Approximately half of all patients with BCR–ABL1 tyrosine-kinase inhibitor (TKI)-resistant chronic myeloid leukaemia (CML) have mutations in the ATP-binding site of the kinase. Now, the results of a phase I trial indicate that asciminib, a potent and specific TKI that mimics an autoinhibitory mechanism in ABL1 that is lost in the fusion protein, demonstrates activity in patients with relapsed or refractory CML.

This trial involved 150 patients with CML, of whom 70% had received ≥3 TKIs and 31% had at least one mutation in the kinase domain of BCR–ABL1, most commonly T315I. Among 113 patients with chronic-phase CML and without a T315I mutation, a major molecular response (MMR, defined according to the International Scale) was achieved or maintained by 6 months in 37 of 99 patients (37%) who could be evaluated, and by 12 months in 44 of 91 patients (48%). The median duration of response (DOR) was >61 weeks. By 12 months, 57 of 91 patients (63%) had an improvement in their molecular-response category. Among 28 patients with chronic-phase CML with a T315I mutation, an MMR was achieved in 4 of 17 patients (24%) and maintained in 1 patient at 12 months, with a median DOR >25 weeks. By 12 months, 9 of 18 patients (50%) had an improvement in their molecular-response category. Among 9 patients with accelerated-phase CML, one had an MMR for >11 weeks.

Eight dose-limiting toxicities were reported. The most common adverse events (AEs) were asymptomatic elevations in serum lipase or amylase levels, rash, fatigue, nausea, headache and arthralgia; of these AEs, lipase elevations were those with a higher incidence as a grade 3 AE (10%). Pancreatitis occurred in 5 patients (grade ≥3 AE in three of them), and resolved after treatment discontinuation.

These results demonstrate that asciminib is a potential treatment option for patients with CML that is relapsed and/or refractory to other TKIs. Several randomized controlled trials are underway, with results eagerly awaited.