Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia

Marina Konopleva, Michael J Thirman, Keith W Pratz, Jacqueline S Garcia, Christian Recher, Vinod Pullarkat, Hagop M Kantarjian, Courtney D DiNardo, Monique Dail, Yinghui Duan, Brenda Chyla, Jalaja Potluri, Catherine L Miller, Andrew H Wei, Marina Konopleva, Michael J Thirman, Keith W Pratz, Jacqueline S Garcia, Christian Recher, Vinod Pullarkat, Hagop M Kantarjian, Courtney D DiNardo, Monique Dail, Yinghui Duan, Brenda Chyla, Jalaja Potluri, Catherine L Miller, Andrew H Wei

Abstract

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with FLT3-mutant acute myeloid leukemia.

Patients and methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle). FLT3 mutation was analyzed centrally on pretreatment bone marrow aspirates.

Results: In the biomarker evaluable population, FLT3 mutation was detected in 42 (15%) and 22 (19%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc; complete remission (CR) + CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) for FLT3-mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among FLT3 wild-type patients were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax + azacitidine, CRc in patients with FLT3-ITD and FLT3-TKD was 63% and 77% and median OS was 9.9 and 19.2 months, and in comutated FLT3-ITD + NPM1 patients, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax + azacitidine group.

Conclusions: When treated with venetoclax + azacitidine, patients with FLT3 mutations and FLT3 wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax + azacitidine in patients harboring FLT3-ITD. See related commentary by Perl and Vyas, p. 2719.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Venetoclax and azacitidine work synergistically to overcome antiapoptotic signals downstream of an activated FLT3 pathway.
Figure 2.
Figure 2.
Study design and molecular classification. *One patient in the venetoclax and azacitidine group and one patient in the azacitidine group had both FLT3-ITD and TKD mutation; †One patient in the venetoclax and azacitidine group was indeterminate for NPM1 comutation status.
Figure 3.
Figure 3.
A, Remission rates in patients with FLT3 mutations and FLT3 wild type by treatment groups. B, Remission rates in patients with FLT3-ITD and FLT3-TKD in the venetoclax and azacitidine group. C, Remission rates in patients with FLT3-ITD+NPM1-mutated versus FLT3-ITD+NPM1 wild type in the venetoclax and azacitidine group. D, Duration of remission among responders with FLT3-ITD+NPM1 mutation versus FLT3-ITD+ NPM1 wild type.
Figure 4.
Figure 4.
Kaplan–Meier curves for OS. A, Patients with FLT3 mutation by treatment groups. B, Patients with FLT3 mutation or FLT3 wild type in the venetoclax and azacitidine group. C, Patients with FLT3-ITD and FLT3-TKD in the venetoclax and azacitidine group. D, Patients with FLT3-ITD+NPM1 mutation versus FLT3-ITD+ NPM1 wild type in the venetoclax and azacitidine group.

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