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FLT3 mutations occur in 20-35% patients with newly diagnosed (ND) acute myeloid leukemia (AML) and confer a higher risk of relapse and inferior overall survival (OS). Given modest benefit with first-generation multikinase inhibitors, second-generation FLT3 inhibitors (FLT3i) have been combined with low-intensity therapies (LIT) with encouraging results but are not curative Venetoclax with hypomethylating agent (HMA) has emerged as the new standard for older/unfit patients with AML 5 . Pre-clinical studies in FLT3 mut cell lines, primary samples, and xenografts have shown synergy between FLT3i's and venetoclax through downregulation of . Clinical studies have demonstrated safety and activity of the combination of FLT3i and HMA with composite complete remission (CRc) rates of 65-80% and median OS 8.5-20 months 1,4,10 , as well as FLT3i and venetoclax which showed CRc rate of 85% in relapsed/ refractory (R/R) FLT3 mut AML including in patients with prior FLT3i exposure 11 . We hypothesized that triplet therapy combining FLT3i, venetoclax, and HMA may further improve outcomes. Hence, we added FLT3i to our regimen of 10-day decitabine with venetoclax (DEC10-VEN) for FLT3 mut AML. We erein describe the first report of such a 'triplet' combination regimen for FLT3 mut AML. This phase 2 trial (NCT03404193) enrolled ND patients with AML > 60 years and R/R patients >18 years. Patients needed to have ECOG performance status 3. Patients with favorable-risk cytogenetics and prior Bcl-2 inhibitor exposure were excluded. Patien s received decitabine 20 mg/m 2 IV for 10-days every 4-6 weeks for induction followed by decitabine for 5-days after CR/CRi, as described previously 12 . Venetoclax dose was 400 mg PO daily or equivalent (with azole co-administration). Reduction of venetoclax duration to <21 days per cycle was permitted in cases of persistent myelosuppression, after confirming 5% blasts or hypo/acellular marrow. Addition of FLT3i of clinician's choice was allowed (Fig. ND patients were admitted for the first cycle and R/R patients were admitted for the initial venetoclax rampup. Cytoreduction to WBC <10 10 9 /L was required prior to starting therapy and all patients received prophylaxis for tumor lysis syndrome, and antimicrobial prophylaxis.
Maiti et al. (Mon,) studied this question.