H&O Which patients with AML are at higher risk for relapse?
CD Unfortunately, most adult patients with acute myeloid leukemia (AML) will relapse. Features associated with a higher risk of relapse include older age and higher-risk disease, based on genomic features, at diagnosis. High-risk genomic features include complex chromosome alterations or certain mutations, such as TP53 or FLT3-ITD mutations. Patients with therapy-related AML also have a higher risk of relapse.
H&O How common are IDH mutations in patients with AML?
CD Isocitrate dehydrogenase (IDH) mutations in the IDH1 and IDH2 genes occur in approximately 20% of patients with AML. IDH2 mutations are slightly more common than IDH1 mutations, occurring in approximately 12% of patients with AML. These mutations occur more frequently in older patients. They are identified through molecular testing, typically as part of the initial bone marrow evaluation. They can also be identified in the peripheral blood if circulating leukemia cells are present. Patients who are newly diagnosed with AML should undergo routine molecular annotation for IDH, along with other mutations of clinical importance, including FLT3, NPM1, and CEBPA.
H&O What is the impact of the IDH mutation?
CD The presence of an IDH1 or IDH2 mutation promotes the development of leukemia by blocking normal differentiation or maturation of hematopoietic precursors (blasts) into normal white blood cells. The IDH2 mutation is particularly important because there are now treatments that target it. Enasidenib (Idhifa, Celgene/Agios), previously known as AG-221, is a first-in-class, selective targeted mutant IDH2 inhibitor. Enasidenib removes the differentiation block that leads to abnormal maturation.
H&O Could you describe your research into enasidenib?
CD The presence of an IDH2 mutation leads to the production of an “oncometabolite” known as 2HG. 2HG can be measured in the blood of patients with IDH mutations. I examined previously collected blood samples of patients who were treated in a multicenter clinical trial of the Eastern Cooperative Oncology Group (ECOG) to see if measurement of 2HG could predict patients who had IDH mutations at diagnosis, and also whether the detection of 2HG at the time of remission could indicate a higher risk of relapse. We found that pretreatment levels of 2HG strongly predicted for the presence of an IDH1 or IDH2 mutation, and that patients with IDH mutations who were treated with intensive chemotherapy and showed an ongoing presence of 2HG at complete remission had shorter overall survival. This original research led to my involvement in the early development of the targeted IDH inhibitors. I have been fortunate to treat many patients in the original clinical trial that led the US Food and Drug Administration (FDA) to approve single-agent enasidenib for relapsed/refractory AML in August 2017.
H&O What did this trial show?
CD This large, multicenter, international phase 1 study treated 239 patients. Results were recently published in Blood. The study identified 100 mg/day orally as the recommended dose. The impressive outcomes included an overall response rate of 40% and a complete remission rate of 20% in patients with relapsed/refractory AML. The median overall survival was more than 9 months. Among patients with a complete remission, the median overall survival was almost 2 years, which was very encouraging.
An important finding from the pivotal clinical trial is that the responses took time. The average time to response was 2 to 3 months, but reached up to 6 months. I encourage patients with stable disease to remain on enasidenib therapy for 6 months to see if they respond. This longer time to response is standard when treating patients with leukemia with other noncytotoxic therapies, including the hypomethylating agents azacitidine (Vidaza, Celgene) and decitabine (Dacogen, Otsuka).
H&O What is the toxicity profile of enasidenib?
CD There are 2 toxicities of special interest that should be mentioned: indirect hyperbilirubinemia and differentiation syndrome. Indirect hyperbilirubinemia refers to elevation of the total bilirubin, but not the direct bilirubin. The increase is not coming from the liver; it is related to off-target effects involving the UGT1A1 metabolism pathway. Indirect hyperbilirubinemia is typically not clinically significant.
Differentiation syndrome may also occur. Because enasidenib is a differentiating agent that releases the differentiation block of the IDH2 mutation, some patients may develop rapid differentiation, which can lead to clinical signs and symptoms, such as pleural effusions, pericardial effusions, edema, weight gain, and leukocytosis. This constellation of symptoms is similar to that seen with all-trans retinoic acid (ATRA) differentiation syndrome. It responds quickly to corticosteroid therapy and hydroxyurea.
H&O What are the benefits and drawbacks to using enasidenib in patients with AML?
CD A clear benefit is that approximately 40% of patients with relapsed AML and an IDH2 mutation benefit from enasidenib and experience an overall response. Also, enasidenib is well-tolerated. Unfortunately, among patients who do respond, most ultimately relapse. My hope is to see improved outcomes using enasidenib in newly diagnosed patients, and in combination with other effective therapies.
H&O Are there any ongoing studies of enasidenib?
CD There are 2 ongoing studies evaluating enasidenib in the frontline setting for patients with newly diagnosed AML. Study AG120-221-C-001 is combining enasidenib with standard intensive chemotherapy in the younger, fit population. Study AG-221-AML-005 is combining enasidenib with azacitidine in patients who are older and/or unfit, to see if the addition of enasidenib to standard therapy leads to more durable responses and improved survival.
A study of enasidenib for patients with myelodysplastic syndrome (MDS) and IDH2 mutations recently opened at MD Anderson. The study will ultimately open to enroll patients from 6 different centers in the United States participating in the MDS Consortium. Approximately 5% to 10% of patients with MDS have an IDH2 mutation. Patients with newly diagnosed, high-risk MDS will receive treatment with enasidenib and azacitidine. Patients who require treatment after standard frontline hypomethylating agents will receive enasidenib alone.
H&O Is enasidenib being studied in diseases other than AML and MDS?
CD The phase 1 trial enrolled a small cohort of patients with other hematologic malignancies, including MDS. These patient groups also had encouraging responses, which led to the ongoing clinical trial of enasidenib in MDS. IDH2 mutations are less common among patients with solid tumors as compared with IDH1 mutations, which occur frequently in patients with gliomas, carcinomas, and cholangiocarcinoma. However, a study of enasidenib for patients with various advanced solid tumors or angioimmunoblastic T-cell lymphoma—another cancer with increased prevalence of IDH2 mutations—was recently completed.
H&O Are there any other promising genetic targets in AML?
CD IDH1 mutations occur in approximately 8% of patients with AML. The IDH1 inhibitor ivosidenib (formerly known as AG-120) is in clinical trials, and results were updated at the 2017 American Society of Hematology meeting. Response and outcome measures appear similar to those seen with enasidenib.
Disclosure
Dr DiNardo is a member of the advisory boards and/or has served as an advisor to Agios, Celgene, Novartis, and Bayer.
Suggested Readings
Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21(2):178-184.
Chaturvedi A, Araujo Cruz MM, Jyotsana N, et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood. 2013;122(16):2877-2887.
ClinicalTrials.gov. A safety and efficacy study of oral AG-120 plus subcutaneous azacitidine and Oral AG-221 plus subcutaneous azacitidine in subjects with newly diagnosed acute myeloid leukemia (AML). https://clinicaltrials.gov/ct2/show/NCT02677922. Identifier: NCT02677922. Accessed March 6, 2018.
ClinicalTrials.gov. Safety study of AG-120 or AG-221 in combination with induction and consolidation therapy in patients with newly diagnosed acute myeloid leukemia with an IDH1 and/or IDH2 mutation. https://clinicaltrials.gov/ct2/show/NCT02632708. Identifier: NCT02632708. Accessed March 6, 2018.
ClinicalTrials.gov. Targeted therapy with the IDH2-inhibitor enasidenib (AG221) for high-risk IDH2-mutant myelodysplastic syndrome. https://clinicaltrials.gov/ct2/show/NCT03383575. Identifier: NCT03383575. Accessed March 2, 2018.
DiNardo CD, de Botton S, Stein EM, et al. Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase 1 dose escalation and expansion study [ASH abstract 725]. Blood. 2017;130(suppl 1).
DiNardo CD, Propert KJ, Loren AW, et al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood. 2013;121(24):4917-4924.
DiNardo CD, Stein AS, Fathi AT, et al. Mutant isocitrate dehydrogenase (mIDH) inhibitors, enasidenib or ivosidenib, in combination with azacitidine (AZA): preliminary results of a phase 1b/2 study in patients with newly diagnosed acute myeloid leukemia (AML) [ASH abstract 639]. Blood. 2017;130(suppl 1).
Fathi AT, DiNardo CD, Kline I, et al; AG221-C-001 Study Investigators. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study [published online January 18, 2018]. JAMA Oncol. doi:10.1001/jamaoncol.2017.4695.
Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia. 2014;28(9):1774-1783.
Ragon BK, DiNardo CD. Targeting IDH1 and IDH2 mutations in acute myeloid leukemia. Curr Hematol Malig Rep. 2017;12(6):537-546.
Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
Stein EM, Stone RM, Pollyea DA, et al. Continuing enasidenib treatment for patients with mutant-IDH2 (mIDH2) relapsed or refractory acute myeloid leukemia (R/R AML) with stable disease may result in improved survival and responses over time [ASH abstract 1299]. Blood. 2017;130(suppl 1).