FLT3 mutation status does not appear to affect response to a venetoclax and azacitidine combination treatment regimen among patients with treatment-naïve acute myeloid leukemia (AML), according to research published in Clinical Cancer Research.

AML is known to be highly genetically heterogeneous, with previously studied abnormalities having established effects on treatment outcomes. FLT3 is, furthermore, known to occur in about one-fifth of patients at least 70 years old, although its implications for treatment and clinical outcomes are not yet fully established.

A pair of allelic mutations, FLT3-internal tandem duplication (ITD)and FLT3-tyrosine kinase domain (TKD), have, furthermore, previously been established as targetable mutations, and may be related to AML development and proliferation. Although fit patients with FLT3 mutations may tolerate intensive therapy, there is no standard therapy for older, less fit, treatment-naïve patients with these aberrations.


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Previous research has suggested that venetoclax with a hypomethylating agent, such as azacitidine, may yield improved outcomes among older patients with FLT3-mutated AML. For this study, researchers evaluated clinical outcomes among treatment-naïve patients with AML with or without a FLT3 mutation treated with venetoclax plus azacitidine or placebo plus azacitidine.

All data were obtained via the randomized phase 3 Viale-a study (ClinicalTrials.gov Identifier: NCT02993523), as well as a prior phase 1b study (ClinicalTrials.gov Identifier: NCT02203773). All patients were at least 75 years old or had comorbidities making them ineligible for intensive therapy.

Overall, data from 280 patients treated with venetoclax plus azacitidine, and 117 patients treated with azacitidine only, were included. In the combination and monotherapy groups, 42 and 22 patients, respectively, had FLT3-mutated disease.

Among patients with a FLT3 mutation, the composite complete remission (CRc) rate, which included CRs and CRs with incomplete hematologic recovery, were 67% in the venetoclax group vs 36% in the azacitidine-only group. In the combination vs monotherapy group, the median duration of remission was 17.3 months vs 5 months, respectively, and the median overall survival (OS) was 12.5 months vs 8.6 months (hazard ratio [HR], 0.63; 95% CI, 0.35-1.13), indicating no significant survival difference.

Among patients with wild-type FLT3, the CRc rate in the combination vs monotherapy group was 67% vs 25%, respectively; median OS was 14.7 months vs 10.1 months (HR, 0.61; 95% CI, 0.46-0.81).

Among all patients treated with venetoclax, the CRc rate among those with FLT3-ITD vs FLT3-TKD mutations was 63% vs 77%, respectively; median OS was 9.9 vs 19.2 months.

Among patients with FLT3 mutations vs FLT3 wild-type who were treated with venetoclax, grade 3 or worse hematologic adverse events occurring in at least 20% included febrile neutropenia (38% vs 42%, respectively), thrombocytopenia (38% vs 35%), neutropenia (33% in both groups), and anemia (31% vs 24%).

“In conclusion, the current data demonstrated promising efficacy of venetoclax and azacitidine in FLT3-mutated subgroups,” the authors wrote. “Future analyses in larger patient populations are warranted to further define the risk/benefit of this combination among patients with FLT3 mutations and establish the efficacy of combining this therapy with targeted inhibitors of FLT3.”

Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Konopleva M, Thirman MJ, Pratz KW, et al. Impact of FLT3 mutation on outcomes after venetoclax and azacitidine for patients with treatment-naïve acute myeloid leukemia. Clin Cancer Res. Published online January 21, 2022. doi:10.1158/1078-0432.CCR-21-3405