Enasidenib as maintenance following allogeneic hematopoietic cell transplantation for IDH2-mutated myeloid malignancies

Abstract

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3x3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100 mg daily. Grade ≥3 toxicities attributable to enasidenib were rare, with the most common being cytopenias. Eight patients stopped maintenance therapy before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft versus host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID-19 infection (n=1). No cases of grade ≥3 acute GVHD were seen, and the 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); only one subject relapsed while receiving maintenance enasidenib. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (950% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at ClinicalTrials.gov (NCT03515512).

IDALLO study: A retrospective multicenter study of the SFGM‐TC evaluating the efficacy and safety of ivosidenib in relapsed IDH1‐mutated AML after allogeneic hematopoietic cell transplantation

“…16 Promising results with ivosidenib were seen in a phase 1 trial. 17 These real-life data confirm the efficacy and good safety profile of ivosidenib as a single agent in relapsed AML after alloHCT, with excellent deep and durable responses in some patients. Data are needed to identify patients most likely to respond and other studies evaluating ivosidenib in combination with other treatments such as hypomethylating agents and in the posttransplant setting as a maintenance therapy are ongoing.…”

“…Finally, the use of ivosidenib as a maintenance post‐alloHCT would be an interesting strategy for relapse prevention, following the example of FLT3‐targeted therapies 16 . Promising results with ivosidenib were seen in a phase 1 trial 17 …”

Test Then Erase? Current Status and Future Opportunities for Measurable Residual Disease Testing in Acute Myeloid Leukemia

“…In this study, the benefit of MRD-negativity on OS was similar at across various time points between one and 4 months, demonstrating prognostic value of late MRD clearance [81]. In another retrospective series, of patients who achieved CR with either HMA/Ven or IC, MRD negativity was achieved in approximately 80% of patients in both arms [79].…”

Droplet digital PCR for sensitive relapse detection in acute myeloid leukaemia patients transplanted by reduced intensity conditioning

“…In both DTA and non-DTA ddPCR targets, MRD negativity at the 3-month follow-up was significantly prognostic for transplantation outcome. As targeted maintenance therapies emerge, [32][33][34] this feature might serve as a valuable tool for response evaluation and optimal application. This finding seems to conflict with Heuser et al 35 who only found a prognostic impact of non-DTA mutations, but no prognostic impact of DTA mutations post-transplantation.…”