AML-241 Sequential Venetoclax and FLT3 Inhibitors in Combination With Hypomethylating Agents or Low-Dose Chemotherapy in Newly Diagnosed, Unfit, FLT3-Mutant Acute Myeloid Leukemia Patients

Abstract

Context: Targetable mutations such as FLT3, a receptor tyrosine kinase, are present in 30% of cases with acute myeloid leukemia (AML). Direct inhibitors of FLT3 are promising therapeutic agents such as midostaurin and gilteritinib. The use of FLT3 inhibitors as single agents remains to be limited with short-lived responses. For treatment-naïve AML patients with FLT3 mutation, the standard treatment entails induction with intensive chemotherapy in physically fit or younger patients and in combination with an FLT3 inhibitor. There is no approved targeted therapy option for treatment-naïve patients with AML harboring an FLT3 mutation ineligible for intensive therapy. Objective: To assess the efficacy and feasibility of sequential administration of venetoclax, a selective inhibitor of Bcl-2, and midostaurin in addition to induction chemotherapy in unfit newly diagnosed FLT3-mutant AML patients. Methods: This is a case series reviewing the clinical data of four consecutive patients with FLT3-mutant AML, ineligible for standard induction chemotherapy, who received induction treatment consisting of low-dose chemotherapy or hypomethylating agents (HMA) with the sequential use of venetoclax for 10 days followed by midostaurin for 14 days, treated at the American University of Beirut Medical Center. Results: Between November 2021 and February 2022, four patients were included in our study. The median age was 68 years (range 66-70). All patients had FLT3 mutation (three with ITD, one with TKD), and three patients had concomitant NPM1 mutation. One patient had trisomy 8 and another patient had deletion 7 on cytogenetics. All patients achieved complete remission on day 21 and day 28. One patient with underlying myelodysplastic syndrome remained to have detectable FLT3 with deletion 7 at day 28 evaluation and had the longest time for absolute neutrophil count (ANC) and platelet count recovery. The median number of days for ANC and platelet count recovery was 40 days (range 27-59) and 34 days (24-not reached) respectively. The main toxicity was febrile neutropenia in 3 out of 4 patients. Conclusions: The sequential use of venetoclax followed by midostaurin in combination with low dose chemotherapy or HMA for newly diagnosed AML, FLT3-mutant patients who are unfit for intensive chemotherapy seems to be a promising approach with an acceptable toxicity profile. © 2022 Elsevier Inc.