Abstract

<h3>Background/Objective:</h3> To provide updated results from a Phase 1b trial (NCT03625505) of BCL-2 inhibitor venetoclax and FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Ven+Gilt) in patients with relapsed/refractory (R/R) FLT3-mutated (<i>FLT3<sup>Mut</sup></i><sup>+</sup>) acute myeloid leukemia (AML). <h3>Methods:</h3> Patients with R/R AML <i>FLT3<sup>Mut</sup></i><sup>+</sup> received up to Ven 400mg daily with Gilt (80 or 120 mg) daily in 28-day cycles, following Ven ramp-up. Primary endpoint was modified composite complete remission (mCRc) to align with Phase 3 ADMIRAL trial CRc responses. Secondary endpoint was mCRc duration of response (DOR); overall survival (OS), and changes in <i>FLT3</i> allelic burden were exploratory. Adverse events (AEs) were monitored. <h3>Results:</h3> At data cutoff (November 30, 2020), 43 patients (median age 63 yrs) with <i>FLT3<sup>Mut</sup></i><sup>+</sup> were enrolled. <i>FLT3</i> internal tandem duplications (ITD) were identified in 86% patients, and 14% had only tyrosine kinase domain (TKD) mutations. Baseline cytogenetic risk was favorable in 5%, 55% intermediate, 31% poor, and 12% had no mitoses/missing data. Median (range) prior lines of therapy were 2 (1–5), and 77% patients had 2 or more prior lines of therapy: 65% received at least one prior FLT3 inhibitor, and 7% received prior Ven; 33% had prior transplant. Grade 3/4 AEs were reported in 98% of patients; grade ≥3 cytopenias occurred in 79% and were predominantly managed by Ven/Gilt dose interruptions. The only grade 3/4 nonhematologic AEs reported in >20% of patients was pneumonia (n=9; 21%) and 1 instance of clinical tumor lysis syndrome. Serious AEs were reported in 74% of patients. Overall, 30- and 60-day mortality rates were 0% and 12%, respectively. AEs led to either Ven or Gilt interruptions in 56% patients, reductions in 7%, and discontinuations in 14%. mCRc was achieved by 86% of <i>FLT3<sup>Mut</sup></i><sup>+</sup> efficacy population (36/42) with median time to first response of 1.0 mo (range: 0.7–4.6) and 86% with prior FLT3 tyrosine kinase inhibitor (TKI) exposure (24/28). FLT3 molecular clearance (<10<sup>–2</sup>) was observed in 69% of mCRc patients with PCR analyzed at baseline and at least 1 follow-up timepoint (18/26). <h3>Conclusions:</h3> Updated analyses show Ven+Gilt achieved high rates of mCRc in patients with heavily pre-treated and prior TKI-exposed R/R <i>FLT3<sup>Mut</sup></i><sup>+</sup>AML with encouraging molecular clearance rates. Using similar criteria to previous <i>FLT3<sup>Mut</sup></i><sup>+</sup> studies, high mCRc rate with Ven+Gilt suggests strong anti-leukemic activity. Cytopenias were prominent but manageable.

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