Background: The outcomes in patients (pts) with newly diagnosed FLT3 mutated AML who are ineligible for intensive induction chemotherapy are poor. Added to a low intensity chemotherapy backbone, FLT3 inhibitors, such as midostaurin, sorafenib, and quizartinib, result in median OS of 8-17 months in the frontline (Gallogly ASH 2017, Ohanian AJH 2018, Swaminathan ASH 2017), and 4-8 months in relapsed/refractory (R/R) settings (Yilmaz JHO 2020, Ravandi Blood 2013). Quizartinib, a potent second generation FLT3 inhibitor demonstrated synergy with venetoclax (VEN) (a BCL-2 inhibitor) in AML cell lines and PDX models (Mali Haematologica 2020). We designed this study to evaluate the safety and efficacy of quizartinib, venetoclax, and decitabine combination in pts with R/R or newly diagnosed FLT3 mutated AML. Methods: Frontline cohort included pts who are ineligible for intensive induction chemotherapy, and R/R cohort included pts who received 5 or less prior treatments. All patients had a performance status of ECOG ≤2, adequate organ functions, and QTcF <450 msec prior to therapy. All pts underwent day 14 bone marrow, and venetoclax (400 mg/day) was put on hold in patients with bone marrow blasts ≤ 5% (or marrow aplasia). Those with day14 bone marrow blast >5% continued venetoclax for 21 days during cycle 1. All pts induced with 10 days of decitabine (20 mg/m2). In subsequent cycles, decitabine administered for 5 days. Quizartinib (30 or 40 mg/day) was administered daily continuously. Results: 21 pts were enrolled and 17 pts evaluable at the time of this report (4 are still within cycle 1). Of 13 pts with R/R AML (median 3 [range 1-5] prior therapies, 85% with ≥1 prior FLT3 inhibitor), 9 (69%) achieved CRc (2 CR, 7 CRi) with 4/9 and 5/9 responders FLT3-PCR and multicolor flow cytometry (MFC) negative, respectively. Thirty and 60-day mortality rates were 0% and 8%. Of 4 patients with newly diagnosed AML (median age 72), all achieved CRc (2 CR, 2 CRi) with 4/4 and 2/3 responders FLT3-PCR and MFC negative, respectively. 60-day mortality was 0% in the frontline cohort. No pts developed a dose limiting toxicity (DLT) with 30 mg/day quizartinib, however with the 40mg/day quizartinib 2 pts developed hematologic DLT (grade ≥3 neutropenia with a <5% cellular bone marrow lasting ≥42 days). Hence, quizartinib 30 mg/day dose was determined as recommended phase 2 dose for the triplet. Grade 3/5 non-hematologic toxicities in >2 pts included lung infections (N=9) and neutropenic fever (N=6). No QTcF prolongations >450 msec were noted. With a median follow-up of 7.2 months, the median OS was not reached in frontline cohort and was 7.1 months in R/R cohort. 2/4 and 5/9 responders underwent ASCT in frontline and R/R cohorts, respectively. All frontline pts were alive at the last follow-up; 3 were in CR and 1 relapsed disease. Of 9 responders in R/R cohort, 4 were alive (3 CR, 1 relapse) and 5 died (4 relapse, 1 CR). Conclusions: Decitabine + venetoclax + quizartinib is highly active in R/R FLT3-ITD mutated AML pts, with CRc rates of 69% and the median OS of 7.1 months. Accrual to the triplet continues and updated clinical and correlative data will be presented. Clinical trial information: NCT03661307