Quizartinib in combination with decitabine and venetoclax for newly diagnosed and relapsed/refractory <i>FLT3</i> -mutated AML.

6504 Background: Hypomethylating agents (HMAs; azacitidine/decitabine) plus venetoclax (VEN) are standard for newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy; however FMS-like tyrosine kinase-3 internal tandem duplication ( FLT3-ITD ) confers resistance and poor overall survival (OS). Addition of quizartinib (QUIZ), a potent FLT3 inhibitor, may improve outcomes. Methods: Phase I/II study of QUIZ+decitabine+VEN in two cohorts: newly diagnosed FLT3-ITD AML pts unfit for intensive chemotherapy and relapsed/refractory (R/R) FLT3-ITD AML pts. Primary endpoints were maximum tolerated dose (MTD) and overall response rate (ORR). Results: Eighty-eight patients (pts) were enrolled (frontline N=42; R/R N=46). QUIZ 26.5mg/day was selected as the recommended phase II dose (RP2D). In the frontline cohort, median age was 70y (62–85); 15 pts (36%) were ≥75y; 25 (60%), 12 (N=28%), and 5 (12%) had de novo, secondary, and therapy-related AML, respectively. DNMT3A (43%), NPM1 (33%), and RUNX1 (31%) were the most common co-mutations. Complete remission (CR), CR with incomplete count recovery (CRi), morphologic leukemia-free state (MLFS), end-of-cycle-1 (EOC1) measurable residual disease (MRD) negativity by multicolor flow cytometry (MFC; 0.01%), and next-generation sequencing (NGS) FLT3-ITD negativity (5×10⁻⁵) were 72% (N=29), 17% (N=7), 2% (N=1), 58% (19/32), and 27% (5/18), respectively; 2 pts in cycle 1 were not evaluable. Best MRD negativity by MFC and FLT3-NGS were 68% (23/34) and 83% (15/18). Median time to absolute neutrophil count (ANC) &gt;500, ANC &gt;1000, and platelets &gt;50K were 40 (19–72), 41 (14–72), and 35 (16–71) days, respectively. The median relapse-free survival (RFS) and OS were 24.7 and 36.5mo. Fifteen pts (36%) proceeded to allogeneic stem cell transplant (ASCT) in CR1, with OS not reached vs 36.6mo without ASCT (p=0.65, landmark analysis). Median 3 cycles (1–39) were delivered; 11 pts remain on study. Thirty-one pts discontinued protocol due to ASCT (N=15), relapse (N=9), physician/pt choice (N=3), induction death (N=1), death in CR (N=1), death with disease (N=1), or hospice (N=1). Grade ≥3 non-hematologic adverse events (&gt;5%) included febrile neutropenia (37%), pneumonia (33%), infections (17%), pain (10%), ALT increase (10%), fracture (10%), sepsis (9%), hypertension (7%), hypotension (7%), hyponatremia (7%), gait disturbance (7%), oral mucositis (7%), and pleural effusion (7%). In the R/R cohort, CR/CRi was 28% (N=13) with 33% (N=15) MLFS; 37% (N=17) proceeded to ASCT; median OS was 6.3mo (further data will be provided at the time of presentation). Conclusions: QUIZ+decitabine+VEN combination resulted in high CR/CRi, deep MRD responses, and encouraging survival in older pts with newly diagnosed FLT3-ITD AML. Clinical trial information: NCT03661307 .