Childhood acute lymphoblastic leukemia (also called ALL or acute lymphocytic leukemia) is a cancer of the blood and bone marrow. This is the most common type of cancer in children. It accounts for about 25% of all childhood cancers in the United States and occurs most often in children aged 1 to 4 years.

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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 myeloid stem cell becomes one of three types of blood cells:

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

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ALL occurs because too many stem cells become lymphoblasts that do not mature into 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 red blood cells, platelets, and white blood cells. This may lead to anemia, easy bleeding, and infection.

ALL usually worsens quickly if it is not treated.

Childhood ALL is caused by changes to how the blood stem cells function, especially how they grow and divide into new cells. The exact cause of these cell changes is often unknown. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Not every child with one or more of these risk factors will develop ALL. And it will develop in some children who don’t have a known risk factor. Risk factors may be genetic or due to other causes.

Possible genetic risk factors for ALL include:

Other possible risk factors for ALL include:

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

It is not always clear from the family medical history whether a child with ALL has an inherited condition that increased their risk. Genetic counseling can assess the likelihood that your child’s cancer is inherited and whether genetic testing is needed. Genetic counselors and other specially trained health professionals can discuss your child’s diagnosis and family medical history to help you understand:

Genetic counselors can also help you cope with your child’s genetic test results, including how to discuss the results with family members. They can advise you about whether other members of your family should receive genetic testing.

Learn more about Genetic Testing for Inherited Cancer Risk.

Symptoms of childhood ALL are caused by not having enough red blood cells and platelets and by having too many white blood cells that don’t work well. It’s important to check with your child’s doctor if your child has:

These symptoms may be caused by problems other than ALL. The only way to know is for your child to see a doctor.

If your child has symptoms that suggest ALL, the doctor will need to find out if these are due to cancer or another problem. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family medical history and do a physical exam. Depending on these results, they may recommend other diagnostic tests. If your child is diagnosed with ALL, the results of these tests will help plan treatment.

The tests used to diagnose childhood acute lymphoblastic leukemia may include:

Complete blood count (CBC)

A CBC 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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Bone marrow aspiration and biopsy

The removal of bone marrow and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow and bone under a microscope to look for cancer.

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Tests done on blood or the bone marrow tissue that is removed include:

• Genetic tests: Many leukemia cells have abnormalities in their genes which can be found by different types of genetic tests. An example of a genetic test that is commonly used is cytogenetic analysis, in which the chromosomes in a sample of blood or bone marrow are counted and checked for any changes, such as broken, missing, rearranged, or extra chromosomes. Genetic testing of blood and bone marrow samples 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 leukemia. For example, the cancer cells are checked to see if they are B lymphocytes or T lymphocytes.

Lumbar puncture

Lumbar puncture is a procedure used to collect a sample of cerebrospinal fluid (CSF) from the spinal column (also called spine) to check for leukemia cells. 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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This procedure is done after leukemia is diagnosed to find out if leukemia cells have spread to the brain and spinal cord. Intrathecal chemotherapy is given after the sample of fluid is removed to treat any leukemia cells that may have spread to the brain and spinal cord.

You may want to get a second opinion to confirm your child’s cancer 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 genetic test results, pathology report, slides, and scans. This doctor may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s tumor.

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 or hospital that can provide a second opinion. For questions you may want to ask at your child’s appointments, visit Questions to Ask Your Doctor About Cancer.

In childhood ALL, risk groups are used to plan treatment. The three risk groups in childhood ALL include:

Other factors that affect the risk group include:

It is important to know the risk group in order to plan treatment. Children with high-risk or very high-risk ALL usually receive more anticancer drugs and/or higher doses of anticancer drugs than children with standard-risk ALL.

There are different types of treatment for children and adolescents with acute lymphoblastic leukemia (ALL). You and your child’s care team will work together to decide treatment. Many factors will be considered, such as your child’s age and overall health, and whether the tumor is newly diagnosed or has come back.

Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s care team before treatment begins about what to expect. For help every step of the way, visit our booklet, Children with Cancer: A Guide for Parents.

Treatment of childhood acute lymphoblastic leukemia in the brain and spinal cord or testicles

Chemotherapy to kill leukemia cells or prevent them from spreading to the brain and spinal cord (central nervous system; CNS) is called CNS-directed therapy. Standard doses of chemotherapy may not cross the blood-brain barrier to get into the fluid that surrounds the brain and spinal cord. Therefore, leukemia cells are able to hide in the CNS. Systemic chemotherapy given in high doses or intrathecal chemotherapy (into the cerebrospinal fluid) is able to reach leukemia cells in the CNS. Sometimes external radiation therapy to the brain is also given.

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These treatments are given in addition to treatment that is used to kill leukemia cells in the rest of the body. All children with ALL receive CNS-directed therapy as part of induction therapy and consolidation/intensification therapy and sometimes during maintenance therapy.

If the leukemia cells spread to the testicles, treatment includes high doses of systemic chemotherapy and sometimes radiation therapy.

Throughout treatment, it’s important that your child take all medicines ordered by the doctor. Not taking the medicines as directed increases the chance the cancer will come back.

If your child has been diagnosed with ALL, you likely have questions about how serious the cancer is and your child’s survival. The likely outcome or course of a disease is called prognosis.

The prognosis depends on:

For leukemia that comes back after treatment, your child’s prognosis depends partly on:

No two people are alike, and responses to treatment can vary greatly. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.

Cancer treatments can cause side effects. Which side effects your child might have depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.

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

Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects.

Late effects of cancer treatment may include:

Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the possible late effects caused by some treatments. Learn more about Late Effects of Treatment for Childhood Cancer.

As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that were done to diagnose 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 child’s condition has changed or if the cancer has recurred (come back).

Bone marrow aspiration and biopsy are done during initial phases of treatment to see how well the treatment is working. Bone marrow aspiration and biopsy are typically not done after treatment has ended, unless there is concern that the leukemia might have come back.

Learn more about the follow-up tests in Tests to diagnose childhood acute lymphoblastic leukemia.

When your child has cancer, every member of the family needs support. Taking care of yourself during this difficult time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, visit Support for Families: Childhood Cancer and the booklet Children with Cancer: A Guide for Parents.

For more childhood cancer information and other general cancer resources, visit:

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has slowly increased since 1975.[1] Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1–3] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%, although cancer remains the leading cause of death by disease past infancy among children in the United States.[1,2,4,5] For ALL, the 5-year survival rate increased over the same time, from 60% to approximately 90% for children younger than 15 years, and from 28% to more than 75% for adolescents aged 15 to 19 years.[2,3,6] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Anatomy

Childhood ALL originates in the T and B lymphoblasts in tissues with hematopoietic progenitor cells, such as the bone marrow and thymus (see Figure 1).

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Marrow involvement of acute leukemia as seen by light microscopy is defined as follows:

• M1: Fewer than 5% blast cells.
• M2: 5% to 25% blast cells.
• M3: Greater than 25% blast cells.

Almost all patients with ALL present with an M3 marrow.

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The 5th edition of the WHO Classification of Haematolymphoid Tumours lists the following entities for acute lymphoid leukemias:[1]

References

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3. Borowitz MJ, Béné MC, Harris NL: Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer, 2008, pp 150-5.
4. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
5. Gerr H, Zimmermann M, Schrappe M, et al.: Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J Haematol 149 (1): 84-92, 2010. [PUBMED Abstract]
6. Shago M, Abla O, Hitzler J, et al.: Frequency and outcome of pediatric acute lymphoblastic leukemia with ZNF384 gene rearrangements including a novel translocation resulting in an ARID1B/ZNF384 gene fusion. Pediatr Blood Cancer 63 (11): 1915-21, 2016. [PUBMED Abstract]
7. Yao L, Cen J, Pan J, et al.: TAF15-ZNF384 fusion gene in childhood mixed phenotype acute leukemia. Cancer Genet 211: 1-4, 2017. [PUBMED Abstract]
8. Alexander TB, Gu Z, Iacobucci I, et al.: The genetic basis and cell of origin of mixed phenotype acute leukaemia. Nature 562 (7727): 373-379, 2018. [PUBMED Abstract]
9. Rubnitz JE, Onciu M, Pounds S, et al.: Acute mixed lineage leukemia in children: the experience of St Jude Children’s Research Hospital. Blood 113 (21): 5083-9, 2009. [PUBMED Abstract]
10. Al-Seraihy AS, Owaidah TM, Ayas M, et al.: Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica 94 (12): 1682-90, 2009. [PUBMED Abstract]
11. Matutes E, Pickl WF, Van’t Veer M, et al.: Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117 (11): 3163-71, 2011. [PUBMED Abstract]
12. Hrusak O, de Haas V, Stancikova J, et al.: International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood 132 (3): 264-276, 2018. [PUBMED Abstract]
13. Orgel E, Alexander TB, Wood BL, et al.: Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children’s Oncology Group Acute Leukemia of Ambiguous Lineage Task Force. Cancer 126 (3): 593-601, 2020. [PUBMED Abstract]

B-ALL cytogenetics/genomics

B-ALL is typified by genomic alterations that include: 1) gene fusions that lead to aberrant activity of transcription factors, 2) chromosomal gains and losses (e.g., hyperdiploidy or hypodiploidy), and 3) alterations leading to activation of tyrosine kinase genes.[1] Figures 2 and 3 illustrate the distribution of NCI standard-risk and high-risk B-ALL cases by 23 cytogenetic/molecular subtypes.[1] The two most common subtypes (hyperdiploid and ETV6::RUNX1 fusion) together account for approximately 60% of NCI standard-risk B-ALL cases, but only approximately 25% of NCI high-risk cases. Most other subtypes are much less common, with most occurring at frequencies less than 2% to 3% of B-ALL cases. The molecular and clinical characteristics of some of the subtypes are discussed below.

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The genomic landscape of B-ALL is characterized by a range of genomic alterations that disrupt normal B-cell development and, in some cases, by variants in genes that provide a proliferation signal (e.g., activating variants in RAS family genes or variants/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., TCF3::PBX1 and ETV6::RUNX1 fusions), single nucleotide variants (e.g., IKZF1 and PAX5), and intragenic/intergenic deletions (e.g., IKZF1, PAX5, EBF, and ERG).[3]

The genomic alterations in B-ALL tend not to occur at random, but rather to cluster within subtypes that can be delineated by biological characteristics such as their gene expression profiles. Cases with recurring chromosomal translocations (e.g., TCF3::PBX1 and ETV6::RUNX1 fusions and KMT2A-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within unique biological subtypes:

• IKZF1 deletions and variants are most commonly observed within cases of BCR::ABL1 ALL and BCR::ABL1-like ALL.[4,5]
• Intragenic ERG deletions occur within a distinctive subtype characterized by gene rearrangements involving DUX4.[6,7]
• TP53 variants, often germline and pathogenic, occur at high frequency in patients with low hypodiploid ALL with 32 to 39 chromosomes.[8] TP53 variants are uncommon in other patients with B-ALL.

Activating single nucleotide variants in kinase genes are uncommon in high-risk B-ALL. JAK genes are the primary kinases that are found to be altered. These variants are generally observed in patients with BCR::ABL1-like ALL who have CRLF2 abnormalities, although JAK2 variants are also observed in approximately 25% of children with Down syndrome and ALL, occurring exclusively in cases with CRLF2 gene rearrangements.[5,9–11] Several kinase genes and cytokine receptor genes are activated by translocations, as described below in the discussion of BCR::ABL1 ALL and BCR::ABL1-like ALL. FLT3 variants occur in a minority of cases (approximately 10%) of hyperdiploid ALL and KMT2A-rearranged ALL, and are rare in other subtypes.[12]

Understanding of the genomics of B-ALL at relapse is less advanced than the understanding of ALL genomics at diagnosis. Childhood ALL is often polyclonal at diagnosis and under the selective influence of therapy, some clones may be extinguished and new clones with distinctive genomic profiles may arise.[13] However, molecular subtype–defining lesions such as translocations and aneuploidy are almost always retained at relapse.[1,13] Of particular importance are new variants that arise at relapse that may be selected by specific components of therapy. As an example, variants in NT5C2 are not found at diagnosis, whereas specific variants in NT5C2 were observed in 7 of 44 (16%) and 9 of 20 (45%) cases of B-ALL with early relapse that were evaluated for this variant in two studies.[13,14] NT5C2 variants are uncommon in patients with late relapse, and they appear to induce resistance to mercaptopurine and thioguanine.[14] Another gene that is found altered only at relapse is PRSP1, a gene involved in purine biosynthesis.[15] Variants were observed in 13.0% of a Chinese cohort and 2.7% of a German cohort, and were observed in patients with on-treatment relapses. The PRSP1 variants observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. CREBBP variants are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids.[13,16] With increased understanding of the genomics of relapse, it may be possible to tailor upfront therapy to avoid relapse or detect resistance-inducing variants early and intervene before a frank relapse.

Several recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-ALL. Some chromosomal alterations are associated with more favorable outcomes, such as favorable trisomies (51–65 chromosomes) and the ETV6::RUNX1 fusion.[17][Level of evidence B4] Other alterations historically have been associated with a poorer prognosis, including the BCR::ABL1 fusion (Philadelphia chromosome–positive [Ph+]; t(9;22)(q34;q11.2)), rearrangements of the KMT2A gene, hypodiploidy, and intrachromosomal amplification of the RUNX1 gene (iAMP21).[18]

In recognition of the clinical significance of many of these genomic alterations, the 5th edition revision of the World Health Organization Classification of Haematolymphoid Tumours lists the following entities for B-ALL:[19]

• B-lymphoblastic leukemia/lymphoma, NOS.
• B-lymphoblastic leukemia/lymphoma with high hyperdiploidy.
• B-lymphoblastic leukemia/lymphoma with hypodiploidy.
• B-lymphoblastic leukemia/lymphoma with iAMP21.
• B-lymphoblastic leukemia/lymphoma with BCR::ABL1 fusion.
• B-lymphoblastic leukemia/lymphoma with BCR::ABL1-like features.
• B-lymphoblastic leukemia/lymphoma with KMT2A rearrangement.
• B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1 fusion.
• B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1-like features.
• B-lymphoblastic leukemia/lymphoma with TCF3::PBX1 fusion.
• B-lymphoblastic leukemia/lymphoma with IGH::IL3 fusion.
• B-lymphoblastic leukemia/lymphoma with TCF3::HLF fusion.
• B-lymphoblastic leukemia/lymphoma with other defined genetic abnormalities.

The category of B-ALL with other defined genetic abnormalities includes potential novel entities, including B-ALL with DUX4, MEF2D, ZNF384 or NUTM1 rearrangements; B-ALL with IG::MYC fusions; and B-ALL with PAX5alt or PAX5 p.P80R (NP_057953.1) abnormalities.

These and other chromosomal and genomic abnormalities for childhood ALL are described below.

1. Chromosome number.
   • High hyperdiploidy (51–65 chromosomes).

     High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in approximately 33% of NCI standard-risk and 14% of NCI high-risk pediatric B-ALL cases.[1,20] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase fluorescence in situ hybridization (FISH) may detect hidden hyperdiploidy.

     High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low white blood cell [WBC] count) and is an independent favorable prognostic factor.[20–22] Within the hyperdiploid range of 51 to 65 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study.[22] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[23] which may explain the favorable outcome commonly observed in these cases.

     While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.[24–26]

     Multiple reports have described the prognostic significance of specific chromosome trisomies among children with hyperdiploid B-ALL.

     • A study combining experience from the Children’s Cancer Group and the Pediatric Oncology Group (POG) found that patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have a particularly favorable outcome.[27]; [17][Level of evidence B4]
     • A report using POG data found that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[28] COG protocols currently use double trisomies of chromosomes 4 and 10 to define favorable hyperdiploidy.
     • A retrospective analysis evaluated patients treated on two consecutive UKALL trials to identify and validate a profile to predict outcome in high hyperdiploid B-ALL. The investigators defined a good-risk group (approximately 80% of high hyperdiploidy patients) that was associated with a more favorable prognosis. Good-risk patients had either trisomies of both chromosomes 17 and 18 or trisomy of one of these two chromosomes along with absence of trisomies of chromosomes 5 and 20. All other patients were defined as poor risk and had a less favorable outcome. End-induction MRD and copy number alterations (such as IKZF1 deletion) were prognostically significant within each hyperdiploid risk group.[29]

     Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified on the basis of the prognostic significance of the translocation. For instance, in one study, 8% of patients with the BCR::ABL1 fusion also had high hyperdiploidy,[30] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-BCR::ABL1 high hyperdiploid patients.

     Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[31] Molecular technologies, such as single nucleotide polymorphism microarrays to detect widespread loss of heterozygosity, can be used to identify patients with masked hypodiploidy.[31] These cases may be interpretable based on the pattern of gains and losses of specific chromosomes (hyperdiploidy with two and four copies of chromosomes rather than three copies). These patients have an unfavorable outcome, similar to those with hypodiploidy.[32]

     Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[33] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6::RUNX1 fusion.[33–35] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[33,35]

     The genomic landscape of hyperdiploid ALL is characterized by variants in genes of the receptor tyrosine kinase (RTK)/RAS pathway in approximately one-half of cases. Genes encoding histone modifiers are also present in a recurring manner in a minority of cases. Analysis of variant profiles demonstrates that chromosomal gains are early events in the pathogenesis of hyperdiploid ALL and may occur in utero, while variants in RTK/RAS pathway genes are late events in leukemogenesis and are often subclonal.[1,36]

   • Hypodiploidy (<44 chromosomes).

     B-ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying on the basis of modal chromosome number into the following four groups:[32]

     • Near-haploid: 24 to 29 chromosomes (n = 46).
     • Low-hypodiploid: 33 to 39 chromosomes (n = 26).
     • High-hypodiploid: 40 to 43 chromosomes (n = 13).
     • Near-diploid: 44 chromosomes (n = 54).

     Near-haploid cases represent approximately 2% of NCI standard-risk and 2% of NCI high-risk pediatric B-ALL.[1]

     Low-hypodiploid cases represent approximately 0.5% of NCI standard-risk and 2.6% of NCI high-risk pediatric B-ALL cases.[1]

     Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases.[32,37] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[32] Several studies have shown that patients with high minimal residual disease (MRD) (≥0.01%) after induction do very poorly, with 5-year event-free survival (EFS) rates ranging from 25% to 47%. Although hypodiploid patients with low MRD after induction fare better (5-year EFS rates, 64%–75%), their outcomes are still inferior to most children with other types of ALL.[38–40]

     The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[8] In near-haploid ALL, alterations targeting RTK signaling, RAS signaling, and IKZF3 are common.[41] In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these variants are germline pathogenic and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.[8] Approximately two-thirds of patients with ALL and germline TP53 pathogenic variants have hypodiploid ALL.[42]

2. Chromosomal translocations and gains/deletions of chromosomal segments.
   • ETV6::RUNX1 fusion (t(12;21)(p13.2;q22.1)).

     Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 is present in approximately 27% of NCI standard-risk and 10% of NCI high-risk pediatric B-ALL cases.[1,34]

     The ETV6::RUNX1 fusion produces a cryptic translocation that is detected by methods such as FISH, rather than conventional cytogenetics, and it occurs most commonly in children aged 2 to 9 years.[43,44] Hispanic children with ALL have a lower incidence of ETV6::RUNX1 fusions than do White children.[45]

     Reports generally indicate favorable EFS and overall survival (OS) rates in children with the ETV6::RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:[26,46–50]; [17][Level of evidence B4]

     • Early response to treatment.
     • NCI risk category (age and WBC count at diagnosis).
     • Treatment regimen.

     In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6::RUNX1 fusion status, to be independent prognostic factors.[46] However, another large trial only enrolled patients classified as having favorable-risk B-ALL, with low-risk clinical features, either trisomies of 4, 10, and 17 or ETV6::RUNX1 fusion, and end induction MRD less than 0.01%. Patients had a 5-year continuous complete remission rate of 93.7% and a 6-year OS rate of 98.2% for patients with ETV6::RUNX1.[17] It does not appear that the presence of secondary cytogenetic abnormalities, such as deletion of ETV6 (12p) or CDKN2A/B (9p), impacts the outcome of patients with the ETV6::RUNX1 fusion.[50,51]

     There is a higher frequency of late relapses in patients with ETV6::RUNX1 fusions compared with other relapsed B-ALL patients.[46,52] Patients with the ETV6::RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[53] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[54] Some relapses in patients with ETV6::RUNX1 fusions may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6::RUNX1 translocation).[55,56]

   • BCR::ABL1 fusion (t(9;22)(q34.1;q11.2); Ph+).

     The BCR::ABL1 fusion leads to production of a BCR::ABL1 fusion protein with tyrosine kinase activity (see Figure 4).[1] The BCR::ABL1 fusion occurs in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1] The BCR::ABL1 fusion is also the leukemogenic driver for chronic myeloid leukemia (CML). The most common BCR breakpoint in CML is different from the most common BCR breakpoint in ALL. The breakpoint that typifies CML produces a larger fusion protein (termed p210) than the breakpoint most commonly observed for ALL (termed p190, a smaller fusion protein).

     Enlarge

     Ph+ ALL is more common in older children with B-ALL and high WBC counts, with the incidence of the BCR::ABL1 fusions increasing to about 25% in young adults with ALL.

     Historically, the BCR::ABL1 fusion was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic hematopoietic stem cell transplant (HSCT) in patients in first remission.[30,57–59] Inhibitors of the BCR::ABL1 tyrosine kinase, such as imatinib mesylate, are effective in patients with BCR::ABL1 ALL.[60] A study by the Children’s Oncology Group (COG), which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 5-year EFS rate of 70% (± 12%), which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era. This result eliminated the recommendation of HSCT for patients with a good early response to chemotherapy using a tyrosine kinase inhibitor.[61,62]

     The International Consensus Classification of acute lymphoblastic leukemia/lymphoma from 2022 divides BCR::ABL1–positive B-ALL into two subtypes: cases with lymphoid-only involvement and cases with multilineage involvement.[63] These subtypes differ in the timing of their transformation event. A multipotent progenitor serves as the target cell of origin for BCR::ABL1–positive B-ALL with multilineage involvement, and a later progenitor is the target cell of origin for BCR::ABL1–positive B-ALL with lymphoid-only involvement.

     • BCR::ABL1–positive B-ALL with lymphoid-only involvement is the predominate subtype. Only a minority of cases in children and adults have multilineage involvement (estimated at 15%–30%).[64]
     • BCR::ABL1–positive B-ALL cases with lymphoid-only involvement and cases with multilineage involvement have similar clinical presentations and immunophenotypes. In addition, both subtypes commonly have the p190 fusion protein.[64,65]
     • One way of distinguishing between patients with lymphoid-only and multilineage involvement is to detect the BCR::ABL1 fusion in normal non-ALL B cells, T cells, and myeloid cells.[65]
     • A second way of distinguishing between patients with lymphoid-only and multilineage involvement is to detect quantitative differences in MRD levels (typically 1 log) using measures that quantify BCR::ABL1 DNA or RNA, compared with measures based on flow cytometry, real-time quantitative polymerase chain reaction (PCR), or next-generation sequencing (NGS) quantitation of leukemia-specific immunoglobulin (IG) or T-cell receptor (TCR) rearrangements.[64–66]
       • For patients with lymphoid-only BCR::ABL1–positive B-ALL, MRD estimates for these methods will be correlated with each other.
       • For patients with multilineage involvement BCR::ABL1–positive B-ALL, posttreatment MRD estimates based on detection of BCR::ABL1 DNA or RNA will often be higher than estimates based on flow cytometry or quantitation of leukemia-specific IG/TCR rearrangements.
     • For patients with BCR::ABL1–positive B-ALL and multilineage involvement, levels of BCR::ABL1 transcripts and DNA may remain stable over time despite continued treatment with chemotherapy and tyrosine kinase inhibitors. In these situations, the persisting BCR::ABL1 DNA or RNA likely represents evidence of a residual preleukemic clone and not leukemia cells. Therefore, the term MRD is a misnomer.
     • A corollary of the difference in MRD detection by methods based on BCR::ABL1 DNA or RNA detection versus MRD detection based on flow cytometry or IG/TCR rearrangements is that the latter methods provide more reliable prognostication.[64,66,67] For example, the presence of MRD by BCR::ABL1 DNA or RNA detection in the absence of MRD detection by IG/TCR rearrangements does not confer inferior prognosis.
     • Based on the limited numbers of patients studied to date, prognosis appears similar in both adults and children with lymphoid-only versus multilineage involvement BCR::ABL1–positive B-ALL.[64,66]
     • There are case reports of patients with multilineage involvement BCR::ABL1–positive B-ALL who relapse years from their initial diagnosis. In addition, their relapsed leukemia has the same BCR::ABL1 breakpoint as their initial leukemia, but it has a different IG/TCR rearrangement.[66] These case reports suggest that patients with multilineage BCR::ABL1–positive B-ALL are at risk of a second leukemogenic event, leading to a second BCR::ABL1 leukemia.
     • There is no evidence that a specific monitoring schedule or prolonged treatment with a tyrosine kinase inhibitor provides clinical benefit for patients with multilineage involvement BCR::ABL1–positive B-ALL who have maintained presence of BCR::ABL1 transcripts or DNA at the completion of a standard-duration course of leukemia therapy.
   • KMT2A-rearranged ALL (t(v;11q23.3)).

     Rearrangements involving the KMT2A gene with more than 100 translocation partner genes result in the production of fusion oncoproteins. KMT2A gene rearrangements occur in up to 80% of infants with ALL. Beyond infancy, approximately 1% of NCI standard-risk and 4% of NCI high-risk pediatric B-ALL cases have KMT2A rearrangements.[1]

     These rearrangements are generally associated with an increased risk of treatment failure, particularly in infants.[68–71] The KMT2A::AFF1 fusion (t(4;11)(q21;q23)) is the most common rearrangement involving the KMT2A gene in children with ALL and occurs in approximately 1% to 2% of childhood ALL.[69,72]

     Patients with KMT2A::AFF1 fusions are usually infants with high WBC counts. These patients are more likely than other children with ALL to have central nervous system (CNS) disease and to have a poor response to initial therapy.[73] While both infants and adults with the KMT2A::AFF1 fusion are at high risk of treatment failure, children with the KMT2A::AFF1 fusion appear to have a better outcome.[68,69,74] Irrespective of the type of KMT2A gene rearrangement, infants with KMT2A-rearranged ALL have much worse event-free survival rates than non-infant pediatric patients with KMT2A-rearranged ALL.[68,69,74]

     Whole-genome sequencing has determined that cases of infant ALL with KMT2A gene rearrangements have frequent subclonal NRAS or KRAS variants and few additional genomic alterations, none of which have clear clinical significance.[12,75] Deletion of the KMT2A gene has not been associated with an adverse prognosis.[76]

     Of interest, the KMT2A::MLLT1 fusion (t(11;19)(q23;p13.3)) occurs in approximately 1% of ALL cases and occurs in both early B-lineage ALL and T-ALL.[77] Outcome for infants with the KMT2A::MLLT1 fusion is poor, but outcome appears relatively favorable in older children with T-ALL and the KMT2A::MLLT1 fusion.[77]

   • TCF3::PBX1 fusion (t(1;19)(q23;p13.3)) and TCF3::HLF fusion (t(17;19)(q22;p13)).

     Fusion of the TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1 is present in approximately 4% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1,78,79] The TCF3::PBX1 fusion may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the pre-B–ALL immunophenotype (cytoplasmic immunoglobulin positive).[80] Black children are relatively more likely than White children to have pre-B–ALL with the TCF3::PBX1 fusion.[81]

     The TCF3::PBX1 fusion had been associated with inferior outcome in the context of antimetabolite-based therapy,[82] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[79,83] More specifically, in a trial conducted by St. Jude Children’s Research Hospital (SJCRH) in which all patients were treated without cranial radiation, patients with the TCF3::PBX1 fusion had an overall outcome comparable to children lacking this translocation, but with a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more intensive CNS therapy may be needed for these patients.[84,85]

     The TCF3::HLF fusion occurs in less than 1% of pediatric ALL cases. ALL with the TCF3::HLF fusion is associated with disseminated intravascular coagulation and hypercalcemia at diagnosis. Outcome is very poor for children with the TCF3::HLF fusion, with a literature review noting mortality for 20 of 21 cases reported.[86] In addition to the TCF3::HLF fusion, the genomic landscape of this ALL subtype was characterized by deletions in genes involved in B-cell development (PAX5, BTG1, and VPREB1) and by variants in RAS pathway genes (NRAS, KRAS, and PTPN11).[80]

   • DUX4-rearranged ALL with frequent ERG deletions.

     Approximately 3% of NCI standard-risk and 6% of NCI high-risk pediatric B-ALL patients have a rearrangement involving DUX4 that leads to its overexpression.[1,6,7] East Asian ancestry was linked to an increased prevalence of DUX4-rearranged ALL (favorable).[87] The most common rearrangement produces IGH::DUX4 fusions, with ERG::DUX4 fusions also observed.[88] DUX4-rearranged cases show a distinctive gene expression pattern that was initially identified as being associated with focal deletions in ERG,[88–91] and one-half to more than two-thirds of these cases have focal intragenic deletions involving ERG that are not observed in other ALL subtypes.[6,88] ERG deletions often appear to be clonal, but using sensitive detection methodology, it appears that most cases are polyclonal.[88] IKZF1 alterations are observed in 20% to 40% of DUX4-rearranged ALL.[6,7]

     ERG deletion connotes an excellent prognosis, with OS rates exceeding 90%. Even when the IZKF1 deletion is present, prognosis remains highly favorable.[89–92] While patients with DUX4-rearranged ALL have an overall favorable prognosis, there is uncertainty as to whether this applies to both ERG-deleted and ERG-intact cases. In a study of 50 patients with DUX4-rearranged ALL, patients with an ERG deletion detected by genomic PCR (n = 33) had a more favorable EFS rate of approximately 90% than did patients with intact ERG (n = 17), with an EFS rate of approximately 70%.[90]

   • MEF2D-rearranged ALL.

     Gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 0.3% of NCI standard-risk and 3% of NCI high-risk pediatric B-ALL cases.[1,93,94]

     Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[93,95] The interstitial deletion producing the MEF2D::BCL9 fusion is too small to be detected by conventional cytogenetic methods. Cases with MEF2D gene fusions show a distinctive gene expression profile, except for rare cases with MEF2D::CSFR1 that have a BCR::ABL1-like gene expression profile.[93,96]

     The median age at diagnosis for cases of MEF2D-rearranged ALL in studies that included both adult and pediatric patients was 12 to 14 years.[93,94] For 22 children with MEF2D-rearranged ALL enrolled in a high-risk ALL clinical trial, the 5-year EFS rate was 72% (standard error, ± 10%), which was inferior to that for other patients.[93]

   • ZNF384-rearranged ALL.

     ZNF384 is a transcription factor that is rearranged in approximately 0.3% of NCI standard-risk and 2.7% of NCI high-risk pediatric B-ALL cases.[1,93,97,98]

     East Asian ancestry was associated with an increased prevalence of ZNF384.[87] Multiple fusion partners for ZNF384 have been reported, including ARID1B, CREBBP, EP300, SMARCA2, TAF15, and TCF3. Regardless of the fusion partner, ZNF384-rearranged ALL cases show a distinctive gene expression profile.[93,97,98] ZNF384 rearrangement does not appear to confer independent prognostic significance.[93,97,98] However, within the subset of patients with ZNF384 rearrangements, patients with EP300::ZNF384 fusions have lower relapse rates than patients with other ZNF384 fusion partners.[99] The immunophenotype of B-ALL with ZNF384 rearrangement is characterized by weak or negative CD10 expression, with expression of CD13 and/or CD33 commonly observed.[97,98] Cases of mixed phenotype acute leukemia (MPAL) (B/myeloid) that have ZNF384 gene fusions have been reported,[100,101] and a genomic evaluation of MPAL found that ZNF384 gene fusions were present in approximately one-half of B/myeloid cases.[102]

   • NUTM1-rearranged B-ALL.

     NUTM1-rearranged B-ALL is most commonly observed in infants, representing 3% to 5% of overall cases of B-ALL in this age group and approximately 20% of infant B-ALL cases lacking the KMT2A rearrangement.[103] The frequency of NUTM1 rearrangement is lower in children after infancy (<1% of cases).[1,103]

     The NUTM1 gene is located on chromosome 15q14, and some cases of B-ALL with NUTM1 rearrangements show chromosome 15q aberrations, but other cases are cryptic and have no cytogenetic abnormalities.[104] RNA sequencing, as well as break-apart FISH, can be used to detect the presence of the NUTM1 rearrangement.[103]

     The NUTM1 rearrangement appears to be associated with a favorable outcome.[103,105] Among 35 infants with NUTM1-rearranged B-ALL who were treated on Interfant protocols, all patients achieved remission and no relapses were observed.[103] For the 32 children older than 12 months with NUTM1-rearranged B-ALL, the 4-year EFS and OS rates were 92% and 100%, respectively.

   • IGH::IL3 fusion (t(5;14)(q31.1;q32.3)).

     This entity is included in the 2016 revision of the World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues.[106] The finding of t(5;14)(q31.1;q32.3) in patients with ALL and hypereosinophilia in the 1980s was followed by the identification of the IGH::IL3 fusion as the underlying genetic basis for the condition.[107,108] The joining of the IGH locus to the promoter region of the IL3 gene leads to dysregulation of IL3 expression.[109] Cytogenetic abnormalities in children with ALL and eosinophilia are variable, with only a subset resulting from the IGH::IL3 fusion.[110]

     The number of cases of IGH::IL3 ALL described in the published literature is too small to assess the prognostic significance of the IGH::IL3 fusion. Diagnosis of cases of IGH::IL3 ALL may be delayed because the ALL clone in the bone marrow may be small, and because it can present with hypereosinophilia in the absence of cytopenias and circulating blasts.[106]

   • Intrachromosomal amplification of chromosome 21 (iAMP21).

     iAMP21 occurs in approximately 5% of NCI standard-risk and 7% of NCI high-risk pediatric B-ALL cases.[1] iAMP21 is generally diagnosed using FISH and is defined by the presence of greater than or equal to five RUNX1 signals per cell (or ≥3 extra copies of RUNX1 on a single abnormal chromosome).[106] iAMP21 can also be identified by chromosomal microarray analysis. Uncommonly, iAMP21 with an atypical genomic pattern (e.g., amplification of the genomic region but with less than 5 RUNX1 signals or having at least 5 RUNX1 signals with some located apart from the abnormal iAMP21-chromosome) is identified by microarray but not RUNX1 FISH.[111] The prognostic significance of iAMP21 defined only by microarray has not been characterized.

     iAMP21 is associated with older age (median, approximately 10 years), presenting WBC count of less than 50 × 109/L, a slight female preponderance, and high end-induction MRD.[112–114] Analysis of variant signatures indicates that gene amplifications in iAMP21 occur later in leukemogenesis, which is in contrast to those of hyperdiploid ALL that can arise early in life and even in utero.[1]

     The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) clinical trials group initially reported that the presence of iAMP21 conferred a poor prognosis in patients treated in the MRC ALL 97/99 trial (5-year EFS rate, 29%).[18] In their subsequent trial (UKALL2003 [NCT00222612]), patients with iAMP21 were assigned to a more intensive chemotherapy regimen and had a markedly better outcome (5-year EFS rate, 78%).[113] Similarly, the COG has reported that iAMP21 was associated with a significantly inferior outcome in NCI standard-risk patients (4-year EFS rate, 73% for iAMP21 vs. 92% in others), but not in NCI high-risk patients (4-year EFS rate, 73% vs. 80%).[112] On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients.[112] The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance and obviates the need for HSCT in first remission.[114]

   • PAX5 alterations.

     Gene expression analysis identified two distinctive ALL subsets with PAX5 genomic alterations, called PAX5alt and PAX5 p.P80R (NP_057953.1).[115] The alterations in the PAX5alt subtype included rearrangements, sequence variants, and focal intragenic amplifications.

     PAX5alt. PAX5 rearrangements have been reported to represent approximately 3% of NCI standard-risk and 11% of NCI high-risk pediatric B-ALL cases.[1] More than 20 partner genes for PAX5 have been described,[115] with PAX5::ETV6, the primary genomic alteration in dic(9;12)(p13;p13),[116] being the most common gene fusion.[115]

     Intragenic amplification of PAX5 was identified in approximately 1% of B-ALL cases, and it was usually detected in cases lacking known leukemia-driver genomic alterations.[117] Cases with PAX5 amplification show male predominance (66%), with most (55%) having NCI high-risk status. For a cohort of patients with PAX5 amplification diagnosed between 1993 and 2015, the 5-year EFS rate was 49% (95% confidence interval [CI], 36%–61%), and the OS rate was 67% (95% CI, 54%–77%), suggesting a relatively poor prognosis for patients with this B-ALL subtype.

     PAX5 p.P80R (NP_057953.1). PAX5 with a p.P80R variant shows a gene expression profile distinctive from that of other cases with PAX5 alterations.[115] Cases with PAX5 p.P80R represent approximately 0.3% of NCI standard-risk and 1.8% of NCI high-risk pediatric B-ALL.[1] PAX5 p.P80R B-ALL appears to occur more frequently in the adolescent and young adult (AYA) and adult populations (3.1% and 4.2%, respectively).[115]

     Outcome for the pediatric patients with PAX5 p.P80R and PAX5alt treated in a COG clinical trial appears to be intermediate (5-year EFS rate, approximately 75%).[115] PAX5alt rearrangements have also been detected in infant patients with ALL, with a reported outcome similar to KMT2A-rearranged infant ALL.[105]

   • BCR::ABL1-like (Ph-like).

     BCR::ABL1-negative patients with a gene expression profile similar to BCR::ABL1-positive patients have been referred to as Ph-like,[118–120] and are now referred to as BCR::ABL1-like.[19] This occurs in 10% to 20% of pediatric B-ALL patients, increasing in frequency with age, and has been associated with an IKZF1 deletion or variant.[1,9,118,119,121,122]

     Retrospective analyses have indicated that patients with BCR::ABL1-like ALL have a poor prognosis.[5,118] In one series, the 5-year EFS rate for NCI high-risk children and adolescents with BCR::ABL1-like ALL was 58% and 41%, respectively.[5] While it is more frequent in older and higher-risk patients, the BCR::ABL1-like subtype has also been identified in NCI standard-risk patients. In a COG study, 13.6% of 1,023 NCI standard-risk B-ALL patients were found to have BCR::ABL1-like ALL; these patients had an inferior EFS rate compared with non–BCR::ABL1-like standard-risk patients (82% vs. 91%), although no difference in OS rate (93% vs. 96%) was noted.[123] In one study of 40 BCR::ABL1-like patients, the adverse prognostic significance of this subtype appeared to be abrogated when patients were treated with risk-directed therapy on the basis of MRD levels.[124]

     The hallmark of BCR::ABL1-like ALL is activated kinase signaling, with approximately 35% to 50% containing CRLF2 genomic alterations [1,120,125] and half of those cases containing concomitant JAK variants.[126]

     Many of the remaining cases of BCR::ABL1-like ALL have been noted to have a series of translocations involving tyrosine-kinase encoding ABL-class fusion genes, including ABL1, ABL2, CSF1R, and PDGFRB.[5,121,127] Fusion proteins from these gene combinations have been noted in some cases to be transformative and have responded to tyrosine kinase inhibitors both in vitro and in vivo,[121,128] suggesting potential therapeutic strategies for these patients. Preclinical drug sensitivity assays have suggested that sensitivity to different tyrosine kinase inhibitors (TKIs) may vary by the specific ABL-class gene involved in the fusion. In one study of ex vivo TKI sensitivity, samples from patients with PDGFRB fusions were sensitive to imatinib. However, these samples were less sensitive to dasatinib and bosutinib than samples from patients with ABL1 fusions (including BCR::ABL1).[128] Clinical studies have not yet confirmed the differing responses to various TKIs by type of ABL-class fusion.

     BCR::ABL1-like ALL cases with non-CRLF2 genomic alterations represent approximately 3% of NCI standard-risk and 8% of NCI high-risk pediatric B-ALL cases.[1] In a retrospective study of 122 pediatric patients (aged 1–18 years) with ABL-class fusions (all treated without tyrosine kinase inhibitors), the 5-year EFS rate was 59%, and the OS rate was 76%.[129]

     Approximately 9% of BCR::ABL1-like ALL cases result from rearrangements that lead to overexpression of a truncated erythropoietin receptor (EPOR).[130] The C-terminal region of the receptor that is lost is the region that is altered in primary familial congenital polycythemia and that controls stability of the EPOR. The portion of the EPOR remaining is sufficient for JAK-STAT activation and for driving leukemia development. Single nucleotide variants in kinase genes, aside from those in JAK1 and JAK2, are uncommon in patients with BCR::ABL1-like ALL.[9]

     CRLF2. Genomic alterations in CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5% to 10% of cases of B-ALL. These alterations represent approximately 50% of cases of BCR::ABL1-like ALL.[131–133] The chromosomal abnormalities that commonly lead to CRLF2 overexpression include translocations of the IGH locus (chromosome 14) to CRLF2 and interstitial deletions in pseudoautosomal regions of the sex chromosomes, resulting in a P2RY8::CRLF2 fusion.[9,125,131,132] These two genomic alterations are associated with distinctive clinical and biological characteristics.

     BCR::ABL1-like B-ALL with CRLF2 genomic alterations is observed in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1]

     ALL with genomic alterations in CRLF2 occurs at a higher incidence in children with Hispanic or Latino genetic ancestry [125,134,135] and American Indian genetic ancestry.[87] In a study of 205 children with high-risk B-ALL, 18 of 51 (35.3%) Hispanic or Latino patients had CRLF2 rearrangements, compared with 11 of 154 (7.1%) cases of other declared ethnicity.[125] In a second study, the frequency of IGH::CRLF2 fusions was increased in Hispanic or Latino children compared with non-Hispanic or non-Latino children with B-ALL (13.2% vs. 3.6%).[134,135] In this study, the percentage of B-ALL with P2RY8::CRLF2 fusions was approximately 6% and was not affected by ethnicity.

     The P2RY8::CRLF2 fusion is observed in 70% to 75% of pediatric patients with CRLF2 genomic alterations, and it occurs in younger patients (median age, approximately 4 years vs. 14 years for patients with IGH::CRLF2).[136,137] P2RY8::CRLF2 occurs not infrequently with established chromosomal abnormalities (e.g., hyperdiploidy, iAMP21, dic(9;20)), while IGH::CRLF2 is generally mutually exclusive with known cytogenetic subgroups. CRLF2 genomic alterations are observed in approximately 60% of patients with Down syndrome and ALL, with P2RY8::CRLF2 fusions being more common than IGH::CRLF2 (approximately 80%–85% vs. 15%–20%).[132,136]

     IGH::CRLF2 and P2RY8::CRLF2 commonly occur as an early event in B-ALL development and show clonal prevalence.[138] However, in some cases they appear to be a late event and show subclonal prevalence.[138] Loss of the CRLF2 genomic abnormality in some cases at relapse confirms the subclonal nature of the alteration in these cases.[136,139]

     CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions. Deletions of IKZF1 are more common in cases with IGH::CRLF2 fusions than in cases with P2RY8::CRLF2 fusions.[137] Hispanic and Latino children have a higher frequency of CRLF2 rearrangements with IKZF1 deletions than non-Hispanic children.[135]

     Other recurring genomic alterations found in association with CRLF2 alterations include deletions in genes associated with B-cell differentiation (e.g., PAX5, BTG1, EBF1, etc.) and cell cycle control (CDKN2A), as well as genomic alterations activating JAK-STAT pathway signaling (e.g., IL7R and JAK variants).[5,125,126,132,140]

     Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance in univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[125,131,132,141,142] For example, in a large European study, increased expression of CRLF2 was not associated with unfavorable outcome in multivariate analysis, while IKZF1 deletion and BCR::ABL1-like expression signatures were associated with unfavorable outcome.[122] Controversy exists about whether the prognostic significance of CRLF2 abnormalities should be analyzed on the basis of CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[141,142]

   • IKZF1 deletions.

     IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of B-ALL cases. Less commonly, IKZF1 can be inactivated by deleterious single nucleotide variants.[119]

     Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore more common in NCI high-risk patients than in NCI standard-risk patients.[3,119,140,143,144] A high proportion of BCR::ABL1-positive cases have a deletion of IKZF1,[4,140] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.[145] IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in BCR::ABL1-like ALL cases.[89,118,140] IKZF1 deletions also occur more commonly in Hispanic children. In one study from a single cancer center, IKZF1 deletions were observed in 29% of Hispanic children, compared with 11% of non-Hispanic children (P = .001).[135]

     Multiple reports have documented the adverse prognostic significance of an IKZF1 deletion, and most studies have reported that this deletion is an independent predictor of poor outcome in multivariate analyses.[89,118,119,122,140,146–153]; [154][Level of evidence B4] However, the prognostic significance of IKZF1 may not apply equally across ALL biological subtypes, as illustrated by the apparent lack of prognostic significance in patients with ERG deletions.[89–91] Similarly, the prognostic significance of the IKZF1 deletion also appeared to be minimized in a cohort of COG patients with DUX4-rearranged ALL and with ERG transcriptional dysregulation that frequently occurred by ERG deletion.[7] The Associazione Italiana di Ematologia e Oncologia Pediatrica–Berlin-Frankfurt-Münster group reported that IKZF1 deletions were significant adverse prognostic factors only in B-ALL patients with high end-induction MRD and in whom co-occurrence of deletions of CDKN2A, CDKN2B, PAX5, or PAR1 (in the absence of ERG deletion) were identified.[155] This combination of IKZF1 deletion with accompanying deletion of select other genes is termed IKZF1PLUS.[155] In a single-center study, the IKZF1PLUS profile was more commonly observed in Hispanic children than in non-Hispanic children (20% vs. 5%, P = .001).[135]

     The poor prognosis associated with IKZF1 alterations appears to be enhanced by the concomitant finding of deletion of 22q11.22. In a study of 1,310 patients with B-ALL, approximately one-half of the patients with IKZF1 alterations also had deletion of 22q11.22. The 5-year EFS rate was 43.3% for those with both abnormalities, compared with 68.5% for patients with IKZF1 alterations and wild-type 22q11.22 (P < .001).[156]

     There are few published results of changing therapy on the basis of IKZF1 gene status. The Malaysia-Singapore group published results of two consecutive trials. In the first trial (MS2003), IKZF1 status was not considered in risk stratification, while in the subsequent trial (MS2010), IKZF1-deleted patients were excluded from the standard-risk group. Thus, more IKZF1-deleted patients in the MS2010 trial received intensified therapy. Patients with IKZF1-deleted ALL had improved outcomes in MS2010 compared with patients in MS2003, but interpretation of this observation is limited by other changes in risk stratification and therapeutic differences between the two trials.[157][Level of evidence B4]

     In the Dutch ALL11 study, patients with IKZF1 deletions had maintenance therapy extended by 1 year, with the goal of improving outcomes.[158] The landmark analysis demonstrated an almost threefold reduction in relapse rate and an improvement in the 2-year EFS rate (from 74.4% to 91.2%), compared with historical controls.

   • MYC-rearranged ALL (8q24).

     MYC gene rearrangements are a rare but recurrent finding in pediatric patients with B-ALL. Patients with rearrangements of the MYC gene and the IGH2, IGK, and IGL genes at 14q32, 2p12, and 22q11.2, respectively, have been reported.[159–161] The lymphoblasts typically exhibit a precursor B-cell immunophenotype, with a French-American-British (FAB) L2 or L3 morphology, with no expression of surface immunoglobulin and kappa or lambda light chains. Concurrent MYC gene rearrangements have been observed along with additional cytogenetic rearrangements such as IGH::BCL2 or KMT2A.[161] Patients reported in the literature have been variably treated with ALL therapy or with mature B leukemia/lymphoma treatment protocols, and the optimal treatment for this patient group remains uncertain.[161]

T-ALL cytogenetics/genomics

T-ALL is characterized by genomic alterations leading to activation of transcriptional programs related to T-cell development and by a high frequency of cases (approximately 60%) with variants in NOTCH1 and/or FBXW7 that result in activation of the NOTCH1 pathway.[162] Cytogenetic abnormalities common in B-ALL (e.g., hyperdiploidy, 51–65 chromosomes) are rare in T-ALL.[163,164]

In Figure 5 below, pediatric T-ALL cases are divided into 10 molecular subtypes based on their RNA expression and gene variant status. These cases were derived from patients enrolled in SJCRH and COG clinical trials.[1] Each subtype is associated with dysregulation of specific genes involved in T-cell development. Within a subtype, multiple mechanisms may drive expression of the dysregulated gene. For example, for the largest subtype, TAL1, overexpression of TAL1 can result from the STIL::TAL1 fusion and a noncoding insertion variant upstream of the TAL1 locus that creates a MYB-binding site.[162,165] As another example, within the HOXA group, overexpression of HOXA9 can result from multiple gene fusions, including KMT2A rearrangements, MLLT10 rearrangements, and SET::NUP214 fusions.[1,162,166] In contrast to the molecular subtypes of B-ALL, the molecular subtypes of T-ALL are not used to define treatment interventions based on their prognostic significance or therapeutic implications.

Enlarge

• Notch pathway signaling.

  Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene variants in T-ALL, and these are the most commonly altered genes in pediatric T-ALL.[162,167] NOTCH1-activating gene variants occur in approximately 50% to 60% of T-ALL cases, and FBXW7-inactivating gene variants occur in approximately 15% of cases. Approximately 60% of T-ALL cases have Notch pathway activation by variants in at least one of these genes.[168,169]

  The prognostic significance of NOTCH1 and FBXW7 variants may be modulated by genomic alterations in RAS and PTEN. The French Acute Lymphoblastic Leukaemia Study Group (FRALLE) and the Group for Research on Adult Acute Lymphoblastic Leukemia reported that patients having altered NOTCH1 or FBXW7 and wild-type PTEN and RAS constituted a favorable-risk group (i.e., low-risk group), while patients with PTEN or RAS variants, regardless of NOTCH1 and FBXW7 status, have a significantly higher risk of treatment failure (i.e., high-risk group).[170,171] In the FRALLE study, the 5-year disease-free survival rate was 88% for the genetic low-risk group of patients and 60% for the genetic high-risk group of patients.[170] However, using the same criteria to define the genetic risk group, the Dana-Farber Cancer Institute consortium was unable to replicate these results. They reported a 5-year EFS rate of 86% for genetic low-risk patients and 79% for the genetic high-risk patients, a difference that was not statistically significant (P = .26).[169]

• Chromosomal translocations.

  Multiple chromosomal translocations have been identified in T-ALL that lead to deregulated expression of the target genes. These chromosome rearrangements fuse genes encoding transcription factors (e.g., TAL1, TAL2, LMO1, LMO2, LYL1, TLX1, TLX3, NKX2-I, HOXA, and MYB) to one of the T-cell receptor loci (or to other genes) and result in deregulated expression of these transcription factors in leukemia cells.[162,163,172–176] These translocations are often not apparent by examining a standard karyotype, but can be identified using more sensitive screening techniques, including FISH or PCR.[163] Variants in a noncoding region near the TAL1 gene that produce a super-enhancer upstream of TAL1 represent nontranslocation genomic alterations that can also activate TAL1 transcription to induce T-ALL.[165]

  Translocations resulting in chimeric fusion proteins are also observed in T-ALL.[170]

  • A NUP214::ABL1 fusion has been noted in 4% to 6% of T-ALL cases and is observed in both adults and children, with a male predominance.[177–179] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or, more rarely, as a small homogeneous staining region.[179] T-ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).[179] ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may demonstrate therapeutic benefits in this T-ALL subtype,[177,178,180] although clinical experience with this strategy is very limited.[181–183]
  • Gene fusions involving SPI1 (encoding the transcription factor PU.1) were reported in 4% of Japanese children with T-ALL.[184] Fusion partners included STMN1 and TCF7. T-ALL cases with SPI1 fusions had a particularly poor prognosis; six of seven affected individuals died within 3 years of diagnosis of early relapse.
  • BCL11B is a zinc finger transcription factor that plays a dual role as a transcription activator and repressor. It is known to play a critical role in T-cell differentiation. In T-ALL, the BCL11B gene is involved in a t(5;14)(q35;q32) translocation where a distal BCL11B enhancer drives aberrant expression of TLX3 (or NKX2-5).[185] In the process of donating its enhancer, one allele of BCL11B is inactivated. However, the resulting haploinsufficient state itself may also play a role in tumor pathogenesis. The role of BCL11B as a tumor suppressor gene is supported by the finding that about 16% of patients have T-ALL that harbors deletions or missense variants.[162,186] As described in the sections for early T-cell precursor (ETP) and T/myeloid mixed phenotype acute leukemia (T/M MPAL), BCL11B may also be leukemogenic through overexpression.
  • Other recurring gene fusions in T-ALL patients include those involving MLLT10, KMT2A, NUP214, and NUP98.[162,166]
• Ploidy.
  • Recurrent abnormalities in chromosome number are much less common in T-ALL than in B-ALL. One study included 2,250 pediatric patients with T-ALL who were treated in Associazione Italiana di Ematologia e Oncologia Pediatrica/Berlin-Frankfurt-Münster protocols. The study found that near tetraploidy (DNA index, 1.79–2.28 or 81–103 chromosomes), observed in 1.4% of patients, was associated with favorable disease features and outcomes.[187]

Early T-cell precursor (ETP) ALL cytogenetics/genomics

Detailed molecular characterization of ETP ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by variant or copy number alteration in more than one-third of cases.[188] Compared with other T-ALL cases, the ETP group had a lower rate of NOTCH1 variants and significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of ETP ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.[188]

Studies have found that the absence of biallelic deletion of the TCR-gamma locus (ABD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-ALL.[189,190] ABD is characteristic of early thymic precursor cells, and many of the T-ALL patients with ABD have an immunophenotype consistent with the diagnosis of ETP phenotype.

Allele-specific, generally high expression of BCL11B plays an oncogenic role in a subset of cases identified as ETP ALL (7 of 58 in one study) as well as in up to 30% to 40% of lineage ambiguous leukemia T/M mixed phenotype acute leukemia (T/M MPAL).[191,192] The dysregulated expression of BCL11B can occur by multiple mechanisms.

• One such alteration is t(2;14)(q22;q32), which produces an in-frame ZEB2::BCL11B fusion gene.
• Other structural variants leading to allele-specific deregulated BCL11B expression include structural variants that juxtapose regulatory sequences of active genes (e.g., ARID1B [chromosome 6], BENC [chromosome 7], and CDK6 [chromosome 7]) upstream or downstream of the BCL11B locus leading to aberrant expression in a process called enhancer hijacking.
• Finally, in about 20% of cases with deregulated BCL11B expression, a translocation cannot be identified. In many such cases, amplification of a downstream enhancer, BCL11B enhancer tandem amplification (BETA), leads to BCL11B promoter driven transcription.
• There is a high prevalence of FLT3 alterations and JAK/STAT activation in acute leukemias driven by genomic alterations leading to BCL11B expression.[191]

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28. Harris MB, Shuster JJ, Carroll A, et al.: Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study. Blood 79 (12): 3316-24, 1992. [PUBMED Abstract]
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31. Carroll AJ, Shago M, Mikhail FM, et al.: Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children’s Oncology Group. Cancer Genet 238: 62-68, 2019. [PUBMED Abstract]
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33. Raimondi SC, Zhou Y, Shurtleff SA, et al.: Near-triploidy and near-tetraploidy in childhood acute lymphoblastic leukemia: association with B-lineage blast cells carrying the ETV6-RUNX1 fusion, T-lineage immunophenotype, and favorable outcome. Cancer Genet Cytogenet 169 (1): 50-7, 2006. [PUBMED Abstract]
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35. Lemez P, Attarbaschi A, Béné MC, et al.: Childhood near-tetraploid acute lymphoblastic leukemia: an EGIL study on 36 cases. Eur J Haematol 85 (4): 300-8, 2010. [PUBMED Abstract]
36. Paulsson K, Lilljebjörn H, Biloglav A, et al.: The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Nat Genet 47 (6): 672-6, 2015. [PUBMED Abstract]
37. Harrison CJ, Moorman AV, Broadfield ZJ, et al.: Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia. Br J Haematol 125 (5): 552-9, 2004. [PUBMED Abstract]
38. Mullighan CG, Jeha S, Pei D, et al.: Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. Blood 126 (26): 2896-9, 2015. [PUBMED Abstract]
39. Pui CH, Rebora P, Schrappe M, et al.: Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study. J Clin Oncol 37 (10): 770-779, 2019. [PUBMED Abstract]
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41. Irving J, Matheson E, Minto L, et al.: Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood 124 (23): 3420-30, 2014. [PUBMED Abstract]
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46. Loh ML, Goldwasser MA, Silverman LB, et al.: Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood 107 (11): 4508-13, 2006. [PUBMED Abstract]
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48. Madzo J, Zuna J, Muzíková K, et al.: Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time quantitative reverse transcriptase-polymerase chain reaction study. Cancer 97 (1): 105-13, 2003. [PUBMED Abstract]
49. Bhojwani D, Pei D, Sandlund JT, et al.: ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia 26 (2): 265-70, 2012. [PUBMED Abstract]
50. Enshaei A, Schwab CJ, Konn ZJ, et al.: Long-term follow-up of ETV6-RUNX1 ALL reveals that NCI risk, rather than secondary genetic abnormalities, is the key risk factor. Leukemia 27 (11): 2256-9, 2013. [PUBMED Abstract]
51. Barbany G, Andersen MK, Autio K, et al.: Additional aberrations of the ETV6 and RUNX1 genes have no prognostic impact in 229 t(12;21)(p13;q22)-positive B-cell precursor acute lymphoblastic leukaemias treated according to the NOPHO-ALL-2000 protocol. Leuk Res 36 (7): 936-8, 2012. [PUBMED Abstract]
52. Forestier E, Heyman M, Andersen MK, et al.: Outcome of ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall survival. Br J Haematol 140 (6): 665-72, 2008. [PUBMED Abstract]
53. Seeger K, Stackelberg AV, Taube T, et al.: Relapse of TEL-AML1–positive acute lymphoblastic leukemia in childhood: a matched-pair analysis. J Clin Oncol 19 (13): 3188-93, 2001. [PUBMED Abstract]
54. Gandemer V, Chevret S, Petit A, et al.: Excellent prognosis of late relapses of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol. Haematologica 97 (11): 1743-50, 2012. [PUBMED Abstract]
55. Zuna J, Ford AM, Peham M, et al.: TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia. Clin Cancer Res 10 (16): 5355-60, 2004. [PUBMED Abstract]
56. van Delft FW, Horsley S, Colman S, et al.: Clonal origins of relapse in ETV6-RUNX1 acute lymphoblastic leukemia. Blood 117 (23): 6247-54, 2011. [PUBMED Abstract]
57. Aricò M, Schrappe M, Hunger SP, et al.: Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol 28 (31): 4755-61, 2010. [PUBMED Abstract]
58. Schrappe M, Aricò M, Harbott J, et al.: Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 92 (8): 2730-41, 1998. [PUBMED Abstract]
59. Ribeiro RC, Broniscer A, Rivera GK, et al.: Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts. Leukemia 11 (9): 1493-6, 1997. [PUBMED Abstract]
60. Biondi A, Schrappe M, De Lorenzo P, et al.: Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol 13 (9): 936-45, 2012. [PUBMED Abstract]
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63. Duffield AS, Mullighan CG, Borowitz MJ: International Consensus Classification of acute lymphoblastic leukemia/lymphoma. Virchows Arch 482 (1): 11-26, 2023. [PUBMED Abstract]
64. Short NJ, Jabbour E, Macaron W, et al.: Ultrasensitive NGS MRD assessment in Ph+ ALL: Prognostic impact and correlation with RT-PCR for BCR::ABL1. Am J Hematol 98 (8): 1196-1203, 2023. [PUBMED Abstract]
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68. Pui CH, Chessells JM, Camitta B, et al.: Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 17 (4): 700-6, 2003. [PUBMED Abstract]
69. Johansson B, Moorman AV, Haas OA, et al.: Hematologic malignancies with t(4;11)(q21;q23)–a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. European 11q23 Workshop participants. Leukemia 12 (5): 779-87, 1998. [PUBMED Abstract]
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71. Harrison CJ, Moorman AV, Barber KE, et al.: Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study. Br J Haematol 129 (4): 520-30, 2005. [PUBMED Abstract]
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73. Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370 (9583): 240-50, 2007. [PUBMED Abstract]
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76. Pui CH, Gaynon PS, Boyett JM, et al.: Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359 (9321): 1909-15, 2002. [PUBMED Abstract]
77. Rubnitz JE, Camitta BM, Mahmoud H, et al.: Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19)(q23;p13.3) translocation. J Clin Oncol 17 (1): 191-6, 1999. [PUBMED Abstract]
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79. Uckun FM, Sensel MG, Sather HN, et al.: Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children’s Cancer Group. J Clin Oncol 16 (2): 527-35, 1998. [PUBMED Abstract]
80. Fischer U, Forster M, Rinaldi A, et al.: Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nat Genet 47 (9): 1020-9, 2015. [PUBMED Abstract]
81. Pui CH, Sandlund JT, Pei D, et al.: Results of therapy for acute lymphoblastic leukemia in black and white children. JAMA 290 (15): 2001-7, 2003. [PUBMED Abstract]
82. Crist WM, Carroll AJ, Shuster JJ, et al.: Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study. Blood 76 (1): 117-22, 1990. [PUBMED Abstract]
83. Andersen MK, Autio K, Barbany G, et al.: Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13): clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols. Br J Haematol 155 (2): 235-43, 2011. [PUBMED Abstract]
84. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360 (26): 2730-41, 2009. [PUBMED Abstract]
85. Jeha S, Pei D, Raimondi SC, et al.: Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1. Leukemia 23 (8): 1406-9, 2009. [PUBMED Abstract]
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88. Zaliova M, Potuckova E, Hovorkova L, et al.: ERG deletions in childhood acute lymphoblastic leukemia with DUX4 rearrangements are mostly polyclonal, prognostically relevant and their detection rate strongly depends on screening method sensitivity. Haematologica 104 (7): 1407-1416, 2019. [PUBMED Abstract]
89. Harvey RC, Mullighan CG, Wang X, et al.: Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood 116 (23): 4874-84, 2010. [PUBMED Abstract]
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91. Clappier E, Auclerc MF, Rapion J, et al.: An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia 28 (1): 70-7, 2014. [PUBMED Abstract]
92. Li Z, Lee SHR, Chin WHN, et al.: Distinct clinical characteristics of DUX4- and PAX5-altered childhood B-lymphoblastic leukemia. Blood Adv 5 (23): 5226-5238, 2021. [PUBMED Abstract]
93. Gu Z, Churchman M, Roberts K, et al.: Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. Nat Commun 7: 13331, 2016. [PUBMED Abstract]
94. Liu YF, Wang BY, Zhang WN, et al.: Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia. EBioMedicine 8: 173-83, 2016. [PUBMED Abstract]
95. Suzuki K, Okuno Y, Kawashima N, et al.: MEF2D-BCL9 Fusion Gene Is Associated With High-Risk Acute B-Cell Precursor Lymphoblastic Leukemia in Adolescents. J Clin Oncol 34 (28): 3451-9, 2016. [PUBMED Abstract]
96. Lilljebjörn H, Ågerstam H, Orsmark-Pietras C, et al.: RNA-seq identifies clinically relevant fusion genes in leukemia including a novel MEF2D/CSF1R fusion responsive to imatinib. Leukemia 28 (4): 977-9, 2014. [PUBMED Abstract]
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98. Qian M, Zhang H, Kham SK, et al.: Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP. Genome Res 27 (2): 185-195, 2017. [PUBMED Abstract]
99. Hirabayashi S, Butler ER, Ohki K, et al.: Clinical characteristics and outcomes of B-ALL with ZNF384 rearrangements: a retrospective analysis by the Ponte di Legno Childhood ALL Working Group. Leukemia 35 (11): 3272-3277, 2021. [PUBMED Abstract]
100. Shago M, Abla O, Hitzler J, et al.: Frequency and outcome of pediatric acute lymphoblastic leukemia with ZNF384 gene rearrangements including a novel translocation resulting in an ARID1B/ZNF384 gene fusion. Pediatr Blood Cancer 63 (11): 1915-21, 2016. [PUBMED Abstract]
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106. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
107. Hogan TF, Koss W, Murgo AJ, et al.: Acute lymphoblastic leukemia with chromosomal 5;14 translocation and hypereosinophilia: case report and literature review. J Clin Oncol 5 (3): 382-90, 1987. [PUBMED Abstract]
108. Grimaldi JC, Meeker TC: The t(5;14) chromosomal translocation in a case of acute lymphocytic leukemia joins the interleukin-3 gene to the immunoglobulin heavy chain gene. Blood 73 (8): 2081-5, 1989. [PUBMED Abstract]
109. Meeker TC, Hardy D, Willman C, et al.: Activation of the interleukin-3 gene by chromosome translocation in acute lymphocytic leukemia with eosinophilia. Blood 76 (2): 285-9, 1990. [PUBMED Abstract]
110. Sutton R, Lonergan M, Tapp H, et al.: Two cases of hypereosinophilia and high-risk acute lymphoblastic leukemia. Leukemia 22 (7): 1463-5, 2008. [PUBMED Abstract]
111. Koleilat A, Smadbeck JB, Zepeda-Mendoza CJ, et al.: Characterization of unusual iAMP21 B-lymphoblastic leukemia (iAMP21-ALL) from the Mayo Clinic and Children’s Oncology Group. Genes Chromosomes Cancer 61 (12): 710-719, 2022. [PUBMED Abstract]
112. Heerema NA, Carroll AJ, Devidas M, et al.: Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children’s oncology group studies: a report from the children’s oncology group. J Clin Oncol 31 (27): 3397-402, 2013. [PUBMED Abstract]
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114. Harrison CJ, Moorman AV, Schwab C, et al.: An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome. Leukemia 28 (5): 1015-21, 2014. [PUBMED Abstract]
115. Gu Z, Churchman ML, Roberts KG, et al.: PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nat Genet 51 (2): 296-307, 2019. [PUBMED Abstract]
116. Strehl S, König M, Dworzak MN, et al.: PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13). Leukemia 17 (6): 1121-3, 2003. [PUBMED Abstract]
117. Schwab C, Nebral K, Chilton L, et al.: Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia? Blood Adv 1 (19): 1473-7, 2017.
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119. Mullighan CG, Su X, Zhang J, et al.: Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 360 (5): 470-80, 2009. [PUBMED Abstract]
120. Reshmi SC, Harvey RC, Roberts KG, et al.: Targetable kinase gene fusions in high-risk B-ALL: a study from the Children’s Oncology Group. Blood 129 (25): 3352-3361, 2017. [PUBMED Abstract]
121. Roberts KG, Morin RD, Zhang J, et al.: Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 22 (2): 153-66, 2012. [PUBMED Abstract]
122. van der Veer A, Waanders E, Pieters R, et al.: Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood 122 (15): 2622-9, 2013. [PUBMED Abstract]
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126. Mullighan CG, Collins-Underwood JR, Phillips LA, et al.: Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 41 (11): 1243-6, 2009. [PUBMED Abstract]
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128. van Outersterp I, Tasian SK, Reichert CEJ, et al.: Tyrosine kinase inhibitor response of ABL-class acute lymphoblastic leukemia: the role of kinase type and SH3 domain. Blood 143 (21): 2178-2189, 2024. [PUBMED Abstract]
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131. Cario G, Zimmermann M, Romey R, et al.: Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol. Blood 115 (26): 5393-7, 2010. [PUBMED Abstract]
132. Ensor HM, Schwab C, Russell LJ, et al.: Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. Blood 117 (7): 2129-36, 2011. [PUBMED Abstract]
133. Schmäh J, Fedders B, Panzer-Grümayer R, et al.: Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene expression in childhood. Pediatr Blood Cancer 64 (10): , 2017. [PUBMED Abstract]
134. Raca G, Abdel-Azim H, Yue F, et al.: Increased Incidence of IKZF1 deletions and IGH-CRLF2 translocations in B-ALL of Hispanic/Latino children-a novel health disparity. Leukemia 35 (8): 2399-2402, 2021. [PUBMED Abstract]
135. Kovach AE, Wengyn M, Vu MH, et al.: IKZF1PLUS alterations contribute to outcome disparities in Hispanic/Latino children with B-lymphoblastic leukemia. Pediatr Blood Cancer 71 (7): e30996, 2024. [PUBMED Abstract]
136. Vesely C, Frech C, Eckert C, et al.: Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia. Leukemia 31 (7): 1491-1501, 2017. [PUBMED Abstract]
137. Russell LJ, Jones L, Enshaei A, et al.: Characterisation of the genomic landscape of CRLF2-rearranged acute lymphoblastic leukemia. Genes Chromosomes Cancer 56 (5): 363-372, 2017. [PUBMED Abstract]
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139. Morak M, Attarbaschi A, Fischer S, et al.: Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL. Blood 120 (26): 5134-42, 2012. [PUBMED Abstract]
140. Schwab CJ, Chilton L, Morrison H, et al.: Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features. Haematologica 98 (7): 1081-8, 2013. [PUBMED Abstract]
141. Chen IM, Harvey RC, Mullighan CG, et al.: Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children’s Oncology Group study. Blood 119 (15): 3512-22, 2012. [PUBMED Abstract]
142. Palmi C, Vendramini E, Silvestri D, et al.: Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia. Leukemia 26 (10): 2245-53, 2012. [PUBMED Abstract]
143. Clappier E, Grardel N, Bakkus M, et al.: IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children’s Leukemia Group study 58951. Leukemia 29 (11): 2154-61, 2015. [PUBMED Abstract]
144. Srinivasan S, Ramanathan S, Kumar S, et al.: Prevalence and prognostic significance of IKZF1 deletion in paediatric acute lymphoblastic leukemia: A systematic review and meta-analysis. Ann Hematol 102 (8): 2165-2179, 2023. [PUBMED Abstract]
145. Buitenkamp TD, Pieters R, Gallimore NE, et al.: Outcome in children with Down’s syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 26 (10): 2204-11, 2012. [PUBMED Abstract]
146. Krentz S, Hof J, Mendioroz A, et al.: Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia 27 (2): 295-304, 2013. [PUBMED Abstract]
147. Feng J, Tang Y: Prognostic significance of IKZF1 alteration status in pediatric B-lineage acute lymphoblastic leukemia: a meta-analysis. Leuk Lymphoma 54 (4): 889-91, 2013. [PUBMED Abstract]
148. Dörge P, Meissner B, Zimmermann M, et al.: IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica 98 (3): 428-32, 2013. [PUBMED Abstract]
149. Olsson L, Castor A, Behrendtz M, et al.: Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011. Leukemia 28 (2): 302-10, 2014. [PUBMED Abstract]
150. Boer JM, van der Veer A, Rizopoulos D, et al.: Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study. Leukemia 30 (1): 32-8, 2016. [PUBMED Abstract]
151. Tran TH, Harris MH, Nguyen JV, et al.: Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia. Blood Adv 2 (5): 529-533, 2018. [PUBMED Abstract]
152. Vrooman LM, Blonquist TM, Harris MH, et al.: Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001. Blood Adv 2 (12): 1449-1458, 2018. [PUBMED Abstract]
153. Öfverholm I, Rezayee F, Heyman M, et al.: The prognostic impact of IKZF1 deletions and UKALL genetic classifiers in paediatric B-cell precursor acute lymphoblastic leukaemia treated according to NOPHO 2008 protocols. Br J Haematol 202 (2): 384-392, 2023. [PUBMED Abstract]
154. van der Veer A, Zaliova M, Mottadelli F, et al.: IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood 123 (11): 1691-8, 2014. [PUBMED Abstract]
155. Stanulla M, Dagdan E, Zaliova M, et al.: IKZF1plus Defines a New Minimal Residual Disease-Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia. J Clin Oncol 36 (12): 1240-1249, 2018. [PUBMED Abstract]
156. Mangum DS, Meyer JA, Mason CC, et al.: Association of Combined Focal 22q11.22 Deletion and IKZF1 Alterations With Outcomes in Childhood Acute Lymphoblastic Leukemia. JAMA Oncol 7 (10): 1521-1528, 2021. [PUBMED Abstract]
157. Yeoh AEJ, Lu Y, Chin WHN, et al.: Intensifying Treatment of Childhood B-Lymphoblastic Leukemia With IKZF1 Deletion Reduces Relapse and Improves Overall Survival: Results of Malaysia-Singapore ALL 2010 Study. J Clin Oncol 36 (26): 2726-2735, 2018. [PUBMED Abstract]
158. Pieters R, de Groot-Kruseman H, Fiocco M, et al.: Improved Outcome for ALL by Prolonging Therapy for IKZF1 Deletion and Decreasing Therapy for Other Risk Groups. J Clin Oncol 41 (25): 4130-4142, 2023. [PUBMED Abstract]
159. Herbrueggen H, Mueller S, Rohde J, et al.: Treatment and outcome of IG-MYC+ neoplasms with precursor B-cell phenotype in childhood and adolescence. Leukemia 34 (3): 942-946, 2020. [PUBMED Abstract]
160. Sakaguchi K, Imamura T, Ishimaru S, et al.: Nationwide study of pediatric B-cell precursor acute lymphoblastic leukemia with chromosome 8q24/MYC rearrangement in Japan. Pediatr Blood Cancer 67 (7): e28341, 2020. [PUBMED Abstract]
161. Bomken S, Enshaei A, Schwalbe EC, et al.: Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement. Haematologica 108 (3): 717-731, 2023. [PUBMED Abstract]
162. Liu Y, Easton J, Shao Y, et al.: The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet 49 (8): 1211-1218, 2017. [PUBMED Abstract]
163. Armstrong SA, Look AT: Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 23 (26): 6306-15, 2005. [PUBMED Abstract]
164. Karrman K, Forestier E, Heyman M, et al.: Clinical and cytogenetic features of a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias: rare T-cell receptor gene rearrangements are associated with poor outcome. Genes Chromosomes Cancer 48 (9): 795-805, 2009. [PUBMED Abstract]
165. Mansour MR, Abraham BJ, Anders L, et al.: Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346 (6215): 1373-7, 2014. [PUBMED Abstract]
166. Steimlé T, Dourthe ME, Alcantara M, et al.: Clinico-biological features of T-cell acute lymphoblastic leukemia with fusion proteins. Blood Cancer J 12 (1): 14, 2022. [PUBMED Abstract]
167. Weng AP, Ferrando AA, Lee W, et al.: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306 (5694): 269-71, 2004. [PUBMED Abstract]
168. Gallo Llorente L, Luther H, Schneppenheim R, et al.: Identification of novel NOTCH1 mutations: increasing our knowledge of the NOTCH signaling pathway. Pediatr Blood Cancer 61 (5): 788-96, 2014. [PUBMED Abstract]
169. Burns MA, Place AE, Stevenson KE, et al.: Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer 68 (1): e28719, 2021. [PUBMED Abstract]
170. Petit A, Trinquand A, Chevret S, et al.: Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia. Blood 131 (3): 289-300, 2018. [PUBMED Abstract]
171. Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, et al.: Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol 31 (34): 4333-42, 2013. [PUBMED Abstract]
172. Bergeron J, Clappier E, Radford I, et al.: Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs. Blood 110 (7): 2324-30, 2007. [PUBMED Abstract]
173. van Grotel M, Meijerink JP, Beverloo HB, et al.: The outcome of molecular-cytogenetic subgroups in pediatric T-cell acute lymphoblastic leukemia: a retrospective study of patients treated according to DCOG or COALL protocols. Haematologica 91 (9): 1212-21, 2006. [PUBMED Abstract]
174. Cavé H, Suciu S, Preudhomme C, et al.: Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood 103 (2): 442-50, 2004. [PUBMED Abstract]
175. Baak U, Gökbuget N, Orawa H, et al.: Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group. Leukemia 22 (6): 1154-60, 2008. [PUBMED Abstract]
176. Ferrando AA, Neuberg DS, Dodge RK, et al.: Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia. Lancet 363 (9408): 535-6, 2004. [PUBMED Abstract]
177. Burmeister T, Gökbuget N, Reinhardt R, et al.: NUP214-ABL1 in adult T-ALL: the GMALL study group experience. Blood 108 (10): 3556-9, 2006. [PUBMED Abstract]
178. Graux C, Stevens-Kroef M, Lafage M, et al.: Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia. Leukemia 23 (1): 125-33, 2009. [PUBMED Abstract]
179. Hagemeijer A, Graux C: ABL1 rearrangements in T-cell acute lymphoblastic leukemia. Genes Chromosomes Cancer 49 (4): 299-308, 2010. [PUBMED Abstract]
180. Quintás-Cardama A, Tong W, Manshouri T, et al.: Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies. Leukemia 22 (6): 1117-24, 2008. [PUBMED Abstract]
181. Clarke S, O’Reilly J, Romeo G, et al.: NUP214-ABL1 positive T-cell acute lymphoblastic leukemia patient shows an initial favorable response to imatinib therapy post relapse. Leuk Res 35 (7): e131-3, 2011. [PUBMED Abstract]
182. Deenik W, Beverloo HB, van der Poel-van de Luytgaarde SC, et al.: Rapid complete cytogenetic remission after upfront dasatinib monotherapy in a patient with a NUP214-ABL1-positive T-cell acute lymphoblastic leukemia. Leukemia 23 (3): 627-9, 2009. [PUBMED Abstract]
183. Crombet O, Lastrapes K, Zieske A, et al.: Complete morphologic and molecular remission after introduction of dasatinib in the treatment of a pediatric patient with t-cell acute lymphoblastic leukemia and ABL1 amplification. Pediatr Blood Cancer 59 (2): 333-4, 2012. [PUBMED Abstract]
184. Seki M, Kimura S, Isobe T, et al.: Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. Nat Genet 49 (8): 1274-1281, 2017. [PUBMED Abstract]
185. Nagel S, Scherr M, Kel A, et al.: Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3′-BCL11B enhancers and coregulation by PU.1 and HMGA1. Cancer Res 67 (4): 1461-71, 2007. [PUBMED Abstract]
186. Gutierrez A, Kentsis A, Sanda T, et al.: The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood 118 (15): 4169-73, 2011. [PUBMED Abstract]
187. Ceppi F, Gotti G, Möricke A, et al.: Near-tetraploid T-cell acute lymphoblastic leukaemia in childhood: Results of the AIEOP-BFM ALL studies. Eur J Cancer 175: 120-124, 2022. [PUBMED Abstract]
188. Zhang J, Ding L, Holmfeldt L, et al.: The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481 (7380): 157-63, 2012. [PUBMED Abstract]
189. Gutierrez A, Dahlberg SE, Neuberg DS, et al.: Absence of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia. J Clin Oncol 28 (24): 3816-23, 2010. [PUBMED Abstract]
190. Yang YL, Hsiao CC, Chen HY, et al.: Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T-cell acute lymphoblastic leukemia. Pediatr Blood Cancer 58 (6): 846-51, 2012. [PUBMED Abstract]
191. Montefiori LE, Bendig S, Gu Z, et al.: Enhancer Hijacking Drives Oncogenic BCL11B Expression in Lineage-Ambiguous Stem Cell Leukemia. Cancer Discov 11 (11): 2846-2867, 2021. [PUBMED Abstract]
192. Di Giacomo D, La Starza R, Gorello P, et al.: 14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia. Blood 138 (9): 773-784, 2021. [PUBMED Abstract]
193. Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009. [PUBMED Abstract]
194. Borowitz MJ, Béné MC, Harris NL, et al.: Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 179-87.
195. Davies SM, Bhatia S, Ross JA, et al.: Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia. Blood 100 (1): 67-71, 2002. [PUBMED Abstract]
196. Krajinovic M, Costea I, Chiasson S: Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet 359 (9311): 1033-4, 2002. [PUBMED Abstract]
197. Krajinovic M, Lemieux-Blanchard E, Chiasson S, et al.: Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 4 (1): 66-72, 2004. [PUBMED Abstract]
198. Schmiegelow K, Forestier E, Kristinsson J, et al.: Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia 23 (3): 557-64, 2009. [PUBMED Abstract]
199. Relling MV, Hancock ML, Boyett JM, et al.: Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 93 (9): 2817-23, 1999. [PUBMED Abstract]
200. Stanulla M, Schaeffeler E, Flohr T, et al.: Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA 293 (12): 1485-9, 2005. [PUBMED Abstract]
201. Yang JJ, Landier W, Yang W, et al.: Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 33 (11): 1235-42, 2015. [PUBMED Abstract]
202. Relling MV, Hancock ML, Rivera GK, et al.: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91 (23): 2001-8, 1999. [PUBMED Abstract]
203. Moriyama T, Nishii R, Perez-Andreu V, et al.: NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 48 (4): 367-73, 2016. [PUBMED Abstract]
204. Tanaka Y, Kato M, Hasegawa D, et al.: Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol 171 (1): 109-15, 2015. [PUBMED Abstract]
205. Diouf B, Crews KR, Lew G, et al.: Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA 313 (8): 815-23, 2015. [PUBMED Abstract]
206. Yang JJ, Cheng C, Yang W, et al.: Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301 (4): 393-403, 2009. [PUBMED Abstract]
207. Gregers J, Christensen IJ, Dalhoff K, et al.: The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood 115 (23): 4671-7, 2010. [PUBMED Abstract]
208. Radtke S, Zolk O, Renner B, et al.: Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood 121 (26): 5145-53, 2013. [PUBMED Abstract]

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55. Gajjar A, Harrison PL, Sandlund JT, et al.: Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 96 (10): 3381-4, 2000. [PUBMED Abstract]
56. Matloub Y, Bostrom BC, Hunger SP, et al.: Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood 118 (2): 243-51, 2011. [PUBMED Abstract]
57. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360 (26): 2730-41, 2009. [PUBMED Abstract]
58. Levinsen M, Taskinen M, Abrahamsson J, et al.: Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 61 (8): 1416-21, 2014. [PUBMED Abstract]
59. Jeha S, Pei D, Choi J, et al.: Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16. J Clin Oncol 37 (35): 3377-3391, 2019. [PUBMED Abstract]
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72. Li Z, Chang TC, Junco JJ, et al.: Genomic landscape of Down syndrome-associated acute lymphoblastic leukemia. Blood 142 (2): 172-184, 2023. [PUBMED Abstract]
73. Mullighan CG, Collins-Underwood JR, Phillips LA, et al.: Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 41 (11): 1243-6, 2009. [PUBMED Abstract]
74. Bercovich D, Ganmore I, Scott LM, et al.: Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down’s syndrome. Lancet 372 (9648): 1484-92, 2008. [PUBMED Abstract]
75. Gaikwad A, Rye CL, Devidas M, et al.: Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol 144 (6): 930-2, 2009. [PUBMED Abstract]
76. Kearney L, Gonzalez De Castro D, Yeung J, et al.: Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood 113 (3): 646-8, 2009. [PUBMED Abstract]
77. Buitenkamp TD, Pieters R, Gallimore NE, et al.: Outcome in children with Down’s syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 26 (10): 2204-11, 2012. [PUBMED Abstract]
78. Hanada I, Terui K, Ikeda F, et al.: Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan. Genes Chromosomes Cancer 53 (11): 902-10, 2014. [PUBMED Abstract]
79. Pui CH, Boyett JM, Relling MV, et al.: Sex differences in prognosis for children with acute lymphoblastic leukemia. J Clin Oncol 17 (3): 818-24, 1999. [PUBMED Abstract]
80. Shuster JJ, Wacker P, Pullen J, et al.: Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study. J Clin Oncol 16 (8): 2854-63, 1998. [PUBMED Abstract]
81. Chessells JM, Richards SM, Bailey CC, et al.: Gender and treatment outcome in childhood lymphoblastic leukaemia: report from the MRC UKALL trials. Br J Haematol 89 (2): 364-72, 1995. [PUBMED Abstract]
82. Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97 (5): 1211-8, 2001. [PUBMED Abstract]
83. Hunger SP, Lu X, Devidas M, et al.: Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol 30 (14): 1663-9, 2012. [PUBMED Abstract]
84. Gupta S, Teachey DT, Chen Z, et al.: Sex-based disparities in outcome in pediatric acute lymphoblastic leukemia: a Children’s Oncology Group report. Cancer 128 (9): 1863-1870, 2022. [PUBMED Abstract]
85. Bhatia S: Influence of race and socioeconomic status on outcome of children treated for childhood acute lymphoblastic leukemia. Curr Opin Pediatr 16 (1): 9-14, 2004. [PUBMED Abstract]
86. Kadan-Lottick NS, Ness KK, Bhatia S, et al.: Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA 290 (15): 2008-14, 2003. [PUBMED Abstract]
87. Tai EW, Ward KC, Bonaventure A, et al.: Survival among children diagnosed with acute lymphoblastic leukemia in the United States, by race and age, 2001 to 2009: Findings from the CONCORD-2 study. Cancer 123 (Suppl 24): 5178-5189, 2017. [PUBMED Abstract]
88. Kahn JM, Cole PD, Blonquist TM, et al.: An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001. Pediatr Blood Cancer 65 (3): , 2018. [PUBMED Abstract]
89. Gupta S, Dai Y, Chen Z, et al.: Racial and ethnic disparities in childhood and young adult acute lymphocytic leukaemia: secondary analyses of eight Children’s Oncology Group cohort trials. Lancet Haematol 10 (2): e129-e141, 2023. [PUBMED Abstract]
90. Kovach AE, Wengyn M, Vu MH, et al.: IKZF1PLUS alterations contribute to outcome disparities in Hispanic/Latino children with B-lymphoblastic leukemia. Pediatr Blood Cancer 71 (7): e30996, 2024. [PUBMED Abstract]
91. Lee SHR, Antillon-Klussmann F, Pei D, et al.: Association of Genetic Ancestry With the Molecular Subtypes and Prognosis of Childhood Acute Lymphoblastic Leukemia. JAMA Oncol 8 (3): 354-363, 2022. [PUBMED Abstract]
92. Harvey RC, Mullighan CG, Chen IM, et al.: Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 115 (26): 5312-21, 2010. [PUBMED Abstract]
93. Bhatia S, Landier W, Shangguan M, et al.: Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children’s oncology group. J Clin Oncol 30 (17): 2094-101, 2012. [PUBMED Abstract]
94. Bhatia S, Landier W, Hageman L, et al.: 6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children’s Oncology Group study. Blood 124 (15): 2345-53, 2014. [PUBMED Abstract]
95. Yang JJ, Cheng C, Devidas M, et al.: Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet 43 (3): 237-41, 2011. [PUBMED Abstract]
96. Xu H, Cheng C, Devidas M, et al.: ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 30 (7): 751-7, 2012. [PUBMED Abstract]
97. Perez-Andreu V, Roberts KG, Harvey RC, et al.: Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet 45 (12): 1494-8, 2013. [PUBMED Abstract]
98. Aldhafiri FK, McColl JH, Reilly JJ: Prognostic significance of being overweight and obese at diagnosis in children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 36 (3): 234-6, 2014. [PUBMED Abstract]
99. Baillargeon J, Langevin AM, Lewis M, et al.: Obesity and survival in a cohort of predominantly Hispanic children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 28 (9): 575-8, 2006. [PUBMED Abstract]
100. Hijiya N, Panetta JC, Zhou Y, et al.: Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia. Blood 108 (13): 3997-4002, 2006. [PUBMED Abstract]
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104. Orgel E, Tucci J, Alhushki W, et al.: Obesity is associated with residual leukemia following induction therapy for childhood B-precursor acute lymphoblastic leukemia. Blood 124 (26): 3932-8, 2014. [PUBMED Abstract]
105. Eissa HM, Zhou Y, Panetta JC, et al.: The effect of body mass index at diagnosis on clinical outcome in children with newly diagnosed acute lymphoblastic leukemia. Blood Cancer J 7 (2): e531, 2017. [PUBMED Abstract]
106. Egnell C, Heyman M, Jónsson ÓG, et al.: Obesity as a predictor of treatment-related toxicity in children with acute lymphoblastic leukaemia. Br J Haematol 196 (5): 1239-1247, 2022. [PUBMED Abstract]
107. Shimony S, Flamand Y, Valtis YK, et al.: Effect of BMI on toxicities and survival among adolescents and young adults treated on DFCI Consortium ALL trials. Blood Adv 7 (18): 5234-5245, 2023. [PUBMED Abstract]
108. den Hoed MA, Pluijm SM, de Groot-Kruseman HA, et al.: The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia. Haematologica 100 (1): 62-9, 2015. [PUBMED Abstract]
109. Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017.
110. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
111. Pui CH, Chessells JM, Camitta B, et al.: Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 17 (4): 700-6, 2003. [PUBMED Abstract]
112. Möricke A, Ratei R, Ludwig WD, et al.: Prognostic factors in CD10 negative precursor b-cell acute lymphoblastic leukemia in children: data from three consecutive trials ALL-BFM 86, 90, and 95. [Abstract] Blood 104 (11): A-1957, 540a, 2004.
113. Hunger SP: Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood 87 (4): 1211-24, 1996. [PUBMED Abstract]
114. Uckun FM, Sensel MG, Sather HN, et al.: Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children’s Cancer Group. J Clin Oncol 16 (2): 527-35, 1998. [PUBMED Abstract]
115. Koehler M, Behm FG, Shuster J, et al.: Transitional pre-B-cell acute lymphoblastic leukemia of childhood is associated with favorable prognostic clinical features and an excellent outcome: a Pediatric Oncology Group study. Leukemia 7 (12): 2064-8, 1993. [PUBMED Abstract]
116. Wagener R, López C, Kleinheinz K, et al.: IG-MYC+ neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas. Blood 132 (21): 2280-2285, 2018. [PUBMED Abstract]
117. Winter SS, Dunsmore KP, Devidas M, et al.: Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children’s Oncology Group AALL0434 Methotrexate Randomization. J Clin Oncol 36 (29): 2926-2934, 2018. [PUBMED Abstract]
118. Slack JL, Arthur DC, Lawrence D, et al.: Secondary cytogenetic changes in acute promyelocytic leukemia–prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: a Cancer and Leukemia Group B study. J Clin Oncol 15 (5): 1786-95, 1997. [PUBMED Abstract]
119. Attarbaschi A, Mann G, Dworzak M, et al.: Mediastinal mass in childhood T-cell acute lymphoblastic leukemia: significance and therapy response. Med Pediatr Oncol 39 (6): 558-65, 2002. [PUBMED Abstract]
120. Coustan-Smith E, Mullighan CG, Onciu M, et al.: Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 10 (2): 147-56, 2009. [PUBMED Abstract]
121. Ma M, Wang X, Tang J, et al.: Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia. Front Med 6 (4): 416-20, 2012. [PUBMED Abstract]
122. Inukai T, Kiyokawa N, Campana D, et al.: Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children’s Cancer Study Group Study L99-15. Br J Haematol 156 (3): 358-65, 2012. [PUBMED Abstract]
123. Patrick K, Wade R, Goulden N, et al.: Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. Br J Haematol 166 (3): 421-4, 2014. [PUBMED Abstract]
124. Pui CH, Rubnitz JE, Hancock ML, et al.: Reappraisal of the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia. J Clin Oncol 16 (12): 3768-73, 1998. [PUBMED Abstract]
125. Uckun FM, Sather HN, Gaynon PS, et al.: Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood 90 (1): 28-35, 1997. [PUBMED Abstract]
126. Corrente F, Bellesi S, Metafuni E, et al.: Role of flow-cytometric immunophenotyping in prediction of BCR/ABL1 gene rearrangement in adult B-cell acute lymphoblastic leukemia. Cytometry B Clin Cytom 94 (3): 468-476, 2018. [PUBMED Abstract]
127. Hirabayashi S, Ohki K, Nakabayashi K, et al.: ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica 102 (1): 118-129, 2017. [PUBMED Abstract]
128. Qian M, Zhang H, Kham SK, et al.: Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP. Genome Res 27 (2): 185-195, 2017. [PUBMED Abstract]
129. Relling MV, Dervieux T: Pharmacogenetics and cancer therapy. Nat Rev Cancer 1 (2): 99-108, 2001. [PUBMED Abstract]
130. van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al.: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352 (9142): 1731-8, 1998. [PUBMED Abstract]
131. Wood B, Wu D, Crossley B, et al.: Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. Blood 131 (12): 1350-1359, 2018. [PUBMED Abstract]
132. Zhou J, Goldwasser MA, Li A, et al.: Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood 110 (5): 1607-11, 2007. [PUBMED Abstract]
133. Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood 111 (12): 5477-85, 2008. [PUBMED Abstract]
134. Borowitz MJ, Wood BL, Devidas M, et al.: Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood 126 (8): 964-71, 2015. [PUBMED Abstract]
135. Conter V, Bartram CR, Valsecchi MG, et al.: Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115 (16): 3206-14, 2010. [PUBMED Abstract]
136. O’Connor D, Enshaei A, Bartram J, et al.: Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia. J Clin Oncol 36 (1): 34-43, 2018. [PUBMED Abstract]
137. Basso G, Veltroni M, Valsecchi MG, et al.: Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 27 (31): 5168-74, 2009. [PUBMED Abstract]
138. Pui CH, Pei D, Coustan-Smith E, et al.: Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol 16 (4): 465-74, 2015. [PUBMED Abstract]
139. Rau RE, Dai Y, Devidas M, et al.: Prognostic impact of minimal residual disease at the end of consolidation in NCI standard-risk B-lymphoblastic leukemia: A report from the Children’s Oncology Group. Pediatr Blood Cancer 68 (4): e28929, 2021. [PUBMED Abstract]
140. Stutterheim J, van der Waarden R, de Groot-Kruseman HA, et al.: Are measurable residual disease results after consolidation therapy useful in children with acute lymphoblastic leukemia? Leukemia 38 (11): 2376-2381, 2024. [PUBMED Abstract]
141. Schrappe M, Valsecchi MG, Bartram CR, et al.: Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood 118 (8): 2077-84, 2011. [PUBMED Abstract]
142. Teachey DT, Devidas M, Wood BL, et al.: Children’s Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma. J Clin Oncol 40 (19): 2106-2118, 2022. [PUBMED Abstract]
143. Bartram J, Wade R, Vora A, et al.: Excellent outcome of minimal residual disease-defined low-risk patients is sustained with more than 10 years follow-up: results of UK paediatric acute lymphoblastic leukaemia trials 1997-2003. Arch Dis Child 101 (5): 449-54, 2016. [PUBMED Abstract]
144. Vora A, Goulden N, Mitchell C, et al.: Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol 15 (8): 809-18, 2014. [PUBMED Abstract]
145. Pieters R, de Groot-Kruseman H, Van der Velden V, et al.: Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol 34 (22): 2591-601, 2016. [PUBMED Abstract]
146. Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997. [PUBMED Abstract]
147. Borowitz MJ, Wood BL, Devidas M, et al.: Assessment of end induction minimal residual disease (MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day 14 marrow examination: A Children’s Oncology Group study. [Abstract] J Clin Oncol 31 (Suppl 15): A-10001, 2013. Also available online. Last accessed June 04, 2021.
148. Möricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111 (9): 4477-89, 2008. [PUBMED Abstract]
149. Griffin TC, Shuster JJ, Buchanan GR, et al.: Slow disappearance of peripheral blood blasts is an adverse prognostic factor in childhood T cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Leukemia 14 (5): 792-5, 2000. [PUBMED Abstract]
150. Volejnikova J, Mejstrikova E, Valova T, et al.: Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior prognosis. Haematologica 96 (12): 1815-21, 2011. [PUBMED Abstract]
151. Schrappe M, Hunger SP, Pui CH, et al.: Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med 366 (15): 1371-81, 2012. [PUBMED Abstract]
152. Möricke A, Zimmermann M, Valsecchi MG, et al.: Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood 127 (17): 2101-12, 2016. [PUBMED Abstract]
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156. Schwab C, Ryan SL, Chilton L, et al.: EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications. Blood 127 (18): 2214-8, 2016. [PUBMED Abstract]
157. den Boer ML, Cario G, Moorman AV, et al.: Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study. Lancet Haematol 8 (1): e55-e66, 2021. [PUBMED Abstract]
158. Dunsmore KP, Winter SS, Devidas M, et al.: Children’s Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol 38 (28): 3282-3293, 2020. [PUBMED Abstract]
159. Gupta S, Devidas M, Loh ML, et al.: Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group (COG). Leukemia 32 (6): 1370-1379, 2018. [PUBMED Abstract]
160. Moghrabi A, Levy DE, Asselin B, et al.: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109 (3): 896-904, 2007. [PUBMED Abstract]
161. Veerman AJ, Kamps WA, van den Berg H, et al.: Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncol 10 (10): 957-66, 2009. [PUBMED Abstract]
162. Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104 (12): 3527-34, 2004. [PUBMED Abstract]
163. Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005 Aug 20-26. [PUBMED Abstract]
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1. Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403, 2005. [PUBMED Abstract]
2. Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881. Pediatr Blood Cancer 49 (3): 344-8, 2007. [PUBMED Abstract]

The treatment of children and adolescents with acute lymphoblastic leukemia (ALL) entails complicated risk assignment, extensive therapies, and intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support). Because of these factors, the evaluation and treatment of these patients are best coordinated by a multidisciplinary team in cancer centers or hospitals with all of the necessary pediatric supportive care facilities.[1] This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[1] Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Because myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy treatment, adequate facilities must be immediately available for both hematological support and treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during the remission induction phase, and another 1% to 3% die after having achieved complete remission from treatment-related complications.[2–6] It is important that the clinical centers and the specialists directing the patient’s care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.

Clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical trials for children with ALL are generally designed to compare standard therapy for a particular risk group with a potentially better treatment approach that may improve survival and/or diminish toxicities associated with the standard treatment regimen. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Many of the therapeutic innovations that produced increased survival rates in children with ALL were achieved through clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial. Information about ongoing clinical trials is available from the NCI website.

Risk-based treatment assignment is an important therapeutic strategy for children with ALL. This approach allows children who historically have a very good outcome to be treated with less intensive therapy and to be spared more toxic treatments, while children with a historically lower probability of long-term survival receive more intensive therapy that may increase their chance of cure. For more information about clinical and laboratory features that have shown prognostic value, see the Risk-Based Treatment Assignment section.

References

1. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.
2. Rubnitz JE, Lensing S, Zhou Y, et al.: Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience. Cancer 101 (7): 1677-84, 2004. [PUBMED Abstract]
3. Christensen MS, Heyman M, Möttönen M, et al.: Treatment-related death in childhood acute lymphoblastic leukaemia in the Nordic countries: 1992-2001. Br J Haematol 131 (1): 50-8, 2005. [PUBMED Abstract]
4. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study–Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013. [PUBMED Abstract]
5. Lund B, Åsberg A, Heyman M, et al.: Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer 56 (4): 551-9, 2011. [PUBMED Abstract]
6. Alvarez EM, Malogolowkin M, Li Q, et al.: Decreased Early Mortality in Young Adult Patients With Acute Lymphoblastic Leukemia Treated at Specialized Cancer Centers in California. J Oncol Pract 15 (4): e316-e327, 2019. [PUBMED Abstract]

Research teams from around the world have made remarkable progress in the past decade in elucidating the genomic landscape of most types of childhood cancer. A decade ago it was possible to hope that targetable oncogenes, such as activated tyrosine kinases, might be identified in a high percentage of childhood cancers. However, it is now clear that the genomic landscape of childhood cancer is highly varied, and in many cases is quite distinctive from that of the common adult cancers.

There are examples of genomic lesions that have provided immediate therapeutic direction, including the following:

For some cancers, the genomic findings have been highly illuminating in the identification of genomically defined subsets of patients within histologies that have distinctive biological features and distinctive clinical characteristics (particularly in terms of prognosis). In some instances, identification of these subtypes has resulted in early clinical translation as exemplified by the WNT subgroup of medulloblastoma. Because of its excellent outcome, the WNT subgroup will be studied separately in future medulloblastoma clinical trials so that reductions in therapy can be evaluated with the goal of maintaining favorable outcome while reducing long-term morbidity. However, the prognostic significance of the recurring genomic lesions for some other cancers remains to be defined.

A key finding from genomic studies is the extent to which the molecular characteristics of childhood cancers correlate with their tissue (cell) of origin. As with most adult cancers, variants in childhood cancers do not arise at random, but rather are linked in specific constellations to disease categories. A few examples include the following:

Another theme across multiple childhood cancers is the contribution of variants of genes involved in normal development of the tissue of origin of the cancer and the contribution of genes involved in epigenomic regulation.

Structural variations play an important role for many childhood cancers. Translocations resulting in oncogenic fusion genes or overexpression of oncogenes play a central role, particularly for the leukemias and sarcomas. However, for other childhood cancers that are primarily characterized by structural variations, functional fusion genes are not produced. Mechanisms by which these recurring structural variations have oncogenic effects have been identified for osteosarcoma (translocations confined to the first intron of TP53) and medulloblastoma (structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements leading to transcriptional activation [enhancer hijacking]).[1,2] However, the oncogenic mechanisms of action for recurring structural variations of other childhood cancers (e.g., the segmental chromosomal alterations in neuroblastoma) need to be elucidated.

Understanding of the contribution of germline variants to childhood cancer etiology is being advanced by the application of whole-genome and exome sequencing to cohorts of children with cancer. Estimates for rates of germline pathogenic variants approaching 10% have emerged from studies applying these sequencing methods to childhood cancer cohorts.[3–5] In some cases, the germline pathogenic variants are clearly contributory to the patient’s cancer (e.g., TP53 variants arising in the context of Li-Fraumeni syndrome), whereas in other cases, the contribution of the germline variant to the patient’s cancer is less clear (e.g., variants in adult cancer predisposition genes such as BRCA1 and BRCA2 that have an undefined role in childhood cancer predisposition).[4,5] The frequency of germline variants differs by tumor type (e.g., lower for neuroblastoma and higher for osteosarcoma),[5] and many of the identified germline variants fit into known predisposition syndromes (e.g., DICER1 for pleuropulmonary blastoma, SMARCB1 and SMARCA4 for rhabdoid tumor and small cell ovarian cancer, TP53 for adrenocortical carcinoma and Li-Fraumeni syndrome cancers, RB1 for retinoblastoma, etc.). The germline contribution to the development of specific cancers is discussed in the disease-specific sections that follow.

Each section of this document is meant to provide readers with a brief summary of current knowledge about the genomic landscape of specific childhood cancers, an understanding that is critical in considering how to apply precision medicine concepts to childhood cancers.

References

1. Northcott PA, Lee C, Zichner T, et al.: Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511 (7510): 428-34, 2014. [PUBMED Abstract]
2. Chen X, Bahrami A, Pappo A, et al.: Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7 (1): 104-12, 2014. [PUBMED Abstract]
3. Mody RJ, Wu YM, Lonigro RJ, et al.: Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth. JAMA 314 (9): 913-25, 2015. [PUBMED Abstract]
4. Parsons DW, Roy A, Yang Y, et al.: Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. JAMA Oncol 2 (5): 616-624, 2016. [PUBMED Abstract]
5. Zhang J, Walsh MF, Wu G, et al.: Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373 (24): 2336-46, 2015. [PUBMED Abstract]