Venetoclax Plus Gilteritinib ‘Potentially Active’ in Wild-Type FLT3 AML

Venetoclax plus gilteritinib is a “potentially active regimen” in patients with high-risk wild-type FLT3 acute myeloid leukemia (AML), according to a recent study published in Blood.

Maike Janssen, MD, of the University Hospital Heidelberg in Germany, and colleagues conducted the research to “identify effective combination partners for venetoclax in AML” because “resistance and relapse represent major clinical challenges” in treating patients with AML.

Dr. Janssen and colleagues performed high-throughput drug screening of 64 antileukemic drugs with or without venetoclax in 31 primary samples from patients with high-risk AML.

Gilteritinib plus venetoclax “increased apoptosis, reduced viability, and was active in venetoclax-azacitidine-resistant cell lines and primary patient samples,” according to the study’s authors. Furthermore, proteomics showed increased wild-type FLT3 signaling in specimens that had low in vitro response to venetoclax and azacitidine.

Gilteritinib plus venetoclax decreased the phosphorylation of ERK and GSK3B “via combined AXL and FLT3 inhibition with subsequent suppression of the antiapoptotic protein MCL-1,” according to Dr. Janssen and colleagues.

Downregulation of MCL-1 was associated with increased MCL-1 phosphorylation of serine 159, decreased phosphorylation of threonine 161, and proteasomal degradation.

Furthermore, gilteritinib plus venetoclax showed activity in xenograft model derived from a patient with wild-type FLT3 AML and a TP53 mutation. An off-label use of the combination treatment also “reduced leukemic burden” in four patients with wild-type FLT3 AML who received it after developing refractory disease on a combination of venetoclax and azacitidine, according to Dr. Janssen and colleagues.

“In summary, our results suggest that combined inhibition of FLT3/AXL potentiates venetoclax response in FLT3 wild-type AML by inducing MCL-1 degradation,” Dr. Janssen and colleagues concluded. “Therefore, the venetoclax-gilteritinib combination merits testing as a potentially active regimen in patients with high-risk FLT3 wild-type AML.”

Reference

Janssen M, Schmidt C, Bruch PM, et al. Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1. Blood. 2022;140(24):2594-2610.