Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia

Abstract

Older adults with acute myeloid leukemia (AML) who are not fit for standard chemotherapy historically have poor outcomes. Approximately 12-15% of older patients with AML harbor isocitrate dehydrogenase 2 (IDH2) gene mutations. Enasidenib is an oral inhibitor of mutant IDH2 proteins. Among 39 patients with newly diagnosed mutant-IDH2 AML who received enasidenib monotherapy in this phase I/II trial, median age was 77 years (range 58-87) and 23 patients (59%) had had an antecedent hematologic disorder. The median number of enasidenib treatment cycles was 6.0 (range 1-35). The most common treatment-related adverse events were indirect hyperbilirubinemia (31%), nausea (23%), and fatigue, decreased appetite, and rash (18% each). Treatment-related grade 3-4 cytopenias were reported for eight patients (21%); there was no treatment-related grade 3-4 infections. Twelve patients achieved a response (overall response rate 30.8% [95% CI 17.0%, 47.6%]), including seven patients (18%) who attained complete remission. At a median follow-up of 8.4 months, the median duration of any response was not reached (NR). Median overall survival for all patients was 11.3 months (95% CI 5.7, 15.1), and was NR for responders. Oral, outpatient targeted treatment with enasidenib may benefit older adults with newly diagnosed mutant-IDH2 AML who are not candidates for cytotoxic regimens.

Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2

“…36560, 6453, 14839, and SCRO-291) relapsed/refractory IDH2-mutant AML, drives erythroid differentiation in CD71 + erythroid precursors independently of IDH2 through modulation of PPIX homeostasis and hemoglobin production. These novel findings provide a mechanism explaining the previous clinical observations that enasidenib promotes increased hemoglobin levels and RBC transfusion independence in patients with AML, even when blast count is unchanged (6,31). This study is the first to present evidence that enasidenib can potentially be repurposed to treat anemia in any clinical context with functional erythroid precursors.…”

How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia

“…Although numbers are small and there are obvious limitations in attempting to compare independent clinical trials, 33 newly diagnosed AML patients with an IDH1 mutation treated with ivosidenib had a 42% CR/CR with partial recovery of blood counts (CRh) and a median OS of 12.6 months [45]. Similarly, 39 newly diagnosed AML patients with an IDH2 mutation treated with single-agent enasidenib had a 21% CR/CRi rate and median OS of 11.3 months [46]. The same applies for patients with a FLT3 mutation, and when one analyzes the very small numbers of newly diagnosed patients with a FLT3 mutation treated with azacitidine and the FLT3 inhibitor sorafenib, the response rate was 50% (3/ 6) [47], compared with 64% (9/14) for patients treated with venetoclax and a hypomethylating agent (HMA) [14].…”

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…In patients with advanced IDH1-mutated R/R AML, ivosidenib demonstrated durable remissions, and molecular remissions in some patients with complete remission [84]. Different IDH inhibitor therapeutic agents are summarized in Table 2 [ [85][86][87][88][89][90].…”