DS-1594b Plus Venetoclax Is Effective in NPM1-Mutated AML

In vivo DS-1594b in combination with venetoclax is a potentially safe and effective therapeutic strategy for patients with acute myeloid leukemia (AML) with mtNPM1 mutations, according to a recent study.

The study, led by Valerio Ciaurro, PhD, of the University of Texas MD Anderson Cancer Center in Houston, tested the combination therapy in a patient-derived xenograft (PDX) model of NPM1-mutated AML. NSG mice were inoculated with NPM1m PDX/luc/GFP (3×10⁶/cells), then randomized into four groups: vehicle, venetoclax, DS-1594b alone, and combination. After 12 days, mice received oral DS-1594b at 50 mg/kg for four weeks and venetoclax at 50 mg/kg for two weeks then 100 mg/kg for two weeks.

Co-treatment with DS-1594b and venetoclax for four weeks further reduced AML burden compared with either agent alone or the vehicle control. The group that received DS-1594b alone experienced modest anti-tumor efficacy, but ultimately the combination group showed the greatest efficacy. Mice in the vehicle and single-agent cohorts lost weight due to rapid disease progression, but the weight of the mice in the combination group was unaffected.

Researchers also analyzed the effects of treatment on cell differentiation. Compared with the control group, the combination treatment enriched two populations of cells that had higher levels of CD33 and CD38 expression. CD33 and CD38 are well-known markers of cellular differentiation, the researchers noted.

“The combination treatment exhibits differentiation-inducing effects, which contribute to its therapeutic effectiveness,” concluded Dr. Ciaurro and colleagues.

Reference

Ciaurro V, Konopleva M, Daver N, et al. Synergistic growth inhibition of NPM1 mutant AML PDX by combined therapy with BCL-2 inhibitor venetoclax (ABT-199) and menin inhibitor DS-1594b in vivo. Abstract #4169. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.