In recent years the discovery that metabolic signals are interconnected with the epigenetic machinery and that this epigenetic-metabolomic interplay has a critical role in tumorigenesis has driven numerous research efforts. Mutations of several metabolic genes have been identified as cancer growth drivers, among those, isocitrate dehydrogenase 2 (IDH2) mutations. IDH2 is a metabolic enzyme that is mutated in a wide range of hematologic and solid neoplasms. In acute myeloid leukemia (AML), IDH2 mutations occur in approximately 12% of tumors. Mutated IDH2 is responsible for the synthesis of an oncometabolite, 2-hydroxyglutarate (2HG), which alters the cells’ genetic programming, so that cancer cells remain in an immature state and proliferate rapidly.

On June 24th, at the 2017 European Hematology Association (EHA) annual meeting in Madrid, Spain, Dr. Eytan M. Stein, MD, highlighted the progress that has been made in researching personalized treatments for AML by reporting updated data on the safety and efficacy of Idhifa (enasidenib), an oral, selective, small-molecule inhibitor of IDH2 in relapsed or refractory (R/R) AML patients with IDH2 mutations.

The Phase I/II study enrolled 239 patients with a median age of 70 years. The dose-escalation part of the study involved 113 patients who received Idhifa once daily at a dose varying from 50 to 650mg. No differences were found in the reduction of 2HG levels in patients receiving different doses of the drug (92%, 90%, and 93% 2HG reduction for <100mg, 100mg, and >100mg/day). The 100mg dose was therefore selected for the expansion phase of the trial, which enrolled an additional 126 patients. Of all the patients enrolled, 176 were R/R and 53% of those had received two or more lines of therapy. The overall response rate in R/R AML subjects was 40.3%. More specifically, complete response (CR) was registered in 19.3% of the patients, 6.8% of the subjects had CR with incomplete hematologic recovery, 6.3% achieved a partial remission and a leukemia-free state was found in 8% of the patients. Median OS was 9.7 months, but in patients who achieved CR the survival benefit was higher (19.7 months). Idhifa was well tolerated; the most common Grade 3/4 adverse events included indirect hyperbilirubinemia and IDH-inhibitor-associated differentiation syndrome.

Idhifa was the result of the improved understanding of the AML biology, which has contributed to a refined disease classification and has led to the development of effective, tolerable, personalized treatments. Emerging novel agents for AML were discussed in a satellite symposium held on June 22nd at EHA 2017. Dr. Hagop Kantarjian, MD, from the MD Anderson Cancer Center suggested that, even though the response to new targeted agents are encouraging as monotherapies, combinations with standard chemotherapy or new immunotherapies will be necessary to achieve higher ORR and durable responses. Celgene is already active in this area and is trying to move Idhifa to the first-line AML setting by investigating the drug in combination with the standard 3+7 (three days of an anthracycline + seven days of cytarabine) induction regimen in newly diagnosed AML patients with IDH2 mutations.

There is currently a high unmet need in the difficult to treat R/R AML setting, where available treatment options have been exhausted. Idhifa, a personalized treatment that can be administered as a single agent and is well tolerated compared with standard chemotherapy regimens, is a promising new candidate for R/R AML. Celgene filed a New Drug Application (NDA) for Idhifa, which is currently under Priority Review with the FDA for the treatment of patients with R/R AML with an IDH2 mutation with a Prescription Drug User Fee Act (PDUFA) action date of Aug. 30, 2017. 

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