Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia

Abstract

Purpose: The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated (FLT3^mut) acute myeloid leukemia (AML) but seldom reduces FLT3^mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3^mut AML.

Methods: This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with FLT3 wild-type and FLT3^mut (escalation) or FLT3^mut (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.

Results: Sixty-one patients were enrolled (n = 56 FLT3^mut); 64% (n = 36 of 56) of FLT3^mut 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 FLT3^mut 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% v 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). FLT3 molecular response (< 10^-2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3^mut patients was 10.0 months.

Conclusion: The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

FIG 1.

Patient enrollment and disposition. Data cutoff, November 10, 2021. ^aSome patients had multiple reasons given for study discontinuation. AE, adverse event; Gilt, gilteritinib; QD, once daily; Ven, venetoclax.

FIG 2.

Response rates in all FLT3^mut patients treated at any dose (n = 56) and in those who did (n = 35) or did not (n = 21) receive prior treatment with a FLT3 TKI. mCRc was defined as CR + CRi + CRp per criteria used in the ADMIRAL study. CR, complete response; CRi, complete response with incomplete blood count recovery; CRp, complete response with incomplete platelet recovery; mCRc, modified composite complete response; MLFS, morphologic leukemia-free state; TKI, tyrosine kinase inhibitor.

FIG 3.

(A) OS in all FLT3^mut patients treated at any dose (n = 56). (B) OS in FLT3^mut patients who did (n = 35) or did not (n = 21) receive prior treatment with a FLT3 TKI. (C) OS in FLT3^mut patients who did (n = 17) or did not (n = 39) receive alloSCT after VenGilt. alloSCT, allogeneic stem-cell transplantation; Gilt, gilteritinib; NR, not reached; OS, overall survival; TKI, tyrosine kinase inhibitor; Ven, venetoclax.

FIG 4.

(A) FLT3-ITD MRD was assessed using next-generation sequencing of DNA isolated from bone marrow aspirates collected before and after the first dose of study drug with a sensitivity threshold of 10⁻⁶ (lowest level of FLT3-ITD clones achieved). The best reported FLT3-ITD MRD value is shown for patients divided by best clinical response achieved. (B) OS in FLT3^mut patients treated at the recommended phase II dose who achieved a modified composite complete response and molecular response (FLT3-ITD variant allele frequency < 10⁻²). CR, complete response; CRi, complete response with incomplete blood count recovery; ITD, internal tandem duplications; MLFS, morphologic leukemia-free state; MRD, minimal residual disease; NR, not reached; OS, overall survival.