The standard treatment for relapsed/refractory FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) is the FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib, although this drug seldom lowers the burden of FLT3mut  or results in long-lasting effectiveness. In preclinical models with FLT3mut AML, gilteritinib and the BCL-2 inhibitor venetoclax work in concert.

Patients with FLT3 wild-type and FLT3mut (escalation) or FLT3mut (expansion) relapsed/refractory AML were included in this phase Ib open-label, dose-escalation/dose-expansion research. Patients were given 80 mg or 120 mg of gilteritinib and 400 mg of venetoclax orally once a day. Safety, determining the phase II dose that should be used, and measuring the modified composite complete response (mCRc) rate using ADMIRAL phase III-defined response criteria (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) were the main goals.

Sixty-one patients (n = 56 FLT3mut) were recruited, and 36 of the 56 FLT3mut patients (or 64% of the total) had previously undergone FLT3 inhibitor medication. A 400 mg/day dosage of venetoclax with a 120 mg/day dose of gilteritinib was suggested for phase II. Cytopenias (n = 49; 80%) accounted for the majority of grade 3/4 adverse events. Venetoclax and gilteritinib dose reductions were caused by adverse events in 51% and 48% of the cases, respectively. In FLT3mut patients, the mCRc rate was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%). The rate was comparable in patients who had received prior FLT3 inhibitor therapy or not (80% v 67%, respectively). 17.5 months were the average follow-up. The overall length of the remission was 4.9 months (95% CI, 3.4 to 6.6), while the median time to respond was 0.9 months. 60% of evaluable mCRc patients (n = 15 of 25) had a FLT3 molecular response (<10-2). For FLT3mut patients, the median overall survival was 10.0 months.

Regardless of past FLT3 inhibitor exposure, the combination of venetoclax and gilteritinib was linked to significant mCRc and FLT3 molecular response rates. Dose breaks were required to lessen myelosuppression