidence of osteonecrosis in children after HSCT has been 1% to 14%. However, these studies were retrospective and underestimated actual incidence because patients may have been asymptomatic early in the course of the disease.[116–118] Two prospective studies showed an incidence of 30% and 44% with routine MRI screening of possible target joints.[100,119] Osteonecrosis generally occurs within 3 years after HSCT, with a median onset of about 1 year. The most common locations include knees (30%–40%), hips (19%–24%), and shoulders (9%). Most patients experience osteonecrosis in two or more joints.[76,116,120,121]

In one prospective report, risk factors by multivariate analysis included age (markedly increased in children older than 10 years; OR, 7.4) and presence of osteonecrosis at the time of transplant. It is important to note that pre-HSCT factors such as corticosteroid exposure are very important in determining patient risk. In this study, 14 of 44 children who developed osteonecrosis had the disease before HSCT.[119] A Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective nested control study of 160 cases and 478 control children suggested older age (>5 years), female sex, and the presence of chronic GVHD as risk factors for developing osteonecrosis.[122]

Treatment has generally consisted of minimization of corticosteroid therapy and surgical joint replacement. Most patients are not diagnosed until they present with symptoms. In one study of 44 patients with osteonecrosis lesions in whom routine yearly MRI was performed, 4 resolved completely and 2 had resolution in one of multiply involved joints.[119] The observation that some lesions can heal over time suggests caution in the surgical management of asymptomatic lesions.

For more information, see the Osteonecrosis section in Late Effects of Treatment for Childhood Cancer.

Reproductive System Late Effects

Pubertal development

Delayed, absent, or incomplete pubertal development commonly occurs after HSCT. Two studies showed pubertal delay or failure in 16% of female children who received cyclophosphamide alone, 72% of those who received busulfan/cyclophosphamide, and 57% of those who underwent fractionated TBI. In males, incomplete pubertal development or failure was noted in 14% of those who received cyclophosphamide alone, 48% of those who received busulfan/cyclophosphamide, and 58% of those who underwent TBI.[74,123] Boys who received more than 24 Gy of radiation to the testicles developed azoospermia and also experienced failure of testosterone production, requiring supplementation to develop secondary sexual characteristics.[124]

Fertility

Women

Pretransplant and transplant cyclophosphamide exposure is the best-studied agent affecting fertility. Postpubertal women younger than 30 years can tolerate up to 20 g/m2 of cyclophosphamide and have preserved ovarian function. Prepubertal females can tolerate as much as 25 g/m2 to 30 g/m2. Although the additional effect added by pretransplant exposures to cyclophosphamide and other agents has not been specifically calculated in studies, these exposures plus transplant-related chemotherapy and radiation therapy lead to ovarian failure in 65% to 84% of females undergoing myeloablative HSCT.[125–128] The use of cyclophosphamide, busulfan, and TBI as part of the preparative regimen are associated with worse ovarian function. Younger age at the time of HSCT is associated with a higher chance of menarche and ovulation.[129,130] For more information, see the Ovarian function after HSCT section in Late Effects of Treatment for Childhood Cancer.

Studies of pregnancy are challenging because data seldom indicate whether individuals are trying to conceive. Nonetheless, a large study of pregnancy in pediatric and adult survivors of myeloablative transplant demonstrated conception in 32 of 708 patients (4.5%).[125] Of those trying to conceive, patients exposed to cyclophosphamide alone (total dose 6.7 g/m2 with no pretransplant exposure) had the best chance of conception (56 of 103, 54%), while those receiving myeloablative busulfan/cyclophosphamide (0 of 73, 0%) or TBI (7 of 532, 1.3%) had much lower rates of conception.

Men

The ability of men to produce functional sperm decreases with exposure to higher doses and specific types of chemotherapy. Most men will become azoospermic at a cyclophosphamide dose of 300 mg/kg.[131] After HSCT, 48% to 85% of men will experience gonadal failure.[125,131,132] One study showed that men who received cyclophosphamide conceived only 24% of the time, compared with 6.5% of men who received busulfan/cyclophosphamide and 1.3% of those who underwent TBI.[125] For more information, see the Testicular function after HSCT section in Late Effects of Treatment for Childhood Cancer.

Effect of reduced-toxicity, reduced-intensity, or nonmyeloablative regimens

Based on clear evidence of dose effect and the lowered gonadotoxicity of some reduced-toxicity chemotherapy regimens, the use of reduced-intensity, reduced-toxicity, or nonmyeloablative regimens will likely lead to a higher chance of preserved fertility after HSCT. Registry reports are beginning to describe pregnancies after these procedures.[128] In addition, a single-center study compared myeloablative busulfan/cyclophosphamide with reduced-intensity fludarabine/melphalan.[133][Level of evidence C1] Spontaneous puberty occurred in 56% of girls and 89% of boys after busulfan/cyclophosphamide, whereas 90% of girls and all of the boys in the fludarabine/melphalan group entered puberty spontaneously (P = .012). Significantly more girls (61%) who received busulfan/cyclophosphamide required hormone replacement than did girls in the fludarabine/melphalan group (10.5%; P = .012). In boys, no difference was noted between the two conditioning groups in time to follicle-stimulating hormone (FSH) elevation (median, 4 years in the fludarabine/melphalan group vs. 6 years in the busulfan/cyclophosphamide group). While the two regimens had similar effects on testicular function, ovarian function seemed to be better preserved in girls undergoing HSCT with reduced-intensity conditioning approaches.

Another study compared serum concentrations of antimüllerian hormone (AMH) and inhibin B in 121 children who survived more than 1 year following a single HSCT and received a treosulfan-based regimen (treosulfan; low-toxicity), a fludarabine/melphalan regimen (Flu/Mel; reduced-intensity), or a busulphan/cyclophosphamide regimen (Bu/Cy; myeloablative). Mean age at HSCT was 3.6 years; mean age at follow-up was 11.8 years. Mean length of follow-up was 9.9 years. Mean AMH standard deviation scores (SDS) were significantly higher after treosulfan (-1.047) and Flu/Mel (-1.255) than after Bu/Cy (-1.543), suggesting less ovarian reserve impairment after treosulfan and Flu/Mel than after Bu/Cy. Mean serum AMH concentration was significantly better with treosulfan (>1.0 μg/l) than with Flu/Mel or Bu/Cy. In males, mean inhibin B SDS was significantly higher after treosulfan (-0.506) than after Flu/Mel (-2.53) or some Bu/Cy (-1.23). The authors concluded that treosulfan-based regimens may confer a more favorable outlook for gonadal reserve in both sexes than Flu/Mel or Bu/Cy regimens.[134] A similar report showed better pubertal attainment and Leydig cell function in children receiving treosulfan regimens compared with busulfan and TBI-based approaches.[135]

An additional study compared gonadal function markers after myeloablative conditioning with Bu/Cy and cyclophosphamide/TBI regimens with a reduced-intensity conditioning regimen using fludarabine/melphalan/alemtuzumab.[136]

• Female patients who received reduced-intensity conditioning were less likely to develop primary ovarian insufficiency, as demonstrated by elevated FSH (P = .02) and low estradiol (P = .01) or elevated luteinizing hormone (P = .09).
• Most females in the reduced-intensity conditioning (75%) and myeloablative conditioning (93%) groups had low AMH levels, indicating low or absent ovarian reserve.
• In males, although median levels of inhibin B were higher after reduced-intensity conditioning, they were not significantly different between the two groups. Ten of 11 males who received reduced-intensity conditioning (91%) and all ten males who received myeloablative conditioning (100%) had azoospermia or oligospermia. The median time from HSCT to semen analysis was 3.7 years (range, 1.3–12.2 years).
• Many of these patients had pre-HSCT exposures to gonadotoxic drugs that were not taken into consideration in the analysis.
• Although this study was small, it provided evidence that risk of infertility after reduced-intensity conditioning regimens such as fludarabine/melphalan/alemtuzumab may be substantial.

A multi-institutional, international, retrospective cohort study included 326 adolescent and young adult patients aged 10 to 40 years. The study assessed AMH, FSH, and estradiol levels to compare fertility potential and gonadal failure 1 to 2 years after HSCT in patients who received myeloablative conditioning versus reduced-intensity conditioning (regimens were not defined further).[137]

• Only 1 of 45 female patients (2.2%) who received myeloablative conditioning had an AMH level of ≥0.5 ng/mL, compared with 4 of 26 (15.4%) who received reduced-intensity conditioning (P = .06).
• Of female patients who received myeloablative conditioning, 8 of 45 (17.8%) had detectable AMH levels of ≥0.03 ng/mL, compared with 12 of 26 who received reduced-intensity conditioning (P = .015).
• The gonadal failure rate was 55.3% in female patients. The only significant risk factor was increased age at time of HSCT in both univariate (median age, 17.6 years vs. 13.9 years; P < .0001) and multivariate analyses (OR, 1.11; 95% CI, 1.03–1.22 for each year increase; P = .012).
• Diagnosis group, conditioning intensity, TBI, chronic GVHD, and cyclophosphamide dose were not significantly associated with risk of gonadal failure in female patients.
• In male patients, 55 of 125 (44.0%) had FSH levels of ≥10.4 mIU/mL, representing likely azoospermia. Univariate analysis showed significant risk factors of older age at time of HSCT (median age, 16.2 years vs. 14.4 years; P = .0005) and TBI dose (P = .002). Multivariate analysis showed significant risk factors of increased age (OR, 1.16; 95% CI, 1.06–1.27 for each year increase; P = .0016) and standard doses of TBI (≥600 cGy) compared with no TBI (OR, 6.23; 95% CI, 2.21–19.15; P = .0008).
• Similar to female patients, diagnosis group, conditioning intensity, chronic GVHD, and cyclophosphamide dose were not significantly associated with the risk of gonadal failure in male patients.
• Patients with Fanconi anemia were excluded from the study based on high rates of baseline infertility. However, other nonmalignant indications for transplant that similarly predispose patients to infertility were not necessarily excluded, which may confound findings in the reduced-intensity conditioning cohort.

Respiratory System Late Effects

Chronic pulmonary dysfunction

The following two forms of chronic pulmonary dysfunction are observed after HSCT:[138–143]

• Obstructive lung disease.
• Restrictive lung disease.

The incidence of both forms of lung toxicity can range from 10% to 40%, depending on donor source, the time interval after HSCT, definition applied, and presence of chronic GVHD. In both conditions, collagen deposition and the development of fibrosis in either the interstitial space (restrictive lung disease) or the peribronchiolar space (obstructive lung disease) are believed to underlie the pathology.[144,145]

Obstructive lung disease

The most common form of obstructive lung disease after allogeneic HSCT is bronchiolitis obliterans.[140,143,146,147] This condition is an inflammatory process resulting in bronchiolar obliteration, fibrosis, and progressive obstructive lung disease.[138]

Historically, the term bronchiolitis obliterans was used to describe chronic GVHD of the lung, and it begins 6 to 20 months after HSCT. Pulmonary function tests show obstructive lung disease with general preservation of forced vital capacity (FVC), reductions in forced expiratory volume in 1 second (FEV1), and associated decreases in the FEV1/FVC ratio with or without significant declines in the diffusion capacity of the lung for carbon monoxide (DLCO).

Risk factors for bronchiolitis obliterans include the following:[138,146,148]

• Lower pretransplant FEV1/FVC values.
• Concomitant pulmonary infections.
• Chronic aspiration.
• Acute and chronic GVHD.
• Older recipient age.
• Use of mismatched donors.
• High-dose (vs. reduced-intensity) conditioning.

The clinical course of bronchiolitis obliterans is variable, but patients frequently develop progressive and debilitating respiratory failure despite the initiation of enhanced immunosuppression.

Standard treatment for obstructive lung disease combines enhanced immunosuppression with supportive care, including antimicrobial prophylaxis, bronchodilator therapy, and supplemental oxygen, when indicated.[148,149] The potential role for tumor necrosis factor-alpha in the pathogenesis of obstructive lung disease suggests that neutralizing agents such as etanercept may have promise.[150]

Restrictive lung disease

Restrictive lung disease is defined by reductions in FVC, total lung capacity (TLC), and DLCO. In contrast to obstructive lung disease, the FEV1/FVC ratio is maintained near 100%. Restrictive lung disease is common after HSCT and has been reported in 25% to 45% of patients by day 100.[138] Importantly, declines in TLC or FVC occurring at 100 days and 1 year after HSCT are associated with an increase in nonrelapse mortality. Early reports suggested that the incidence of restrictive lung disease increases with advancing recipient age, but subsequent studies have revealed significant restrictive lung disease in children receiving HSCT.[151]

The most recognizable form of restrictive lung disease is bronchiolitis obliterans organizing pneumonia (BOOP), more recently called cryptogenic organizing pneumonia (COP). Clinical features include dry cough, shortness of breath, and fever. Radiographic findings show diffuse, peripheral, fluffy infiltrates consistent with airspace consolidation. Although reported in fewer than 10% of HSCT recipients, the development of BOOP/COP is strongly associated with previous acute and chronic GVHD.[144]

Patients with restrictive lung disease have limited responses to multiple agents such as corticosteroids, cyclosporine, tacrolimus, and azathioprine.[149] The potential role for tumor necrosis factor-alpha in the pathogenesis of restrictive lung disease suggests that neutralizing agents such as etanercept may have promise.[150]

For more information, see the Respiratory Complications Associated With HSCT section in Late Effects of Treatment for Childhood Cancer.

Urinary System Late Effects

Renal disease

Chronic kidney disease is frequently diagnosed after transplant. There are many clinical forms of chronic kidney disease, but the most commonly described ones include thrombotic microangiopathy, nephrotic syndrome, calcineurin inhibitor toxicity, acute kidney injury, and GVHD-related chronic kidney disease. Various risk factors associated with the development of chronic kidney disease have been described. However, recent studies suggest that acute and chronic GVHD may be a proximal cause of renal injury.[34]

In a systematic review of 9,317 adults and children from 28 cohorts who underwent HSCT, approximately 16.6% of patients (range, 3.6% to 89%) developed chronic kidney disease, defined as a decrease in estimated glomerular filtration rate of at least 24.5 mL/min/1.73 m2 within the first year after transplant.[152] The cumulative incidence of chronic kidney disease developing approximately 5 years after transplant ranged from 4.4% to 44.3%, depending on the type of transplant and stage of chronic kidney disease.[153–155] Mortality rates among patients with chronic kidney disease in this setting were higher than those in transplant recipients who retained normal renal function, even when studies controlled for comorbidities.[156]

It is important to aggressively treat hypertension in patients post-HSCT, especially in those treated with prolonged courses of calcineurin inhibitors. Whether patients with post-HSCT albuminuria and hypertension benefit from treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers requires further study, but careful control of hypertension with captopril, an ACE inhibitor, did show a benefit in a small study.[157]

Quality of Life

Health-related quality of life (HRQL)

HRQL is a multidimensional construct, incorporating a subjective appraisal of one’s functioning and well-being, with reference to the impact of health issues on overall quality of life.[158,159] Many studies have shown that HRQL varies according to the following:[160]

• Time after HSCT: HRQL is worse with more recent HSCT.
• Transplant type: Unrelated-donor HSCT recipients have worse HRQL than do autologous or allogeneic related-donor HSCT recipients.
• Presence or absence of HSCT-related sequelae: HRQL is worse with chronic GVHD.

Pre-HSCT factors, such as family cohesion and a child’s adaptive functioning, have been shown to affect HRQL.[161] Several groups have also identified the importance of pre-HSCT parenting stress on parental ratings of children’s HRQL post-HSCT.[161–165] A report of the trajectories of HRQL over the 12 months after HSCT noted that the poorest HRQL was seen at 3 months post-HSCT, with steady improvement thereafter. Recipients of unrelated-donor transplants had the steepest declines in HRQL from baseline to 3 months. Another study reported that compromised emotional functioning, high levels of worry, and reduced communication during the acute recovery period had a negative impact on HRQL at 1-year post-HSCT.[166] Longitudinal studies identified an association of the following additional baseline risk factors with the trajectory of HRQL after HSCT:

• Child’s age: Older children had worse HRQL.[161,167,168]
• Child’s sex: Females had worse HRQL.[168]
• Rater: Mothers reported lower HRQL than did fathers; parents reported lower HRQL than did children.[169,170]
• Concordance by primary language or by sex of the raters: Concordant pairs reported higher HRQL.[171]
• Parental emotional distress: Greater parental distress led to worse HRQL.[167]
• Child’s race: African American children had better HRQL.[168]

A report that investigated the impact of specific HSCT complications indicated that HRQL was worse among children with severe end-organ toxicity, systemic infection, or GVHD.[162] Cross-sectional studies reported that the HRQL among pediatric HSCT survivors of 5 years or longer was reasonably good, although psychological, cognitive, or physical problems appeared to negatively influence HRQL. Female sex, causal diagnosis for HSCT (e.g., acute myelogenous leukemia patients had worse HRQL), and intensity of pre-HSCT therapy were all identified as affecting HRQL post-HSCT.[172,173] Finally, another cross-sectional study of children 5 to 10 years post-HSCT cautioned that parental concerns about the child’s vulnerability may induce overprotective parenting.[165]

Functional outcomes

Physician-reported physical performance

Clinician reports of long-term disability among childhood HSCT survivors suggest that the prevalence and severity of functional loss is low, as described in the following studies:

• A study from the European Society for Blood and Marrow Transplantation used the Karnofsky performance scale to report outcomes among 647 HSCT survivors (surviving ≥5 years).[174] In this cohort, 40% of survivors were younger than 18 years when they underwent transplant; only 19% had Karnofsky scores lower than 100. Seven percent had scores lower than 80, defined as the inability to work. Similar low rates of clinician-graded poor functional outcomes were reported by two other groups.[172,175]
• Among 50 survivors of childhood allogeneic HSCT treated at the City of Hope National Medical Center and Stanford University Hospital, all had Karnofsky scores of 90 or 100.[175]
• Among 73 young adults (mean age, 26 years) treated at the Karolinska University Hospital, the median Karnofsky score at 10 years post-HSCT was 90.[172]

Self-reported physical performance

Self-reported and proxy data among survivors of childhood HSCT indicated similar low rates of functional loss in the following studies:

• One study evaluated 22 survivors of childhood allogeneic HSCT (mean age at HSCT, 11 years; mean age at questionnaire, 25 years) and reported no differences between survivors’ scores and population-expected values on standardized physical performance scales.[176]
• Another study compared a group of survivors who underwent transplant for childhood leukemia (n = 142) with a group of childhood leukemia survivors treated with chemotherapy alone (n = 288).[177] There were no differences between the groups on the physical function and leisure scales using multiple standardized measures.

Other studies that have reported functional limitations include the following:

• In the Bone Marrow Transplant Survivors Study (BMTSS) that included 235 survivors of childhood HSCT, 17% reported long-term physical performance limitations, compared with 8.7% of a sibling comparison group.[178]
• A Seattle study evaluated physical function in 214 young adults (median age at questionnaire, 28.7 years; 118 males) who underwent transplant at a median age of 11.9 years. When compared with age- and sex-matched controls, the HSCT survivors in this cohort scored one-half standard deviation lower on the physical component score of the SF-36 and the physical function and role physical subscales, quality-of-life measures.[173]
• A Swedish study also identified lower self-reported physical health among 73 young adult (median age, 26 years) HSCT survivors who were a median of 10 years after transplant. HSCT survivors scored significantly below population normative values on physical functioning (90.2 for HSCT survivors vs. 95.3 for population), satisfaction with physical health (66.0 for HSCT survivors vs. 78.7 for population), and role limitation because of physical health (72.7 for HSCT survivors vs. 84.9 for population).[172]

Measured physical performance

Objective measurements of function in the pediatric HSCT patient and survivor population hint that loss of physical capacity may be a bigger problem than revealed in studies that rely on clinician or self-report data. Studies measuring cardiopulmonary fitness have observed the following:

• One study used exercise capacity with cycle ergometry in a group of 20 children and young adults before HSCT, 31 patients at 1 year post-HSCT, and 70 healthy controls.[179] The average peak oxygen consumption was 21 mL/kg/min in the pre-HSCT group, 24 mL/kg/min in the post-HSCT group, and 34 mL/kg/min in the healthy controls. Among the HSCT survivors, 62% of those with cancer diagnoses scored in the lowest fifth percentile for peak oxygen consumption, compared with healthy controls.
• Another study examined exercise capacity with a Bruce treadmill protocol in 31 survivors of pediatric HSCT. In this cohort, 25.8% of HSCT survivors had exercise capacities in the 70% to 79% of predicted category, and 41.9% had exercise capacities in the lower than 70% of predicted category.[180]
• A third study investigated exercise capacity among 33 HSCT survivors who underwent transplant at a mean age of 11.3 years. At 5 years post-HSCT, only 4 of 33 survivors scored above the 75th percentile on a serial cycle ergometry test.[181]

Predictors of poor physical performance

The BMTSS found associations between poor physical performance outcomes and chronic GVHD, cardiac conditions, immune suppression, or treatment for a second malignant neoplasm.[182] In a study from the Fred Hutchison Cancer Research Center, poor performance was associated with myeloid disease.[173]

Published Guidelines for Long-Term Follow-Up

Several organizations have published consensus guidelines for follow-up for late effects after HSCT. The CIBMTR, along with the American Society of Blood and Marrow Transplant (ASBMT), and in cooperation with five other international transplant groups, published consensus recommendations for screening and preventive practices for long-term survivors of HSCT.[183]

Although some pediatric-specific challenges are addressed in these guidelines, many important pediatric issues are not. Some of these issues have been partially covered by general guidelines published by the Children’s Oncology Group (COG) and other children’s cancer groups (United Kingdom, Scotland). The COG has also published more specific recommendations for late effects surveillance after HSCT.[184] To address the lack of detailed, pediatric-specific, late-effects data and guidelines for long-term follow-up after HSCT, the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) published six detailed papers outlining existing data and summarizing recommendations from key groups (CIBMTR/ASBMT, COG, and the United Kingdom), along with expert recommendations for pediatric-specific issues.[9,34,64,185–187]

Although international efforts at further standardization and harmonization of pediatric-specific follow-up guidelines are under way, the PTCTC summary and guideline recommendations provide a consensus outline for monitoring children for late effects after HSCT.[64]

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91. Boirie Y: Physiopathological mechanism of sarcopenia. J Nutr Health Aging 13 (8): 717-23, 2009. [PUBMED Abstract]
92. Baker KS, Chow E, Goodman P, et al.: Adverse Impact of hematopoietic cell transplantation (HCT) on body composition and insulin resistance (IR) is associated with increased cardiovascular risk. [Abstract] Biol Blood Marrow Transplant 17 (2 Suppl): A-61, S174, 2011.
93. Cook S, Weitzman M, Auinger P, et al.: Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med 157 (8): 821-7, 2003. [PUBMED Abstract]
94. Genuth S, Alberti KG, Bennett P, et al.: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26 (11): 3160-7, 2003. [PUBMED Abstract]
95. Grundy SM, Brewer HB, Cleeman JI, et al.: Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109 (3): 433-8, 2004. [PUBMED Abstract]
96. Petryk A, Bergemann TL, Polga KM, et al.: Prospective study of changes in bone mineral density and turnover in children after hematopoietic cell transplantation. J Clin Endocrinol Metab 91 (3): 899-905, 2006. [PUBMED Abstract]
97. Bhatia S, Ramsay NK, Weisdorf D, et al.: Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies. Bone Marrow Transplant 22 (1): 87-90, 1998. [PUBMED Abstract]
98. Nysom K, Holm K, Michaelsen KF, et al.: Bone mass after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant 25 (2): 191-6, 2000. [PUBMED Abstract]
99. Daniels MW, Wilson DM, Paguntalan HG, et al.: Bone mineral density in pediatric transplant recipients. Transplantation 76 (4): 673-8, 2003. [PUBMED Abstract]
100. Kaste SC, Shidler TJ, Tong X, et al.: Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant 33 (4): 435-41, 2004. [PUBMED Abstract]
101. Perkins JL, Kunin-Batson AS, Youngren NM, et al.: Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer 49 (7): 958-63, 2007. [PUBMED Abstract]
102. Carpenter PA, Hoffmeister P, Chesnut CH, et al.: Bisphosphonate therapy for reduced bone mineral density in children with chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (6): 683-90, 2007. [PUBMED Abstract]
103. Weilbaecher KN: Mechanisms of osteoporosis after hematopoietic cell transplantation. Biol Blood Marrow Transplant 6 (2A): 165-74, 2000. [PUBMED Abstract]
104. Rodgers C, Monroe R: Osteopenia and osteoporosis in pediatric patients after stem cell transplant. J Pediatr Oncol Nurs 24 (4): 184-9, 2007 Jul-Aug. [PUBMED Abstract]
105. McClune BL, Polgreen LE, Burmeister LA, et al.: Screening, prevention and management of osteoporosis and bone loss in adult and pediatric hematopoietic cell transplant recipients. Bone Marrow Transplant 46 (1): 1-9, 2011. [PUBMED Abstract]
106. Schulte CM, Beelen DW: Bone loss following hematopoietic stem cell transplantation: a long-term follow-up. Blood 103 (10): 3635-43, 2004. [PUBMED Abstract]
107. Schimmer AD, Minden MD, Keating A: Osteoporosis after blood and marrow transplantation: clinical aspects. Biol Blood Marrow Transplant 6 (2A): 175-81, 2000. [PUBMED Abstract]
108. Banfi A, Podestà M, Fazzuoli L, et al.: High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer 92 (9): 2419-28, 2001. [PUBMED Abstract]
109. Castañeda S, Carmona L, Carvajal I, et al.: Reduction of bone mass in women after bone marrow transplantation. Calcif Tissue Int 60 (4): 343-7, 1997. [PUBMED Abstract]
110. Lee WY, Baek KH, Rhee EJ, et al.: Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation. Bone Marrow Transplant 34 (1): 89-94, 2004. [PUBMED Abstract]
111. Baker KS, Gurney JG, Ness KK, et al.: Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study. Blood 104 (6): 1898-906, 2004. [PUBMED Abstract]
112. Stern JM, Sullivan KM, Ott SM, et al.: Bone density loss after allogeneic hematopoietic stem cell transplantation: a prospective study. Biol Blood Marrow Transplant 7 (5): 257-64, 2001. [PUBMED Abstract]
113. Ebeling PR, Thomas DM, Erbas B, et al.: Mechanisms of bone loss following allogeneic and autologous hemopoietic stem cell transplantation. J Bone Miner Res 14 (3): 342-50, 1999. [PUBMED Abstract]
114. Tauchmanovà L, De Rosa G, Serio B, et al.: Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: a single center experience and a review. Cancer 97 (10): 2453-61, 2003. [PUBMED Abstract]
115. Kananen K, Volin L, Tähtelä R, et al.: Recovery of bone mass and normalization of bone turnover in long-term survivors of allogeneic bone marrow transplantation. Bone Marrow Transplant 29 (1): 33-9, 2002. [PUBMED Abstract]
116. Socié G, Cahn JY, Carmelo J, et al.: Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Société Française de Greffe de Moëlle (SFGM). Br J Haematol 97 (4): 865-70, 1997. [PUBMED Abstract]
117. Faraci M, Calevo MG, Lanino E, et al.: Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy. Haematologica 91 (8): 1096-9, 2006. [PUBMED Abstract]
118. Enright H, Haake R, Weisdorf D: Avascular necrosis of bone: a common serious complication of allogeneic bone marrow transplantation. Am J Med 89 (6): 733-8, 1990. [PUBMED Abstract]
119. Sharma S, Yang S, Rochester R, et al.: Prevalence of osteonecrosis and associated risk factors in children before allogeneic BMT. Bone Marrow Transplant 46 (6): 813-9, 2011. [PUBMED Abstract]
120. Bürger B, Beier R, Zimmermann M, et al.: Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)–experiences from trial ALL-BFM 95. Pediatr Blood Cancer 44 (3): 220-5, 2005. [PUBMED Abstract]
121. Mattano LA, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children’s Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000. [PUBMED Abstract]
122. Li X, Brazauskas R, Wang Z, et al.: Avascular necrosis of bone after allogeneic hematopoietic cell transplantation in children and adolescents. Biol Blood Marrow Transplant 20 (4): 587-92, 2014. [PUBMED Abstract]
123. Baker KS, Petryk A: Growth and development after hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas’ Hematopoietic Cell Transplantation: Stem Cell Transplantation. 5th ed. John Wiley & Sons Inc., 2015, pp 1257-65.
124. Sanders JE, Flournoy N, Thomas ED, et al.: Marrow transplant experience in children with acute lymphoblastic leukemia: an analysis of factors associated with survival, relapse, and graft-versus-host disease. Med Pediatr Oncol 13 (4): 165-72, 1985. [PUBMED Abstract]
125. Sanders JE, Hawley J, Levy W, et al.: Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 87 (7): 3045-52, 1996. [PUBMED Abstract]
126. Carter A, Robison LL, Francisco L, et al.: Prevalence of conception and pregnancy outcomes after hematopoietic cell transplantation: report from the Bone Marrow Transplant Survivor Study. Bone Marrow Transplant 37 (11): 1023-9, 2006. [PUBMED Abstract]
127. Salooja N, Szydlo RM, Socie G, et al.: Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet 358 (9278): 271-6, 2001. [PUBMED Abstract]
128. Loren AW, Chow E, Jacobsohn DA, et al.: Pregnancy after hematopoietic cell transplantation: a report from the late effects working committee of the Center for International Blood and Marrow Transplant Research (CIBMTR). Biol Blood Marrow Transplant 17 (2): 157-66, 2011. [PUBMED Abstract]
129. Shalet SM, Didi M, Ogilvy-Stuart AL, et al.: Growth and endocrine function after bone marrow transplantation. Clin Endocrinol (Oxf) 42 (4): 333-9, 1995. [PUBMED Abstract]
130. Schubert MA, Sullivan KM, Schubert MM, et al.: Gynecological abnormalities following allogeneic bone marrow transplantation. Bone Marrow Transplant 5 (6): 425-30, 1990. [PUBMED Abstract]
131. Howell SJ, Shalet SM: Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr (34): 12-7, 2005. [PUBMED Abstract]
132. Anserini P, Chiodi S, Spinelli S, et al.: Semen analysis following allogeneic bone marrow transplantation. Additional data for evidence-based counselling. Bone Marrow Transplant 30 (7): 447-51, 2002. [PUBMED Abstract]
133. Panasiuk A, Nussey S, Veys P, et al.: Gonadal function and fertility after stem cell transplantation in childhood: comparison of a reduced intensity conditioning regimen containing melphalan with a myeloablative regimen containing busulfan. Br J Haematol 170 (5): 719-26, 2015. [PUBMED Abstract]
134. Leiper A, Houwing M, Davies EG, et al.: Anti-Müllerian hormone and Inhibin B after stem cell transplant in childhood: a comparison of myeloablative, reduced intensity and treosulfan-based chemotherapy regimens. Bone Marrow Transplant 55 (10): 1985-1995, 2020. [PUBMED Abstract]
135. Cattoni A, Nicolosi ML, Capitoli G, et al.: Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment. Front Endocrinol (Lausanne) 14: 1292683, 2023. [PUBMED Abstract]
136. Bender JD, Oquendo-Del Toro H, Benoit J, et al.: Reduced-Intensity Conditioning Mitigates Risk for Primary Ovarian Insufficiency but Does Not Decrease Risk for Infertility in Pediatric and Young Adult Survivors of Hematopoietic Stem Cell Transplantation. Transplant Cell Ther 29 (2): 130.e1-130.e8, 2023. [PUBMED Abstract]
137. Rotz SJ, Hamilton BK, Wei W, et al.: Fertility Potential and Gonadal Function in Survivors of Reduced-Intensity Hematopoietic Stem Cell Transplantation. Transplant Cell Ther 30 (5): 534.e1-534.e13, 2024. [PUBMED Abstract]
138. Yoshihara S, Yanik G, Cooke KR, et al.: Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 13 (7): 749-59, 2007. [PUBMED Abstract]
139. Chien JW, Duncan S, Williams KM, et al.: Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant 16 (1 Suppl): S106-14, 2010. [PUBMED Abstract]
140. Hildebrandt GC, Fazekas T, Lawitschka A, et al.: Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant 46 (10): 1283-95, 2011. [PUBMED Abstract]
141. Chien JW, Martin PJ, Gooley TA, et al.: Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation. Am J Respir Crit Care Med 168 (2): 208-14, 2003. [PUBMED Abstract]
142. Cerveri I, Zoia MC, Fulgoni P, et al.: Late pulmonary sequelae after childhood bone marrow transplantation. Thorax 54 (2): 131-5, 1999. [PUBMED Abstract]
143. Uhlving HH, Bang CL, Christensen IJ, et al.: Lung function after allogeneic hematopoietic stem cell transplantation in children: a longitudinal study in a population-based cohort. Biol Blood Marrow Transplant 19 (9): 1348-54, 2013. [PUBMED Abstract]
144. Freudenberger TD, Madtes DK, Curtis JR, et al.: Association between acute and chronic graft-versus-host disease and bronchiolitis obliterans organizing pneumonia in recipients of hematopoietic stem cell transplants. Blood 102 (10): 3822-8, 2003. [PUBMED Abstract]
145. Houdouin V, Dubus JC, Crepon SG, et al.: Late-onset pulmonary complications following allogeneic hematopoietic cell transplantation in pediatric patients: a prospective multicenter study. Bone Marrow Transplant 59 (6): 858-866, 2024. [PUBMED Abstract]
146. Chien JW, Zhao LP, Hansen JA, et al.: Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation. Blood 107 (5): 2200-7, 2006. [PUBMED Abstract]
147. Hildebrandt GC, Granell M, Urbano-Ispizua A, et al.: Recipient NOD2/CARD15 variants: a novel independent risk factor for the development of bronchiolitis obliterans after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 14 (1): 67-74, 2008. [PUBMED Abstract]
148. Shanthikumar S, Gower WA, Srinivasan S, et al.: Detection of Bronchiolitis Obliterans Syndrome after Pediatric Hematopoietic Stem Cell Transplantation: An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 210 (3): 262-280, 2024. [PUBMED Abstract]
149. Cooke KR, Yanik G: Lung injury following hematopoietic stem cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas’ Hematopoietic Cell Transplantation: Stem Cell Transplantation. 5th ed. John Wiley & Sons Inc., 2015, pp 1156-69.
150. Yanik GA, Mineishi S, Levine JE, et al.: Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation. Biol Blood Marrow Transplant 18 (7): 1044-54, 2012. [PUBMED Abstract]
151. Norman BC, Jacobsohn DA, Williams KM, et al.: Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients. Bone Marrow Transplant 46 (10): 1369-73, 2011. [PUBMED Abstract]
152. Ellis MJ, Parikh CR, Inrig JK, et al.: Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant 8 (11): 2378-90, 2008. [PUBMED Abstract]
153. Choi M, Sun CL, Kurian S, et al.: Incidence and predictors of delayed chronic kidney disease in long-term survivors of hematopoietic cell transplantation. Cancer 113 (7): 1580-7, 2008. [PUBMED Abstract]
154. Ando M, Ohashi K, Akiyama H, et al.: Chronic kidney disease in long-term survivors of myeloablative allogeneic haematopoietic cell transplantation: prevalence and risk factors. Nephrol Dial Transplant 25 (1): 278-82, 2010. [PUBMED Abstract]
155. Avcı B, Bilir ÖA, Özlü SG, et al.: Acute kidney injury and risk factors in pediatric patients undergoing hematopoietic stem cell transplantation. Pediatr Nephrol 39 (7): 2199-2207, 2024. [PUBMED Abstract]
156. Cohen EP, Piering WF, Kabler-Babbitt C, et al.: End-stage renal disease (ESRD)after bone marrow transplantation: poor survival compar ed to other causes of ESRD. Nephron 79 (4): 408-12, 1998. [PUBMED Abstract]
157. Cohen EP, Irving AA, Drobyski WR, et al.: Captopril to mitigate chronic renal failure after hematopoietic stem cell transplantation: a randomized controlled trial. Int J Radiat Oncol Biol Phys 70 (5): 1546-51, 2008. [PUBMED Abstract]
158. Wilson IB, Cleary PD: Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA 273 (1): 59-65, 1995. [PUBMED Abstract]
159. Eisen M, Donald CA, Ware JE, et al.: Conceptualization and Measurement of Health for Children in the Health Insurance Study. Rand Corporation, 1980.
160. Parsons SK, Barlow SE, Levy SL, et al.: Health-related quality of life in pediatric bone marrow transplant survivors: according to whom? Int J Cancer Suppl 12: 46-51, 1999. [PUBMED Abstract]
161. Barrera M, Atenafu E, Hancock K: Longitudinal health-related quality of life outcomes and related factors after pediatric SCT. Bone Marrow Transplant 44 (4): 249-56, 2009. [PUBMED Abstract]
162. Parsons SK, Shih MC, Duhamel KN, et al.: Maternal perspectives on children’s health-related quality of life during the first year after pediatric hematopoietic stem cell transplant. J Pediatr Psychol 31 (10): 1100-15, 2006 Nov-Dec. [PUBMED Abstract]
163. Barrera M, Boyd-Pringle LA, Sumbler K, et al.: Quality of life and behavioral adjustment after pediatric bone marrow transplantation. Bone Marrow Transplant 26 (4): 427-35, 2000. [PUBMED Abstract]
164. Jobe-Shields L, Alderfer MA, Barrera M, et al.: Parental depression and family environment predict distress in children before stem cell transplantation. J Dev Behav Pediatr 30 (2): 140-6, 2009. [PUBMED Abstract]
165. Vrijmoet-Wiersma CM, Kolk AM, Grootenhuis MA, et al.: Child and parental adaptation to pediatric stem cell transplantation. Support Care Cancer 17 (6): 707-14, 2009. [PUBMED Abstract]
166. Felder-Puig R, di Gallo A, Waldenmair M, et al.: Health-related quality of life of pediatric patients receiving allogeneic stem cell or bone marrow transplantation: results of a longitudinal, multi-center study. Bone Marrow Transplant 38 (2): 119-26, 2006. [PUBMED Abstract]
167. Parsons SK, Ratichek SJ, Rodday AM: Caring for the caregiver: eHealth interventions for parents of pediatric hematopoietic stem cell transplant recipients. [Abstract] Pediatr Blood Cancer 56 (7): 1157, 2011.
168. Brice L, Weiss R, Wei Y, et al.: Health-related quality of life (HRQoL): the impact of medical and demographic variables upon pediatric recipients of hematopoietic stem cell transplantation. Pediatr Blood Cancer 57 (7): 1179-85, 2011. [PUBMED Abstract]
169. Kaplan SH, Barlow S, Spetter D: Assessing functional status and health-related quality of life among school-aged children: reliability and validity of a new self-reported measure. [Abstract] Qual Life Res 4 (5): 444-45, 1995.
170. Barrera M, Atenafu E, Doyle J, et al.: Differences in mothers’ and fathers’ health-related quality of life after pediatric SCT: a longitudinal study. Bone Marrow Transplant 47 (6): 855-9, 2012. [PUBMED Abstract]
171. Feichtl RE, Rosenfeld B, Tallamy B, et al.: Concordance of quality of life assessments following pediatric hematopoietic stem cell transplantation. Psychooncology 19 (7): 710-7, 2010. [PUBMED Abstract]
172. Löf CM, Winiarski J, Giesecke A, et al.: Health-related quality of life in adult survivors after paediatric allo-SCT. Bone Marrow Transplant 43 (6): 461-8, 2009. [PUBMED Abstract]
173. Sanders JE, Hoffmeister PA, Storer BE, et al.: The quality of life of adult survivors of childhood hematopoietic cell transplant. Bone Marrow Transplant 45 (4): 746-54, 2010. [PUBMED Abstract]
174. Duell T, van Lint MT, Ljungman P, et al.: Health and functional status of long-term survivors of bone marrow transplantation. EBMT Working Party on Late Effects and EULEP Study Group on Late Effects. European Group for Blood and Marrow Transplantation. Ann Intern Med 126 (3): 184-92, 1997. [PUBMED Abstract]
175. Schmidt GM, Niland JC, Forman SJ, et al.: Extended follow-up in 212 long-term allogeneic bone marrow transplant survivors. Issues of quality of life. Transplantation 55 (3): 551-7, 1993. [PUBMED Abstract]
176. Helder DI, Bakker B, de Heer P, et al.: Quality of life in adults following bone marrow transplantation during childhood. Bone Marrow Transplant 33 (3): 329-36, 2004. [PUBMED Abstract]
177. Michel G, Bordigoni P, Simeoni MC, et al.: Health status and quality of life in long-term survivors of childhood leukaemia: the impact of haematopoietic stem cell transplantation. Bone Marrow Transplant 40 (9): 897-904, 2007. [PUBMED Abstract]
178. Ness KK, Bhatia S, Baker KS, et al.: Performance limitations and participation restrictions among childhood cancer survivors treated with hematopoietic stem cell transplantation: the bone marrow transplant survivor study. Arch Pediatr Adolesc Med 159 (8): 706-13, 2005. [PUBMED Abstract]
179. Larsen RL, Barber G, Heise CT, et al.: Exercise assessment of cardiac function in children and young adults before and after bone marrow transplantation. Pediatrics 89 (4 Pt 2): 722-9, 1992. [PUBMED Abstract]
180. Eames GM, Crosson J, Steinberger J, et al.: Cardiovascular function in children following bone marrow transplant: a cross-sectional study. Bone Marrow Transplant 19 (1): 61-6, 1997. [PUBMED Abstract]
181. Hogarty AN, Leahey A, Zhao H, et al.: Longitudinal evaluation of cardiopulmonary performance during exercise after bone marrow transplantation in children. J Pediatr 136 (3): 311-7, 2000. [PUBMED Abstract]
182. Fraser CJ, Bhatia S, Ness K, et al.: Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood 108 (8): 2867-73, 2006. [PUBMED Abstract]
183. Rizzo JD, Wingard JR, Tichelli A, et al.: Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant 37 (3): 249-61, 2006. [PUBMED Abstract]
184. Chow EJ, Anderson L, Baker KS, et al.: Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Children’s Oncology Group Report. Biol Blood Marrow Transplant 22 (5): 782-95, 2016. [PUBMED Abstract]
185. Bunin N, Small T, Szabolcs P, et al.: NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: persistent immune deficiency in pediatric transplant survivors. Biol Blood Marrow Transplant 18 (1): 6-15, 2012. [PUBMED Abstract]
186. Dvorak CC, Gracia CR, Sanders JE, et al.: NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: endocrine challenges-thyroid dysfunction, growth impairment, bone health, & reproductive risks. Biol Blood Marrow Transplant 17 (12): 1725-38, 2011. [PUBMED Abstract]
187. Parsons SK, Phipps S, Sung L, et al.: NCI, NHLBI/PBMTC First International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: health-related quality of life, functional, and neurocognitive outcomes. Biol Blood Marrow Transplant 18 (2): 162-71, 2012. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Hematopoietic Stem Cell Transplant (HSCT)–Related Acute Complications

Added text to state that another retrospective multicenter study that examined the use of eculizumab demonstrated a 6-month response rate of 62% and a 1-year overall survival rate of 55% (cited Benítez Carabante et al. as reference 52).

Added text to state that an analysis of the Center for International Blood and Marrow Transplant Research registry showed similar relapse-free survival for mismatched unrelated-donor recipients using abatacept or posttransplant cyclophosphamide (cited Kean et al. as reference 96).

Added Admiraal et al. as reference 102.

Added text to state that similar to unrelated-donor bone marrow and cord blood HSCT, outcomes improved after T-cell receptor alpha beta/CD19 depletion when rabbit antithymocyte globulin was targeted to specific pre- and post-HSCT exposures (cited Dvorak et al. as reference 109).

Added Locatelli et al. as reference 115.

Late Effects After Hematopoietic Stem Cell Transplant (HSCT) in Children

Added text about the results of a multi-institutional, international, retrospective cohort study that included 326 adolescent and young adult patients and assessed fertility potential and gonadal failure 1 to 2 years after HSCT in patients who received myeloablative conditioning versus reduced-intensity conditioning (cited Rotz et al. as reference 137).

Added Houdouin et al. as reference 145, Shanthikumar et al. as reference 148, and Avcı et al. as reference 155.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the complications, graft-versus-host disease, and late effects after hematopoietic stem cell transplant for the treatment of pediatric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Complications, Graft-Versus-Host Disease, and Late Effects After Pediatric Hematopoietic Stem Cell Transplant are:

• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Michael A. Pulsipher, MD (Huntsman Cancer Institute at University of Utah)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Complications, Graft-Versus-Host Disease, and Late Effects After Pediatric Hematopoietic Stem Cell Transplant. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/childhood-cancers/hp-stem-cell-transplant/gvhd. Accessed <MM/DD/YYYY>. [PMID: 35133768]

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T cells attack cellular targets (viruses or cancer cells) by binding to class I major histocompatibility complex (MHC) molecules on the surface of the target cells. T cells also have to avoid suppressor signals sent by regulatory T cells and other surface molecule interactions. Gene transfer technologies can modify T cells to express MHC-independent, antibody-binding domains (CAR molecules) on the surface of the modified T cells. The CAR molecules aim at specific target proteins on the surface of tumors. Lymphodepleting chemotherapy is generally given before CAR T-cell infusions to minimize the chance of suppressor mechanisms (affecting CAR T-cell function) and to create a cytokine milieu favorable for CAR T-cell expansion.[1] CAR T-cell–mediated responses are further enhanced by adding intracellular costimulatory domains (e.g., CD28, 4-1BB), which cause significant CAR T-cell expansion and may increase the lifespan of these cells in the recipient.[1]

CAR T-Cell Therapy Indications for Pediatric Cancer

Investigators using this technology have targeted a variety of tumors/surface molecules, but the best-studied example in pediatric patients is CAR T cells aimed at CD19, a surface receptor on B cells. Several research groups have reported significant rates of remission (70%–90%) in children and adults with refractory B-cell acute lymphoblastic leukemia (ALL),[2–5] with some groups reporting persistence of CAR T cells and remission beyond 6 months in most patients studied.[5,6] Early loss of the CAR T cells is associated with relapse, and the best use of this therapy (bridge to transplant vs. definitive therapy) is under study.

Indications for hematopoietic stem cell transplant vary over time as risk classifications for a given malignancy change and the efficacy of primary therapy improves. It is best to include specific indications in the context of complete therapy for any given disease. With this in mind, links to sections in specific summaries that cover the most common pediatric CAR T-cell therapy indications are provided below.

1. B-cell acute lymphoblastic leukemia.
   • For more information, see the Treatment of Relapsed Childhood ALL section in Childhood Acute Lymphoblastic Leukemia Treatment.
2. B-cell non-Hodgkin lymphoma.
   • For more information, see the Treatment options for recurrent or refractory Burkitt lymphoma section in Childhood Non-Hodgkin Lymphoma Treatment.

CAR T-Cell Toxicities

Cytokine release syndrome (CRS)

Responses to CAR T-cell therapies have been associated with a significant increase in inflammatory cytokines, termed cytokine release syndrome (CRS). CRS can be successfully treated with anti–interleukin-6 receptor (IL-6R) therapies (e.g., tocilizumab), often in combination with steroids.[7,8] CRS presents as a sepsis-like situation, with fever, headache, myalgias, hypotension, capillary leak, hypoxia, and renal dysfunction. The severity of the CRS determines whether patients require therapy. The progression of CRS can be measured by staging. The American Society for Transplantation and Cellular Therapy Consensus guidelines for CRS have been broadly adopted (see Table 1).[9] While treatment of grade 1 and early grade 2 CRS is generally not offered, patients with some forms of grade 2 and all patients with grades 3 and 4 CRS receive therapy.[10]

Table 1. ASTCT CRS Consensus Gradinga,b

CRS Parameter	Grade 1	Grade 2	Grade 3	Grade 4
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events.
aReprinted from Biology of Blood and Marrow Transplantation, Volume 25, Issue 4, Daniel W. Lee, Bianca D. Santomasso, Frederick L. Locke et al., ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells, Pages 625–638, Copyright 2019, with permission from Elsevier.[9]
bOrgan toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.
cFever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
dCRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.
eLow-flow nasal cannula is defined as oxygen delivered at ≤6L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6L/minute.
Fever c	Temperature ≥38°C	Temperature ≥38°C	Temperature ≥38°C	Temperature ≥38°C
With
Hypotension	None	Not requiring vasopressors	Requiring a vasopressor with or without vasopressin	Requiring multiple vasopressors (excluding vasopressin)
And/or d
Hypoxia	None	Requiring low-flow nasal cannulae or blow-by	Requiring high-flow nasal cannulae, facemask, nonrebreather mask, or Venturi mask	Requiring positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation)

Approaches to mitigating CRS toxicities

Early studies of CD19-targeted CAR T cells using both CD28 and 4-1BB costimulatory domains varied in approach. The use of tocilizumab or steroids was limited to patients who experienced severe toxicities because of concern about the loss of CAR T-cell persistence (with excessive use of immune suppressive agents). These toxicities included hypotension requiring high-dose vasopressors, severe hypoxia, or intubation. After one early study showed similar efficacy in patients treated with and without tocilizumab,[11] investigators designed approaches aimed at early treatment of CRS to limit organ damage secondary to grade 4 CRS. Some approaches have decreased toxicity without obvious effects on efficacy.

Evidence (early interventions for CRS):

1. Investigators at Seattle Children’s Hospital compared a strategy of early intervention versus standard practice. Early intervention included treatment with tocilizumab for patients with a fever higher than 39°C that was unresponsive to acetaminophen, persistent hypotension after a 10 mL/kg bolus, or initiation of oxygen. Steroids were given after tocilizumab if symptoms persisted or worsened 6 to 12 hours later.[12]
   • The early intervention approach doubled the number of patients requiring tocilizumab or steroids but did not affect the overall minimal residual disease–negative remission rate, infection rate, long-term persistence of CAR T cells, or overall survival (OS).
   • In addition, early intervention for patients with CRS resulted in a decreased need for intubation or inotropic support, from 30% to 15%. However, this finding was not statistically significant (P = .29), possibly because of the small number of patients.
2. Investigators at Children’s Hospital of Philadelphia performed a prospective trial of a different strategy of early intervention. Because of earlier findings that showed that high disease burden at the time of CAR T-cell treatment was associated with severe CRS,[6] they defined a high–tumor burden cohort as patients with 40% or more marrow blasts before infusion. Planned early intervention for this cohort was tocilizumab, given for two fevers of 38.5°C or higher, at least 4 hours apart, in a 24-hour period.[13]
   • Grade 4 CRS decreased from 50% (in a comparator cohort) to 27% in the high–tumor burden cohort (P = .18), with no change in efficacy and long-term CAR T-cell persistence.

Immune effector cell–associated neurotoxicity syndrome (ICANS)

Neurological toxicities, including aphasia, altered mental status, and seizures, have also been observed with CAR T-cell therapy. This clinical syndrome (ICANS) is graded according to the most severe event of the following five measures that are not attributable to any other cause:[9]

1. Standardized neurological responsiveness score (tests vary by age: Immune Effector Cell-Associated Encephalopathy [ICE] score for children aged ≥12 years and Cornell Assessment of Pediatric Delirium [CAPD] for children aged <12 years).
2. Level of consciousness.
3. Seizure activity.
4. Motor weakness.
5. Elevated intracranial pressure/cerebral edema.

Most neurological toxicities after CD19-targeted CAR T-cell therapy have been short lived (1–5 days). However, rare, fatal events such as severe cerebral edema have been reported.[14] The pathophysiology of central nervous system (CNS) toxicity is likely related to disruption of the blood-brain barrier secondary to systemic cytokine release,[14] high levels of cytokines in the cerebrospinal fluid,[14] and/or direct attack of CD19-positive brain mural cells in the CNS tissue by the CAR T cells.[15] CNS symptoms have not responded well to IL-6R–targeting agents and have generally been treated with high-dose steroids or other approaches. The exact timing of required treatment for ICANS is controversial, but concerns about its rare, fatal form have led to near-uniform recommendations for the treatment of patients with grade 3 or higher ICANS.[16]

Hemophagocytic lymphohistiocytosis (HLH)–like toxicities

A portion of patients undergoing CAR T-cell therapy will have HLH-like toxicities associated with CRS (hyperferritinemia with organ dysfunction). Severity of symptoms and outcomes vary by CAR construct. It is not known whether early or preventive treatment can improve patient outcomes.

Evidence (effect of HLH-like toxicities on patient outcomes):

1. Investigators at the National Cancer Institute noted increased HLH-like toxicities in a trial of CD22-targeted CAR T-cell therapy.[17]
   • HLH-like toxicity was seen in 19 of 58 patients (32.8%). The average time to onset of HLH-like toxicity was 14 days after CAR T-cell therapy. CRS had resolved or was resolving before the onset of HLH-like features.
   • CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility. However, after this modification, patients experienced heightened HLH-like toxicities, which led to dose de-escalation.
   • HLH-like toxicity did not alter survival outcomes but often required intense interventions such as anakinra.
2. Investigators from the Pediatric Real World CAR Consortium analyzed 183 evaluable children and adolescent and young adult patients treated with tisagenlecleucel for B-cell ALL and found that 14% had HLH-like toxicities.[18]
   • HLH-like toxicity was associated with poor OS (hazard ratio [HR], 4.61; 95% confidence interval [CI], 2.41–8.83) and relapse-free survival (RFS) (HR, 3.68; 95% CI, 2.15–6.32). The 1-year RFS and OS rates were 25.7% and 4.7%, respectively, for patients with HLH-like toxicities, compared with 80.1% and 57.6%, respectively, for patients without HLH-like toxicities.
   • Patients who developed HLH-like toxicity had higher pre-infusion disease burden, ferritin levels, and C-reactive protein levels, compared with patients who did not develop HLH-like toxicity. Patients who developed HLH-like toxicity also had lower pre-infusion platelet and absolute neutrophil counts.
   • Patients who developed HLH-like toxicity subsequently had higher rates of infection, relapse, and nonrelapse mortality.

Other side effects of CAR T-cell therapy

Other CAR T-cell therapy side effects include the following:

• Coagulopathy.
• Cardiac dysfunction.

Early studies of patients with high levels of disease and delayed CRS therapy resulted in 20% to 40% of patients requiring treatment in the intensive care unit (ICU) (mostly vasopressor support, with 10% to 20% of patients requiring intubation and/or dialysis).[2,5,6] However, current real-world data show that ICU requirements are now approximately 10% to 20%.[19]

Approved CAR T-Cell Therapies

An international trial in children led to U.S. Food and Drug Administration approval of tisagenlecleucel for patients aged 1 to 25 years with CD19-positive B-cell ALL that is refractory or in second or later relapse.[20]

Tisagenlecleucel has also been approved for adults with relapsed or refractory B-cell lymphoma, as has axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel.[21,22]

References

1. Kalos M, Levine BL, Porter DL, et al.: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3 (95): 95ra73, 2011. [PUBMED Abstract]
2. Grupp SA, Kalos M, Barrett D, et al.: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368 (16): 1509-18, 2013. [PUBMED Abstract]
3. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al.: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385 (9967): 517-28, 2015. [PUBMED Abstract]
4. Davila ML, Riviere I, Wang X, et al.: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6 (224): 224ra25, 2014. [PUBMED Abstract]
5. Gardner RA, Finney O, Annesley C, et al.: Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129 (25): 3322-3331, 2017. [PUBMED Abstract]
6. Maude SL, Frey N, Shaw PA, et al.: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371 (16): 1507-17, 2014. [PUBMED Abstract]
7. Lee DW, Gardner R, Porter DL, et al.: Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124 (2): 188-95, 2014. [PUBMED Abstract]
8. Maude SL, Barrett D, Teachey DT, et al.: Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 20 (2): 119-22, 2014 Mar-Apr. [PUBMED Abstract]
9. Lee DW, Santomasso BD, Locke FL, et al.: ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant 25 (4): 625-638, 2019. [PUBMED Abstract]
10. McNerney KO, Hsieh EM, Shalabi H, et al.: INSPIRED Symposium Part 3: Prevention and Management of Pediatric Chimeric Antigen Receptor T Cell-Associated Emergent Toxicities. Transplant Cell Ther 30 (1): 38-55, 2024. [PUBMED Abstract]
11. Mueller KT, Waldron E, Grupp SA, et al.: Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. Clin Cancer Res 24 (24): 6175-6184, 2018. [PUBMED Abstract]
12. Gardner RA, Ceppi F, Rivers J, et al.: Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood 134 (24): 2149-2158, 2019. [PUBMED Abstract]
13. Kadauke S, Myers RM, Li Y, et al.: Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial. J Clin Oncol 39 (8): 920-930, 2021. [PUBMED Abstract]
14. Gust J, Ponce R, Liles WC, et al.: Cytokines in CAR T Cell-Associated Neurotoxicity. Front Immunol 11: 577027, 2020. [PUBMED Abstract]
15. Parker KR, Migliorini D, Perkey E, et al.: Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies. Cell 183 (1): 126-142.e17, 2020. [PUBMED Abstract]
16. Ragoonanan D, Khazal SJ, Abdel-Azim H, et al.: Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer. Nat Rev Clin Oncol 18 (7): 435-453, 2021. [PUBMED Abstract]
17. Shah NN, Highfill SL, Shalabi H, et al.: CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial. J Clin Oncol 38 (17): 1938-1950, 2020. [PUBMED Abstract]
18. McNerney KO, Si Lim SJ, Ishikawa K, et al.: HLH-like toxicities predict poor survival after the use of tisagenlecleucel in children and young adults with B-ALL. Blood Adv 7 (12): 2758-2771, 2023. [PUBMED Abstract]
19. Pasquini MC, Hu ZH, Curran K, et al.: Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv 4 (21): 5414-5424, 2020. [PUBMED Abstract]
20. Maude SL, Laetsch TW, Buechner J, et al.: Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med 378 (5): 439-448, 2018. [PUBMED Abstract]
21. Chow VA, Shadman M, Gopal AK: Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Blood 132 (8): 777-781, 2018. [PUBMED Abstract]
22. Neelapu SS, Locke FL, Bartlett NL, et al.: Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 377 (26): 2531-2544, 2017. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of CAR T-cell therapy in treating pediatric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Pediatric Chimeric Antigen Receptor (CAR) T-Cell Therapy are:

• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Michael A. Pulsipher, MD (Huntsman Cancer Institute at University of Utah)
• Sarah K. Tasian, MD (Children’s Hospital of Philadelphia)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Pediatric Chimeric Antigen Receptor (CAR) T-Cell Therapy. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/childhood-cancers/hp-stem-cell-transplant/car-t-cell-therapy. Accessed <MM/DD/YYYY>. [PMID: 35133769]

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During the past two decades, significant advances have led to improved outcomes after allogeneic HSCT.[1–3] The most significant improvements in survival occurred in unrelated and alternative donor procedures.[4–6] Possible explanations for these improvements in survival include improved patient selection, better supportive care, refined treatment regimens, improved approaches specific to stem cell sources, better intensive care unit experience, and better HLA typing. The sections below focus on modifiable aspects of HSCT, including the optimization of HLA typing and selection of stem cell sources.

References

1. Hahn T, McCarthy PL, Hassebroek A, et al.: Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol 31 (19): 2437-49, 2013. [PUBMED Abstract]
2. Horan JT, Logan BR, Agovi-Johnson MA, et al.: Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol 29 (7): 805-13, 2011. [PUBMED Abstract]
3. Wood WA, Lee SJ, Brazauskas R, et al.: Survival improvements in adolescents and young adults after myeloablative allogeneic transplantation for acute lymphoblastic leukemia. Biol Blood Marrow Transplant 20 (6): 829-36, 2014. [PUBMED Abstract]
4. MacMillan ML, Davies SM, Nelson GO, et al.: Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant 14 (9 Suppl): 16-22, 2008. [PUBMED Abstract]
5. Harvey J, Green A, Cornish J, et al.: Improved survival in matched unrelated donor transplant for childhood ALL since the introduction of high-resolution matching at HLA class I and II. Bone Marrow Transplant 47 (10): 1294-300, 2012. [PUBMED Abstract]
6. Majhail NS, Chitphakdithai P, Logan B, et al.: Significant improvement in survival after unrelated donor hematopoietic cell transplantation in the recent era. Biol Blood Marrow Transplant 21 (1): 142-50, 2015. [PUBMED Abstract]

Indications for HSCT vary over time as risk classifications for a given malignancy change and the efficacy of primary therapy improves. It is best to include specific indications in the context of complete therapy for any given disease. With this in mind, links to sections in specific summaries that cover the most common pediatric allogeneic HSCT indications are provided below.

HLA Overview

Appropriate matching between donor and recipient HLA in the major histocompatibility complex located on chromosome 6 is essential to successful allogeneic hematopoietic stem cell transplant (HSCT) (see Figure 1, Table 1, and Table 2).

Enlarge

HLA class I (A, B, C, etc.) and class II (DRB1, DRB3, DRB4, DRB5, DQB1, DPB1, etc.) alleles are highly polymorphic. Therefore, finding appropriately matched unrelated donors is a challenge for some patients, especially those of certain racial groups (e.g., patients with African, Hispanic, Asian, or Pacific-Islander ancestry).[1,2] Full siblings of cancer patients have a 25% chance of being HLA matched.

Early serological techniques of HLA assessment defined a number of HLA antigens, but more precise DNA methodologies have shown HLA allele-level mismatches in up to 40% of serological HLA antigen matches. These differences are clinically relevant because the use of donors with allele-level mismatches affects survival and rates of graft-versus-host disease (GVHD) to a degree similar to that in patients with antigen-level mismatches.[3] Because of this, DNA-based allele-level HLA typing is standard when unrelated donors are being chosen.

The National Marrow Donor Program has published guidelines for HLA matching. The term for allele-level matching used in their guidelines is antigen recognition domain, which refers to the fact that the allele-level similarities used to define the specific HLA type are associated with areas directly used for antigen recognition. Polymorphisms of the HLA proteins outside of these areas are not involved in the function of these molecules. Therefore, they are often not assessed as part of HLA testing and unlikely to contribute to HLA mismatch.[4]

Table 1. Level of HLA Typing Currently Used for Different Hematopoietic Stem Cell Sourcesa,b,c

	Class I Antigens			Class II Antigens
BM = bone marrow; N/A = not applicable; PBSCs = peripheral blood stem cells.
aHLA antigen: A serologically defined, low-resolution method of defining an HLA protein. Differs from allele-level typing at least 40% of the time. Designated by the first two numbers (i.e., for HLA B 35:01, the antigen is HLA B 35).
bHLA allele: A higher-resolution method of defining unique HLA proteins by typing their gene through sequencing or other DNA-based methods that detect unique differences. Designated by at least four numbers (i.e., for HLA B 35:01, 35 is the antigen and 01 is the allele).
cConsensus recommendations for HLA typing, including extended class II typing of mismatched donors, have been published by the National Cancer Institute/National Heart, Lung, and Blood Institute–sponsored Blood and Marrow Transplant Clinical Trials Network.[5]
dSiblings need confirmation that they have fully matched haplotypes with no crossovers in the A to DRB1 region. If parental typing is performed and haplotypes are established, antigen-level typing of class I is adequate. With no parental haplotypes, allele-level typing of eight alleles is recommended.
eParents, cousins, or other family members, with a phenotypic match or near-complete HLA match.
Stem Cell Source	HLA A	HLA B	HLA C	HLA DRB1	HLA DQB1; HLA DPB1; HLA DRB3,4,5
Matched siblingd BM/PBSCs	Antigen or allele	Antigen or allele	Optional	Allele	N/A
Mismatched sibling/other related-donore BM/PBSCs	Allele	Allele	Allele	Allele	Recommended
Unrelated-donor BM/PBSCs	Allele	Allele	Allele	Allele	Recommended
Unrelated-donor cord blood	Antigen (allele recommended)	Antigen (allele recommended)	Allele recommended	Allele	N/A

Table 2. Definitions of the Numbers Describing HLA Antigens and Alleles Matching

If These HLA Antigens and Alleles Match:	Then the Donor Is Considered to be This Type of Match:
A, B, and DRB1	6/6
A, B, C, and DRB1	8/8
A, B, C, DRB1, and DQB1	10/10
A, B, C, DRB1, DQB1, and DPB1	12/12

HLA Matching Considerations for Sibling and Related Donors

The most commonly used related donor is a sibling from the same parents who, at a minimum, is HLA matched for HLA A, HLA B, and HLA DRB1 at the antigen level. Given the distance between HLA A and HLA DRB1 on chromosome 6, there is approximately a 1% possibility of a crossover event occurring in a possible sibling match. Because a crossover event could involve the HLA C antigen and because parents may share HLA antigens that actually differ at the allele level, many centers perform allele-level typing of possible sibling donors at all of the key HLA antigens (HLA A, B, C, and DRB1). Any related donor that is not a full sibling should have full HLA typing because similar haplotypes from different parents could differ at the allele level.

Although single-antigen mismatched related donors (5/6 antigen matched) were used interchangeably with matched sibling donors in some studies, a large Center for International Blood and Marrow Transplant Research (CIBMTR) study in pediatric HSCT recipients showed that the use of 5/6 antigen-matched related donors resulted in rates of GVHD and overall survival (OS) equivalent to rates in 8/8-allele-level-matched unrelated donors and slightly inferior survival than in fully matched siblings.[6] Any siblings with single mismatches should have extended typing to ensure that if the mismatch is caused by a crossover, it only occurs with one antigen. If clinicians choose siblings with multiple antigen mismatches as donors, haploidentical approaches may be warranted.

HLA Matching Considerations for Unrelated Donors

Optimal outcomes are achieved in unrelated allogeneic bone marrow transplant when the pairs of antigens at HLA A, B, C, and DRB1 are matched between the donor and the recipient at the allele level (termed an 8/8 match) (see Table 2).[7] A single antigen/allele mismatch at any of these antigens (7/8 match) lowers the probability of survival between 5% and 10%, with a similar increase in the amount of significant (grades III–IV) acute GVHD.[7] Of these four antigen pairs, different reports have shown HLA A, C, and DRB1 mismatches to potentially be more highly associated with mortality than the other antigens,[3,7,8] but the differences in outcome are small and inconsistent, making it very difficult to conclude that one can pick a more favorable mismatch by choosing one type of antigen mismatch over another. Many study groups are attempting to define specific antigens or pairs of antigens that are associated with either good or poor outcomes. For example, a specific HLA C mismatch (HLA-C*03:03/03:04) produces outcomes similar to a match. Therefore, selection of this mismatch is desirable in an otherwise matched donor/pair combination.[9]

It is well understood that class II antigen DRB1 mismatches increase GVHD incidence and worsen survival.[8] Subsequent data have also shown that multiple mismatches of DQB1, DPB1, and DRB3,4,5 lead to worse outcomes in the setting of less-than-8/8 matches.[10] DPB1 mismatches have been extensively studied and classified as permissive or nonpermissive on the basis of T-cell epitope matching. Patients with 10/10 matches and nonpermissive DPB1 mismatches have more transplant-related mortality but have survival rates similar to those with DPB1 matches or permissive matches. Those with 9/10 matches who have nonpermissive DPB1 mismatches have worse survival than those with permissive mismatches or DPB1 matches.[11–13]

With these findings in mind, a 7/8- or 8/8-matched unrelated donor can be used routinely. However, outcomes may be further improved with the following:

• Extended typing of DQB1, DPB1, and DRB3,4,5.[4,11–13]
• Extended HLA testing to select appropriate donors in the context of HLA-sensitized patients to avoid the potential risk of graft failure.[14,15] HLA sensitization is detected by testing for the presence of specific anti-HLA antibodies and avoiding donors who have any HLA antigens associated with the antibodies present in the recipient.
• Use of younger donors.[5]
• Matching cytomegalovirus (CMV)-positive recipients with CMV-positive donors and matching CMV-negative recipients with CMV-negative donors.[16]
• Use of blood type–compatible unrelated donors.[5]

Enlarge

If a donor or recipient has a duplication of one of their HLA alleles, they will have a half match and a mismatch only in one direction. Figure 2 illustrates that these mismatches will occur in either a direction that promotes GVHD (GVH-O, donor cells can detect a mismatch in a recipient which could cause GVHD) or a direction that promotes rejection (R-O, recipient cells can detect a mismatch in a donor that could lead to rejection). When 8/8-matched unrelated donors are compared with 7/8 donors mismatched in the GVH-O direction, 7/8 mismatched in the R-O direction, or 7/8 mismatched in both directions, the mismatch in the R-O direction leads to rates of grades III and IV acute GVHD similar to rates in the 8/8 matched and better than in the other two combinations. The 7/8 mismatched in only the R-O direction is preferred over GVH-O and bidirectional mismatches.[17] It is important to note that this observation in unrelated donors differs from observations in cord blood recipients, outlined below.

HLA Matching and Cell Dose Considerations for Unrelated Cord Blood HSCT

Another commonly used hematopoietic stem cell source is unrelated umbilical cord blood, which is harvested from donor placentas moments after birth. The cord blood is processed, HLA typed, cryopreserved, and banked.

Unrelated cord blood transplant has been successful with less-stringent HLA matching requirements compared with standard related or unrelated donors, probably because of limited antigen exposure experienced in utero and different immunological composition. Cord blood matching has traditionally been performed at an intermediate level for HLA A and B and at an allele level (high resolution) for DRB1. However, as outlined below, more extended typing can be helpful.

Although better outcomes occur when 6/6 or 5/6 HLA-matched units are used,[18] successful HSCT has occurred even with 4/6 or less HLA-matched units. In a large CIBMTR/Eurocord study, better matching at the allele level using eight antigens (matching for HLA A, B, C, and DRB1) resulted in less transplant-related mortality and improved survival. Best outcome was noted with 8/8 allele matching versus 4/8 to 7/8 matches, with poor survival in patients with five or more allele mismatches. Patients receiving 8/8-matched cord blood did not require higher cell doses for better outcomes. However, patients with one to three allele mismatches had less transplant-related mortality with total nucleated cell counts higher than 3 × 107/kg, and those with four allele mismatches required a total nucleated cell count higher than 5 × 107/kg to decrease transplant-related mortality.[19] This observation was noted to be especially important in cord blood transplants for nonmalignant disorders, where any mismatching below 7/8 alleles led to inferior survival.[20] Many centers will type additional alleles and use the best match possible, but the impact of DQB1, DPB1, and DRB3,4,5 mismatches has not been studied in detail.

As in unrelated peripheral blood stem cells (PBSCs) or bone marrow donors, extended HLA testing can support the selection of appropriate cord blood units in HLA-sensitized patients to avoid the potential risk of graft failure.[21,22] Evidence also suggests that selecting a mismatched cord blood unit, where the mismatch involves a noninherited maternal antigen, may improve survival.[23,24]

As with unrelated donors, individuals can occasionally have duplicate HLA alleles (e.g., the HLA A allele is 01:01 on both chromosomes). When this occurs in a donor product and the allele is matched to one of the recipient alleles, the recipient immune response will see the donor allele as matched (matched, in the rejection direction), but the donor immune response will see a mismatch in the recipient (mismatched in the GVHD direction). This variation of partial mismatching has been shown to be important in cord blood transplant outcomes. Mismatches that are only in the GVHD direction (i.e., GVH-O) lead to lower transplant-related mortality and overall mortality than those with rejection direction only (i.e., R-O) mismatches.[25] R-O mismatches have outcomes similar to those of bidirectional mismatches.[26] Although these studies suggest that using unidirectional mismatching as a criteria for cord blood selection may be beneficial, a Eurocord–European Society for Blood and Marrow Transplantation analysis disputes the value of this type of mismatching.[27]

Two aspects of umbilical cord blood HSCT have made the practice more widely applicable. First, because a successful procedure can occur with multiple HLA mismatches, more than 95% of patients from a wide variety of ethnicities are able to find at least a 4/6-matched cord blood unit.[1,28] Second, as mentioned above, adequate cell dose (minimum 2.5–3 × 107 total nucleated cells/kg and 1.5 × 105 CD34+ cells/kg) has been shown to be associated with improved survival.[29,30] Total nucleated cells are generally used to judge units because techniques to measure CD34-positive doses have not been standardized. Because even large single umbilical cord blood units are only able to supply these minimum doses to recipients weighing up to 40 kg to 50 kg, early umbilical cord blood HSCT focused mainly on smaller children. Later studies showed that barriers of this smaller size could be overcome by using two umbilical cord blood units if each of the units is at least a 4/6 HLA match with the recipient. Because two cord blood units provide higher cell doses, umbilical cord blood transplant is now used widely for larger children and adults.[31]

If a single unit provides an adequate cell dose, there may be disadvantages to adding a second unit.[32][Level of evidence A1] Two randomized trials showed that in children who had adequately sized single units, the addition of a second unit did not alter relapse, transplant-related mortality, or survival rates, but was associated with higher rates of extensive chronic GVHD.[32,33]

Investigators have shown that by using combinations of cytokines and other compounds to expand cord blood before infusion, engraftment of cord blood cells can occur more rapidly than after standard approaches.[34–37] Although some studies that used multiple units or split units showed that expanded units will engraft early and then give way to nonexpanded units for long-term reconstitution,[38] other studies are showing persistence of expanded cells, implying preservation of stem cells through the expansion process.[36,37] A number of these approaches are under investigation. The U.S. Food and Drug Administration (FDA) approved an approach that uses a single unit split into two fractions, expanding one in culture with nicotinamide and infusing the second fraction without manipulation (omidubicel). One randomized trial compared omidubicel with standard cord blood transplant. Patients who received omidubicel had faster neutrophil and platelet engraftment, fewer bacterial and fungal infections, and fewer hospital days in the first 3 months after HSCT.[39] Notably, there was no difference in survival and GVHD outcomes.

Haploidentical HSCT

Early HSCT studies demonstrated progressively higher percentages of patients experiencing severe GVHD and lower survival rates as the number of donor/recipient HLA mismatches increased.[40] Other studies showed that even with very high numbers of donors in unrelated-donor registries, patients with rare HLA haplotypes and patients with certain ethnic backgrounds (e.g., patients with African, Hispanic, Asian, or Pacific-Islander ancestry) have a low chance of achieving desired levels of HLA matching (7/8 or 8/8 match at the allele level).[2]

To allow access to HSCT for patients without fully HLA-matched donor options, investigators have developed techniques allowing the use of siblings, parents, or other relatives who share only a single haplotype of the HLA complex with the patient and are thus half matches. Most approaches developed to date rely on T-cell depletion of the product before infusion into the patient. The main challenge associated with this approach is intense immune suppression with delayed immune recovery, which can result in lethal infections,[41] increased risk of Epstein-Barr virus (EBV)–associated lymphoproliferative disorder, and high rates of relapse.[42] This led to inferior survival compared with matched-donor HSCTs in the past and resulted in the procedure being used mainly at larger academic centers with a specific research focus on studying and developing this approach.

Improvements in haploidentical approaches, however, have resulted in better outcomes, with many groups reporting survival similar to that of unrelated marrow or cord blood approaches.[43–46] These improvements include the following:

• Newer techniques of T-cell depletion and add-back of specific cell populations (e.g., CD3 or alpha-beta CD3/CD19-negative selection) have decreased transplant-related mortality.[47]; [45,46,48,49][Level of evidence C2]
• Reduced toxicity preparative regimens have led to decreased transplant-related mortality.[45,50]
• Better supportive care has decreased the chance of morbidity from infection or EBV-associated lymphoproliferative disorder.[51]
• Patient-donor combinations that have specific killer immunoglobulin-like receptor mismatches have shown decreased likelihood of relapse in some studies. For more information, see the Role of killer immunoglobulin-like receptor (KIR) mismatching in HSCT section.
• Certain techniques, such as using combinations of granulocyte colony-stimulating factor–primed bone marrow and PBSCs with posttransplant antibody–based T-cell depletion [52] or post-HSCT cyclophosphamide (chemotherapeutic T-cell depletion),[45,46,53]; [54][Level of evidence C1] have made these procedures more accessible because they do not use the expensive and complicated processing necessary for traditional T-cell depletion.

Reported survival rates using many different types of haploidentical approaches range from 25% to 80%, depending on the technique and the risk of the patient undergoing the procedure.[42,43,52,53]; [54][Level of evidence C1] Retrospective trials in adults have shown similar outcomes after haploidentical-donor transplants compared with matched-unrelated donor or cord blood transplants.[55,56] One prospective randomized trial in adults with hematologic malignancies that used reduced-intensity regimens showed similar progression-free survival, but lower relapse rates and better OS using haploidentical donors.[57] Pediatric trials using haploidentical donors have shown better outcomes with myeloablative preparative regimens, and survival is comparable to nonhaploidentical approaches.[45,46,49,58] One prospective trial in pediatric patients showed that disease-free survival (DFS) was superior using haploidentical approaches compared with mismatched unrelated-donor approaches. DFS rates in patients treated with haploidentical approaches were similar to those in patients treated with other stem cell sources.[45]

Patients who have been sensitized to HLA antigens and develop antibodies to HLA alleles that are present among the mismatched alleles of their haploidentical donor are at increased risk of rejection of their haploidentical graft. Clinicians should choose donors with HLA types against whom the recipient does not have an antibody present, if possible. Guidelines on how to best approach this issue have been published.[59]

Comparison of Stem Cell Products

Currently, the following three stem cell products are used from both related and unrelated donors:

• Bone marrow.
• PBSCs.
• Cord blood.

Bone marrow or PBSCs, including partially HLA-matched (half or more antigens [haploidentical]) related bone marrow or PBSCs, can be used after in vitro or in vivo T-cell depletion, and these products behave differently from other stem cell products. A comparison of stem cell products is presented in Table 3.

Table 3. Comparison of Hematopoietic Stem Cell Products

	PBSCs	BM	Cord Blood	T-cell–Depleted BM/PBSCs	Haploidentical T-cell–Depleted BM/PBSCs
BM = bone marrow; EBV-LPD = Epstein-Barr virus–associated lymphoproliferative disorder; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplant; PBSCs = peripheral blood stem cells.
aAssuming no development of GVHD. If patients develop GVHD, immune reconstitution is delayed until resolution of the GVHD and discontinuation of immune suppression.
bIf a haploidentical donor is used, longer times to immune reconstitution may occur.
T-cell content	High	Moderate	Low	Very low	Very low
CD34+ content	Moderate–high	Moderate	Low (but higher potency)	Moderate–high	Moderate–high
Time to neutrophil recovery	Rapid: median, 16 d (11–29 d) [60]	Moderate: median, 21 d (12–35 d) [60]	Slower: median, 23 d (11–133 d) [33]	Rapid: median, 16 d (9–40 d) [61]	Rapid: median, 13 d (10–20 d) [62]
Early post-HSCT risk of infections, EBV-LPD	Low–moderate	Moderate	High	Very high	Very high
Risk of graft rejection	Low	Low–moderate	Moderate–high	Moderate–high	Moderate–high
Time to immune reconstitutiona	Rapid (6–12 mo)	Moderate (6–18 mo)	Slow (6–24 mo)	Slow (6–24 mo)	Slow (9–24 mo)b
Risk of acute GVHD	Moderate	Moderate	Moderate	Low	Low
Risk of chronic GVHD	High	Moderate	Low	Low	Low

The main differences between the products are the numbers of T cells and CD34-positive progenitor cells present. Very high levels of T cells are present in PBSCs, intermediate numbers in bone marrow, and low numbers in cord blood and T-cell–depleted products. Patients receiving T-cell–depleted products or cord blood generally have slower hematopoietic recovery, increased risk of infection, late immune reconstitution, higher risks of nonengraftment, and increased risk of EBV-associated lymphoproliferative disorder. This is countered by lower rates of GVHD and an ability to offer transplant to patients for whom full HLA matching is not available. Higher doses of T cells and other cells in PBSCs result in rapid neutrophil recovery and immune reconstitution but also increase rates of chronic GVHD.

Only a few studies have directly compared outcomes of different stem cell sources/products in pediatric patients.

Evidence (comparison of outcomes of stem cell sources/products in children):

1. A retrospective registry study of pediatric patients who underwent HSCT for acute leukemia compared those who received related-donor bone marrow with those who received related-donor PBSCs.[63]
   • Although the bone marrow and PBSC recipient cohorts differed some in their risk profiles, after statistical correction, increased risk of GVHD and transplant-related mortality associated with PBSCs led to poorer survival in the PBSC group.
2. A retrospective study of Japanese children with acute leukemia compared 90 children who received PBSCs with 571 children who received bone marrow.[64]
   • The study confirmed higher transplant-related mortality caused by GVHD and inferior survival among the children who received PBSCs.
3. A large Blood and Marrow Transplant Clinical Trials Network trial for patients requiring unrelated donors included a number of pediatric patients. Patients were randomly assigned to receive either bone marrow or PBSCs. This trial demonstrated the following:[65]
   • OS was identical using either source, but rates of chronic GVHD were significantly higher in the PBSC arm, with a small increase in rejection in the bone marrow arm.
   • Rejections were rare in pediatric patients.
   • There was an insufficient number of patients to draw specific conclusions about rejection risk in children who received bone marrow.

These reports, combined with a lack of prospective studies comparing bone marrow and PBSCs, have led most pediatric transplant protocols to prefer bone marrow over PBSCs from related donors. This approach is further supported by a meta-analysis that included additional retrospective trials.[66]

Published studies comparing unrelated cord blood and bone marrow have been retrospective, with weaknesses inherent in such analyses.

Evidence (comparison of unrelated cord blood versus bone marrow outcomes):

1. In one study, pediatric patients with acute lymphoblastic leukemia (ALL) who underwent HSCT and received 8/8 HLA-matched unrelated-donor bone marrow were compared with those who received unrelated cord blood.[18]
   • The analysis showed that the best survival occurred in recipients of 6/6 HLA-matched cord blood.
   • Survival after 8/8 HLA-matched unrelated bone marrow was slightly worse and was statistically identical to survival for patients receiving 5/6 and 4/6 HLA-matched cord blood units.
2. In another study from a single center consisting of mostly adult patients with acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and ALL, outcomes for cord blood recipients were compared with outcomes for recipients of matched and mismatched unrelated-donor bone marrow/PBSCs.[67]
   • Better survival because of less relapse was noted in cord blood recipients. This result was mainly due to superior survival in patients with minimal residual disease (MRD) present just before transplant.
   • No difference was seen in relapse or survival between patients with pre-HSCT MRD and patients without pre-HSCT MRD if they received cord blood.
   • These results are controversial because they contradict many other studies that showed that the presence of pre-HSCT MRD in cord blood recipients led to increased relapse and inferior survival rates.[68–71]
3. The CIBMTR compared outcomes of children with low-risk and intermediate-risk ALL and AML who underwent transplant between 2000 and 2014 using alternative donors (non–HLA-matched related or unrelated), including 7/8 HLA-matched bone marrow (n = 172) and 4/6 or greater HLA-matched umbilical cord blood (n = 1,613).[72]
   • In multivariate analysis, patients who received 7/8 HLA-matched bone marrow versus umbilical cord blood had similar GVHD-free, relapse-free survival (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.87–1.45; P = .39), chronic GVHD-free, relapse-free survival (HR, 1.06; 95% CI, 0.82–1.38; P = .66), and OS (HR, 1.07; 95% CI, 0.80–1.44; P = .66).
   • Relapse may have been higher in the 7/8 HLA-matched bone marrow group (HR, 1.44; 95% CI, 1.03–2.02; P = .03; the publication called this a trend as they chose a cutoff value of 0.01% to control for multiple comparisons).
   • The patients in the 7/8 HLA-matched bone marrow group had a significantly higher risk of grades III to IV acute GVHD (HR, 1.70; 95% CI, 1.16–2.48; P = .006) and chronic GVHD (HR, 6.17; 95% CI, 2.2–17.33; P = .0006) than did the patients in the umbilical cord blood group.

On the basis of these studies, most transplant centers consider matched sibling bone marrow to be the preferred stem cell source/product. If a sibling donor is not available, fully matched unrelated-donor bone marrow, HLA-matched (4/6 to 6/6 or 6/8 to 8/8) cord blood from a single unit with an adequate cell dose, or a haploidentical HSCT lead to similar survival rates.[49][Level of evidence C2] For more information about the prevention of acute GVHD, see the Prevention and treatment of acute GVHD section in Complications, Graft-Versus-Host Disease, and Late Effects After Pediatric Hematopoietic Stem Cell Transplant.

Other Donor Characteristics Associated With Outcome

HLA matching has consistently been the most important factor associated with improved survival in allogeneic HSCT, but a number of other donor characteristics have been shown to affect key outcomes. Higher cell dose from the donor has also been shown to be important when related, unrelated, or haploidentical bone marrow or PBSC donors are used.[73,74] For more information, see the HLA Matching and Cell Dose Considerations for Unrelated Cord Blood HSCT section. The effects of donor age, blood type, CMV status, sex, and parity of female donors have also been studied.

Ideally, after HLA matching, transplant centers should select donors based on the following characteristics:

• Donor age. The youngest donor available is generally preferred (when considering pediatric donors, the size and ability to obtain an adequate cell dose comes into consideration).[75,76]
• CMV status of the recipient. CMV-negative donor matched to CMV-negative recipient and CMV-positive donor matched to CMV-positive recipient are preferred.[77]
• Donor blood type. Matching of blood type between donor and recipient is preferred, although not required. If only blood type–mismatched donors are available, a minor mismatch is preferred over a major mismatch.[78–80]
• Donor sex and parity of female donors. Male or nonparous female donors are preferred over parous female donors.[76,81]

It is rare for a donor-recipient pair to fit perfectly into this algorithm, and determining which of these characteristics should be chosen over others has been controversial.

Evidence (donor-recipient characteristics):

1. A CIBMTR study examined 6,349 patients who underwent transplant for hematological malignancies from 1988 to 2006. The study tested the effect of donor characteristics while adjusting for disease risk and other key transplant characteristics. The data from this study showed the following:[76]
   • In addition to HLA mismatching, older donor age and major or minor ABO blood type mismatching increased overall mortality.
   • Parous female graft recipients experienced lower rates of relapse.
   • Recipients of younger donor grafts had lower rates of acute GVHD.
   • Recipients of parous female grafts had higher rates of chronic GVHD.
   • Recipient CMV status was more important than donor CMV status (recipients who are CMV positive are at higher risk of mortality independent of the donor CMV status), although a CMV-negative donor to a CMV-negative recipient combination improves survival.
2. A cohort of 4,690 patients who underwent transplant between 2007 and 2011 was tested by a multivariate analysis for independent predictors of survival in an EBMT study. The study demonstrated the following:[82]
   • Older donor age was confirmed to be independently associated with worse OS; every 10 years of donor age increased the risk of mortality by 5.5%.
   • HLA matching continued to have the most important effect on survival; ABO mismatching was not confirmed to have a continuing effect.
3. A study of over 10,000 matched donor-recipient pairs attempted to define a hierarchy that could prioritize the non-HLA characteristics (donor age, sex, blood type, CMV status, etc.) that have been described to affect outcomes.[83]
   • Although the study was unable to create a hierarchical algorithm of modifiable factors, it showed that, by far, younger donor age is the most important factor. The study found a decrease in OS of 3% for every 10-year increment of increased donor age.

Thus, after HLA matching, donor age is likely the most important factor to optimize. Of note, if the recipient is CMV negative, finding a CMV-negative donor is also a high priority.

Several studies have attempted to identify characteristics of the best donors for haploidentical procedures. As with conventional bone marrow transplant, use of younger donors appears to be beneficial, but data regarding donor sex are inconclusive. Studies involving intense T-cell depletion have noted better outcomes using maternal donors,[84] but studies using posttransplant cyclophosphamide or intense immune suppression seem to favor male donors.[85,86] Further study is needed to clarify this important issue.

One large comparison of haploidentical donors showed an effect of ABO incompatibility on engraftment (risk of rejection doubling from 6% to 12%, ABO match vs. ABO major mismatch), and patients receiving bidirectionally mismatched donors had a 2.4-fold increase in grades II to IV acute GVHD.[87] As with nonhaploidentical donors, significant improvement of outcomes was noted when younger donors were used for haploidentical procedures compared with older donors, with an HR of 1.13 for each decade of life that the donor is older.[88]

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45. Pulsipher MA, Ahn KW, Bunin NJ, et al.: KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial. Blood 140 (24): 2556-2572, 2022. [PUBMED Abstract]
46. Merli P, Algeri M, Galaverna F, et al.: TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. Blood 143 (3): 279-289, 2024. [PUBMED Abstract]
47. Handgretinger R, Chen X, Pfeiffer M, et al.: Feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci 1106: 279-89, 2007. [PUBMED Abstract]
48. Locatelli F, Merli P, Pagliara D, et al.: Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Blood 130 (5): 677-685, 2017. [PUBMED Abstract]
49. Bertaina A, Zecca M, Buldini B, et al.: Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood 132 (24): 2594-2607, 2018. [PUBMED Abstract]
50. Bethge WA, Faul C, Bornhäuser M, et al.: Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update. Blood Cells Mol Dis 40 (1): 13-9, 2008. [PUBMED Abstract]
51. Leen AM, Christin A, Myers GD, et al.: Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood 114 (19): 4283-92, 2009. [PUBMED Abstract]
52. Huang XJ, Liu DH, Liu KY, et al.: Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 38 (4): 291-7, 2006. [PUBMED Abstract]
53. Luznik L, Fuchs EJ: High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res 47 (1-3): 65-77, 2010. [PUBMED Abstract]
54. Berger M, Lanino E, Cesaro S, et al.: Feasibility and Outcome of Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant High-Dose Cyclophosphamide for Children and Adolescents with Hematologic Malignancies: An AIEOP-GITMO Retrospective Multicenter Study. Biol Blood Marrow Transplant 22 (5): 902-9, 2016. [PUBMED Abstract]
55. Baker M, Wang H, Rowley SD, et al.: Comparative Outcomes after Haploidentical or Unrelated Donor Bone Marrow or Blood Stem Cell Transplantation in Adult Patients with Hematological Malignancies. Biol Blood Marrow Transplant 22 (11): 2047-2055, 2016. [PUBMED Abstract]
56. Rashidi A, Slade M, DiPersio JF, et al.: Post-transplant high-dose cyclophosphamide after HLA-matched vs haploidentical hematopoietic cell transplantation for AML. Bone Marrow Transplant 51 (12): 1561-1564, 2016. [PUBMED Abstract]
57. Fuchs EJ, O’Donnell PV, Eapen M, et al.: Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood 137 (3): 420-428, 2021. [PUBMED Abstract]
58. Symons HJ, Zahurak M, Cao Y, et al.: Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults. Blood Adv 4 (16): 3913-3925, 2020. [PUBMED Abstract]
59. Ciurea SO, Cao K, Fernandez-Vina M, et al.: The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation. Bone Marrow Transplant 53 (5): 521-534, 2018. [PUBMED Abstract]
60. Bensinger WI, Martin PJ, Storer B, et al.: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344 (3): 175-81, 2001. [PUBMED Abstract]
61. Rocha V, Cornish J, Sievers EL, et al.: Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 97 (10): 2962-71, 2001. [PUBMED Abstract]
62. Bertaina A, Merli P, Rutella S, et al.: HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood 124 (5): 822-6, 2014. [PUBMED Abstract]
63. Eapen M, Horowitz MM, Klein JP, et al.: Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 22 (24): 4872-80, 2004. [PUBMED Abstract]
64. Shinzato A, Tabuchi K, Atsuta Y, et al.: PBSCT is associated with poorer survival and increased chronic GvHD than BMT in Japanese paediatric patients with acute leukaemia and an HLA-matched sibling donor. Pediatr Blood Cancer 60 (9): 1513-9, 2013. [PUBMED Abstract]
65. Anasetti C, Logan BR, Lee SJ, et al.: Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 367 (16): 1487-96, 2012. [PUBMED Abstract]
66. Shimosato Y, Tanoshima R, Tsujimoto SI, et al.: Allogeneic Bone Marrow Transplantation versus Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies in Children: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant 26 (1): 88-93, 2020. [PUBMED Abstract]
67. Milano F, Gooley T, Wood B, et al.: Cord-Blood Transplantation in Patients with Minimal Residual Disease. N Engl J Med 375 (10): 944-53, 2016. [PUBMED Abstract]
68. Ruggeri A, Michel G, Dalle JH, et al.: Impact of pretransplant minimal residual disease after cord blood transplantation for childhood acute lymphoblastic leukemia in remission: an Eurocord, PDWP-EBMT analysis. Leukemia 26 (12): 2455-61, 2012. [PUBMED Abstract]
69. Bachanova V, Burke MJ, Yohe S, et al.: Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol Blood Marrow Transplant 18 (6): 963-8, 2012. [PUBMED Abstract]
70. Sutton R, Shaw PJ, Venn NC, et al.: Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia. Br J Haematol 168 (3): 395-404, 2015. [PUBMED Abstract]
71. Sanchez-Garcia J, Serrano J, Serrano-Lopez J, et al.: Quantification of minimal residual disease levels by flow cytometry at time of transplant predicts outcome after myeloablative allogeneic transplantation in ALL. Bone Marrow Transplant 48 (3): 396-402, 2013. [PUBMED Abstract]
72. Mehta RS, Holtan SG, Wang T, et al.: GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia. Blood Adv 3 (9): 1441-1449, 2019. [PUBMED Abstract]
73. Pulsipher MA, Chitphakdithai P, Logan BR, et al.: Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34+ cell dose. Blood 114 (13): 2606-16, 2009. [PUBMED Abstract]
74. Aversa F, Terenzi A, Tabilio A, et al.: Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 23 (15): 3447-54, 2005. [PUBMED Abstract]
75. Kollman C, Howe CW, Anasetti C, et al.: Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 98 (7): 2043-51, 2001. [PUBMED Abstract]
76. Kollman C, Spellman SR, Zhang MJ, et al.: The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood 127 (2): 260-7, 2016. [PUBMED Abstract]
77. Boeckh M, Nichols WG: The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 103 (6): 2003-8, 2004. [PUBMED Abstract]
78. Seebach JD, Stussi G, Passweg JR, et al.: ABO blood group barrier in allogeneic bone marrow transplantation revisited. Biol Blood Marrow Transplant 11 (12): 1006-13, 2005. [PUBMED Abstract]
79. Logan AC, Wang Z, Alimoghaddam K, et al.: ABO mismatch is associated with increased nonrelapse mortality after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 21 (4): 746-54, 2015. [PUBMED Abstract]
80. Stussi G, Muntwyler J, Passweg JR, et al.: Consequences of ABO incompatibility in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 30 (2): 87-93, 2002. [PUBMED Abstract]
81. Loren AW, Bunin GR, Boudreau C, et al.: Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 12 (7): 758-69, 2006. [PUBMED Abstract]
82. Canaani J, Savani BN, Labopin M, et al.: ABO incompatibility in mismatched unrelated donor allogeneic hematopoietic cell transplantation for acute myeloid leukemia: A report from the acute leukemia working party of the EBMT. Am J Hematol 92 (8): 789-796, 2017. [PUBMED Abstract]
83. Shaw BE, Logan BR, Spellman SR, et al.: Development of an Unrelated Donor Selection Score Predictive of Survival after HCT: Donor Age Matters Most. Biol Blood Marrow Transplant 24 (5): 1049-1056, 2018. [PUBMED Abstract]
84. Stern M, Ruggeri L, Mancusi A, et al.: Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood 112 (7): 2990-5, 2008. [PUBMED Abstract]
85. Ciurea SO, Champlin RE: Donor selection in T cell-replete haploidentical hematopoietic stem cell transplantation: knowns, unknowns, and controversies. Biol Blood Marrow Transplant 19 (2): 180-4, 2013. [PUBMED Abstract]
86. Wang Y, Chang YJ, Xu LP, et al.: Who is the best donor for a related HLA haplotype-mismatched transplant? Blood 124 (6): 843-50, 2014. [PUBMED Abstract]
87. Canaani J, Savani BN, Labopin M, et al.: Impact of ABO incompatibility on patients’ outcome after haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia – a report from the Acute Leukemia Working Party of the EBMT. Haematologica 102 (6): 1066-1074, 2017. [PUBMED Abstract]
88. DeZern AE, Franklin C, Tsai HL, et al.: Relationship of donor age and relationship to outcomes of haploidentical transplantation with posttransplant cyclophosphamide. Blood Adv 5 (5): 1360-1368, 2021. [PUBMED Abstract]

In the days just before infusion of the stem cell product (bone marrow, peripheral blood stem cells [PBSCs], or cord blood), HSCT recipients receive chemotherapy/immunotherapy, sometimes combined with radiation therapy. This is called a preparative regimen, and the original intent of this treatment was to:

With the recognition that donor T cells can facilitate engraftment and kill tumors through graft-versus-leukemia (GVL) effects (obviating the need to create bone marrow space and intensely treat cancer), reduced-intensity or minimal-intensity HSCT approaches focusing on immune suppression rather than myeloablation have been developed. The resulting lower toxicity associated with these regimens has led to lower rates of transplant-related mortality and expanded eligibility for allogeneic HSCT to older individuals and younger patients with pre-HSCT comorbidities that put them at risk of severe toxicity after standard HSCT approaches.[1]

Existing preparative regimens vary tremendously in the amount of immunosuppression and myelosuppression they cause, with the lowest-intensity regimens relying heavily on a strong graft-versus-tumor (GVT) effect (see Figure 3).

Enlarge

Although these regimens lead to varying degrees of myelosuppression and immune suppression, they have been grouped clinically into the following three major categories (see Figure 4):[2]

Enlarge

For years, retrospective studies showed similar outcomes using reduced-intensity and myeloablative approaches.[3,4] However, a Blood and Marrow Transplant Clinical Trials Network trial of adult patients with acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) who were randomly assigned to receive either myeloablative or reduced-intensity HSCT approaches demonstrated the importance of regimen intensity.[5]

With this in mind, the use of reduced-intensity conditioning and nonmyeloablative regimens is well established in older adults who cannot tolerate more intense myeloablative approaches,[6–8] but these approaches have been studied in a limited number of younger patients with malignancies.[9–13] A large Pediatric Blood and Marrow Transplant Consortium study identified patients at high risk of transplant-related mortality with myeloablative regimens (e.g., history of previous myeloablative transplant, severe organ system dysfunction, or active, invasive fungal infection) and successfully treated these patients with a reduced-intensity regimen.[14] Transplant-related mortality was low in this high-risk group, and long-term survival occurred in most patients with minimal or no detectable disease at the time of transplant. Because the risks of relapse are higher with these approaches, their use in pediatric cancer is currently limited to patients ineligible for myeloablative regimens and is most likely to be successful when patients have achieved minimal residual disease (MRD)–negative remissions.[14]

In pediatric HSCT, there has been an effort to develop preparative regimens that are myeloablative but do not have the severe toxicities associated with traditional, highly intense myeloablative approaches such as full-dose total-body irradiation, busulfan and cyclophosphamide, or busulfan, cyclophosphamide, and melphalan. These less-intense regimens are called reduced toxicity and include approaches such as full-dose busulfan and fludarabine or treosulfan and fludarabine. These approaches have been especially useful in transplant for nonmalignant disorders that require full chimerism,[15] but they have often shown similar outcomes when used for patients with malignancies.[16]

Establishing Donor Chimerism

Intense myeloablative approaches almost invariably result in hematopoiesis derived from donor cells upon count recovery after the transplant. The introduction of reduced-toxicity, reduced-intensity, and nonmyeloablative conditioning into HSCT practice has resulted in a slower pace of transition to donor hematopoiesis (gradually increasing from partial to full donor hematopoiesis over months) that sometimes remains partially long-term. DNA-based techniques have been established to differentiate donor from recipient hematopoiesis, applying the word chimerism to describe whether all or part of hematopoiesis after HSCT is from the donor or recipient.

There are several implications regarding the pace and extent of donor chimerism achieved by an HSCT recipient. For patients receiving reduced-intensity conditioning or nonmyeloablative regimens, rapid progression to full donor chimerism is associated with lower relapse rates but more graft-versus-host disease (GVHD).[17] The delayed pace of obtaining full donor chimerism after reduced-intensity regimens has led to late-onset acute GVHD, occurring as late as 6 to 7 months after HSCT (acute GVHD generally occurs within 100 days after myeloablative approaches).[18] A portion of patients achieve stable mixed chimerism of both donor and recipient. Mixed chimerism is associated with more relapse after HSCT for malignancies and less GVHD. However, this condition is often advantageous for nonmalignant HSCT, where usually only a percentage of normal hematopoiesis is needed to correct the underlying disorder and GVHD is not beneficial.[19] Finally, serially measured decreasing donor chimerism, especially T-cell–specific chimerism, has been associated with increased risk of rejection.[20]

Because of the implications of persistent recipient chimerism, most transplant programs test for chimerism shortly after engraftment and continue testing regularly until stable full donor hematopoiesis has been achieved. Investigators have defined two approaches to treat the increased risks of relapse and rejection associated with increasing recipient chimerism: rapid withdrawal of immune suppression and donor lymphocyte infusions (DLI). These approaches are frequently used to address this issue, and they have been shown to decrease relapse risk and stop rejection in some cases.[21–23] The timing of immune suppression and dose tapers and approaches to administration of DLI to increase or stabilize donor chimerism vary between stem cell sources. There is also a wide institutional variability, with some institutions proactively following chimerism and often intervening, and others having a more limited approach to interventions. For more information, see the Using donor lymphocyte infusions (DLI) or early withdrawal of immune suppression to enhance GVL section.

References

1. Deeg HJ, Sandmaier BM: Who is fit for allogeneic transplantation? Blood 116 (23): 4762-70, 2010. [PUBMED Abstract]
2. Bacigalupo A, Ballen K, Rizzo D, et al.: Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 15 (12): 1628-33, 2009. [PUBMED Abstract]
3. Luger SM, Ringdén O, Zhang MJ, et al.: Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant 47 (2): 203-11, 2012. [PUBMED Abstract]
4. Pulsipher MA, Chitphakdithai P, Logan BR, et al.: Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34+ cell dose. Blood 114 (13): 2606-16, 2009. [PUBMED Abstract]
5. Scott BL, Pasquini MC, Logan BR, et al.: Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol 35 (11): 1154-1161, 2017. [PUBMED Abstract]
6. Giralt S, Estey E, Albitar M, et al.: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 89 (12): 4531-6, 1997. [PUBMED Abstract]
7. Slavin S, Nagler A, Naparstek E, et al.: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91 (3): 756-63, 1998. [PUBMED Abstract]
8. Storb R, Yu C, Sandmaier BM, et al.: Mixed hematopoietic chimerism after marrow allografts. Transplantation in the ambulatory care setting. Ann N Y Acad Sci 872: 372-5; discussion 375-6, 1999. [PUBMED Abstract]
9. Bradley MB, Satwani P, Baldinger L, et al.: Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases. Bone Marrow Transplant 40 (7): 621-31, 2007. [PUBMED Abstract]
10. Del Toro G, Satwani P, Harrison L, et al.: A pilot study of reduced intensity conditioning and allogeneic stem cell transplantation from unrelated cord blood and matched family donors in children and adolescent recipients. Bone Marrow Transplant 33 (6): 613-22, 2004. [PUBMED Abstract]
11. Gómez-Almaguer D, Ruiz-Argüelles GJ, Tarín-Arzaga Ldel C, et al.: Reduced-intensity stem cell transplantation in children and adolescents: the Mexican experience. Biol Blood Marrow Transplant 9 (3): 157-61, 2003. [PUBMED Abstract]
12. Pulsipher MA, Woolfrey A: Nonmyeloablative transplantation in children. Current status and future prospects. Hematol Oncol Clin North Am 15 (5): 809-34, vii-viii, 2001. [PUBMED Abstract]
13. Roman E, Cooney E, Harrison L, et al.: Preliminary results of the safety of immunotherapy with gemtuzumab ozogamicin following reduced intensity allogeneic stem cell transplant in children with CD33+ acute myeloid leukemia. Clin Cancer Res 11 (19 Pt 2): 7164s-7170s, 2005. [PUBMED Abstract]
14. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009. [PUBMED Abstract]
15. Cseh A, Galimard JE, de la Fuente J, et al.: Busulfan-fludarabine- or treosulfan-fludarabine-based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties. Br J Haematol 204 (1): e1-e5, 2024. [PUBMED Abstract]
16. Pulsipher MA, Ahn KW, Bunin NJ, et al.: KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial. Blood 140 (24): 2556-2572, 2022. [PUBMED Abstract]
17. Baron F, Baker JE, Storb R, et al.: Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 104 (8): 2254-62, 2004. [PUBMED Abstract]
18. Vigorito AC, Campregher PV, Storer BE, et al.: Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD. Blood 114 (3): 702-8, 2009. [PUBMED Abstract]
19. Marsh RA, Vaughn G, Kim MO, et al.: Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood 116 (26): 5824-31, 2010. [PUBMED Abstract]
20. McSweeney PA, Niederwieser D, Shizuru JA, et al.: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97 (11): 3390-400, 2001. [PUBMED Abstract]
21. Bader P, Kreyenberg H, Hoelle W, et al.: Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22 (9): 1696-705, 2004. [PUBMED Abstract]
22. Horn B, Soni S, Khan S, et al.: Feasibility study of preemptive withdrawal of immunosuppression based on chimerism testing in children undergoing myeloablative allogeneic transplantation for hematologic malignancies. Bone Marrow Transplant 43 (6): 469-76, 2009. [PUBMED Abstract]
23. Haines HL, Bleesing JJ, Davies SM, et al.: Outcomes of donor lymphocyte infusion for treatment of mixed donor chimerism after a reduced-intensity preparative regimen for pediatric patients with nonmalignant diseases. Biol Blood Marrow Transplant 21 (2): 288-92, 2015. [PUBMED Abstract]

Graft-Versus-Leukemia (GVL) Effect

Early studies in HSCT focused on the delivery of intense myeloablative preparative regimens followed by rescue of the hematopoietic system with either an autologous or allogeneic bone marrow transplant. Investigators quickly showed that allogeneic approaches led to a decreased risk of relapse caused by an immunotherapeutic reaction of the new bone marrow graft against tumor antigens. This phenomenon came to be termed the GVL or graft-versus-tumor (GVT) effect and has been associated with mismatches to both major and minor HLA antigens.

The GVL effect is challenging to use therapeutically because of a strong association between GVL and clinical graft-versus-host disease (GVHD). For standard approaches to HSCT, the highest survival rates have been associated with mild or moderate GVHD (grades I to II in acute myeloid leukemia [AML] and grades I to III in acute lymphoblastic leukemia [ALL]), compared with patients who have no GVHD and experience more relapse or patients with severe GVHD who experience more transplant-related mortality.[1–3]; [4][Level of evidence C2]

Understanding when GVL occurs and how to use GVL optimally is challenging. One method of study compares rates of relapse and survival between patients undergoing myeloablative HSCT with either autologous or allogeneic donors for a given disease.

• Leukemia and myelodysplastic neoplasms (MDS): A clear advantage has been noted when allogeneic approaches are used for ALL, AML, chronic myelogenous leukemia (CML), and MDS. For ALL and AML specifically, autologous HSCT approaches for most high-risk patient groups have shown results similar to those obtained with chemotherapy, while allogeneic approaches produced superior results and are therefore useful for chemoresistant or relapsed patients.[5,6]
• Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL): Patients with HL or NHL generally fare better with autologous approaches, although there may be a role for allogeneic approaches in relapsed lymphoblastic lymphoma, lymphoma that is poorly responsive to chemotherapy, or lymphoma that has relapsed after autologous HSCT.[7]

Further insights into the therapeutic benefit of GVL/GVT for given diseases have come from the use of reduced-intensity preparative regimens. This approach to transplant relies on GVL because, in most cases, the intensity of the preparative regimen is not sufficient for cure. Although studies have shown benefit for patients pursuing this approach when they are ineligible for standard transplant,[8] this approach has not been used for most children with cancer who require HSCT because pediatric cancer patients can generally undergo myeloablative approaches safely. For more information, see the Allogeneic HSCT Preparative Regimens section.

Using donor lymphocyte infusions (DLI) or early withdrawal of immune suppression to enhance GVL

GVL can be achieved therapeutically through the infusion of cells after transplant that either specifically or nonspecifically target the tumor. The most common approach is the use of DLI. This approach relies on the persistence of donor T-cell engraftment after transplant to prevent rejection of donor lymphocytes infused to induce GVL.

Therapeutic DLI results in potent responses in patients with CML who relapse after transplant (60%–80% enter into long-term remission),[9] but responses in patients with other diseases (such as AML and ALL) have been less potent, with long-term survival rates of only 20% to 30%.[10] DLI works poorly in patients with acute leukemia who relapse early and who have high levels of active disease. Late relapse (>6 months after transplant) and the treatment of patients into complete remission with chemotherapy before DLI have been associated with improved outcomes.[11] Infusions of donor lymphocytes modified to enhance GVL or other donor cells (e.g., natural killer [NK] cells) have also been studied but have yet to be generally adopted.

Another method of delivering GVL therapeutically is the rapid withdrawal of immune suppression after HSCT. Some studies have scheduled more rapid immune suppression tapers based on donor type (related donors are tapered more quickly than are unrelated donors because of less GVHD risk), and others have used sensitive measures of either low levels of persistent recipient cells (recipient chimerism) or minimal residual disease to assess the risk of relapse and trigger rapid taper of immune suppression.

A combination of early withdrawal of immune suppression after HSCT with DLI to prevent relapse in patients at high risk of relapse because of persistent/progressive recipient chimerism has been tested in patients who underwent transplant for both ALL and AML.[12][Level of evidence B4]; [13][Level of evidence C2]

• ALL: One study found increasing recipient chimerism in 46 of 101 patients with ALL. Thirty-one of those patients had withdrawal of immune suppression, and a portion went on to receive DLI if GVHD did not occur. This group had a survival rate of 37%, compared with 0% in the 15 patients who did not undergo this approach (P < .001).[14]
• AML: About 20% of patients with AML experienced mixed chimerism after HSCT and were identified as high risk. Of these patients, 54% survived if they underwent withdrawal of immune suppression with or without DLI. There were no survivors among those who did not receive this therapy.[15]

Other immunological and cell therapy approaches under evaluation

Role of killer immunoglobulin-like receptor (KIR) mismatching in HSCT

Donor-derived NK cells in the post-HSCT setting have been shown to promote the following:[16–18]

• Engraftment.
• Decreased GVHD.
• Fewer relapses of hematological malignancies.
• Improved survival.

NK-cell function is modulated by interactions with a number of receptor families, including activating and inhibiting KIR. The KIR effect in the allogeneic HSCT setting hinges on the expression of specific inhibitory KIR on donor-derived NK cells and either the presence or absence of their matching HLA class I molecules (KIR ligands) on recipient leukemic and normal cells. Normally, the presence of specific KIR ligands interacting with paired inhibitory KIR molecules prevents NK cell attacks on healthy cells. In the allogeneic transplant setting, recipient leukemia cells genetically differ from donor NK cells, and they may not have the appropriate inhibitory KIR ligand. Mismatch of ligand and receptor allows NK-cell–based killing of recipient leukemia cells to proceed for certain donor-recipient genetic combinations.

The original observation of decreased relapse with certain KIR-ligand combinations was made in the setting of T-cell–depleted haploidentical transplant and was strongest after HSCT for AML.[17,19] However, some haploidentical transplant studies have not shown this effect.[20] Along with decreasing relapse, these studies have suggested a decrease in GVHD with appropriate KIR-ligand combinations. Many subsequent studies did not detect survival effects for KIR-incompatible HSCT using standard transplant methods,[21–24] which has led to the conclusion that T-cell depletion may be necessary to remove other forms of inhibitory cellular interactions.

Decreased relapse and better survival have been noted with donor/recipient KIR-ligand incompatibility after cord blood HSCT, a relatively T-cell–depleted procedure.[25,26] In contrast to this notion, one study demonstrated that some KIR mismatching combinations (activating receptor KIR2DS1 with the HLA C1 ligand) can lead to decreased relapse after AML HSCT without T-cell depletion.[27] The role of KIR incompatibility in sibling donor HSCT and in diseases other than AML is controversial, but in pediatrics, at least two groups have found better outcomes with specific types of KIR mismatching in ALL.[28–30]

A current challenge associated with studies of KIR is that several different approaches have been used to determine what is KIR incompatible and what are the most favorable combinations of KIR molecules in donor-recipient pairs.[19,31,32] Activating KIR molecules have also been shown to contribute to the effect.[33] The standardization of KIR classification and prospective studies should help clarify the utility and importance of this approach. Because a limited number of centers perform haploidentical HSCT and the results of other approaches to HSCT are preliminary, most transplant programs do not use KIR mismatching as part of their strategy for choosing a donor. Full HLA matching is considered most important for outcome, with considerations of KIR mismatching or choosing donors with favorable KIR activation profiles remaining secondary.

NK-cell transplant

With a low risk of GVHD and demonstrated efficacy in decreasing relapse in posthaploidentical HSCT settings, NK-cell infusions as a method of treating high-risk patients and consolidating patients in remission have been studied:

Evidence (NK-cell transplant outcomes):

1. A University of Minnesota research group compared approaches with different NK-cell populations.[34]
   • The study initially failed to demonstrate efficacy with autologous NK cells, but it found that intense immunoablative therapy followed by purified haploidentical NK cells and interleukin-2 (IL-2) maintenance led to remission in 5 of 19 high-risk patients with AML.
2. Researchers at St. Jude Children’s Research Hospital treated ten intermediate-risk patients with AML who had completed chemotherapy and were in remission. The patients received lower-dose immunosuppression followed by haploidentical NK-cell infusions and IL-2 for consolidation.[35]
   • Expansion of NK cells was noted in all nine of the KIR-incompatible donor-recipient pairs.
   • All ten children remained in remission at 2 years.
   • A follow-up phase II study is under way, as are many investigations into NK-cell therapy for a number of cancer types.

   Although early survival rates are high in this high-risk AML cohort, multicenter confirmatory studies will be necessary to establish the efficacy of these types of NK-cell approaches.

3. Other investigators have used expanded/activated NK cells before and after HSCT.[36] One approach that included the culturing of haploidentical NK cells with membrane-bound IL-21 showed marked expansion and high activity. These cells were then infused just before haploidentical HSCT, followed by additional infusions on day 7 and 28 after HSCT.[36]

References

1. Yeshurun M, Weisdorf D, Rowe JM, et al.: The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia. Blood Adv 3 (4): 670-680, 2019. [PUBMED Abstract]
2. Pulsipher MA, Langholz B, Wall DA, et al.: The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children’s Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood 123 (13): 2017-25, 2014. [PUBMED Abstract]
3. Neudorf S, Sanders J, Kobrinsky N, et al.: Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival. Blood 103 (10): 3655-61, 2004. [PUBMED Abstract]
4. Boyiadzis M, Arora M, Klein JP, et al.: Impact of Chronic Graft-versus-Host Disease on Late Relapse and Survival on 7,489 Patients after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Leukemia. Clin Cancer Res 21 (9): 2020-8, 2015. [PUBMED Abstract]
5. Woods WG, Neudorf S, Gold S, et al.: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97 (1): 56-62, 2001. [PUBMED Abstract]
6. Ribera JM, Ortega JJ, Oriol A, et al.: Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25 (1): 16-24, 2007. [PUBMED Abstract]
7. Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010. [PUBMED Abstract]
8. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009. [PUBMED Abstract]
9. Porter DL, Collins RH, Shpilberg O, et al.: Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions. Biol Blood Marrow Transplant 5 (4): 253-61, 1999. [PUBMED Abstract]
10. Levine JE, Barrett AJ, Zhang MJ, et al.: Donor leukocyte infusions to treat hematologic malignancy relapse following allo-SCT in a pediatric population. Bone Marrow Transplant 42 (3): 201-5, 2008. [PUBMED Abstract]
11. Warlick ED, DeFor T, Blazar BR, et al.: Successful remission rates and survival after lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies postallogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 18 (3): 480-6, 2012. [PUBMED Abstract]
12. Horn B, Petrovic A, Wahlstrom J, et al.: Chimerism-based pre-emptive immunotherapy with fast withdrawal of immunosuppression and donor lymphocyte infusions after allogeneic stem cell transplantation for pediatric hematologic malignancies. Biol Blood Marrow Transplant 21 (4): 729-37, 2015. [PUBMED Abstract]
13. Horn B, Wahlstrom JT, Melton A, et al.: Early mixed chimerism-based preemptive immunotherapy in children undergoing allogeneic hematopoietic stem cell transplantation for acute leukemia. Pediatr Blood Cancer 64 (8): , 2017. [PUBMED Abstract]
14. Bader P, Kreyenberg H, Hoelle W, et al.: Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22 (9): 1696-705, 2004. [PUBMED Abstract]
15. Rettinger E, Willasch AM, Kreyenberg H, et al.: Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation. Blood 118 (20): 5681-8, 2011. [PUBMED Abstract]
16. Ruggeri L, Capanni M, Urbani E, et al.: Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295 (5562): 2097-100, 2002. [PUBMED Abstract]
17. Giebel S, Locatelli F, Lamparelli T, et al.: Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 102 (3): 814-9, 2003. [PUBMED Abstract]
18. Bari R, Rujkijyanont P, Sullivan E, et al.: Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 31 (30): 3782-90, 2013. [PUBMED Abstract]
19. Ruggeri L, Mancusi A, Capanni M, et al.: Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 110 (1): 433-40, 2007. [PUBMED Abstract]
20. Merli P, Algeri M, Galaverna F, et al.: TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. Blood 143 (3): 279-289, 2024. [PUBMED Abstract]
21. Davies SM, Ruggieri L, DeFor T, et al.: Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 100 (10): 3825-7, 2002. [PUBMED Abstract]
22. Farag SS, Bacigalupo A, Eapen M, et al.: The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant 12 (8): 876-84, 2006. [PUBMED Abstract]
23. Davies SM, Iannone R, Alonzo TA, et al.: A Phase 2 Trial of KIR-Mismatched Unrelated Donor Transplantation Using in Vivo T Cell Depletion with Antithymocyte Globulin in Acute Myelogenous Leukemia: Children’s Oncology Group AAML05P1 Study. Biol Blood Marrow Transplant 26 (4): 712-717, 2020. [PUBMED Abstract]
24. Verneris MR, Miller JS, Hsu KC, et al.: Investigation of donor KIR content and matching in children undergoing hematopoietic cell transplantation for acute leukemia. Blood Adv 4 (7): 1350-1356, 2020. [PUBMED Abstract]
25. Cooley S, Trachtenberg E, Bergemann TL, et al.: Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Blood 113 (3): 726-32, 2009. [PUBMED Abstract]
26. Willemze R, Rodrigues CA, Labopin M, et al.: KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia 23 (3): 492-500, 2009. [PUBMED Abstract]
27. Venstrom JM, Pittari G, Gooley TA, et al.: HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med 367 (9): 805-16, 2012. [PUBMED Abstract]
28. Leung W: Use of NK cell activity in cure by transplant. Br J Haematol 155 (1): 14-29, 2011. [PUBMED Abstract]
29. Leung W, Campana D, Yang J, et al.: High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood 118 (2): 223-30, 2011. [PUBMED Abstract]
30. Oevermann L, Michaelis SU, Mezger M, et al.: KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL. Blood 124 (17): 2744-7, 2014. [PUBMED Abstract]
31. Leung W, Iyengar R, Triplett B, et al.: Comparison of killer Ig-like receptor genotyping and phenotyping for selection of allogeneic blood stem cell donors. J Immunol 174 (10): 6540-5, 2005. [PUBMED Abstract]
32. Pulsipher MA, Ahn KW, Bunin NJ, et al.: KIR-favorable TCR-αβ/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial. Blood 140 (24): 2556-2572, 2022. [PUBMED Abstract]
33. Cooley S, Weisdorf DJ, Guethlein LA, et al.: Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 116 (14): 2411-9, 2010. [PUBMED Abstract]
34. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al.: Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105 (8): 3051-7, 2005. [PUBMED Abstract]
35. Rubnitz JE, Inaba H, Ribeiro RC, et al.: NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 28 (6): 955-9, 2010. [PUBMED Abstract]
36. Ciurea SO, Schafer JR, Bassett R, et al.: Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood 130 (16): 1857-1868, 2017. [PUBMED Abstract]

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of allogeneic hematopoietic stem cell transplant in treating pediatric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Pediatric Allogeneic Hematopoietic Stem Cell Transplant are:

• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Michael A. Pulsipher, MD (Huntsman Cancer Institute at University of Utah)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Pediatric Allogeneic Hematopoietic Stem Cell Transplant. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/childhood-cancers/hp-stem-cell-transplant/allogeneic. Accessed <MM/DD/YYYY>. [PMID: 35133766]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Rationale for HSCT

Blood and marrow transplant, or HSCT, is a procedure that involves infusion of hematopoietic stem cells (along with hematopoietic progenitor cells) to reconstitute the hematopoietic system of a patient. The infusion of hematopoietic stem cells generally follows a preparative regimen consisting of agents designed to do the following:

• Create marrow space.
• Suppress the patient’s immune system to prevent rejection.
• Eradicate malignant cells in patients with cancer.

HSCT is currently used in the:

• Treatment of malignancies,
• Replacement or modulation of an absent or poorly functioning hematopoietic or immune system, or for the
• Treatment of certain genetic diseases. In these cases, insufficient expression of the affected gene product can be partially or completely overcome by circulating hematopoietic stem cells transplanted from a donor with normal gene expression.

This summary focuses on the use of HSCT in the treatment of childhood malignancies.

Autologous Versus Allogeneic HSCT

The two major HSCT approaches currently in use are the following:

• Autologous (using the patient’s own hematopoietic stem cells).
• Allogeneic (using related- or unrelated-donor hematopoietic stem cells).

An autologous transplant treats cancer by exposing patients to high-dose therapy with the intent of overcoming chemotherapy resistance in tumor cells, followed by infusion of the patient’s previously stored hematopoietic stem cells. The transplant can be performed in a single procedure or tandem sequential procedures.

Allogeneic transplant approaches to cancer treatment also may involve high-dose therapy, but because of immunologic differences between the donor and recipient, an additional graft-versus-tumor or graft-versus-leukemia treatment effect can occur. Although autologous approaches are associated with less short-term mortality, many malignancies are resistant to even high doses of chemotherapy and/or involve the bone marrow. Therefore, patients may require allogeneic approaches for optimal outcomes.

Determining When HSCT Is Indicated: Comparison of HSCT and Chemotherapy Outcomes

Because the outcomes using chemotherapy and HSCT treatments have been changing over time, these approaches should be compared regularly to continually redefine optimal therapy for a given patient. For some diseases, randomized trials or intent-to-treat trials using an HLA-matched sibling donor have established the benefit of HSCT by direct comparison.[1,2] However, for very high-risk patients, such as those with early relapse of acute lymphoblastic leukemia, randomized trials have not been feasible because of investigator bias.[3,4]

In general, HSCT typically benefits only children at high risk of relapse with standard chemotherapy approaches. Accordingly, treatment schemas that accurately identify these high-risk patients and offer HSCT if appropriate allogeneic donors are available are the preferred approach for many diseases.[5] Less well-established, higher-risk approaches to HSCT, such as haploidentical transplant, are sometimes reserved for only the very highest-risk patients. However, these higher-risk approaches are becoming safer and more efficacious and are increasingly used interchangeably with fully matched allogeneic approaches.[6–9] For more information, see the Haploidentical HSCT section in Pediatric Allogeneic Hematopoietic Stem Cell Transplant.

When comparisons of similar patients treated with HSCT or chemotherapy are made in the setting where randomized or intent-to-treat studies are not feasible, the following issues should be considered:

1. Remission/disease status: Comparisons of HSCT and chemotherapy should include only patients who obtain remission, preferably after similar approaches to salvage therapy, because patients who fail to obtain remission have poor outcomes with any therapy.[10]

   To account for time-to-transplant bias, the chemotherapy comparator arm should include only patients who maintained remission until the median time to HSCT. The HSCT comparator arm should also include only patients who achieved the initial remission mentioned above and maintained that remission until the time of HSCT.[10]

   High-risk and intermediate-risk patient groups should not be combined because benefit or lack of benefit of HSCT in the high-risk group can be masked by different levels of benefit in the intermediate-risk group.[10]

2. Therapy approaches used for comparison: Comparisons should be made with the best or most used chemotherapy/immunotherapy or HSCT approaches used during the time frame under study.
3. HSCT approach: HSCT approaches that are very high risk or have documented lower rates of survival should not be combined for analysis with standard-risk HSCT approaches.
4. Criteria for relapse: Risk factors for relapse should be carefully defined, and analysis should be based on the most current knowledge of risk.
5. Selection bias: Attempts should be made to understand and eliminate or correct for selection bias. Examples include the following:
   • Higher-risk patients preferentially undergoing HSCT (i.e., patients who take several rounds to achieve remission or have disease relapse after obtaining remission and go back into a subsequent remission before HSCT).
   • Sicker patients deferred from HSCT because of comorbidities.
   • Related to the time-to-transplant bias noted above, patients who undergo HSCT after relapse or recurrence are a subset of all patients with a disease recurrence and will be selected from those who are able to obtain a remission and remain healthy enough to undergo HSCT.
   • Patient or parent refusal.
   • Lack of or inability to obtain insurance approval for HSCT.
   • Lack of access to HSCT because of distance or inability to travel.

Physician bias, for or against HSCT, is difficult to control for or detect. The effects of access to HSCT and therapeutic bias on outcomes of pediatric malignancies for which HSCT may be indicated have been poorly studied.

For more information about pediatric HSCT, see the following summaries:

1. Pediatric Autologous Hematopoietic Stem Cell Transplant.
2. Pediatric Allogeneic Hematopoietic Stem Cell Transplant.
3. Pediatric Chimeric Antigen Receptor (CAR) T-Cell Therapy.
4. Complications, Graft-Versus-Host Disease, and Late Effects after Pediatric Hematopoietic Stem Cell Transplant.

References

1. Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 341 (16): 1165-73, 1999. [PUBMED Abstract]
2. Woods WG, Neudorf S, Gold S, et al.: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97 (1): 56-62, 2001. [PUBMED Abstract]
3. Lawson SE, Harrison G, Richards S, et al.: The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study. Br J Haematol 108 (3): 531-43, 2000. [PUBMED Abstract]
4. Gaynon PS, Harris RE, Altman AJ, et al.: Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children’s Oncology Group study CCG-1941. J Clin Oncol 24 (19): 3150-6, 2006. [PUBMED Abstract]
5. Merli P, Algeri M, Del Bufalo F, et al.: Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia. Curr Hematol Malig Rep 14 (2): 94-105, 2019. [PUBMED Abstract]
6. Bertaina A, Merli P, Rutella S, et al.: HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood 124 (5): 822-6, 2014. [PUBMED Abstract]
7. Handgretinger R, Chen X, Pfeiffer M, et al.: Feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci 1106: 279-89, 2007. [PUBMED Abstract]
8. Huang XJ, Liu DH, Liu KY, et al.: Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 38 (4): 291-7, 2006. [PUBMED Abstract]
9. Luznik L, Fuchs EJ: High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res 47 (1-3): 65-77, 2010. [PUBMED Abstract]
10. Pulsipher MA, Peters C, Pui CH: High-risk pediatric acute lymphoblastic leukemia: to transplant or not to transplant? Biol Blood Marrow Transplant 17 (1 Suppl): S137-48, 2011. [PUBMED Abstract]

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of hematopoietic stem cell transplant and cellular therapy in treating pediatric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer are:

• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Michael A. Pulsipher, MD (Huntsman Cancer Institute at University of Utah)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/childhood-cancers/hp-stem-cell-transplant. Accessed <MM/DD/YYYY>. [PMID: 26389503]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Autologous hematopoietic stem cell transplant (HSCT) procedures require collection of growth-factor–mobilized peripheral blood stem cells (PBSCs) from patients using leukapheresis. Bone marrow can be used for autologous transplants, but PBSCs lead to quicker blood count recovery, resulting in less transplant-related toxicity.

Patients being considered for autologous HSCT are generally given chemotherapy to determine tumor responsiveness and minimize the risk of tumor contamination in their bone marrow. After a number of rounds of chemotherapy, patients undergo the leukapheresis procedure, either as their blood counts recover from chemotherapy or during a break between chemotherapy treatments. Growth factors such as granulocyte colony-stimulating factor are used to increase the number of circulating stem and progenitor cells (CD34+ cells). Collection centers monitor the number of CD34-positive cells in the patient and product each day to determine the best time to begin collection and when collection is complete. Patients with low numbers of CD34-positive cells before collection can often have their cells successfully collected using alternative mobilization approaches (e.g., addition of plerixafor).[1] The collected PBSCs are cryopreserved for later use. After completion of an intensive preparative regimen using high-dose chemotherapy, which varies according to the tumor type, the PBSCs are given to the patient at the time of transplant.

References

1. Patel B, Pearson H, Zacharoulis S: Mobilisation of haematopoietic stem cells in paediatric patients, prior to autologous transplantation following administration of plerixafor and G-CSF. Pediatr Blood Cancer 62 (8): 1477-80, 2015. [PUBMED Abstract]

Autologous Hematopoietic Stem Cell Transplant (HSCT) Indications for Solid Tumors and Lymphomas

In pediatrics, the most common autologous HSCT indications are for the treatment of some solid tumors and lymphomas.

Autologous transplants have also been used to reset the immune system in patients with severe autoimmune disorders and to enable engraftment of genetically modified autologous hematopoietic stem cell progenitors to correct or ameliorate inherited disorders (e.g., immunodeficiencies, metabolic disorders, and hemoglobinopathies). These indications are not covered in this summary.

Indications for HSCT vary over time as risk classifications for a given malignancy change and the efficacy of primary therapy improves. It is best to include specific indications in the context of complete therapy for any given disease.

With this in mind, links to sections in specific summaries that cover the most common pediatric autologous HSCT indications are provided below.

1. Neuroblastoma.
   • For more information, see the sections on Treatment of High-Risk Neuroblastoma and Recurrent Neuroblastoma in Patients Initially Classified as High Risk in Neuroblastoma Treatment.
2. Brain tumors. Indications for young patients to reduce or eliminate cranial radiation therapy; indications for responsive tumors at relapse.
   • For more information, see the Treatment of Pediatric-Type Diffuse High-Grade Gliomas section in Childhood Astrocytomas, Other Gliomas, and Glioneuronal/Neuronal Tumors Treatment.
   • For more information, see the Treatment of Childhood CNS Atypical Teratoid/Rhabdoid Tumor section in Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment.
   • For more information, see the sections on Treatment of Childhood Medulloblastoma, Treatment of Childhood Pineoblastoma, and Treatment of Recurrent Childhood Medulloblastoma and Other CNS Embryonal Tumors in Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment.
3. Germ cell tumors (GCTs) (intracranial and extracranial).
   • For more information, see the Nonstandard Treatment Options for Recurrent Malignant GCTs in Children section in Childhood Extracranial Germ Cell Tumors Treatment.
   • For more information, see the Treatment of Recurrent Childhood CNS Germ Cell Tumors section in Childhood Central Nervous System Germ Cell Tumors Treatment.
4. Retinoblastoma.
   • For more information, see the sections on Treatment of CNS Disease, Treatment of Synchronous Trilateral Retinoblastoma, Treatment of Extracranial Metastatic Retinoblastoma, and Treatment of Progressive or Recurrent Extraocular Retinoblastoma in Retinoblastoma Treatment.
5. Hodgkin lymphoma.
   • For more information, see the Treatment of Primary Refractory or Recurrent Hodgkin Lymphoma in Children and Adolescents section in Childhood Hodgkin Lymphoma Treatment.
6. Non-Hodgkin lymphoma.
   • For more information, see the sections on Treatment options for recurrent or refractory Burkitt lymphoma, Treatment Options for Recurrent or Refractory Lymphoblastic Lymphoma, Treatment Options for Recurrent or Refractory Anaplastic Large Cell Lymphoma, Treatment options for lymphoproliferative disease associated with primary immunodeficiency, Treatment options for peripheral T-cell lymphoma, and Treatment options for cutaneous T-cell lymphoma in Childhood Non-Hodgkin Lymphoma Treatment.

For autologous transplants to result in cure of malignancies, the following must apply:

The tumor-specific activity and intensity of agents used for autologous regimens have been shown to be important in improving survival.

The contamination of the collected stem cell product by persistent tumor cells is a concern with autologous approaches. Although techniques have been developed to remove or purge tumor cells from products, studies to date have shown no benefit to tumor purging.[1]

References

1. Kreissman SG, Seeger RC, Matthay KK, et al.: Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol 14 (10): 999-1008, 2013. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of autologous hematopoietic stem cell transplant in treating pediatric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Pediatric Autologous Hematopoietic Stem Cell Transplant are:

• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Michael A. Pulsipher, MD (Huntsman Cancer Institute at University of Utah)

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PDQ® Pediatric Treatment Editorial Board. PDQ Pediatric Autologous Hematopoietic Stem Cell Transplant. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/childhood-cancers/hp-stem-cell-transplant/autologous. Accessed <MM/DD/YYYY>. [PMID: 35133767]

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Hodgkin lymphoma is a disease in which malignant (cancer) cells form in the lymph system.

Hodgkin lymphoma is a type of cancer that develops in the lymph system. The lymph system is part of the immune system. It helps protect the body from infection and disease.

The lymph system is made up of:

• Lymph: Colorless, watery fluid that travels through the lymph vessels and carries T and B lymphocytes. Lymphocytes are a type of white blood cell.
• Lymph vessels: A network of thin tubes that collect lymph from different parts of the body and return it to the bloodstream.
• Lymph nodes: Small, bean-shaped structures that filter lymph and store white blood cells that help fight infection and disease. Lymph nodes are found along a network of lymph vessels throughout the body. Groups of lymph nodes are found in the mediastinum (the area between the lungs), neck, underarm, abdomen, pelvis, and groin. Hodgkin lymphoma most commonly forms in the lymph nodes above the diaphragm and often in the lymph nodes in the mediastinum.
• Spleen: An organ that makes lymphocytes, stores red blood cells and lymphocytes, filters the blood, and destroys old blood cells. The spleen is on the left side of the abdomen near the stomach.
• Thymus: An organ in which T lymphocytes mature and multiply. The thymus is in the chest behind the breastbone.
• Bone marrow: The soft, spongy tissue in the center of certain bones, such as the hip bone and breastbone. White blood cells, red blood cells, and platelets are made in the bone marrow.
• Tonsils: Two small masses of lymph tissue at the back of the throat. There is one tonsil on each side of the throat. Hodgkin lymphoma rarely forms in the tonsils.

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Lymph tissue is also found in other parts of the body, such as the lining of the digestive tract, bronchus, and skin.

There are two general types of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of Hodgkin lymphoma in adults, including during pregnancy.

The two main types of Hodgkin lymphoma are classic and nodular lymphocyte-predominant.

Most Hodgkin lymphomas are the classic type. When a sample of lymph node tissue is looked at under a microscope, Hodgkin lymphoma cancer cells, called Reed-Sternberg cells, may be seen. The classic type is broken down into the following four subtypes:

• Nodular sclerosing Hodgkin lymphoma.
• Mixed cellularity Hodgkin lymphoma.
• Lymphocyte-depleted Hodgkin lymphoma.
• Lymphocyte-rich classic Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is rare and tends to grow slower than classic Hodgkin lymphoma. NLPHL often presents as a swollen lymph node in the neck, chest, armpit, or groin. Most people do not have any other signs or symptoms of cancer at diagnosis. Treatment is often different from classic Hodgkin lymphoma.

Being in early or late adulthood, being male, past Epstein-Barr infection, and a family history of Hodgkin lymphoma can increase the risk of Hodgkin lymphoma.

Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop Hodgkin lymphoma, and it can develop in people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk. Risk factors for Hodgkin lymphoma include:

• Age. Hodgkin lymphoma is most common in early adulthood (age 20–39 years) and in late adulthood (age 65 years and older).
• Being male. The risk of Hodgkin lymphoma is slightly higher in males than in females.
• Past Epstein-Barr virus infection. Having an infection with the Epstein-Barr virus in the teenage years or early childhood increases the risk of Hodgkin lymphoma.
• A family history of Hodgkin lymphoma. Having a parent, brother, or sister with Hodgkin lymphoma increases the risk of developing Hodgkin lymphoma.

Signs and symptoms of Hodgkin lymphoma include swollen lymph nodes, fever, drenching night sweats, weight loss, and fatigue.

These and other signs and symptoms may be caused by Hodgkin lymphoma or by other conditions. Check with your doctor if you have any of the following symptoms that do not go away:

• Painless, swollen lymph nodes in the neck, underarm, or groin.
• Fever for no known reason.
• Drenching night sweats.
• Weight loss for no known reason in the past 6 months.
• Pruritus (itchy skin), especially after bathing or drinking alcohol.
• Feeling very tired.

Tests that examine the lymph system and other parts of the body are used to help diagnose and stage Hodgkin lymphoma.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

• Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for:
  • The number of red blood cells, white blood cells, and platelets.
  • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
  • The portion of the sample made up of red blood cells.

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• Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
• LDH test: A procedure in which a blood sample is checked to measure the amount of lactic dehydrogenase (LDH). An increased amount of LDH in the blood may be a sign of tissue damage, lymphoma, or other diseases.
• Hepatitis B and hepatitis C test: A procedure in which a sample of blood is checked to measure the amounts of hepatitis B virus-specific antigens and/or antibodies and the amounts of hepatitis C virus-specific antibodies. These antigens or antibodies are called markers. Different markers or combinations of markers are used to determine whether a patient has a hepatitis B or C infection, has had a prior infection or vaccination, or is susceptible to infection. Knowing whether a patient has hepatitis B or C may help plan treatment.
• HIV test: A test to measure the level of HIV antibodies in a sample of blood. Antibodies are made by the body when it is invaded by a foreign substance. A high level of HIV antibodies may mean the body has been infected with HIV. Knowing whether a patient has HIV may help plan treatment.
• Sedimentation rate: A procedure in which a sample of blood is drawn and checked for the rate at which the red blood cells settle to the bottom of the test tube. The sedimentation rate is a measure of how much inflammation is in the body. A higher than normal sedimentation rate may be a sign of lymphoma or another condition. Also called erythrocyte sedimentation rate, sed rate, or ESR.
• PET-CT scan: A procedure that combines the pictures from a positron emission tomography (PET) scan and a computed tomography (CT) scan. The PET and CT scans are done at the same time on the same machine. The pictures from both scans are combined to make a more detailed picture than either test would make by itself. A PET-CT scan may be used to help diagnose disease, such as cancer, determine stage, plan treatment, or find out how well treatment is working. A PET-magnetic resonance imaging (MRI) scan may be done in place of a PET-CT scan and uses a lower dose of radiation.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the neck, chest, abdomen, pelvis, and lymph nodes, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. If a PET-CT scan is not available, a CT scan alone may be done.
  • PET scan (positron emission tomography scan): A PET scan is a procedure to find cancer cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Cancer cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
• Lymph node biopsy: The removal of all or part of a lymph node. A pathologist views the tissue under a microscope to look for cancer cells called Reed-Sternberg cells. Reed-Sternberg cells are common in classic Hodgkin lymphoma.
  

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  One of the following types of biopsies may be done:

  • Excisional biopsy: The removal of an entire lymph node.
  • Incisional biopsy: The removal of part of a lymph node.
  • Core biopsy: The removal of tissue from a lymph node using a wide needle.

  Other areas of the body, such as the liver, lung, bone, bone marrow, and brain, may also have a sample of tissue removed and checked by a pathologist for signs of cancer.

  The following test may be done on tissue that was removed:

  • Immunophenotyping: A laboratory test that uses antibodies to identify cancer cells based on the types of antigens or markers on the surface of the cells. This test is used to help diagnose specific types of lymphoma.

For pregnant women with Hodgkin lymphoma, imaging tests that protect the fetus from the harms of radiation are used. These include:

• MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI). In women who are pregnant, contrast dye is not used during the procedure.
• Ultrasound exam: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on:

• The patient’s signs and symptoms, including whether or not they have B symptoms (fever for no known reason, weight loss for no known reason, or drenching night sweats).
• The stage of the cancer (the size of the cancer tumors and whether the cancer has spread to the abdomen or more than one group of lymph nodes).
• The type of Hodgkin lymphoma.
• Blood test results.
• The patient’s age, sex, and general health.
• Whether the cancer is newly diagnosed, continues to grow during treatment, or has come back after treatment.

For Hodgkin lymphoma during pregnancy, treatment options also depend on:

• The wishes of the patient.
• The age of the fetus.

Hodgkin lymphoma can usually be cured if found and treated early.

After Hodgkin lymphoma has been diagnosed, tests are done to find out if cancer cells have spread within the lymph system or to other parts of the body.

The process used to find out if cancer has spread within the lymph system or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage to plan treatment. The results of the tests and procedures done to diagnose and stage Hodgkin lymphoma are used to help make decisions about treatment.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

• Tissue. The cancer spreads from where it began by growing into nearby areas.
• Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
• Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

The following stages are used for Hodgkin lymphoma:

Stage I

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Stage I Hodgkin lymphoma is divided into stages I and IE.

• In stage I, cancer is found in one of the following places in the lymph system:
  • One or more lymph nodes in a group of lymph nodes.
  • Waldeyer’s ring.
  • Thymus.
  • Spleen.
• In stage IE, cancer is found in one area outside the lymph system.

Stage II

Stage II Hodgkin lymphoma is divided into stages II and IIE.

• In stage II, cancer is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm.
  

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• In stage IIE, cancer has spread from a group of lymph nodes to a nearby area that is outside the lymph system. Cancer may have spread to other lymph node groups on the same side of the diaphragm.
  

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In stage II, the term bulky disease refers to a larger tumor mass. The size of the tumor mass that is referred to as bulky disease varies based on the type of lymphoma.

Stage III

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In stage III Hodgkin lymphoma, cancer is found:

• in groups of lymph nodes both above and below the diaphragm; or
• in lymph nodes above the diaphragm and in the spleen.

Stage IV

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In stage IV Hodgkin lymphoma, cancer:

• has spread throughout one or more organs outside the lymph system; or
• is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm and in one organ that is outside the lymph system and not near the affected lymph nodes; or
• is found in groups of lymph nodes both above and below the diaphragm and in any organ that is outside the lymph system; or
• is found in the liver, bone marrow, more than one place in the lung, or cerebrospinal fluid (CSF). The cancer has not spread directly into the liver, bone marrow, lung, or CSF from nearby lymph nodes.

Hodgkin lymphoma may be grouped for treatment as follows:

Early Favorable

Early favorable Hodgkin lymphoma is stage I or stage II, without risk factors that increase the chance that the cancer will come back after it is treated.

Early Unfavorable

Early unfavorable Hodgkin lymphoma is stage I or stage II with one or more of the following risk factors that increase the chance that the cancer will come back after it is treated:

• Having a tumor in the chest that is larger than 1/3 of the width of the chest or is at least 10 centimeters.
• Having cancer in an organ other than the lymph nodes.
• Having a high sedimentation rate (in a sample of blood, the red blood cells settle to the bottom of the test tube more quickly than normal).
• Having three or more lymph nodes with cancer.
• Having B symptoms (fever for no known reason, weight loss for no known reason, or drenching night sweats).

Advanced

Advanced Hodgkin lymphoma is stage III or stage IV. Advanced favorable Hodgkin lymphoma means that the patient has 0–3 of the risk factors below. Advanced unfavorable Hodgkin lymphoma means that the patient has 4 or more of the risk factors below. The more risk factors a patient has, the more likely it is that the cancer will come back after it is treated:

• Having a low blood albumin level (below 4).
• Having a low hemoglobin level (below 10.5).
• Being male.
• Being aged 45 years or older.
• Having stage IV disease.
• Having a high white blood cell count (15,000 or higher).
• Having a low lymphocyte count (below 600 or less than 8% of the white blood cell count).

Hodgkin lymphoma can recur (come back) after it has been treated.

The cancer may come back in the lymph system or in other parts of the body.

There are different types of treatment for patients with Hodgkin lymphoma.

Different types of treatment are available for patients with Hodgkin lymphoma. Some treatments are standard (currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

For pregnant women with Hodgkin lymphoma, treatment is carefully chosen to protect the fetus. Treatment decisions are based on the mother’s wishes, the stage of the Hodgkin lymphoma, and the trimester of the pregnancy. The treatment plan may change as the signs and symptoms, cancer, and pregnancy change. Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.

Patients with Hodgkin lymphoma should have their treatment planned by a team of health care providers with expertise in treating lymphomas.

Treatment will be overseen by a medical oncologist, a doctor who specializes in treating cancer. The medical oncologist may refer you to other health care providers who have experience and expertise in treating Hodgkin lymphoma and who specialize in certain areas of medicine. These may include the following specialists:

• Radiation oncologist.
• Rehabilitation specialist.
• Hematologist.
• Fertility specialist.
• Other oncology specialists.

Treatment for Hodgkin lymphoma may cause side effects.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Side effects from cancer treatment that begin after treatment and continue for months or years are called late effects. Treatment with chemotherapy and/or radiation therapy for Hodgkin lymphoma may increase the risk of second cancers and other health problems for many months or years after treatment. These late effects depend on the type of treatment and the patient’s age when treated, and may include:

• Second cancers.
  • Solid tumors, such as mesothelioma and cancer of the lung, breast, thyroid, bone, soft tissue, stomach, esophagus, colon, rectum, cervix, and head and neck.
  • Acute myelogenous leukemia.
• Infertility.
• Hypothyroidism (too little thyroid hormone in the blood).
• Heart disease, such as heart attack.
• Lung problems, such as trouble breathing.
• Avascular necrosis of bone (death of bone cells caused by lack of blood flow).
• Severe infection.
• Chronic fatigue.
• Cognitive impairment.

Regular follow-up by doctors who are experts in finding and treating late effects is important for the long-term health of patients treated for Hodgkin lymphoma.

The following types of treatment are used:

Chemotherapy

Chemotherapy is a cancer treatment that uses one or more drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Cancer treatment using more than one chemotherapy drug is called combination chemotherapy. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy).

When a pregnant woman is treated with chemotherapy for Hodgkin lymphoma, it isn’t possible to protect the fetus from being exposed to the chemotherapy. Some chemotherapy regimens may cause birth defects if given in the first trimester. Vinblastine is an anticancer drug that has not been linked with birth defects when given in the second or third trimester of pregnancy.

For more information, see Drugs Approved for Hodgkin Lymphoma.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Sometimes total-body irradiation is given before a stem cell transplant.

Proton beam radiation therapy is a type of high-energy, external radiation therapy that uses streams of protons (tiny particles with a positive charge) to kill tumor cells. This type of treatment can lower the amount of radiation damage to healthy tissue near a tumor such as the heart or breast.

External radiation therapy is used to treat Hodgkin lymphoma and may also be used as palliative therapy to relieve symptoms and improve quality of life.

For a pregnant woman with Hodgkin lymphoma, radiation therapy should be postponed until after delivery, if possible, to avoid any risk of radiation exposure during fetal development. If treatment is needed right away, the woman may decide to continue the pregnancy and receive radiation therapy. A lead shield is used to cover the pregnant woman’s abdomen to help protect the fetus from radiation as much as possible.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells.

• Monoclonal antibodies: Monoclonal antibodies are immune system proteins made in the laboratory to treat many diseases, including cancer. As a cancer treatment, these antibodies can attach to a specific target on cancer cells or other cells that may help cancer cells grow. The antibodies are able to then kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Brentuximab vedotin and rituximab are monoclonal antibodies used to treat Hodgkin lymphoma.

For more information, see Drugs Approved for Hodgkin Lymphoma.

Immunotherapy

Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer.

• PD-1 and PD-L1 inhibitor therapy: PD-1 is a protein on the surface of T cells that helps keep the body’s immune responses in check. PD-L1 is a protein found on some types of cancer cells. When PD-1 attaches to PD-L1, it stops the T cell from killing the cancer cell. PD-1 and PD-L1 inhibitors keep PD-1 and PD-L1 proteins from attaching to each other. This allows the T cells to kill cancer cells. Pembrolizumab and nivolumab are types of PD-1 inhibitors used to treat Hodgkin lymphoma that has recurred (come back).

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For more information, see Drugs Approved for Hodgkin Lymphoma.

Chemotherapy with stem cell transplant

High doses of chemotherapy are given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy and radiation therapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

For patients with nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL), treatment options also include:

Watchful waiting

Watchful waiting is closely monitoring a patient’s condition without giving any treatment until signs or symptoms appear or change.

Active surveillance

Active surveillance is a treatment plan that involves closely watching a patient’s condition but not giving any treatment unless there are changes in test results that show the condition is getting worse. During active surveillance, certain exams and tests are done on a regular schedule.

For pregnant patients with Hodgkin lymphoma, treatment options also include:

Watchful waiting

Watchful waiting is closely monitoring a patient’s without giving any treatment unless signs or symptoms appear or change. Labor may be induced when the fetus is 32 to 36 weeks so that the mother can begin treatment.

Steroid therapy

Steroids are hormones made naturally in the body by the adrenal glands and by reproductive organs. Some types of steroids are made in a laboratory. Certain steroid drugs have been found to help chemotherapy work better and help stop the growth of cancer cells. When an early delivery is likely, steroids can also help the lungs of the fetus develop faster than normal. This gives babies who are born early a better chance of survival.

For more information, see Drugs Approved for Hodgkin Lymphoma.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI website.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up care may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of early favorable classic Hodgkin lymphoma in adults may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of early unfavorable classic Hodgkin lymphoma in adults may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of advanced classic Hodgkin lymphoma in adults may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of recurrent classic Hodgkin lymphoma in adults may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of NLPHL in adults may include:

For information about the treatments listed below, see the Treatment Option Overview section.

Hodgkin Lymphoma During the First Trimester of Pregnancy

When Hodgkin lymphoma is diagnosed in the first trimester of pregnancy, it does not necessarily mean that the woman will be advised to end the pregnancy. Each woman’s treatment will depend on the stage of the lymphoma, how fast it is growing, and her wishes. Treatment of Hodgkin lymphoma during the first trimester of pregnancy may include:

• Watchful waiting when the cancer is above the diaphragm and is slow-growing. Labor may be induced early so the mother can begin treatment.
• Radiation therapy when the cancer is above the diaphragm. A lead shield is used to protect the fetus from the radiation as much as possible.
• Chemotherapy using one or more drugs.

Hodgkin Lymphoma During the Second or Third Trimester of Pregnancy

When Hodgkin lymphoma is diagnosed in the second half of pregnancy, most women can delay treatment until after delivery. Treatment of Hodgkin lymphoma during the second or third trimester of pregnancy may include:

• Watchful waiting, with plans to induce labor when the fetus is 32 to 36 weeks.
• Radiation therapy to relieve breathing problems caused by a large tumor in the chest.
• Combination chemotherapy using one or more drugs.
• Steroid therapy.

For more information from the National Cancer Institute about Hodgkin lymphoma, visit:

For general cancer information and other resources from the National Cancer Institute, visit:

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of adult Hodgkin lymphoma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/patient/adult-hodgkin-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389245]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

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Incidence and Mortality

Estimated new cases and deaths from HL in the United States in 2025:[1]

• New cases: 8,720.
• Deaths: 1,150.

Up to 90% of all newly diagnosed patients with HL can be cured with combination chemotherapy and/or radiation therapy.[2]

Anatomy

Enlarge

HL most frequently presents in lymph node groups above the diaphragm and/or in mediastinal lymph nodes. Involvement of Waldeyer’s ring or tonsillar lymph glands is rarely seen.

Risk Factors

Risk factors for HL include:

• Being in early adulthood (aged 20–39 years) (most often) or late adulthood (aged 65 years and older) (less often).
• Being male.
• Having a previous infection with the Epstein-Barr virus in the teenage years or early childhood.
• Having a first-degree relative with HL.

Clinical Features

These and other signs and symptoms may be caused by HL or by other conditions:

• Painless, swollen lymph nodes in the neck, axilla, or inguinal area.
• Fever defined as 38ºC or higher.
• Drenching and recurrent night sweats.
• Weight loss of 10% or more of baseline weight in the previous 6 months.
• Pruritus, especially after bathing or after ingesting alcohol.
• Fatigue.

Treatment of HL should relieve these symptoms within days. For more information, see Hot Flashes and Night Sweats, Pruritus, and Fatigue.

Diagnostic Evaluation

Diagnostic evaluation of patients with lymphoma may include:

1. Biopsy (preferably excisional), with interpretation by a qualified pathologist.
2. History, with special attention given to the presence and duration of fever, night sweats, and unexplained weight loss of 10% or more of body weight in the previous 6 months.
3. Physical examination.
4. Laboratory tests.
   • Complete blood cell count and platelet count.
   • Erythrocyte sedimentation rate.
   • Chemistry panel (electrolytes, blood urea nitrogen, creatinine, calcium, aspartate transaminase, alanine aminotransferase, bilirubin, and alkaline phosphatase) plus lactate dehydrogenase, uric acid, and phosphorus.
5. Radiographic examination.
   • Computed tomography (CT) of the neck, chest, abdomen, and pelvis; or metabolic imaging (fluorine F 18-fludeoxyglucose positron emission tomography [PET]) with PET-CT. PET-magnetic resonance imaging scans may be equivalent to PET-CT in obtaining staging information at 25% of the radiation dose.[3]
6. HIV testing.
7. Hepatitis B and hepatitis C serology.

All stages of HL can be subclassified into A and B categories: B for those with defined general symptoms (described below) and A for those without B symptoms. The B designation is given to patients with any of the following symptoms:

• Unexplained weight loss (more than 10% of body weight in the 6 months before diagnosis).
• Unexplained fever with temperatures above 38°C.
• Drenching and recurrent night sweats.

The most significant B symptoms are fevers and weight loss. Night sweats alone do not confer an adverse prognosis.

Prognostic Factors

The prognosis for a given patient depends on several factors. The most important factors include:[1,4,5]

• Presence or absence of systemic B symptoms.
• Stage of disease.
• Presence of large masses.
• Quality and suitability of the treatment administered.

Other important factors are:[1,4,5]

• Age.
• Sex.
• Erythrocyte sedimentation rate.
• Hematocrit.
• Extent of abdominal involvement.
• Absolute number of nodal sites of involvement.

The best predictor of treatment failure is a PET-CT scan obtained after two cycles of chemotherapy (PET2 scan).[6,7] For limited-stage disease, there are frequent false-positive tests because the relapse risk is low (low-positive predictive value). For advanced-stage disease, up to 15% of patients have a relapse despite a negative PET2 scan (lowering the negative predictive value).[6,7] Combining biomarkers with PET-CT scanning responses or calculating metabolic tumor volume with PET-CT scanning are methods under evaluation to improve prognostic predictions.[6,8–11]

Follow-Up

Recommendations for posttreatment follow-up are not evidence based, but a variety of opinions have been published for high-risk patients who present with advanced-stage disease and for patients who achieve less-than-complete remission by PET-CT scans at the end of therapy.[12–15] For patients at high risk of relapse, conventional CT scans are used to avoid increased false-positive test results and increased radiation exposure of serial PET-CT scans.[16]

For patients with negative findings from a PET-CT scan at the end of therapy, routine scans are not advised because of the very low risk of recurrence.[17] Opportunistic scanning is applied when patients present with suspicious symptoms, physical findings, or laboratory test results. The 5-year risk of relapse from diagnosis is 5.6% for patients remaining event-free for 2 years after induction therapy.[18]

Among 6,840 patients enrolled in German Hodgkin Study Group (GHSG) trials, with a median follow-up of 10.3 years, 141 patients had a relapse after 5 years, compared with 466 patients who had a relapse within 5 years. Treatment-related adverse effects and late relapses may occur beyond 20 years of follow-up.[19]

Adverse Long-Term Effects of Therapy

Patients who complete therapy for HL are at risk of developing long-term side effects, ranging from direct damage to organ function or the immune system to second malignancies. For the first 15 years after treatment, HL is the main cause of death. By 15 to 20 years after therapy, the cumulative mortality from a second malignancy, cardiovascular disease, or pulmonary fibrosis exceeds the cumulative mortality from HL.[20–23] This risk of developing a second malignancy is even higher for individuals with a family history of cancer.[24]

Compared with the general population, long-term survivors of HL have a significantly lower life expectancy.[25] A multicenter cohort study of 4,919 patients treated between 1965 and 2000 and before age 51 years had a median follow-up of 20.2 years. Patients with HL had an absolute excess mortality (AEM) of 123 excess deaths per 10,000 person-years. This risk (standardized mortality ratio, 5.2; 95% confidence interval [CI], 4.2–6.5; AEM, 619) was maintained for 40-year survivors.[25] For example, at age 54 years, the cumulative mortality of 20.0% for HL survivors was commensurate with that of a 71-year-old person from the general population. While mortality from HL dropped precipitously from 1965 to 2000, solid tumor mortality did not change over that time.[25]

Second malignancies

Recommendations for screening for secondary malignancies or follow-up of long-term survivors are consensus based and not derived from randomized trials.[26]

Solid tumors

An increase in second solid tumors has also been observed, especially mesothelioma and cancers of the lung, breast, thyroid, bone/soft tissue, stomach, esophagus, colon and rectum, uterine cervix, and head and neck.[27–34] These tumors occur primarily after radiation therapy or with combined-modality treatment (especially when involving mechlorethamine or procarbazine), and approximately 75% occur within radiation ports. The risk of developing a second solid tumor (cumulative incidence of a second cancer) increases with time after treatment.

• At 15-years of follow-up, the risk is approximately 13%.[30]
• At 20-years of follow-up, the risk is approximately 17%.[35]
• At 25-years of follow-up, the risk is approximately 22%.[27,36]
• At 40-years of follow-up, the risk is approximately 48%.[37]

In a cohort of 18,862 5-year survivors from 13 population-based registries, the younger patients had elevated risks for breast, colon, and rectal cancers for 10 to 25 years before the ages when routine screening is recommended in the general population.[29] Even with involved-field doses of 15 Gy to 25 Gy, sarcomas, breast cancers, and thyroid cancers occurred with similar incidence in young patients, compared with those receiving higher-dose radiation.[35]

Lung cancer and breast cancer are among the most-common second solid tumors that develop after therapy for HL.

• Lung cancer. Lung cancer is seen with increased frequency, even after chemotherapy alone, and the risk of this cancer increases with cigarette smoking.[38–41] In a retrospective Surveillance, Epidemiology, and End Results (SEER) Program analysis, stage-specific survival was decreased by 30% to 60% in HL survivors, compared with patients with de novo non-small cell lung cancer.[42]
• Breast cancer. Breast cancer is seen with increased frequency after radiation therapy or combined-modality therapy.[27,28,43–45] The risk appears greatest for females treated with radiation before age 30 years, especially for girls close to menarche.[46] The incidence of breast cancer increases substantially after 15 years of posttherapy follow-up.[27,47,48] In a cohort of 1,964 female 5-year HL survivors treated between 1975 and 2008, doxorubicin also increased breast cancer risk independent of age at first treatment or prior chest radiation therapy.[49] Survivors who received more than 200 mg/m2 of doxorubicin had a 1.5-fold increased risk (95% CI, 1.08–2.10) versus survivors who did not receive doxorubicin.

  In two case-control studies of 479 patients who developed breast cancer after therapy for HL, cumulative absolute risks for developing breast cancer were calculated as a function of radiation therapy dose and the use of chemotherapy.[50,51] With a 30-year to 40-year follow-up, cumulative absolute risks of breast cancer with exposure to radiation range from 8.5% to 39.6%, depending on age at diagnosis. These cohort studies show a continued increase in cumulative excess risk of breast cancer beyond 20 years of follow-up.[50,51]

  In a nested case-control study and subsequent cohort study, patients who received both chemotherapy and radiation therapy had a statistically significant lower risk of developing breast cancer than did those treated with radiation therapy alone.[43,52] Reaching early menopause with fewer than 10 years of intact ovarian function appeared to account for the reduction in risk among patients who received combined-modality therapy.[52] Reduction of radiation volume also decreased the risk of breast cancer after HL.[52]

Late effects of autologous stem cell transplant for failure of induction chemotherapy include second malignancies, hypothyroidism, hypogonadism, herpes zoster, depression, and cardiac disease.[53]

Hematologic cancers

• Acute myelogenous leukemia (AML). Acute nonlymphocytic leukemia may occur in patients treated with combined-modality therapy or with combination chemotherapy alone, especially with increased exposure to alkylating agents.[30,54]
  • At 10 years after therapy with regimens containing MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), the risk of AML is approximately 3%, with the peak incidence occurring 5 to 9 years after therapy.[30,54] The risk of acute leukemia at 10 years after therapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) appears to be less than 1%.[55]
  • A population-based study of more than 35,000 survivors during a 30-year time span identified 217 patients who developed AML. The excess absolute risk (EAR) was significantly higher for older patients (>35 years at diagnosis) than for younger survivors (EAR, 9.9 vs. 4.2 per 10,000 patient-years, P < .001).[56]

Other adverse long-term effects

Treatment of HL also affects the endocrine, cardiac, pulmonary, skeletal, and immune systems. Chronic fatigue can be a debilitating symptom for some long-term survivors.[57] A retrospective survey of 20,007 patients with early- and advanced-stage classical HL treated between 2000 and 2016 (i.e., the era in which ABVD became the preferred frontline chemotherapy regimen) showed 1,321 deaths not attributable to lymphoma (39% of total deaths). Heart disease (estimated EAR: 6.6 per 10,000 patient-years, standardized mortality ratio, 1.7 for early-stage disease and 15.1 per 10,000 patient-years, standardized mortality ratio, 2.1 for advanced-stage disease) and infection (estimated EAR: 3.1 per 10,000 patient-years, standardized mortality ratio, 2.2 for early-stage disease and 10.6 per 10,000 patient-years, standardized mortality ratio, 3.9 for advanced-stage disease) were the leading causes of death, especially in patients older than 60 years.[58]

Infertility. A toxic effect that is primarily related to chemotherapy is infertility, usually after regimens containing MOPP or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).[59–61] After six to eight cycles of BEACOPP, most men had testosterone levels within reference range; however, 82% of women younger than 30 years recovered menses (mostly within 12 months), but only 45% of women older than 30 years recovered menses.[62] ABVD appears to spare long-term testicular and ovarian function.[60,63,64] Increasing age and alkylator-based regimens are the two major factors increasing the risk of premature ovarian insufficiency.[62,65,66] A prospective evaluation of gonadal function embedded in the randomized Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) study for patients with newly diagnosed advanced-stage HL found good recovery of anti-Müllerian hormone concentration and reduction in follicle-stimulating hormone after ABVD or AVD (doxorubicin, vinblastine, dacarbazine), but less recovery after BEACOPP and for women older than 35 years.[65] A PET scan-adapted treatment regimen to reduce the use of BEACOPP also resulted in less infertility and gonadal dysfunction.[67] While cryopreservation of oocytes or sperm remains the first choice for preservation of fertility, luteinizing hormone-releasing hormone agonists can be tried in this setting, although efficacy for patients with HL has not been confirmed as has been confirmed for patients with breast cancer.[68] A national Danish registry of 793 HL survivors showed that patients who did not have a relapse had similar parenthood rates to the general population, but assistive reproduction methods were required more often for HL survivors (male, 21.6% vs. 6.3%; female, 13.6% vs. 5.5%; P ≤ .001 for both comparisons).[69]

Hypothyroidism. Hypothyroidism is a late complication primarily related to radiation therapy.[70–72] Long-term survivors who receive radiation therapy to the neck are followed up with annual thyroid-stimulating hormone testing.

Cardiac disease. A late complication primarily related to radiation therapy is cardiac disease, the risk of which may persist for over 30 years after the first treatment.[70,73–81] The EAR of fatal cardiovascular disease ranges from 11.9 to 48.9 per 10,000 patient-years and is mostly attributable to fatal myocardial infarction (MI).[73–75,77] A retrospective survey of over 6,000 patients with HL treated in trials between 1964 and 2004 found that cardiac exposure to radiation and use of doxorubicin were significant predictors of ischemic heart disease, congestive heart failure, arrhythmias, and vascular disease.[79] In a cohort of 7,033 patients with HL, MI mortality risk persisted for 25 years after first treatment with supradiaphragmatic radiation therapy (dependent on the details of treatment planning), doxorubicin, or vincristine.[77,78] A nested case-control study of 2,617 5-year survivors of HL diagnosed before age 51 years and treated between 1965 and 1995 found that the 25-year risk of moderate to severe heart failure increased for patients receiving anthracyclines. The risk ranged from 11.2% for patients exposed to 0 Gy to 15 Gy radiation up to 32.9% for patients exposed to radiation equal or greater than 21 Gy.[82] The use of subcranial blocking did not reduce the incidence of fatal MI in a retrospective review, perhaps because of the exposure of the proximal coronary arteries to radiation.[74] Compared with a general matched population, HL patients treated with mediastinal radiation were at increased risk of complications, especially during cardiac surgery.[83] Risk prediction models rely on the dose of mediastinal radiation, smoking history, male sex, and anthracycline exposure to define the patients at highest risk.[81] These risk prediction models found that mediastinal radiation therapy combined with doxorubicin exposure conferred the highest risk, followed by mediastinal radiation therapy alone.[81]

In the U.K. RAPID trial, performed between 2003 and 2010, 183 patients with early-stage HL were PET-negative but still received involved-field radiation therapy (IFRT) (20 Gy) after receiving ABVD.[80] The average predicted 30-year cardiovascular mortality was 5.02%, which included 3.52% expected in the general population, 0.94% EAR from the doxorubicin, and 0.56% from the IFRT. Since 2010, radiation therapy techniques have advanced by using smaller target volumes, lower-dose IFRT (20 Gy), deep inspiration breath holding, intensity-modulated radiation therapy, and proton beam therapy.[80] These techniques will need further evaluation to better assess cardiovascular risks from radiation therapy.

Pulmonary impairment. Impairment of pulmonary function may occur as a result of mantle-field radiation therapy; this impairment is not usually clinically evident, and recovery in pulmonary testing often occurs after 2 to 3 years.[84] Pulmonary toxic effects from bleomycin as used in ABVD are seen in patients older than 40 years.[85]

Bone necrosis. Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.[86]

Bacterial sepsis. Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL;[87] it is much more common in children than in adults.

Fatigue. Fatigue is a commonly reported symptom among patients who have completed chemotherapy and radiation therapy. In a case-control study design, most HL survivors reported significant fatigue lasting for more than 6 months after therapy, compared with age-matched controls. Quality-of-life questionnaires given to 5,306 patients on GHSG trials showed that 20% of patients complained of severe fatigue 5 years after therapy, and those patients had significantly increased problems with employment and financial stability.[88–90] For more information, see Fatigue.

Neurocognitive impairment. After a median of 23 years from diagnosis, 1,760 HL survivors treated in childhood were compared with 3,180 siblings. Significantly higher rates of memory loss (8.1% vs. 5.7%; P < .05), anxiety (7.0% vs. 5.4%; P < .05), unemployment (9.6% vs. 4.4%; P < .05), depression (9.1% vs. 7.0%; P < .05), and impaired physical quality of life (11.2% vs. 3.0%; P < .05) were reported.[91] Lower risks were associated with survivors who adhered to exercise guidelines and did not smoke, but the design of this study did not allow a cause-and-effect conclusion.

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60. van der Kaaij MA, Heutte N, Le Stang N, et al.: Gonadal function in males after chemotherapy for early-stage Hodgkin’s lymphoma treated in four subsequent trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 25 (19): 2825-32, 2007. [PUBMED Abstract]
61. Scholz M, Engert A, Franklin J, et al.: Impact of first- and second-line treatment for Hodgkin’s lymphoma on the incidence of AML/MDS and NHL–experience of the German Hodgkin’s Lymphoma Study Group analyzed by a parametric model of carcinogenesis. Ann Oncol 22 (3): 681-8, 2011. [PUBMED Abstract]
62. Behringer K, Mueller H, Goergen H, et al.: Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials. J Clin Oncol 31 (2): 231-9, 2013. [PUBMED Abstract]
63. Viviani S, Santoro A, Ragni G, et al.: Pre- and post-treatment testicular dysfunction in Hodgkin’s disease (HD). [Abstract] Proceedings of the American Society of Clinical Oncology 7: A-877, 227, 1988.
64. van der Kaaij MA, Heutte N, Meijnders P, et al.: Premature ovarian failure and fertility in long-term survivors of Hodgkin’s lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d’Etude des Lymphomes de l’Adulte Cohort Study. J Clin Oncol 30 (3): 291-9, 2012. [PUBMED Abstract]
65. Anderson RA, Remedios R, Kirkwood AA, et al.: Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin’s lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial. Lancet Oncol 19 (10): 1328-1337, 2018. [PUBMED Abstract]
66. Weibull CE, Johansson ALV, Eloranta S, et al.: Contemporarily Treated Patients With Hodgkin Lymphoma Have Childbearing Potential in Line With Matched Comparators. J Clin Oncol 36 (26): 2718-2725, 2018. [PUBMED Abstract]
67. Demeestere I, Racape J, Dechene J, et al.: Gonadal Function Recovery in Patients With Advanced Hodgkin Lymphoma Treated With a PET-Adapted Regimen: Prospective Analysis of a Randomized Phase III Trial (AHL2011). J Clin Oncol 39 (29): 3251-3260, 2021. [PUBMED Abstract]
68. Lambertini M, Demeestere I: Another step towards improving oncofertility counselling of young women with Hodgkin’s lymphoma. Lancet Oncol 19 (10): 1264-1266, 2018. [PUBMED Abstract]
69. Øvlisen AK, Jakobsen LH, Eloranta S, et al.: Parenthood Rates and Use of Assisted Reproductive Techniques in Younger Hodgkin Lymphoma Survivors: A Danish Population-Based Study. J Clin Oncol 39 (31): 3463-3472, 2021. [PUBMED Abstract]
70. Tarbell NJ, Thompson L, Mauch P: Thoracic irradiation in Hodgkin’s disease: disease control and long-term complications. Int J Radiat Oncol Biol Phys 18 (2): 275-81, 1990. [PUBMED Abstract]
71. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin’s disease. N Engl J Med 325 (9): 599-605, 1991. [PUBMED Abstract]
72. Cella L, Conson M, Caterino M, et al.: Thyroid V30 predicts radiation-induced hypothyroidism in patients treated with sequential chemo-radiotherapy for Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 82 (5): 1802-8, 2012. [PUBMED Abstract]
73. Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, et al.: Ischemic heart disease after mantlefield irradiation for Hodgkin’s disease in long-term follow-up. Radiother Oncol 51 (1): 35-42, 1999. [PUBMED Abstract]
74. Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA 270 (16): 1949-55, 1993. [PUBMED Abstract]
75. Heidenreich PA, Schnittger I, Strauss HW, et al.: Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol 25 (1): 43-9, 2007. [PUBMED Abstract]
76. Dabaja B, Cox JD, Buchholz TA: Radiation therapy can still be used safely in combined modality approaches in patients with Hodgkin’s lymphoma. J Clin Oncol 25 (1): 3-5, 2007. [PUBMED Abstract]
77. Swerdlow AJ, Higgins CD, Smith P, et al.: Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst 99 (3): 206-14, 2007. [PUBMED Abstract]
78. van Nimwegen FA, Schaapveld M, Cutter DJ, et al.: Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma. J Clin Oncol 34 (3): 235-43, 2016. [PUBMED Abstract]
79. Maraldo MV, Giusti F, Vogelius IR, et al.: Cardiovascular disease after treatment for Hodgkin’s lymphoma: an analysis of nine collaborative EORTC-LYSA trials. Lancet Haematol 2 (11): e492-502, 2015. [PUBMED Abstract]
80. Cutter DJ, Ramroth J, Diez P, et al.: Predicted Risks of Cardiovascular Disease Following Chemotherapy and Radiotherapy in the UK NCRI RAPID Trial of Positron Emission Tomography-Directed Therapy for Early-Stage Hodgkin Lymphoma. J Clin Oncol 39 (32): 3591-3601, 2021. [PUBMED Abstract]
81. de Vries S, Haaksma ML, Jóźwiak K, et al.: Development and Validation of Risk Prediction Models for Coronary Heart Disease and Heart Failure After Treatment for Hodgkin Lymphoma. J Clin Oncol 41 (1): 86-95, 2023. [PUBMED Abstract]
82. van Nimwegen FA, Ntentas G, Darby SC, et al.: Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines. Blood 129 (16): 2257-2265, 2017. [PUBMED Abstract]
83. Galper SL, Yu JB, Mauch PM, et al.: Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 117 (2): 412-8, 2011. [PUBMED Abstract]
84. Horning SJ, Adhikari A, Rizk N, et al.: Effect of treatment for Hodgkin’s disease on pulmonary function: results of a prospective study. J Clin Oncol 12 (2): 297-305, 1994. [PUBMED Abstract]
85. Martin WG, Ristow KM, Habermann TM, et al.: Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin’s lymphoma. J Clin Oncol 23 (30): 7614-20, 2005. [PUBMED Abstract]
86. Prosnitz LR, Lawson JP, Friedlaender GE, et al.: Avascular necrosis of bone in Hodgkin’s disease patients treated with combined modality therapy. Cancer 47 (12): 2793-7, 1981. [PUBMED Abstract]
87. Schimpff SC, O’Connell MJ, Greene WH, et al.: Infections in 92 splenectomized patients with Hodgkin’s disease. A clinical review. Am J Med 59 (5): 695-701, 1975. [PUBMED Abstract]
88. Behringer K, Goergen H, Müller H, et al.: Cancer-Related Fatigue in Patients With and Survivors of Hodgkin Lymphoma: The Impact on Treatment Outcome and Social Reintegration. J Clin Oncol 34 (36): 4329-4337, 2016. [PUBMED Abstract]
89. Loge JH, Abrahamsen AF, Ekeberg O, et al.: Hodgkin’s disease survivors more fatigued than the general population. J Clin Oncol 17 (1): 253-61, 1999. [PUBMED Abstract]
90. Kreissl S, Mueller H, Goergen H, et al.: Cancer-related fatigue in patients with and survivors of Hodgkin’s lymphoma: a longitudinal study of the German Hodgkin Study Group. Lancet Oncol 17 (10): 1453-1462, 2016. [PUBMED Abstract]
91. Williams AM, Mirzaei Salehabadi S, Xing M, et al.: Modifiable risk factors for neurocognitive and psychosocial problems after Hodgkin lymphoma. Blood 139 (20): 3073-3086, 2022. [PUBMED Abstract]

Pathologists currently use the World Health Organization (WHO) modification of the Revised European-American Lymphoma (REAL) classification for the histological classification of Hodgkin lymphoma (HL).[1,2]

WHO Modification of the REAL Classification

• Classic HL.
  • Nodular sclerosis HL.
  • Mixed-cellularity HL.
  • Lymphocyte-depleted HL. Among 10,019 patients who underwent central expert pathology review for the German Hodgkin Study Group, 84 patients (<1%) were identified as having lymphocyte-depleted classic HL.[3] These patients presented more frequently with advanced-stage HL and B symptoms.
  • Lymphocyte-rich classic HL.
• Nodular lymphocyte–predominant HL (NLPHL). NLPHL is a clinicopathological entity of B-cell origin that is distinct from classic HL.[4,5]

  The typical immunophenotype for classic HL is CD15+, CD20-, CD30+, CD45-, while the profile for lymphocyte-predominant disease is CD15-, CD20+, CD30-, CD45+.

References

1. Lukes RJ, Craver LF, Hall TC, et al.: Report of the Nomenclature Committee. Cancer Res 26 (1): 1311, 1966.
2. Harris NL: Hodgkin’s lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999. [PUBMED Abstract]
3. Klimm B, Franklin J, Stein H, et al.: Lymphocyte-depleted classical Hodgkin’s lymphoma: a comprehensive analysis from the German Hodgkin study group. J Clin Oncol 29 (29): 3914-20, 2011. [PUBMED Abstract]
4. Eichenauer DA, Plütschow A, Fuchs M, et al.: Long-Term Follow-Up of Patients With Nodular Lymphocyte-Predominant Hodgkin Lymphoma Treated in the HD7 to HD15 Trials: A Report From the German Hodgkin Study Group. J Clin Oncol 38 (7): 698-705, 2020. [PUBMED Abstract]
5. Bartlett NL: Treatment of Nodular Lymphocyte Hodgkin Lymphoma: The Goldilocks Principle. J Clin Oncol 38 (7): 662-668, 2020. [PUBMED Abstract]

Clinical staging for patients with Hodgkin lymphoma (HL) includes:

Staging laparotomy is no longer recommended and should be considered only when the results will allow substantially less treatment. Staging laparotomy should not be done in patients who require chemotherapy. If the laparotomy is required for treatment decisions, the risks of potential morbidity should be considered.[3–6]

Bone marrow involvement occurs in 5% of patients and is more prevalent in the context of constitutional B symptoms and anemia, leukopenia, or thrombocytopenia. In a retrospective review and meta-analysis of 955 patients in nine studies, fewer than 2% of patients with positive bone marrow biopsy results had only stage I or stage II disease on PET-CT scans.[7] Omission of the bone marrow biopsy for PET-CT–designated early-stage patients did not change treatment selection.[7] In addition, focal skeletal bone lesions on PET-CT predicted bone marrow involvement with a 96.9% (95% confidence interval [CI], 93.0%–99.08%) sensitivity and 99.7% (95% CI, 98.9%–100%) specificity.[7] For these reasons, PET-CT has replaced bone marrow biopsy in the clinical staging of newly diagnosed HL.

Massive mediastinal disease has been defined by the Cotswolds meeting as a thoracic ratio of maximum transverse mass diameter of 33% or more of the internal transverse thoracic diameter measured at the T5/6 intervertebral disc level on chest radiography.[1] Some investigators have designated a lymph node mass measuring 10 cm or more in greatest dimension as massive disease.[8] Other investigators use a measurement of the maximum width of the mediastinal mass divided by the maximum intrathoracic diameter.[9]

Staging Subclassification System

Lugano Classification

The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma.[10] The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference,[11] with some modifications 18 years later from the Cotswolds meeting.[1]

Table 1. Lugano Classification for Hodgkin and Non-Hodgkin Lymphomaa

Stage	Stage Description	Illustration
CSF = cerebrospinal fluid; CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.
aHodgkin and Non-Hodgkin Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 937–58.
bStage II bulky may be considered either early or advanced stage based on lymphoma histology and prognostic factors.
cThe definition of disease bulk varies according to lymphoma histology. In the Lugano classification, bulk ln Hodgkin lymphoma is defined as a mass greater than one-third of the thoracic diameter on CT of the chest or a mass >10 cm. For NHL, the recommended definitions of bulk vary by lymphoma histology. In follicular lymphoma, 6 cm has been suggested based on the Follicular Lymphoma International Prognostic Index-2 and its validation. In DLBCL, cutoffs ranging from 5 cm to 10 cm have been used, although 10 cm is recommended.
Limited stage
I	Involvement of a single lymphatic site (i.e., nodal region, Waldeyer’s ring, thymus, or spleen).	Enlarge
IE	Single extralymphatic site in the absence of nodal involvement (rare in Hodgkin lymphoma).
II	Involvement of two or more lymph node regions on the same side of the diaphragm.	Enlarge
IIE	Contiguous extralymphatic extension from a nodal site with or without involvement of other lymph node regions on the same side of the diaphragm.	Enlarge
II bulkyb	Stage II with disease bulk.c
Advanced stage
III	Involvement of lymph node regions on both sides of the diaphragm; nodes above the diaphragm with spleen involvement.	Enlarge
IV	Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; or noncontiguous extralymphatic organ involvement in conjunction with nodal stage II disease; or any extralymphatic organ involvement in nodal stage III disease. Stage IV includes any involvement of the CSF, bone marrow, liver, or multiple lung lesions (other than by direct extension in stage IIE disease).	Enlarge
Note: Hodgkin lymphoma uses A or B designation with stage group. A/B is no longer used in NHL.

The E designation is used when well-localized extranodal lymphoid malignancies arise in or extend to tissues beyond, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathological proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Table 2. Notations for Identifying Sites

N = nodes	H = liver	L = lung	M = bone marrow
S = spleen	P = pleura	O = bone	D = skin

Prognostic Groups

Many investigators and many new clinical trials employ a clinical staging system that divides patients into three major groups that are also useful for the clinician:[12]

• Early favorable.
• Early unfavorable.
• Advanced.

The group assignment depends on:

• Whether the patient has early or advanced disease.
• The type and number of adverse prognostic factors present.

Early-stage adverse prognostic factors:

• Large mediastinal mass (>33% of the thoracic width on chest x-ray, ≥10 cm on CT scan).
• Extranodal involvement.
• Elevated erythrocyte sedimentation rate (>30 mm/h for B stage [symptoms], >50 mm/h for A stage [symptoms]).
• Involvement of three or more lymph node areas.
• Presence of B symptoms.

Early favorable group: Clinical stage I or II without any of the adverse prognostic factors listed above.

Early unfavorable group: Clinical stage I or II with one or more of the adverse prognostic factors listed above.

Advanced-stage adverse prognostic factors:

For patients with advanced-stage HL, the International Prognostic Factors Project on Advanced Hodgkin’s Disease developed the International Prognostic Index with a score that is based on the following seven adverse prognostic factors:[13]

• Albumin level lower than 40 g/L.
• Hemoglobin level lower than 105 g/L.
• Male sex.
• Age 45 years or older.
• Stage IV disease.
• White blood cell (WBC) count of 15 × 109/L or higher.
• Absolute lymphocytic count lower than 0.6 × 109/L or lymphocyte count higher than 8% of the total WBC count.

Advanced group: Clinical stage III or IV with up to three of the adverse risk factors listed above. Patients with advanced disease have a 60% to 80% rate of freedom from progression of disease at 5 years from treatment with first-line chemotherapy.[13][Level of evidence C2] An updated clinical prediction model uses continuous variables listed for the International Prognostic Index above, with an online calculator available.[14]

References

1. Lister TA, Crowther D, Sutcliffe SB, et al.: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7 (11): 1630-6, 1989. [PUBMED Abstract]
2. Barrington SF, Kirkwood AA, Franceschetto A, et al.: PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study. Blood 127 (12): 1531-8, 2016. [PUBMED Abstract]
3. Urba WJ, Longo DL: Hodgkin’s disease. N Engl J Med 326 (10): 678-87, 1992. [PUBMED Abstract]
4. Sombeck MD, Mendenhall NP, Kaude JV, et al.: Correlation of lymphangiography, computed tomography, and laparotomy in the staging of Hodgkin’s disease. Int J Radiat Oncol Biol Phys 25 (3): 425-9, 1993. [PUBMED Abstract]
5. Mauch P, Larson D, Osteen R, et al.: Prognostic factors for positive surgical staging in patients with Hodgkin’s disease. J Clin Oncol 8 (2): 257-65, 1990. [PUBMED Abstract]
6. Dietrich PY, Henry-Amar M, Cosset JM, et al.: Second primary cancers in patients continuously disease-free from Hodgkin’s disease: a protective role for the spleen? Blood 84 (4): 1209-15, 1994. [PUBMED Abstract]
7. Adams HJ, Kwee TC, de Keizer B, et al.: Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? Ann Oncol 25 (5): 921-7, 2014. [PUBMED Abstract]
8. Bradley AJ, Carrington BM, Lawrance JA, et al.: Assessment and significance of mediastinal bulk in Hodgkin’s disease: comparison between computed tomography and chest radiography. J Clin Oncol 17 (8): 2493-8, 1999. [PUBMED Abstract]
9. Mauch P, Goodman R, Hellman S: The significance of mediastinal involvement in early stage Hodgkin’s disease. Cancer 42 (3): 1039-45, 1978. [PUBMED Abstract]
10. Hodgkin and non-Hodgkin lymphoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 937–58.
11. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 31 (11): 1860-1, 1971. [PUBMED Abstract]
12. Jost LM, Stahel RA; ESMO Guidelines Task Force: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Hodgkin’s disease. Ann Oncol 16 (Suppl 1): i54-5, 2005. [PUBMED Abstract]
13. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339 (21): 1506-14, 1998. [PUBMED Abstract]
14. Rodday AM, Parsons SK, Upshaw JN, et al.: The Advanced-Stage Hodgkin Lymphoma International Prognostic Index: Development and Validation of a Clinical Prediction Model From the HoLISTIC Consortium. J Clin Oncol 41 (11): 2076-2086, 2023. [PUBMED Abstract]

After initial clinical staging for Hodgkin lymphoma (HL), patients with early favorable disease or early unfavorable disease are treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy with or without involved-field or nodal radiation.

Patients with advanced-stage disease are primarily treated with chemotherapy alone, although subsequent radiation therapy may be applied for initial bulky disease (≥10 cm mediastinal mass) or for residual adenopathy (>2.5 cm) with positive findings after a postchemotherapy positron emission tomography (PET) scan.[1] Treatment regimen preferences and application, as well as relative risks, differ regionally.

Patients with HL who are older than 60 years may have more treatment-related morbidity and mortality; maintaining the dose intensity of standard chemotherapy may be difficult.[2,3] Other therapies have been proposed for older patients with lower tolerance for conventional regimens, but no randomized trials have been conducted with these regimens.[4] Twenty-seven previously untreated patients older than 60 years, judged by the investigator to be in poor condition and unable to undergo chemotherapy, received brentuximab vedotin. A 92% overall response rate and 73% complete remission rate were reported.[5][Level of evidence C3] Brentuximab vedotin has been combined with dacarbazine [6] or sequentially with AVD (doxorubicin, vinblastine, dacarbazine) [7], reporting acceptable toxicities in an older population. A retrospective review of 287 patients aged 60 years or older with early-stage favorable HL in two German Hodgkin Study Group (GHSG) trials (HD10 and HD13) showed increased bleomycin-induced lung toxicity with more than two cycles of exposure to bleomycin.[8]

Table 3. Treatment Options for Hodgkin Lymphoma

Prognostic Group	Treatment Options
HL = Hodgkin lymphoma; NLPHL = nodular lymphocyte-predominant Hodgkin lymphoma.
Early favorable classic HL	Chemotherapy with or without radiation therapy
Early unfavorable classic HL	Chemotherapy with or without radiation therapy
Advanced classic HL	Chemotherapy with or without nivolumab or brentuximab vedotin
Recurrent classic HL	Pembrolizumab or nivolumab (alone or with chemotherapy)
	Brentuximab vedotin
	Brentuximab vedotin plus nivolumab
	Chemotherapy with stem cell transplant
	Combination chemotherapy
	Radiation therapy
NLPHL	Watchful waiting/active surveillance
	Radiation therapy
	Chemotherapy
	Rituximab

Chemotherapy

Table 4 describes the chemotherapy regimens used in the treatment of HL.

Table 4. Chemotherapy Regimens Used to Treat Hodgkin Lymphoma

Combination Name	Drugs Included	Prognostic Group
HL = Hodgkin lymphoma.
ABVD	Doxorubicin, bleomycin, vinblastine, and dacarbazine	Early favorable classic HL
		Early unfavorable classic HL
		Advanced classic HL
BEACOPP	Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone	Early unfavorable classic HL
		Advanced classic HL
GVD	Gemcitabine, vinorelbine, and liposomal doxorubicin	Recurrent classic HL
ICE	Ifosfamide, carboplatin, and etoposide	Recurrent classic HL
MOPP	Mechlorethamine, vincristine, procarbazine, and prednisone	Advanced classic HL

Radiation Therapy

Radiation therapy alone is almost never used to treat patients newly diagnosed with early favorable classic HL.[9] In HL, the appropriate dose of radiation alone is 20 Gy to 30 Gy to clinically uninvolved sites and 30 Gy to 36 Gy to regions of initial nodal involvement.[9–11] When mediastinal radiation will encompass the left side of the heart or will increase breast cancer risk in young female patients, proton therapy may be considered to reduce the radiation dose to organs at risk.[12] When used as a single modality, radiation therapy is delivered to the neck, chest, and axilla (mantle field) and then to an abdominal field to treat para-aortic nodes and the spleen (splenic pedicle). In some patients, pelvic nodes are treated with a third field. The three fields constitute total nodal radiation therapy. In some cases, the pelvic and para-aortic nodes are treated in a single field called an inverted Y.[9–11]

References

1. Engert A, Haverkamp H, Kobe C, et al.: Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 379 (9828): 1791-9, 2012. [PUBMED Abstract]
2. Böll B, Görgen H, Fuchs M, et al.: ABVD in older patients with early-stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD10 and HD11 trials. J Clin Oncol 31 (12): 1522-9, 2013. [PUBMED Abstract]
3. Evens AM, Hong F: How can outcomes be improved for older patients with Hodgkin lymphoma? J Clin Oncol 31 (12): 1502-5, 2013. [PUBMED Abstract]
4. Kolstad A, Nome O, Delabie J, et al.: Standard CHOP-21 as first line therapy for elderly patients with Hodgkin’s lymphoma. Leuk Lymphoma 48 (3): 570-6, 2007. [PUBMED Abstract]
5. Forero-Torres A, Holkova B, Goldschmidt J, et al.: Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood 126 (26): 2798-804, 2015. [PUBMED Abstract]
6. Friedberg JW, Forero-Torres A, Bordoni RE, et al.: Frontline brentuximab vedotin in combination with dacarbazine or bendamustine in patients aged ≥60 years with HL. Blood 130 (26): 2829-2837, 2017. [PUBMED Abstract]
7. Evens AM, Advani RH, Helenowski IB, et al.: Multicenter Phase II Study of Sequential Brentuximab Vedotin and Doxorubicin, Vinblastine, and Dacarbazine Chemotherapy for Older Patients With Untreated Classical Hodgkin Lymphoma. J Clin Oncol 36 (30): 3015-3022, 2018. [PUBMED Abstract]
8. Böll B, Goergen H, Behringer K, et al.: Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials. Blood 127 (18): 2189-92, 2016. [PUBMED Abstract]
9. Herst J, Crump M, Baldassarre FG, et al.: Management of Early-stage Hodgkin Lymphoma: A Practice Guideline. Clin Oncol (R Coll Radiol) 29 (1): e5-e12, 2017. [PUBMED Abstract]
10. Dühmke E, Franklin J, Pfreundschuh M, et al.: Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin’s disease: long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 19 (11): 2905-14, 2001. [PUBMED Abstract]
11. Mendenhall NP, Rodrigue LL, Moore-Higgs GJ, et al.: The optimal dose of radiation in Hodgkin’s disease: an analysis of clinical and treatment factors affecting in-field disease control. Int J Radiat Oncol Biol Phys 44 (3): 551-61, 1999. [PUBMED Abstract]
12. Dabaja BS, Hoppe BS, Plastaras JP, et al.: Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines. Blood 132 (16): 1635-1646, 2018. [PUBMED Abstract]

Patients are designated as having early favorable classic Hodgkin lymphoma (HL) when they have clinical stage I or stage II disease and none of the following adverse prognostic factors:

Treatment Options for Early Favorable Classic HL

Treatment options for early favorable classic HL include:

1. Chemotherapy with or without radiation therapy.

Chemotherapy with or without radiation therapy

Treatment options include:

• ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for three to six cycles.[1]
• ABVD for two to four cycles plus involved-field radiation therapy (IFRT) (20 Gy or 30 Gy).
• Radiation therapy alone in certain circumstances (such as for older adults with absolute contraindications for using chemotherapy).[2,3]

Historically, radiation therapy alone was the primary treatment for patients with early favorable classic HL, often after confirmatory negative staging laparotomy.

The late mortality from solid tumors (especially in the lung, breast, gastrointestinal tract, and connective tissue) and cardiovascular disease makes radiation therapy a less-attractive option for the best-risk patients, who have the highest probability of cure and long-term survival.[4–8] Clinical trials have focused on regimens with chemotherapy and IFRT or with chemotherapy alone.[1]

Evidence (chemotherapy and/or radiation therapy):

For patients with early favorable classic HL, the following four trials established ABVD alone for four cycles or ABVD for two cycles plus 20 Gy of IFRT.

1. A randomized, prospective trial from the National Cancer Institute of Canada involving 123 patients with early favorable classic HL compared ABVD for four to six cycles with subtotal nodal radiation.[9][Level of evidence A1]
   • With a median follow-up of 11.3 years, no difference was observed in event-free survival rates (89% vs. 86%; P = .64) or in overall survival rates (OS) (98% vs. 98%; P = .95).
2. A randomized study from the Milan Cancer Institute of patients with clinical early-stage HL compared 4 months of ABVD followed by IFRT with 4 months of ABVD followed by extended-field radiation therapy (EFRT).[10][Level of evidence B1]
   • The results showed similar OS and freedom from progression of disease with a 10-year median follow-up, but the study had inadequate statistical power to determine noninferiority of IFRT versus EFRT.
3. In the HD10 trial, the German Hodgkin Study Group (GHSG) randomly assigned 1,190 patients with early favorable HL to receive one of the following:[11,12][Level of evidence A1]
   • Two cycles of ABVD plus 30 Gy of IFRT.
   • Two cycles of ABVD plus 20 Gy of IFRT.
   • Four cycles of ABVD plus 30 Gy of IFRT.
   • Four cycles of ABVD plus 20 Gy of IFRT.

   The following results were observed for the trial:

   • With an 8.2-year median follow-up, no differences were observed (hazard ratio [HR], 1.0; 95% confidence interval [CI], 0.6–1.5) in 10-year progression-free survival (PFS) rates (87%) or OS rates (94%) for all four groups.
4. A follow-up study by the GHSG (HD13 trial) compared modified versions of ABVD with elimination of dacarbazine, bleomycin, or both in combination with 30 Gy of radiation therapy in 1,502 patients with early favorable HL.[13]
   • After 5 years, freedom from treatment failure was significantly worse when dacarbazine, bleomycin, or both were omitted.
   • This trial suggests that ABVD remains the standard chemotherapy regimen.

Other trials have investigated the role of positron emission tomography (PET) scans for early favorable HL.

1. Three prospective randomized trials (EORTC/LYSA/FIL H10 [NCT00433433][14,15]; RAPID [NCT00943423][16,17]; and GHSG HD16 [NCT00736320][18]) of 2,889 patients with early-stage disease investigated the use of PET‒computed tomography (CT) scans to modify therapy.[14–18]
   • Among patients with early favorable HL who had negative PET-CT scan results (Deauville score of 1 or 2) after two or three cycles of ABVD, radiation therapy could be omitted with no significant loss of OS in all three trials.[14,16,18][Level of evidence B1]

     However, two of the trials showed an increased risk of relapse when radiation therapy was omitted. In the GHSG HD16 trial, for the 628 patients with PET2-negative disease (PET after two cycles of ABVD), the 5-year PFS rate was 93.4% (95% CI, 90.4%–96.5%) with combined modality therapy and 86.1% (95% CI, 81.4%–90.0%) with ABVD alone (HR, 1.78; 95% CI, 1.02–3.12).[18] A subsequent analysis of the GHSG HD16 trial showed that most of the recurrences occurred in the proposed radiation field.[15] In the EORTC/LYSA/FIL H10 trial, the 10-year PFS rate was 98.8% with three cycles of ABVD plus radiation therapy and 85.4% with four cycles of ABVD without radiation therapy (HR, 13.2; 95% CI, 3.1–55.8; P < .001).[17]

     In summary, this 7% to 13% difference in PFS without a difference in OS can be seen either as a mandate to combine radiation therapy with ABVD to avoid recurrences or as a rationale to give four or more cycles of ABVD when omitting radiation therapy.

   • ABVD was given for three cycles (six doses) in the RAPID study,[16] for four cycles (eight doses) in the EORTC/LYSA/FIL H10 study,[14] and for two cycles (four doses) in the GHSG HD16 study [18] when applied without radiation therapy.
   • None of the studies randomly assigned therapy for positive results from an interim PET-CT scan (Deauville score of 3, 4, or 5) after two or three cycles of ABVD because this occurred in only 15% to 25% of the patients studied. One of the studies (RAPID) added an extra cycle of ABVD and IFRT to 30 Gy,[16] another study (EORTC H10F) switched to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone)–escalated therapy for two cycles plus involved nodal radiation therapy to 30 Gy,[14] and the other study (GHSG HD16) added IFRT to 30 Gy.[18]

     In the RAPID study (NCT00943423), patients with postchemotherapy PET-CT Deauville scores of 5 (uptake ≥3 times maximum liver uptake) had inferior 5-year PFS rates (61.9%; 95% CI, 41.1%–82.7%) and 5-year OS rates (85.2%; 95% CI, 69.7%–100%) (P = .002) when compared with patients with Deauville scores of 1 to 4 (P < .001).[19]

Older patients with early favorable HL have also been studied.

1. In 287 patients older than 60 years or with early favorable disease, a retrospective review of pulmonary toxicity in the HD10 and HD13 trials showed the following:[20]
   • Two cycles of ABVD plus IFRT (137 patients): 2% pulmonary toxicity.
   • Two cycles of AVD (omitting bleomycin) plus IFRT (82 patients): 2% pulmonary toxicity.
   • Four cycles of ABVD plus IFRT (68 patients): 10% pulmonary toxicity.

For older patients (>60 years) with early favorable disease, when more than two cycles of ABVD are required, bleomycin may be omitted to avoid pulmonary toxicity.

Summary of early favorable classic HL:

• ABVD alone for three to four cycles is recommended for patients with early favorable classical HL when the interim PET-CT scan results are negative after two or three cycles of chemotherapy.[21] These patients are also unlikely to ever have a relapse, so routine CT scans are not recommended in follow-up.
• With positive interim PET-CT scan results, extra cycles of ABVD and involved nodal radiation therapy are recommended.
• A combined-modality approach with two cycles of ABVD and 20 Gy of IFRT can also be used for patients with early favorable classic HL.[21] In this situation, a PET-CT scan to assess response after completion of therapy would suffice.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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