Multicenter Pilot Clinical Trial of Enasidenib As Maintenance Therapy after Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia (AML) Carrying IDH2 Mutations

Somatic mutations in IDH genes are seen in ∼20% of patients with AML, with mutations in IDH2 (R172, R140) being more common (15%) than IDH1 (R132). We previously reported a higher 1-year relapse rate after HCT in patients with IDH mutations (mIDH; PMC9129101). We hypothesized that enasidenib, an IDH2 inhibitor, is well-tolerated as post-HCT maintenance, and can improve leukemia free survival (LFS) in AML patients carrying mIDH2. Here, we are reporting the final results of our completed multicenter [City of Hope (COH) and Moffitt Cancer Center] pilot trial (NCT03728335), previously reported in 2022 ASH meeting with a shorter follow-up period.The primary objective was to evaluate the safety and tolerability of enasidenib as post-HCT maintenance in mIDH2 AML patients. Secondary objectives were to assess survival outcomes, relapse, and 1-year chronic graft-versus-host disease (cGVHD)-free and relapse-free survival (CRFS).Recipients of alloHCT who had mIDH2 AML (n=15) were included (8 at COH and 7 at Moffitt). Patients were eligible for maintenance therapy irrespective of conditioning, if in complete remission (CR) at day +30 post-HCT, had ECOG PS ≤2 and adequate marrow function. Patients with active acute GVHD (grade ≥2) were excluded. Enasidenib was given at the FDA approved dose of 100 mg/day between days 50 and 120 post-HCT and continued for 2 years in 28-day cycles. (Fig 1a).The median age was 58 years (range 24-77); Male: Female ratio was 40:60% and 67% of patients were Caucasian. Pre-HCT remission status was CR1 in 73%, CR2 in 20%, and measurable residual disease positive in 6%. Cytogenetic risk classification was favorable, intermediate, and adverse in 13%, 60%, and 26%, respectively. Donors were unrelated (53%), related (20%), or haploidentical (26%). Most patients (80%) underwent reduced intensity conditioning, and all received PBSCs as graft source. GVHD prophylaxis was PTCy (60%), or tacrolimus based.At the last data cutoff, 12/15 (80%) patients completed all planned 24 cycles. Reasons for maintenance discontinuation were toxicity, loss of F/U, and MD discretion. Median follow up duration was 23.6 months (range: 20.0-33.4). We collected all grades of adverse effects (AEs) during the first 2 cycles, and grade ≥3 AEs for subsequent cycles. In the first 2 cycles, grade ≥3 AEs were mainly due to hematologic toxicity including: lymphopenia (46%; n=7), anemia (53%; n=8), neutropenia (13%; n=2), and thrombocytopenia (33%; n=5). Non-hematologic AEs included grade 1-2 nausea (60%; n=9), and vomiting/diarrhea (26%; n=4). The 1 and 2-year overall survival and LFS were 100% resulting in high 1 and 2-year CRFS of 93% and 87%, respectively. (Fig 1b).In conclusion, post-HCT maintenance therapy with enasidenib is safe and feasible with highly favorable survival outcomes in mIDH2 AML. Treatment delays and dose reductions were commonly seen; however, most patients completed their 2-years maintenance.