Molecular remission and response patterns in patients with mutant- IDH2 acute myeloid leukemia treated with enasidenib

Abstract

Approximately 8% to 19% of patients with acute myeloid leukemia (AML) have isocitrate dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), which leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase 1/2 study evaluated enasidenib doses of 50 to 650 mg/d, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies. Overall, 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8% (95% confidence interval [CI], 32.2-45.7). Median overall survival was 8.8 months (95% CI, 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%) or were refractory to intensive (37.5%) or nonintensive (43.2%) therapies. Sixty-six (43.1%) red blood cell transfusion-dependent and 53 (40.2%) platelet transfusion-dependent patients achieved transfusion independence. The magnitude of 2-HG reduction on study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered at www.clinicaltrials.gov as #NCT01915498.

Graphical abstract

Figure 1.

IDH2 VAF changes during enasidenib treatment. (A) Baseline-normalized VAFs measured at the beginning of cycles 2 through 12. Outlier points with normalized VAF values >4 are not shown for clarity. (B) Median minimum baseline-normalized VAF measures during treatment by mutant-IDH2 allele and clinical response category. Baseline-normalized VAFs for visit X = VAF at visit X divided by the average VAF at screening and at cycle 1 day 1. Outcomes are reported for patients with R/R AML who received enasidenib, 100 mg/d, and had longitudinal IDH2 VAF data (n = 101).

Figure 2.

Association between baseline mutation burden and clinical response to enasidenib. (A) Number of known somatic mutations by response status. Dots represent individual patients. (B) Response in patients with low (≤3 mutations) or high (≥6 mutations) mutation burden at baseline. Outcomes are reported for the subgroup of patients with R/R AML who received enasidenib, 100 mg/d, and had baseline mutation data (n = 127).

Figure 3.

Changes in 2-HG concentrations during enasidenib treatment. (A) Box plots of evaluable baseline-normalized serum 2-HG levels during the first 12 cycles of enasidenib treatment. Dotted lines indicate baseline 2-HG level. (B) Baseline-normalized median maximum reductions in 2-HG as a function of mutant-IDH2 allele and clinical response category. Baseline-normalized 2-HG for visit X = 2-HG at visit X divided by the average 2-HG at screening and at cycle 1 day 1. Outcomes are reported for the subgroup of patients with R/R AML who received enasidenib, 100 mg/d, and had longitudinal 2-HG data (n = 155).

Figure 4.

OS. (A) OS among all patients with R/R AML who received enasidenib, 100 mg/d (n = 214). (B) OS by response to prior AML treatment(s).