Ivosidenib, Venetoclax, Azacitidine Shows Promise in IDH1-Mutated Myeloid Malignancies

A phase Ib/II study found the triplet regimen ivosidenib and venetoclax plus azacitidine to be effective and well-tolerated in patients with IDH1-mutated myeloid malignancies. The findings were published in Blood Cancer Discovery.

Lead author Curtis A Lachowiez, MD, of the University of Texas MD Anderson Cancer Center in Houston, highlighted as encouraging that this triplet “appears to overcome resistance mechanisms observed with single-agent [isocitrate dehydrogenase]-inhibitor use, with high [measurable residual disease (MRD)]-negative remission rates.”

The study involved 31 patients in four cohorts who received ivosidenib plus venetoclax with or without azacitidine. The composite complete remission rate calculated for patients who received the triplet was 90%, higher than the 83% of patients who received the doublet ivosidenib plus venetoclax.

Sixteen patients had evaluable MRD, and 63% attained MRD-negative remission. MRD-negative rates were greater among the patients who received triplet therapy when compared with those who received the doublet, at 75% versus 50%, respectively (P=.60); however, this finding was not considered statistically significant.

Both the triplet and doublet were well-tolerated by patients, with 91% of the adverse events in the total study cohort being grade 1 or 2. The maximal tolerated dose in the study was not reached.

Dr. Lachowiez noted that the study’s cytogenetic and molecular analysis findings demonstrated that “[p]atients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones.”

Translational analyses in the study also identified several resistance mechanisms behind relapsed disease. The authors consider these mechanisms, such as mutations in signaling pathways, transcription factors, and tumor suppressor genes, to merit further investigation as potential avenues to manage treatment-resistant IDH1-mutated myeloid malignancies.

Reference

Lachowiez CA, Loghavi S, Zeng Z, et al. A phase Ib/II study of ivosidenib with venetoclax ± azacitidine in IDH1-mutated myeloid malignancies. Blood Cancer Discov. 2023;4(4):276-293. doi.org/10.1158/2643-3230.BCD-22-0205