Paper Details

ABSTRACT

The addition of FLT3 inhibitors to induction therapy has been shown to significantly improve outcomes for acute myeloid leukemia (AML), both in the setting of intensive anthracycline-containing regimens as well as triplet therapies with hypomethylating agents and venetoclax. Composite CR rates for midostaurin in RATIFY were 58.9 - 70% and for quizartinib in QuANTUM-First were 55 – 70%. Preclinical data suggest venetoclax can overcome FLT3-inhibitor-associated resistance mediated by BCL-xL and MCL-1 upregulation, providing rationale for combining venetoclax with intensive chemotherapy and a FLT3 inhibitor to deepen and prolong remissions beyond either doublet approach. At our institution, AML patients fit for intensive therapy receive FLAG/Ida+VEN as previously published with 14 days of VEN. FLT3 inhibitors have been routinely added in the last several years for eligible patients for days 6-19. We herein present a retrospective review of outcomes for newly diagnosed AML patients with FLT3 aberrations. Patients (n=40) receiving induction therapy at our center between June of 2023 and March of 2026 were included if they received FLAG/Ida+VEN + an approved FLT3 inhibitor (quizartinib, gilteritinib, or midostaurin). Median age was 57 (19-73), males 60% (26/40). Race was 26 (65%) White, 11 (27.5%) African Americans, and 2 (5%) Asian. Median WBC at presentation was 31 K/microL (0.6 – 299). Median marrow blast count was 57%. Distribution of ELN2022 risk was as follows, 15% favorable, 55% intermediate, and 30% adverse risk. FLT3-ITD accounted for most of these mutations 80% (32), 30% (12) patients had TKD, and 12.5% (5) patients had both. NPM1 was the most common co-mutation at 47.5% (19), followed by DNMT3a at 20% (8). NRAS and PTPN11 mutations were each present in 7 patients (17.5% each; 35% combined). Midostaurin was given in 65% (26) and Quizartinib in 25% (10). One patient received Gilteritinib and 3 patients alternated between more than 1. At day 30 bone marrow assessment, 97.5% (39/40) of the patients achieved a CRi or better with 36 (90%) of them achieving a CR. All patients were assessed for MRD and 19 (47.5%) were MRD negative by an ultrasensitive assay. Nineteen (47.5%) patients proceeded to transplant, the rest received consolidation therapy with cytarabine. With a median follow-up of 536 days, median overall survival (OS) for all patients has not been reached. Kaplan-Meier OS estimates at 6 months, 1 year, and 3 years were 89.4% (79.9-99%), 86.6% (76-97.2%), 79.9% (65.6-94.2%). Median progression-free survival was also not reached and there were too few events to calculate time-dependent estimates. Death within 60 days of induction occurred in 2.5% (1/40). Cause of death was a bacterial infection at day 11. In the ELN adverse risk group, 11/12 patients achieved a CR with one being unevaluable due to a grade 5 event. Three patients switched FLT3 inhibitors for intolerance, most often hyperbilirubinemia or hepatotoxicity. Five (12.5%) required dose modification or interruption during induction, most commonly with midostaurin for pneumonitis or hyperbilirubinemia; cytarabine (n=2) and venetoclax (n=1) were each held for hepatotoxicity or cerebellar toxicity. Aside from the single early death noted above, no other unexpected safety signals were observed.

The addition of FLT3 inhibitors to standard FLAG-Ida+VEN induction produces very high response rates (97.5% CR/CRi), including in ELN adverse-risk disease, with manageable toxicity and low treatment-related mortality, comparing favorably to historical induction regimens. While survival outcomes will depend on subsequent therapy, including transplant, these high remission rates position patients well for durable disease control.