IDH-mutated AML is sensitive to azacytidine combinations with venetoclax or ivosidenib. Lachowiez et al. tested triple combination of these agents, as well as oral doublet of ivodesinib with venetoclax, in a phase 1b clinical trial of 31 patients with IDH1-mutated myeloid cancers. The double as well as triple combination demonstrated durable efficacy without reaching dose-limiting toxicity, comparing favorably to historical controls. Mutant IDH1 allele clearance occurred in the majority of cases within 5 cycles of therapy. Survival benefit was higher in patients with additional mutations affecting DNA methylation. Single-cell multiomic analyses reveal complex clonal dynamics underscoring potential mechanisms of response and relapse. If safety and efficacy of these findings is reproduced in the expansion phase of the trial, these regimens could be broadly applicable to high-risk IDH-mutated patients.

See article, p. 276.

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