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Ziftomenib 600 mg daily achieved a CR/CRh rate of 22% (61% MRD-negative among responders) and an overall response rate (ORR) of 33% in heavily pretreated R/R NPM1-mutated AML, with a median duration of response (DOR) of 4.6 months and median overall survival (OS) of 6.6 months (18.4 months in responders). Efficacy was consistent across subgroups, including prior venetoclax and FLT3/IDH co-mutations, and safety was manageable with on-target differentiation syndrome in 25% (15% grade 3; no grade 4–5), low myelosuppression, rare QTc prolongation (3%), and only 3% discontinuations for drug-related AEs. This non-cytotoxic, oral menin inhibitor offers meaningful activity in a high-risk population and is a practical option while we await combination data.

It does not seem that all NPM1 mutations are created equally. Type A and B mutations had favorable outcomes and type D mutations do much worse, something to consider when risk stratifying in patients with AML.

This study compared double induction vs. standard induction and a reduced dose of daunorubicin 90mg/m2 vs. 60mg/m2. The reduced dose was just as efficacious and double inductions do not seem to be beneficial. Probably less is more in this setting and once you get the CR, one can move forward with consolidation and start planning for transplant.

Compelling study showing Asciminib vs. investigator’s choice TKi. Asciminib was better tolerated and with deeper molecular responses. This may become a preferred option for many new chronic myeloid leukemia (CML) patients. Cost may be an issue.