S137: impact of allogeneic hematopoietic cell transplantation in first complete remission plus flt3 inhibition with quizartinib in acute myeloid leukemia with flt3-itd: results from quantum-first

Background: Patients (pts) with acute myeloid leukemia (AML) and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)+ or FLT3 mutations face poor outcomes. The randomized, double-blind, placebo-controlled, phase 3 QuANTUM-First (NCT02668653) study evaluated the novel, highly potent, and selective type II FLT3 inhibitor quizartinib (Quiz) with standard chemotherapy in pts with FLT3-ITD+ newly diagnosed AML (ndAML). Quiz plus standard intensive induction, consolidation including allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1), followed by single-agent continuation therapy (Tx) for up to 3 years (y) significantly improved overall survival (OS). Aims: We evaluated 1) the impact of allo-HCT in CR1 and the interrelationship with Quiz on clinical results and 2) the association between FLT3-ITD minimal residual disease (MRD) pre‒allo-HCT and OS. Methods: Patients aged 18-75 y with ndAML were centrally screened for FLT3-ITD before starting standard induction Tx. Pts were randomized to Quiz (40 mg/d, on days 8-21) or placebo (PBO) and stratified by region (North/South America, Europe, and Asia/other regions), age (<60 y, ≥60 y), and white blood cell (WBC; <40×109/L, ≥40×109/L) at diagnosis. Pts achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 y of Quiz continuation Tx (30-60 mg/d) or PBO. The primary endpoint was OS. We assessed the impact of allo-HCT in CR1 on OS as a time-dependent covariable in multivariable regression analyses. P values were not adjusted for multiplicity. Results: In QuANTUM-First, 539 pts were randomized to Quiz (n=268) or PBO (n=271). The median age was 56 y (range, 20-75 y). There were 294 (54.5%) women and 245 (45.5%) men. Of the 539 randomized patients, 147 pts (54.9%) on Quiz and 150 (55.4%) on PBO achieved CR whereas 45 (16.8%) on Quiz and 26 (9.6%) on PBO achieved CRi after induction. Among pts who achieved CR (Quiz, n=147; PBO, n=150), 84 (57.1%) on Quiz and 73 (48.7%) on PBO underwent allo-HCT in CR1, predominantly with grafts from unrelated donors (49.7%), followed by siblings (32.5%) and other related donors (17.8%). The median time to allo-HCT in CR1 was 3.5 months in Quiz pts and 3.3 months in PBO pts. After completion of allo-HCT, 61 pts (72.6%) on Quiz and 36 (49.3%) on PBO started 3 y of continuation Tx. Another 115 allo-HCTs were performed outside CR1 (Quiz, n=60; PBO, n=55). A multivariable extended Cox regression was conducted in all randomized pts, stratified by region, age, and WBC, including allo-HCT in CR1 as time dependent and adjusted for FLT3-ITD variant allele frequency and sex. This analysis revealed Quiz treatment (hazard ratio [HR], 0.770; 95% CI, 0.609-0.973; P = 0.0284) and allo-HCT in CR1 (HR, 0.424; 95% CI, 0.301-0.597; P < 0.0001) as favorable factors to OS (Fig. 1). Simon-Makuch plot, used to analyze time-dependent effect of allo-HCT in CR1 on OS, showed that CR pts on Quiz had longer OS regardless of undergoing allo-HCT in CR1 or not (Fig. 2). Kaplan-Meier plot of OS in pts undergoing allo-HCT in CR1 by latest pre–allo-HCT FLT3-ITD MRD status (cutoff 10−4), showed longer OS with Quiz vs PBO particularly in pts with pre–allo-HCT MRD+ status (Fig. 3). Summary/Conclusion: Pts on Quiz had longer OS than pts on PBO, irrespective of allo-HCT in CR1. Pts on Quiz who underwent allo-HCT in CR1 had longer OS than pts on PBO, irrespective of pre–allo-HCT MRD status.Keywords: AML, flt3 inhibitor, Allogeneic hematopoietic stem cell transplant, Flt3-ITD