Venetoclax Plus Gilteritinib for <i>FLT3</i>-Mutated Relapsed/Refractory Acute Myeloid Leukemia.

Abstract

The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory <i>FLT3</i>-mutated (<i>FLT3</i>^<i>mut</i>) acute myeloid leukemia (AML) but seldom reduces <i>FLT3</i>^<i>mut</i> burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of <i>FLT3</i>^<i>mut</i> AML. This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with <i>FLT3</i> wild-type and <i>FLT3</i>^<i>mut</i> (escalation) or <i>FLT3</i>^<i>mut</i> (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria. Sixty-one patients were enrolled (n = 56 <i>FLT3</i>^<i>mut</i>); 64% (n = 36 of 56) of <i>FLT3</i>^<i>mut</i> patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for <i>FLT3</i>^<i>mut</i> patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% <i>v</i> 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). <i>FLT3</i> molecular response (< 10^-2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for <i>FLT3</i>^<i>mut</i> patients was 10.0 months. The combination of venetoclax and gilteritinib was associated with high mCRc and <i>FLT3</i> molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.