The ASC4FIRST trial has shown asciminib, a novel BCR::ABL1 inhibitor, as a promising alternative to current tyrosine kinase inhibitors (TKIs) for chronic phase (CP) chronic myeloid leukaemia (CML). However, experts caution that the study’s design and outcomes raise significant questions, suggesting that imatinib, the original TKI, remains a reliable first-line therapy.
Since its approval, imatinib has transformed the treatment landscape for CML, extending life expectancy to near-normal levels for patients. The ASC4FIRST trial aimed to evaluate whether asciminib could improve upon imatinib and second-generation TKIs like dasatinib, bosutinib, and nilotinib. Despite initial enthusiasm, the trial’s design, grouping all TKIs together as a single comparator, has been criticised for failing to provide a clear comparison between asciminib and second-generation TKIs independently. While asciminib showed superiority over the combined group and imatinib alone, it did not demonstrate a significant advantage over second-generation TKIs.
The trial also focused on the 48-week major molecular response (MMR) as its primary endpoint, a measure that does not directly correlate with long-term survival or quality of life outcomes.
Another concern is the open-label nature of the trial, which can introduce bias in reporting side effects and outcomes. Without blinding, participants may perceive and report adverse events differently, and researchers may unconsciously interpret results in favour of the investigational drug. Future studies should consider double-blind designs to provide a more reliable assessment of asciminib’s safety and efficacy.
While asciminib shows potential, the trial’s findings do not definitively establish it as a superior option to second-generation TKIs. Given this, many experts maintain that imatinib remains the preferred first-line therapy for most CML patients.
The ASC4FIRST trial marks a step forward in CML research, but further rigorous studies are needed to validate asciminib’s role in CML management.
Aleksandra Zurowska, EMJ
Reference
Srinivasan et al. Imatinib remains the best frontline therapy in patients with chronic myeloid leukemia: Critical analysis of the ASC4FIRST trial. Am J Hematol. 2024;DOI: 10.1002/ajh.27477.
