Promising results for quizartinib, venetoclax, and decitabine in FLT3-ITD mutated AML

The triple combination of quizartinib, venetoclax, and decitabine displayed encouraging activity in participants with either newly diagnosed or relapsed or refractory (R/R) FLT3-ITD mutated acute myeloid leukaemia (AML) in a phase 1/2 study. Based on these findings, the combination therapy is further explored in an expansion of the trial.

Evidence suggests that synergistic effects may arise from combining quizartinib and venetoclax concerning the targeting of leukaemic cells in FLT3-ITD positive AML [1]. Dr Musa Yilmaz (MD Anderson Cancer Center, TX, USA) and colleagues designed a phase 1/2 study (NCT03661307) to assess the combination of the FLT3 inhibitor quizartinib with decitabine and venetoclax in participants with newly diagnosed or R/R FLT3-ITD-mutated AML [2]. The primary objective was to establish the recommended phase 2 dose of quizartinib in this combination regimen. In total, 43 R/R participants and 14 newly diagnosed participants were enrolled in the trial

After treating 11 participants in the phase 1 cohort of the study, the recommended phase 2 dose of quizartinib was established at 30 mg once daily. For the 43 R/R participants, the composite complete remission (CRc) rate was 65%, with a CR rate of 12%, a CR rate with incomplete hematologic recovery of 19%, and a morphologic leukaemia-free state rate of 34%. Notably, these findings were independent of previous gilteritinib treatment and similar in gilteritinib-treated and -untreated participants. “In addition, the 60-day mortality rate for R/R AML participants was 7% and 40% in participants who bridged to autologous stem cell transplantation (autoSCT),” added Dr Yilmaz. The median overall survival (OS) in this cohort was 7.5 months. Correspondingly, the CRc rate was 100% for the newly diagnosed AML participants, with a CR rate of 79% and a CR with incomplete haematological recovery of 21%. In this cohort, the 60-day mortality rate was also 7% and 19% for participants who bridged to autoSCT. The median OS had not been reached at the time of the analysis.

Grade 3–5 febrile neutropenia (42%), lung infection (35%), and other infections (16%) were the most common adverse events. “To tackle the issue of prolonged myelosuppression, we reduced quizartinib to days 1–14 in cycle 1 instead of days 1–28,” commented Dr Yilmaz. After this adjustment, the median time-to-recovery of an absolute neutrophil count > 500 cells/µL reduced from 43 days to 36 days.

In conclusion, quizartinib added to decitabine and venetoclax appeared to be an active combination in a heavily pretreated population of participants with R/R FLT3-ITD mutated AML, irrespective of prior gilteritinib use, although the number of participants treated were still rather low.

1. Mali RS, et al. Haematologica. 2021;106(4):1034-1046.
2. Yilmaz M, et al. Phase I/II study of quizartinib, venetoclax, and decitabine triple combination in FLT3-ITD mutated AML. Abstract 158, 65^th ASH Annual Meeting, 9–12 December 2023, San Diego, CA, USA.

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Posted on 7 February 202415 February 2024