Enasidenib Treatment Active in Pretreated Patients With IDH2-Mutant MDS


Treatment with enasidenib (AG221) was active and was well tolerated in pretreated patients with IDH2-mutated myelodysplastic syndrome, including those who failed hypomethylating agents, according to findings from a phase I/II study.

Eytan M. Stein, MD


Treatment with enasidenib (AG221) was active and was well tolerated in pretreated patients withIDH2-mutated myelodysplastic syndrome (MDS), including those who failed hypomethylating agents (HMA), according to findings from a phase I/II study presented at the 2016 ASH Annual Meeting.

In the study, which included 17 patients with MDS, the overall response rate (ORR) was 59% for the IDH2 inhibitor enasidenib. In 13 patients who received prior HMAs, the ORR was 54%. After a median follow-up of 7.5 months, the median overall survival was not yet reached. At this assessment, just 2 patients had experienced disease progression during treatment.

"Daily treatment with oral enasidenib monotherapy was well tolerated and induced responses in most of these MDS patients with mutations inIDH2, most of whom had higher-risk disease, and three-fourths of whom had failed prior HMA treatment," said lead investigator Eytan M. Stein, MD, Leukemia Service, Memorial Sloan Kettering Cancer Center. "Notably, more than half of patients who had failed prior HMA treatment had a response with enasidenib monotherapy."

In the study, which enrolled patients with several types of advanced hematologic malignancies withIDH2mutations, 17 patients received oral enasidenib at 100 mg daily. The median age of patients was 67 years (range, 45-78) and most were males (71%). The ECOG status was 0 to 1 (76%) and 2 (24%). HMAs were received by 76% of patients, and 35% had received ≥2 prior regimens. There were 4 untreated patients in the study. Overall, 47% of patients had high to very high risk disease, by IPSS-R criteria.

The complete remission (CR) rate with enasidenib was 9% and the partial remission (PR) rate was 9%. Additionally, 27% of patients had a CR in the marrow. The median time to response was 21 days (range, 10-87). Three patients went on to receive a stem cell transplant.

Hematologic improvement (HI) was experienced by 29% of patients, including improvements in erythrocytes (20%), platelets (33%), and neutrophils (40%). Of those who obtained an HI, 2 had trilineage responses and 2 had bilineage improvements. Four of the 5 patients with HI continued to experience an ongoing improvement at the time of the analysis.

Next-generation sequencing was used to assess co-occurring mutations for those treated with enasidenib. Although the numbers were small, intriguingly, 5 of 7 patients (71.4%) with ASXL1 had a response or HI with treatment. However, Stein warned that although these findings were intriguing, asASXL1predicts poor outcomes, that the study was a "small cohort of patients, which prevents definitive conclusions regarding potential correlations between response and co-mutations."

"Mutational testing is rapidly becoming essential to diagnosis, prognostication, and the identification of eligibility for clinical trials for MDS," he added. "Assessment ofIDH2mutations can identify MDS patients who may benefit from targeted treatment with enasidenib."

Grade 3/4 treatment-emergent adverse events (AEs) were experienced by 82% of patients in the trial. The most frequently observed treatment-emergent AEs were hyperbilirubinemia (30%), pneumonia (24%), thrombocytopenia (24%), anemia (18%), hypokalemia (18%), dyspnea (12%), and tumor lysis syndrome (12%). Serious treatment-emergent AEs included tumor lysis syndrome (n = 2), blood bilirubin increase (n = 1), and transaminitis (n = 1). There were no treatment related deaths.

"Hyperbilirubinemia seen with this drug is an on-target effect, related to the IDH2 enzyme," Stein said. "This is typically mild and does not have clinically significant sequelae."

In addition to MDS, enasidenib has also shown impressive activity for those with acute myeloid leukemia (AML). At the 2015 ASH Annual Meeting, Stein presented updated findings from the AML cohort of the same study, which included 198 patients at a median age of 69 years (range, 19-100). In this group, the IDH2 inhibitor was given at an escalating dose that started at 30 mg or 50 mg daily. The median number of prior therapies was 2 (range, 1-6).

In this group, the ORR was 41%, with a CR rate of 17% and a PR rate of 14%. The CR rate without platelet recovery was 2% and the CR rate with incomplete hematologic recovery was 1%. The molecular CR rate was 8%. An additional 45% of patients had stable disease.

In September 2017, Agios, and its development partner Celgene, announced plans to submit data from the phase I/II trial to the FDA for approval of enasidenib for patients with relapsed/refractory AML. In 2014 the agent received a fast track designation, under which a rolling submission of data to the FDA is permitted. The companies plan to complete the new drug application filing before the end of 2016.


  1. Stein EM, Fathi AT, DiNardo CD, et al. Enasidenib (AG-221), a Potent Oral Inhibitor of Mutant Isocitrate Dehydrogenase 2 (IDH2) Enzyme, Induces Hematologic Responses in Patients with Myelodysplastic Syndromes (MDS). Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 343.
  2. Stein EM, DiNardo CD, Altman JK, et al. Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial.Blood.2015;126(23):323.
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