Asciminib Is Tolerable and Effective in Refractory Chronic Myeloid Leukemia

Treatment with tyrosine kinase inhibitors (TKI) can produce durable responses in patients with chronic myeloid leukemia (CML), but resistance or unacceptable side effects limit the use of TKIs in some patients. In a phase I clinical trial, Hughes, Mauro, and colleagues investigated the use of asciminib in 141 patients with chronic-phase and 9 patients with accelerated-phase CML, all 150 of whom were positive for the Philadelphia chromosome. Asciminib is unique among currently available TKIs in that it does not interact with the ATP-binding site of the ABL1 kinase but rather allosterically inhibits the enzyme; thus, disease resistant to other TKIs may respond to asciminib treatment. All enrolled patients had been treated with at least two prior TKIs or had been treated with one prior TKI but had no other effective options. All patients experienced at least one side effect, with the most common being rash, constitutional symptoms (e.g., fatigue, headache, nausea), and increased lipase or amylase levels. Of the 110 evaluable patients without the T315I “gatekeeper” mutation in BCR–ABL1, complete cytogenetic response was attained in 77 (70%) patients. Of the 25 evaluable patients with the T315I mutation, 11 (44%) patients experienced a complete cytogenetic response. This response rate is notable because the only clinically available agent with much efficacy in patients with the T315I mutation is ponatinib, but ponatinib's side-effect profile makes it unsuitable for some patients. In line with predictions from preclinical in vitro studies, higher doses of asciminib were required in the group with the T315I mutation. However, contrasting with predictions from earlier in vitro studies, the preliminary evidence from this trial does not support the notion that asciminib treatment frequently results in mutations in ABL1′s myristoyl-binding pocket, asciminib's binding site. In summary, this trial demonstrates that asciminib is tolerable and exhibits preliminary evidence of efficacy in patients with CML who have not attained responses from treatment with other TKIs.

Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med 2019;381:2315–26.

• ©2019 American Association for Cancer Research.