A combination treatment of quizartinib plus venetoclax plus decitabine was highly active in patients with relapsed/refractory FLT3-ITD-mutated acute myeloid leukemia (AML). Patients with RAS/MAPK and FLT3-F691L mutations displayed treatment resistance. The safety profile of this combination did not show unexpected issues .
FLT3 mutations in AML are associated with an increased risk of relapse and reduced overall survival. Although FLT3 inhibitors plus intensive chemotherapy may improve outcomes in younger patients, older or unfit patients continue to display poor outcomes. Dr. Musa Yilmaz (MD Anderson Cancer Center, TX, USA) and colleagues designed a trial to investigate a triplet combination regimen of quizartinib, decitabine, and venetoclax in relapsed/refractory FLT3-mutated patients with AML (n=23) or newly diagnosed FLT3-mutated patients who were unfit for intensive chemotherapy (n=5). During 28-day cycles, patients received decitabine (20 mg/m2, once daily on day 1 to 5 [consolidation] or 10 [induction]), venetoclax (400 mg, once daily on day 1 to 14/21), and quizartinib (30–40 mg, once daily on day 1 to 14/28). In the relapsed/refractory cohort, a complete response (CR) composite rate of 78% was established: 13%, 22%, and 43% of the patients showed CR, CRi, or morphological leukemia-free state (MLFS), respectively. The 60-day mortality rate was 5%. In addition, 34% of the patients were bridged to allogeneic bone marrow transplants. In the frontline cohort, the CR composite rate was 100%: 40% displayed CR and 60% displayed CRi. The 60-day mortality rate was 0%, and 60% underwent bone marrow transplants. Subgroup analysis showed consistent efficacy of the triplet regimen among patients with prior HMA plus venetoclax therapy or patients who received prior gilteritinib treatment. Patients with a RAS/MAPK mutation were associated with lower response rates (40%), compared with RAS/MAPK-negative patients (94%). The most common non-haematologic any-grade adverse events (AEs) were electrolyte disturbances, diarrhea, and kidney or liver function abnormalities. Pneumonia (42%), febrile neutropenia (30%), and other infections (33%) were the most common grade 3 or higher AEs. The median time to absolute neutrophil count recovery was 51 days but could be reduced to 40 days if quizartinib administration was interrupted on day 28. Grade 2 or higher corrected QT interval by Fredericia (QTcF) events were not observed.
- Yilmaz M, et al. Quizartinib (Quiz) with Decitabine (DAC) and Venetoclax (VEN) is Highly Active in Patients with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) – RAS/MAPK Mutations Continue to Drive Primary and Secondary Resistance. O616, ASH 2021 Scientific Sessions, 11–14 December.
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