Correspondence to: “Combination therapies with ponatinib and asciminib in a preclinical model of chronic myeloid leukemia blast crisis with compound mutations”, Curik N et al. Leukemia. 2024; 38: 1415–1418

Abstract

Despite progress in chronic myeloid leukemia (CML) treatment, blast crisis remains challenging, characterized by clonal and molecular heterogeneity and resistance to tyrosine kinase inhibitors (TKIs). Recently, Curik et al. published “Combination therapies with ponatinib and asciminib in a preclinical model of chronic myeloid leukemia blast crisis with compound mutations” in Leukemia [1]. They showed in a murine CML blast crisis model with T315I-inclusive compound mutations that ponatinib plus asciminib effectively suppressed tumor growth and significantly prolonged survival, compared to single-agent therapies. Ponatinib plus venetoclax also delayed tumor growth, particularly in resistant clones. Manageable toxicity suggested potential clinical applications with dose adjustments. Their study highlighted the promise of combination therapies for improving outcomes in CML blast crisis [1]. Targeted therapies with TKIs have transformed the management and prognoses of patients with CML [2]. However, treatment resistance, affecting approximately 10% of patients [3], remains a substantial clinical challenge. Drug-resistant compound mutations in the BCR::ABL1 kinase domain present an emerging clinical challenge for patients undergoing sequential TKI therapy [4, 5]. One promising strategy involves combining TKIs that target different binding sites. For instance, using ponatinib, which targets the ATP-binding site, with asciminib, which targets the allosteric site, has demonstrated potential in preclinical and clinical studies [1, 6].

In our study, previously established Ba/F3 asc-R cells harboring compound BCR::ABL1 mutations, specifically T315I and Y139D [7], were screened with a high-throughput assay of 1700 clinically available compounds, identifying ponatinib as a candidate against Ba/F3 asc-R cells. Asciminib activity was initially evaluated across BCR::ABL1 mutant cell lines, including Ba/F3 PR cells harboring Y253H, E255K, and T315I mutations [8], Ba/F3 asc-R cells, Ba/F3 T315I cells, and Ba/F3 BCR::ABL cells.