Triplet therapy with venetoclax, FLT3 inhibitor and decitabine for FLT3-mutated acute myeloid leukemia
Authors: Abhishek Maiti, Courtney D. DiNardo, Naval G. Daver, Caitlin R. Rausch, Farhad Ravandi, Tapan M. Kadia, Naveen Pemmaraju, Gautam Borthakur, Prithviraj Bose, Ghayas C. Issa, Nicholas J. Short, Musa Yilmaz, Guillermo Montalban-Bravo, Alessandra Ferrajoli, Elias J. Jabbour, Nitin Jain, Maro Ohanian, Koichi Takahashi, Philip A. Thompson, Sanam Loghavi, Kathryn S. Montalbano, Sherry Pierce, William G. Wierda, Hagop M. Kantarjian, Marina Y. Konopleva
Journal: Blood Cancer Journal (2021)

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 [1][2][3][4] .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. Patiens 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. S1).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.Responses were graded per the IWG criteria for AML with adapted CRc criteria per the gilteritinib ADMIRAL and quizartinib QUANTUM-R studies 13,14 .The CRc included CR, CR with incomplete platelet recovery, and CR with incomplete hematologic recovery 13 .OS was measured from start of therapy until death or censored at last follow-up.Progression-free survival was defined from the time of response until relapse, death, or censored at last follow-up.Duration of response was determined from the time of response till relapse or censored at last followup or at the time of death without relapse.Measurable residual disease (MRD) was assessed on bone marrow (BM) specimens using 8-color multiparametric flow