FLT3 Gene Cluster Expression, Not FLT3 Mutation Status Predicts Quizartinib Response in AML

Benefit from treatment with quizartinib, a FLT3 inhibitor, was accurately predicted by a “FLT3-like” gene expression signature identified in patients with acute myeloid leukemia (AML) both with and without FLT3 mutations, according to a study presented at the 65th American Society of Hematology Annual Meeting & Exposition.

Notably, “patients without the FLT3-like signature did not demonstrate a benefit compared with placebo,” stated the study’s lead author, Adrian Mosquera Orgueira, MD, PhD, from the University Hospital of Santiago de Compostela in Spain.

Researchers reported these findings after conducting a preplanned correlative RNA-sequencing analysis of bone marrow and peripheral blood samples, including 161 samples from patients without FLT3-ITD mutations that were enrolled in QUIWI and 55 samples from patients with FLT3-ITD mutations that had failed screening.

FLT3 Expression Signature Predicts Treatment Response

Based on their analysis, the authors reported the FLT3-like gene cluster was specifically enriched in FLT3-mutated AML at 71.1% of mutated samples, while it was present in 112 of the 206 (54.37%) total samples — including 80 of the 161 (49.67%) FLT3 wild-type samples, which the authors termed “FLT3-like patients.”

Comparing patients without the FLT3-like expression in the placebo and quizartinib groups, the investigators found no significant differences in the total number of deaths (Fisher’s P-value=.63), event-free survival (EFS; hazard ratio [HR], 1.07; 95% CI, 0.56-2.06; P=.83), relapse-free survival (RFS; HR, 0.88; 95% CI, 0.38-2.01; P=.76), and overall survival (OS; HR, 1.22; 95% CI, 0.55-2.67; P=.62).

Conversely, between patients with FLT3-like expression in the placebo and quizartinib groups, there were significant differences in the total number of deaths (Fisher’s P-value=.004), EFS (HR, 0.45; 95% CI, 0.25-0.82; P=.009;), RFS (HR, 0.37; 95% CI, 0.18-0.79; P=.01,) and OS (HR, 0.41; 95% CI, 0.20-0.84; P=.01)

The report added that no statistically significant association was identified between the FLT3-like expression signature and European LeukemiaNet 2017 risk classifications, as the stratification in the FLT3-like subgroup was 30.4% low risk, 40.5% intermediate risk, and 29.1% high risk.

Ultimately, “these findings support the use of the FLT3-like signature as a potential biomarker to identify those wild-type FLT3 AML patients who may benefit from [quizartinib], providing a valuable insight for personalized treatment in AML,” Dr. Orgueira and colleagues concluded.

Reference

Orgueira AM, Encinas PM, Arias JAD, et al. The FLT3-like gene expression signature predicts response to quizartinib in wild-type FLT3 acute myeloid leukemia: an analysis of the Pethema Quiwi trial. Abstract #974. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.