Addition of Enasidenib to Azacitidine in Newly Diagnosed IDH2-Mutant Acute Myeloid Leukemia

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As reported in The Lancet Oncology by Courtney D. DiNardo, MD, and colleagues, an interim analysis of the phase II portion of a phase Ib/II trial (AG221-AML-005) showed that the addition of the oral mutant IDH2 protein inhibitor enasidenib to azacitidine significantly improved overall response rate in patients with newly diagnosed IDH2-mutant acute myeloid leukemia who were ineligible for intensive chemotherapy.

Courtney D. DiNardo, MD

Courtney D. DiNardo, MD

Study Details

In the open-label phase II portion of the trial, 101 patients were enrolled from sites in 12 countries between June 2016 and August 2018. They were randomly assigned 2:1 to receive  enasidenib at 100 mg/d continuously in 28-day cycles plus subcutaneous azacitidine at 75 mg/m²/d on days 1 to 7 of each cycle (n = 68) or azacitidine alone (n = 33). Treatment was continued until disease progression, unacceptable toxicity, or eligibility to undergo hematopoietic stem cell transplantation.

The primary endpoint was overall response rate in the intention-to-treat population at a prespecified interim analysis (August 2019) when all patients had at least 1 year of follow-up. Response was defined as complete remission, complete remission with incomplete blood count or platelet recovery, partial remission, or morphologic leukemia-free state.


Response was observed in 50 patients (74%, 95% confidence interval [CI] = 61%–84%) in the enasidenib-plus-azacitidine group vs 12 (36%, 95% CI = 20%–55%) in the azacitidine group (odds ratio = 4.9, 95% CI = 2.0–11.9, P = .0003). Responses included complete remission in 37 patients (54%, 95% CI = 42%–67%) vs 4 patients (12%, 95% CI = 3%–28%; P < .0001) and complete remission or complete remission with partial hematologic recovery in 39 (57%) vs 6 (18%; P = .0002).

Among responders, median time to first response was 1.9 vs 3.6 months; median time to complete remission was 5.4 vs 4.4 months. Median duration of response was 24.1 months (95% CI = 10.0 months–not reached) vs 9.9 months (95% CI = 5.5–13.6 months) and median duration of complete remission was not reached (95% CI = 7.7 months–not reached) vs 12.7 months (95% CI = 11.7 months–not reached).

As noted by the investigators, survival outcomes in the study may have been confounded by use of subsequent acute myeloid leukemia–directed therapies in more than half of patients in the azacitidine group, including subsequent enasidenib in one-third. Estimated median event-free survival was 15.9 months vs 11.9 months (hazard ratio [HR] = 0.59, 95% CI = 0.30–1.13, P = .11) and estimated median overall survival was 22.0 vs 22.3 months (HR = 0.99, 95% CI = 0.52–1.87, P = .97).


  • In the enasidenib plus azacitidine vs azacitidine alone groups, response rates were 74% vs 36%, with complete remission seen in 54% vs 12%.
  • Median durations of response and complete response were 24.1 vs 9.9 months and not reached vs 12.7 months.

Adverse Events

The most common treatment-related grade 3 or 4 adverse events in the enasidenib-plus-azacitidine group were thrombocytopenia (37% vs 19% in the azacitidine-alone group), neutropenia (37% vs 25%), anemia (19% vs 22%), and febrile neutropenia (16% vs 16%). Serious treatment-related adverse events occurred in 43% vs 44% of patients, with the most common in either group being febrile neutropenia (13% vs 16%), differentiation syndrome (10% vs 0%), and pneumonia (4% vs 6%).

Adverse events led to discontinuation of either drug in 7% of the combination group. No treatment-related deaths were reported.

The investigators concluded, “Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, IDH2-[mutant] acute myeloid leukemia.”

Dr. DiNardo, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit

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