Quizartinib with Decitabine +/- Venetoclax Is Highly Active in Patients (Pts) with FLT3-ITD Mutated (mut) Acute Myeloid Leukemia (AML): Clinical Report and Signaling Cytof Profiling from a Phase IB/II Trial
Abstract
Background: Single-agent gilteritinib and quizartinib (quiz) met their primary endpoints of improved overall survival (OS) in relapsed/refractory (R/R) FLT3-mut AML in phase III studies, but CRc durations were short (4-11 months). Quiz demonstrated potent synergy with venetoclax (VEN) (a BCL-2 inhibitor) in AML cell lines and PDX models (Mali et al. Haematologica 2020).
Methods: Newly diagnosed or R/R AML with ECOG ≤2, and adequate organ function were eligible. The protocol initially evaluated safety of the doublet of decitabine (DAC) plus quiz regardless of FLT3 status [Fig 1A]. After the first 10 pts were treated on the doublet, the protocol was amended to add VEN (triplet) in a safety dose escalation lead in [Fig 1B]. CRc criteria were as published in the phase III ADMIRAL and QUANTUM-R studies.
Results: 21 pts including DAC10 + quiz (phase 1: N=10) and DAC10 + VEN + quiz (phase IB/II: n=11) were evaluable at the time of this report (Table 1).
DAC10 + Quiz
Of 10 pts treated with DAC10 + quiz (Table 1), CRc rate was 40% (1 CRp and 3 CRi). No FLT3 R/R WT (n=3) pts responded. Four of 7 FLT3-ITD mut pts (1 frontline and 5/6 R/R, who had all received ≥1 FLT3 TKI) achieved CRc (57%), with 3/6 FLT3-PCR negative at response. 1 pt experienced QTcF prolongation > 500 msec on quiz 40mg/day (resolved after holding quiz with no clinical cardiac events). Grade 3/4 toxicities in >/= 2 pts, irrespective of attribution, included infection (12), neutropenic fever (3), mucositis (3),…
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