Category: Hem/Onc Updates

Screening Mammography Starting at Age 40 years May Reduce Breast Cancer Deaths by 40 percent

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In the US, about 33 million screening mammograms are performed each year. Currently, the major national health care organizations in the US have different recommendations for screening mammography which has led to some confusion and emotional counterarguments. These several different recommendations include 1) Annual screening at ages 40 to 84 years. 2) Annual screening at ages 45 to 54 years and then biennially at ages 55 to 79 years. 3) Biennial screening at ages 50 to 74 years.

In a recently published study (CANCER,  August 21, 2017), it was noted  that the greatest breast cancer-specific mortality reduction was achieved with annual screening of women starting at age 40 years, saving 29,369 lives from breast cancer. This is the first study to compare the three most widely discussed recommendations for screening mammography, head to head.

First CAR T-Cell Immunotherapy Approved by the FDA for Acute Lymphoblastic Leukemia

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SUMMARY: The FDA on August 30, 2017, granted regular approval to KYMRIAH® (Tisagenlecleucel) for the treatment of patients up to age 25 years with B-cell precursor Acute Lymphoblastic Leukemia (ALL), that is refractory or in second or later relapse. KYMRIAH® is the first Chimeric Antigen Receptor (CAR) T-cell immunotherapy approved by the FDA.

What is (CAR) T-cell immunotherapy? Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen. KYMRIAH® (genetically engineered T-cells) seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum Ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome.

The CAR T-cells have been shown to also access sanctuary sites such as the central nervous system and eradicate cancer cells. CD19 antigen is expressed by majority of the B cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies such as Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) and Non Hodgkin lymphoma (NHL), such as Diffuse Large B-Cell Lymphoma (DLBCL). Previously published studies have shown significant responses with CAR T-cell therapy in patients with relapsed and refractory B-cell ALL. But the durability of remission has remained unclear.

This FDA approval was based on ELIANA, an ongoing single-arm, open-label, multicenter, global, phase II study, that has enrolled 88 pediatric/young adult patients with CD19-positive Relapsed/Refractory B-cell ALL and with 5% or more bone marrow lymphoblasts by morphology. The median age was 12 years, 59% of patients had prior allogeneic Stem Cell Transplant and patients had received a median of 3 lines of therapy previously. Following completion of lymphodepleting chemotherapy which in most patients consisted of Fludarabine/Cyclophosphamide, patients were infused with a single dose of KYMRIAH® within 2 to 14 days following the completion of lymphodepleting chemotherapy. The primary endpoint was Overall Remission Rate – Complete Remission [CR] + CR with incomplete blood count recovery [CRi], within 3 months. Secondary endpoints included Duration of Remission (DOR), Overall Survival, Safety, and cellular kinetics.

The authors reported an updated interim analysis with a median study follow up of 6.4 months. Of the 63 patients who were evaluable for efficacy, the Overall Remission Rate was 83%, with 63% of patients achieving a Complete Remission (CR) and 19% achieving a Complete Remission with incomplete hematological recovery (CRi) within 3 months of KYMRIAH® infusion. All patients with a confirmed CR or CRi were Minimal Residual Disease (MRD) negative by flow cytometry. The relapse-free probability at 6 months after remission onset was 75% and the median Duration of Remission has not been reached. The probability of survival at 6 months was 89% and at 12 months was 79%. Thirteen percent (13%) of responders went on to have allogeneic Stem Cell Transplant within 6 months, while in remission.

The most common adverse reactions were Cytokine Release Syndrome (CRS), hypogammaglobulinemia, nausea, diarrhea, vomiting, fever, infections, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, hypoxia and fatigue. Grade 3 or 4 adverse events were noted in 84% of patients. Patients with Severe Cytokine Release Syndrome were effectively treated with the Interleukin-6 receptor blocking antibody Tocilizumab (ACTEMRA®). The expansion of the genetically engineered T-cells in vivo correlated with CRS severity, and persistence of these reprogrammed T cells along with B-cell aplasia in peripheral blood was observed for 1 year or more in some responders.

The authors concluded that the ELIANA trial is the first multicenter trial of a CAR T-cell therapy and a single infusion of KYMRIAH® was highly efficacious, in patients with relapsed and refractory ALL, and was associated with a high and durable remission rate. This technology may be applied to other malignancies, as new antigen targets are identified. Buechner J, Grupp SA, Maude SL, et al. Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL): update to the interim analysis. Presented at: 2017 EHA Congress; June 22-25, 2017; Madrid, Spain. Abstract S476.

Antibiotics May Impair the Efficacy of Immune Checkpoint Inhibitors

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SUMMARY: The American Cancer Society estimates that about 63,990 new cases of kidney cancer will be diagnosed in the United States in 2017 and about 14,400 patients will die from this disease. The understanding of the Immune checkpoints has lead to the development of novel immunotherapies. Immune checkpoints or gate keepers are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as PD-1(Programmed cell Death-1), etc. Following inhibition of PD-1 by specific antibodies, T cells are unleashed, resulting in T cell proliferation and activation with subsequent therapeutic responses.

Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. Broad-spectrum antibiotics can alter the bacterial composition and bacterial diversity of our gut, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes. Previously published studies have shown that intestinal microbiota modulates the anticancer immune effects of YERVOY® (Ipilimumab), an Immune checkpoint inhibitor.

The authors in this publication evaluated the effect of broad-spectrum antibiotic use, in patients with metastatic Renal Cell Carcinoma (mRCC), treated with Immune checkpoint inhibitors. In this study, 80 mRCC patients treated in prospective trials with checkpoint inhibitors were enrolled. These patients had received anti-PD-1/PD-L1 monotherapy, primarily Nivolumab (N=67), a combination of a PD-1 inhibitor and a CTLA-4 inhibitor such as Ipilimumab (N=10), and a combination of anti-PD-L1 therapy and Bevacizumab (N=3). A majority of the patients (65%) were male, 88% had mRCC with clear cell histology, and 80% of the patients had prior nephrectomy. Using IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) criteria, 21% had favorable risk disease, 57% had intermediate risk and 22% had poor risk disease. Sixteen patients (20%) had been treated with broad-spectrum antibiotics, mostly Beta-lactamases or Fluoroquinolones, for up to 1 month prior to starting treatment with immunotherapy. A retrospective analysis was conducted and the Progression Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS), in the group that received broad-spectrum antibiotics, were compared with the group that did not receive broad-spectrum antibiotics.

It was noted that the PFS was four-fold higher in patients who did not receive antibiotics compared to those who received antibiotics (8.1 months vs 2.3 months, P<0.001) and this was statistically significant. This benefit was maintained after adjusting for age, gender, IMDC risk groups, tumor burden and proton pump inhibitors. Additionally, the ORR was higher in those who did not receive antibiotics compared to those who were treated with antibiotics (P<0.002). At a median follow up of less than 6 months, there was already a negative trend in Overall Survival, driven by broad-spectrum antibiotic usage.

It was concluded that in this first analysis, broad-spectrum antibiotics had a negative impact on outcomes, among patients with metastatic Renal Cell Carcinoma, treated with Immune checkpoint inhibitors. Caution should therefore be exercised when prescribing antibiotics to this patient group, so that the efficacy of immunotherapy is not compromised. These concerns may be true across different tumor types and additional follow up is underway. Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. Derosa L, Routy B, Enot D, et al. J Clin Oncol 35, 2017 (suppl 6S; abstract 462)

Study Finds Dramatic Increase in ColoRectal Cancer Incidence among Young Adults

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. The lifetime risk of developing ColoRectal Cancer is about 1 in 20 (5%).

Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall, primarily driven by screening, the incidence however has been increasing among adults younger than age 50 years. To understand this trend, the authors in this publication conducted a retrospective cohort study among 490,305 patients aged 20 years and older, who were diagnosed with colorectal cancer between 1974 and 2013, using data from nine oldest Surveillance, Epidemiology, and End Results (SEER) registries. The SEER program is considered the gold standard for cancer registration worldwide because of the high quality of data and is the only source for historical population-based cancer incidence in the United States. This study included people born in 1890 thru 1990. Colorectal cancer incidence trends were analyzed by 5-year age group and birth cohorts.

The authors noted variations in CRC incidence patterns by age, tumor location in the colon, calendar period, and birth cohort. The study found that in adults aged 20-39 years, after a decrease in the previous decade, colon cancer incidence rates increased by 1.0-2.4% per year since the mid-1980s thru 2013. For adults aged 40-54 years during the same period, colon cancer incidence rates increased by 0.5-1.3%. Conversely, from the mid-1980s thru 2013, colon cancer rates declined in adults aged 55 years and older. In adults younger than age 50 years, there was an increasing trend for tumors to be confined to the distal colon, with the exception of adults aged 40-49 years, among whom there was an also an increasing trend for proximal tumors.

The incidence of rectal cancer has been increasing even longer and faster than colon cancer, rising about 3.2% per year from 1974-2013 in adults aged 20-29 years and from 1980-2013 in adults aged 30-39 years. In adults aged 40 to 54, rectal cancer rates increased by 2.3% per year from the 1990s to 2013. Again, rectal cancer rates declined, in adults aged 55 years and older, from 1974-2013.

Compared with adults born around 1950, those born around 1990 had double the risk of colon cancer and quadruple the risk of rectal cancer. The increase in the incidence of CRC in young adults has been attributed to western style, high carbohydrate, high fat, low fiber diet which can initiate inflammation and proliferation in the colonic mucosa within two weeks. Other lifestyle factors associated with CRC include obesity, high consumption of processed meat and alcohol, low levels of physical activity and cigarette smoking. Further, young patients are 58% more likely than older patients to be diagnosed with advanced versus localized stage CRC, due to delayed follow-up of symptoms, sometimes for years and these young adults are less likely to be screened for colon cancer, despite their symptoms.

The authors concluded that there is an increasing rate of colon and rectal cancer among young and middle-aged adults in the US and compared with adults born around 1950 when the risk was at the lowest, those born around 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer. They added that as nearly a third of rectal cancer patients are younger than age 55 years, screening initiation before age 50 years should be considered. Colorectal Cancer Incidence Patterns in the United States, 1974-2013. Siegel RL, Fedewa SA, Anderson WF, et al. J Natl Cancer Inst. 2017 Aug 1;109(8). doi: 10.1093/jnci/djw322.

Late Breaking Abstract – ASCO 2017 Single Dose Radiation Therapy as Effective as Multiple Fractions for Metastatic Spinal Cord Compression

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SUMMARY: Metastatic Spinal Cord Compression (MSCC) first described by Spiller in 1925, is an oncologic emergency and is a well recognized complication of cancer. Approximately 10% of all patients with cancer develop metastatic disease to the spinal column. Even though any solid tumor can metastasize to the spine, more than 50% of MSCC cases are caused by breast cancer, prostate cancer and lung cancer. The risk of MSCC is particularly high in those patients with widespread malignancy and those with known spinal metastases. Pathological compression fracture of the vertebral body or direct tumor invasion can cause compression of the spinal cord or cauda equina resulting in irreversible neurological deficit as well as paraplegia. Common symptoms include back pain, tingling, numbness and difficulty walking. Early recognition of symptoms and prompt intervention is therefore imperative to prevent neurological damage.

Patients with MSCC, in addition to steroids, are often treated with Radiation Therapy (RT) to relieve pain and improve neurological function and mobility. There is however no standard Radiation Therapy schedule. ASTRO (American Society for Radiation Oncology) in its “Choosing Wisely” guidelines recommended not using extended fractionated schemes (more than 10 fractions) for palliation of bone metastases. Equivalent pain relief can be accomplished following 30 Gy in 10 fractions, 20 Gy in 5 fractions, or a single 8 Gy fraction. It was also recommended that strong consideration should be given to a single 8 Gy fraction, for patients with a limited prognosis or with transportation difficulties.

SCORAD III is a randomized phase III study which evaluated whether a single-dose Radiation Therapy (RT) was as effective as multifraction RT administered over 5 days, without compromising patient outcomes. Enrolled patients (N=688) were randomized 1:1 to receive External Beam spinal canal RT as a single dose of 8 Gy (N=345) or 20 Gy in 5 fractions (N=343). Eligible patients had spinal cord or cauda equina (C1-S2) compression, confirmed by MRI/CT scan, treatable within a single radiation field, with no prior RT to the same area and had a life expectancy of more than 8 weeks. The median age was 70 years, 73% were male and 44% had metastatic prostate, 18% had metastatic lung, 11% had metastatic breast and another 11% had metastatic GastroIntestinal cancers. Patients were stratified by Ambulatory Status (AS), site of primary, and presence or absence of non-skeletal metastases. The primary endpoint of the study was Ambulatory Status, measured on a four-point scale – Grade 1: Able to walk normally, Grade 2: Able to walk with a walking aid (such as a cane or walker), Grade 3: Has difficulty walking even with walking aids and Grade 4: Dependent on wheelchair. Two third of the patients (66%) were ambulatory with or without walking aids (Ambulatory Status of 1 to 2) at study entry.

It was noted that at 8 weeks, 69.5% of patients who received single-dose radiation therapy and 73.3% of those who received five doses had an Ambulatory Status of 1 to 2 and could walk normally or with a walking aid such as a cane or a walker, suggesting that both single dose and longer course radiation treatments helped patients with their mobility. The median Overall Survival was similar in the two treatment groups – 12.4 weeks with a single dose versus 13.7 weeks with five doses, and this was not statistically significant (HR=1.02; P=0.81). The proportion of patients experiencing severe side effects was similar in the two treatment groups (20.6% vs 20.4%), but mild side effects were less common in the single dose of 8 Gy group compared to those receiving multiple fractions (51% vs 56.9%).

The authors concluded that a single radiation dose of 8 Gy in patients with metastatic Spinal Cord Compression was non-inferior and was as effective as longer course multiple fractions, for Ambulatory Status at 8 weeks, as well as Overall Survival. They added that this would mean fewer hospital visits and more time with the family, at least for patients with a short life expectancy. It should however be noted that in this study, at the time of enrollment, majority of patients were fully ambulatory or were able to walk with a walking aid. Whether single dose radiation therapy is adequate for those patients with very advanced involvement of the spine, however remains to be seen. SCORAD III: Randomized non-inferiority phase III trial of single dose radiotherapy (RT) compared to multifraction RT in patients (pts) with metastatic spinal canal compression (SCC). Hoskin P, Misra V, Hopkins K, et al. J Clin Oncol. 35;2017 (suppl; abstr LBA10004).

Screening Mammography Starting at Age 40 years May Reduce Breast Cancer Deaths by 40 percent

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that 252,710 new cases of invasive breast cancer and 63,410 new cases of non-invasive breast cancer will be diagnosed in women in 2017 and 40,610 women are expected to die from the disease. In the US, about 33 million screening mammograms are performed each year.

Currently, the major national health care organizations in the US have different recommendations for screening mammography which has led to some confusion and emotional counterarguments. These several different recommendations include 1) Annual screening at ages 40 to 84 years 2) Annual screening at ages 45 to 54 years and then biennially at ages 55 to 79 years 3) Biennial screening at ages 50 to 74 years.

To address this varied recommendations and help women make informed decisions regarding mammography screening, the authors used computer modeling (CISNET models) to assess the three major screening mammography recommendations, and estimate the number of breast cancer deaths that might be prevented with the different screening mammography schedules. Cancer Intervention and Surveillance Modeling Network (CISNET) is a consortium of NCI-sponsored investigators who use statistical modeling to improve understanding of cancer control interventions in prevention, screening and treatment, and their effects on population trends in incidence and mortality. CISNET has been cited by the International Society Pharmacoeconomics and Outcomes Research (ISPOR) Task Force on Good Modeling Practices for its role in establishing a forum that enables researchers to compare results and articulate reasons for discrepancies.

It was noted in this study that the mean mortality reduction in breast cancer-specific deaths was greatest with the recommendation of annual screening at ages 40 to 84 years (39.6%), which meant that 29,369 lives were saved from breast cancer, compared with the recommendation of screening annually at ages 45 to 54 years, then biennially at ages 55 to 79 years (30.8%), which meant that 22,829 were lives saved from breast cancer, and the recommendation of biennial screening at ages 50 to 74 years (23.2%) which meant that 17,153 lives were saved from breast cancer.

The study also took into consideration risks associated with screening, including callbacks for additional imaging following indeterminate or suspicious mammographic finding and in some cases, a breast biopsy, only to find out that the findings were benign. The authors commented that the average woman in her 40s getting annual screening can expect additional and unnecessary screening about once every 12 years and unnecessary breast biopsy recommendations once every 150 years. Other rare risks with screening mammography include breast cancer that could be missed and breast cancer caused by mammogram radiation.

It was concluded that based on the CISNET models, the greatest breast cancer-specific mortality reduction is achieved with annual screening of women starting at age 40 years. They added that this is the first study to compare the three most widely discussed recommendations for screening mammography, head to head. These findings will guide women and their Health Care Providers in deciding when to begin screening mammography and how often to get screened. Comparison of recommendations for screening mammography using CISNET models. Arleo EK, Hendrick E, Helvie MA, et al. CANCER; Published Online: August 21, 2017. http://doi.wiley.com/10.1002/cncr.30842

DACOGEN® May Be Superior to VIDAZA® in Higher-Risk MDS Patients

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SUMMARY: It is estimated that in the United States approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are aged 65 years and older and die as a result of infection and/or bleeding consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years.

Management of patients with MDS includes supportive care with Erythropoiesis Stimulating Agents (ESA), hypomethylating agents such as VIDAZA® (Azacitidine) and DACOGEN® (Decitabine), immunomodulatory agents such as REVLIMID® (Lenalidomide), and immunosuppressive agents such as AntiThymocyte Globulin (ATG) and Cyclosporine. Symptomatic patients with MDS are often treated with either VIDAZA® or DACOGEN® as these agents have been shown to improve survival in higher-risk MDS patients. It has remained unclear however, if one is better than the other.

To address this question the authors conducted a phase II study, in which 113 patients with low (36%), intermediate (30%), and high (20%) – risk MDS, as determined by the Revised International Prognostic Scoring System (IPSS-R), were randomly assigned to receive either VIDAZA® 75 mg/m2 IV/SC daily (N=40) or DACOGEN® 20 mg/m2 IV daily (N=73), for 3 consecutive days, with the cycle repeated every 28 days. Patients received a median of 9 cycles. The primary endpoint was Overall Response Rate (ORR).

It was noted that the ORR was 70% and 49% for patients treated with DACOGEN® and VIDAZA® respectively (P=0.03). Cytogenetic response rates were 61% and 25% respectively (P=0.02). Thirty-two percent (32%) of patients treated with DACOGEN® became transfusion independent compared with 16% of patients treated with VIDAZA® Among patients with 5% or more bone marrow blasts, all responded to DACOGEN® whereas only 36% responded to VIDAZA® (P<0.001). With a median follow up of 20 months, the median Event Free Survival for patients treated with DACOGEN® was 20 months and 13 months for those treated with VIDAZA®, and these outcomes were negatively impacted by the presence of TP53 and ZRSR2 mutations. More patients in the DACOGEN® group experienced myelosuppression, and grade 3 toxicities were rare.

The authors concluded that lower doses of DACOGEN® and VIDAZA® are safe and effective in symptomatic patients with MDS, and DACOGEN® is more effective compared to VIDAZA®, in patients with higher-risk features. A randomized phase II study of low-dose decitabine versus low-dose azacitidine in lower risk MDS and MDS/MPN. Jabbour E, Short NJ, Montalban-Bravo G, et al. Blood. 2017 Aug 3. pii: blood-2017-06-788497. doi: 10.1182/blood-2017-06-788497. [Epub ahead of print]

FDA Approves IDHIFA® for Patients with Relapsed or Refractory Acute Myeloid Leukemia

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SUMMARY: The FDA on August 1, 2017 granted regular approval to IDHIFA® (Enasidenib), for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) with an Isocitrate DeHydrogenase-2 (IDH2) mutation, as detected by an FDA-approved test. The American Cancer Society estimates that in 2017, 21,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,590 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations may thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

IDHIFA® is an oral, selective, small molecule inhibitor of mutated IDH2 protein. The approval of IDHIFA® was based on an open label, single arm, multicenter, clinical trial that included 199 adults with relapsed or refractory AML, who had an IDH2 mutation as detected by the RealTime IDH2 Assay. Patients received IDHIFA® 100 mg orally daily. The median age was 67 years, the median number of prior therapies was 2 and a third of the patients had unfavorable cytogenetics. Study endpoints included Complete Response (CR) and Complete Response with partial hematologic recovery (CRh) rates, CR/CRh duration, and conversion from transfusion dependence to transfusion independence.

After a median follow up of 6.6 months, 23% of patients experienced CR or CRh lasting a median of 8.2 months, with 19% of patients having a CR lasting a median 8.2 months, and 4% with a CRh lasting a median 9.6 months. The median time to first response was 1.9 months and the median time to best response of CR/CRh was 3.7 months. Of the 157 patients who required transfusions at the initiation of the trial, 34% of the patients no longer required transfusions during at least one 8 week time period on IDHIFA®. Of the 42 patients who did not require transfusions at the start of the study, 76% maintained transfusion independence. The most common toxicities were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. Differentiation syndrome occurred in 14% of patients and these patients should be promptly managed, as this could be fatal.

The authors concluded that IDHIFA® is well tolerated and induced lasting Complete Responses in patients who had failed prior AML therapies, with the clinical efficacy related to differentiation of myeloblasts rather than cytotoxicity. This is the first FDA approval for relapsed or refractory AML specifically with an IDH2 mutation. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study. Stein EM, Dinardo CD, Pollyea DA, et al. J Clin Oncol 35, 2017 (suppl; abstr 7004).

ASTRO Guideline for Stereotactic Body Radiation Therapy in Early Stage Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the implementation of Lung Cancer screening programs. Patients with early stage disease unless medically unfit, undergo surgical resection with a curative intent. Those who are not surgical candidates, are often treated with conventional Radiation Therapy, which can result in high rates of local failure and treatment-related toxicities.

Stereotactic Body Radiation Therapy (SBRT) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional Radiation Therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SBRT include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized hydrogen or Protons, Linear Accelerator (LINAC) and CYBER KNIFE® which use Photons, to target the tumor tissue. Because SBRT is fractionated and delivered over 1-5 days, the short-and long-term side effects of radiation therapy are decreased and may allow higher total dosage to be given.

This guideline is based on systematic review of literature which included 172 articles, from January 1995 and August, 2016. This literature search evaluated adults with T1-2, N0, Non Small Cell Lung Cancer (NSCLC) receiving primary or salvage SBRT. Developed by the American Society for Radiation Oncology, this guideline is also endorsed by the European Society for Radiotherapy & Oncology, the Royal Australian and New Zealand College of Radiologists, and the International Association for the Study of Lung Cancer.

KEY QUESTIONS (KQ)

KQ 1: When is SBRT appropriate for patients with T1-2, N0, NSCLC who are medically operable?

Statement KQ 1A: Any patient with operable Stage I NSCLC being considered for SBRT should be evaluated by a thoracic surgeon, preferably in a multidisciplinary setting, to reduce specialty bias.

Statement KQ 1B: For patients with “standard operative risk” (ie, with anticipated operative mortality of <1.5%) and stage I NSCLC, SBRT is not recommended as an alternative to surgery outside of a clinical trial. Discussions about SBRT are appropriate, with the disclosure that long-term outcomes with SBRT >3 years are not well established. For this population, lobectomy with systematic mediastinal lymph node evaluation remains the recommended treatment, though a sublobar resection may be considered in select clinical scenarios.

Statement KQ 1C: For patients with “high operative risk” (ie, those who cannot tolerate lobectomy, but are candidates for sublobar resection) stage I NSCLC, discussions about SBRT as a potential alternative to surgery are encouraged. Patients should be informed that while SBRT may have decreased risks from treatment in the short term, the longer term outcomes >3 years are not well-established.

KQ 2: When is SBRT appropriate for medically inoperable patients with T1-2, N0, NSCLC?

For patients with centrally located tumors

Statement KQ 2A: SBRT directed toward centrally located lung tumors (tumor within 2 cm of the proximal tracheobronchial tree) carries unique and significant risks when compared to treatment directed at peripherally located tumors. The use of 3-fraction regimens should be avoided in this setting.

Statement KQ 2B: SBRT directed at central lung tumors should be delivered in 4 or 5 fractions. Adherence to volumetric and maximum dose constraints may optimize the safety profile of this treatment. For central tumors for which SBRT is deemed too high risk, hypofractionated radiation therapy utilizing 6 to 15 fractions can be considered.

For patients with tumors >5 cm in diameter

Statement KQ 2C: SBRT is an appropriate option for tumors >5 cm in diameter with an acceptable therapeutic ratio. Adherence to volumetric and maximum dose constraints may optimize the safety profile of this treatment.

For patients lacking tissue confirmation

Statement KQ 2D: Whenever possible, obtain a biopsy prior to treatment with SBRT to confirm a histologic diagnosis of a malignant lung nodule.

Statement KQ 2E: SBRT can be delivered in patients who refuse a biopsy, have undergone non-diagnostic biopsy, or who are thought to be at prohibitive risk of biopsy. Prior to SBRT in patients lacking tissue confirmation of malignancy, patients are recommended to be discussed in a multidisciplinary manner with a consensus that the lesion is radiographically and clinically consistent with a malignant lung lesion based on tumor, patient, and environmental factors

For patients with synchronous primary or multifocal tumors

Statement KQ 2F: Multiple Primary Lung Cancers (MPLCs) can be difficult to differentiate from intrathoracic metastatic lung cancer and pose unique issues for parenchymal preservation; therefore, it is recommended that they are evaluated by a multidisciplinary team.

Statement KQ 2G: Positron Emission Tomography/Computed Tomography and brain Magnetic Resonance Imaging are recommended in patients suspected of having MPLC to help differentiate from intrathoracic metastatic lung cancer. Invasive mediastinal staging should be addressed on a case-by-case basis.

Statement KQ 2H: SBRT may be considered as a curative treatment option for patients with synchronous MPLC. SBRT for synchronous MPLC has equivalent rates of local control and toxicity, but decreased rates of overall survival compared with those with single tumors.

Statement KQ 2I: SBRT is recommended as a curative treatment option for patients with metachronous MPLC. SBRT for metachronous MPLC has equivalent rates of local control and toxicity and overall survival compared with those with single tumors.

For patients who underwent pneumonectomy and now have a new primary tumor in their remaining lung

Statement KQ 2J: SBRT may be considered a curative treatment option for patients with metachronous MPLC in a postpneumonectomy setting. While SBRT for metachronous MPLC appears to have equivalent rates of local control and acceptable toxicity compared to single tumors, SBRT in the post-pneumonectomy setting might have a higher rate of toxicity than in patients with higher baseline lung capacity.

KQ 3: For medically inoperable early-stage lung cancer patients, how can SBRT techniques be individually tailored to provide an adequate dose for tumor eradication with minimal risk to normal structures in “high-risk” clinical scenarios?

For tumors with intimal proximity/involvement of mediastinal structures (bronchial tree, esophagus, heart, etc.)

Statement KQ 3A: For tumors in close proximity to the proximal bronchial tree, SBRT should be delivered in 4 to 5 fractions. Physicians should endeavor to meet the constraints that have been utilized in prospective studies given the severe toxicities that have been reported.

Statement KQ 3B: For tumors in close proximity to the esophagus, physicians should endeavor to meet the constraints that have been utilized in prospective studies or otherwise reported in the literature given the severe esophageal toxicities that have been reported.

Statement KQ 3C: For tumors in close proximity to the heart and pericardium, SBRT should be delivered in 4 to 5 fractions with low incidence of serious toxicities to the heart, pericardium, and large vessels observed. Adherence to volumetric and maximum dose constraints utilized in prospective trials or reported in the literature may optimize the safety profile of this treatment.

For tumors abutting or invading the chest wall

Statement KQ 3D: SBRT is an appropriate option for treatment and should be offered for T1-2 tumors that abut the chest wall. Grade 1 and 2 chest wall toxicity is a common occurrence post SBRT that usually resolves with conservative management. Patients with peripheral tumors approximating the chest wall should be counseled on the possibility of this common toxicity.

Statement KQ 3E: SBRT may be utilized in patients with cT3 disease due to chest wall invasion without clear evidence of reduced efficacy or increased toxicity compared to tumors abutting the chest wall.

KQ 4: In medically inoperable patients, what is the role of SBRT as salvage therapy for early-stage lung cancer that recurs?

After conventionally fractionated Radiation Therapy

Statement KQ 4A: The use of salvage SBRT after primary conventionally fractionated radiation may be offered to selected patients due to reported favorable local control and survival. These patients should be informed of significant (including fatal) toxicities.

Statement KQ 4B: Patient selection for salvage SBRT after primary conventionally fractionated radiation is a highly individualized process. Radiation oncologists should assess evidence-based patient, tumor, and treatment factors prior to treatment initiation.

After SBRT and sublobar resection

Statement KQ 4C: Patient selection for salvage SBRT after previous SBRT and after prior Sublobar resection is a highly individualized process. Radiation oncologists should assess evidence-based patient, tumor, and treatment factors before treatment initiation.

Stereotactic Body Radiation Therapy for early-stage Non-Small Cell Lung Cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Videtic GM, Donington J, Giuliani M, et al. http://dx.doi.org/10.1016/j.prro.2017.04.014

FDA Approves OPDIVO® for MSI-H or dMMR Metastatic Colorectal Cancer

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SUMMARY: The FDA on July 31, 2017, granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients 12 years and older with MisMatch Repair deficient (dMMR) and MicroSatellite Instability-High (MSI-H) metastatic ColoRectal Cancer, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. The lifetime risk of developing ColoRectal Cancer is about 1 in 20 (5%).

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and when sporadic, the DNA MisMatchRepair gene is MLH1. Defective MisMatchRepair can also manifest as a germline mutation occurring in 1 of the 4 MisMatchRepair genes which include MLH1, MSH2, MSH6, PMS2. This produces Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC), an Autosomal Dominant disorder and is the most common form of hereditary colon cancer, accounting for 35% of the MSI colorectal cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to PD-1 blockade with immune checkpoint inhibitors.

MSI (Micro Satellite Instability) testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). MLH1 gene is often lost in association with PMS2. NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer.

This latest approval for OPDIVO® was based on results from the phase II CheckMate-142 trial, which is a multicenter, open label, single arm study, involving 53 patients with dMMR or MSI-H metastatic ColoRectal Cancer, who had disease progression during, after, or were intolerant to prior treatment with Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy. These 53 patients were a subset of the 74 patients who received at least one prior treatment regimen containing a Fluoropyrimidine with Oxaliplatin or Irinotecan for metastatic disease. All patients received OPDIVO® 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or radiographic progression. The median age was 53 years. The Primary endpoint was Objective Response Rate (ORR) and exploratory endpoints included Safety, Progression Free Survival, Overall Survival and efficacy in biomarker-defined populations.

The Objective Response Rate as assessed by independent radiographic review committee, was 28% in the 53 patients who received prior Fluoropyrimidine, Oxaliplatin, and Irinotecan and responses lasted 6 months or more for the 67% of the responding patients. There was 1 complete response and 14 partial responses. The ORR was 32% among the 74 patients in the overall population. These responses and Clinical Benefit was seen regardless of PD-L1 expression, BRAF mutation status, KRAS mutation status, and clinical history of Lynch Syndrome. The most common adverse reactions related to OPDIVO® included fatigue, asthenia, rash, fever, nausea, diarrhea, musculoskeletal pain, cough and dyspnea.

The authors concluded that patients with metastatic ColoRectal Cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy and OPDIVO® demonstrated durable responses and disease control in this heavily pretreated patient group. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: Update from CheckMate 142. Overman MJ, Lonardi S, Leone F, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 519).