Asciminib in chronic myeloid leukemia after Abl kinase inhibitor failure

Timothy P. Hughes, Michael J. Mauro, Jorge E. Cortes, Hironobu Minami, Delphine Rea, Daniel J. DeAngelo, Massimo Breccia, Yeow Tee Goh, Moshe Talpaz, Andreas Hochhaus, Philipp le Coutre, Oliver Ottmann, Michael C. Heinrich, Juan L. Steegmann, Michael W.N. Deininger, Jeroen J.W.M. Janssen, Francois Xavier Mahon, Yosuke Minami, David Yeung, David M. RossMartin S. Tallman, Jae H. Park, Brian J. Druker, David Hynds, Yuyan Duan, Christophe Meille, Florence Hourcade-Potelleret, K. Gary Vanasse, Fabian Lang, Dong Wook Kim

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Abstract

BACKGROUND Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome–positive leukemia are unknown. METHODS In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation.

Original languageEnglish (US)
Pages (from-to)2315-2326
Number of pages12
JournalNew England Journal of Medicine
Volume381
Issue number24
DOIs
StatePublished - Dec 12 2019

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ASJC Scopus subject areas

  • Medicine(all)

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Hughes, T. P., Mauro, M. J., Cortes, J. E., Minami, H., Rea, D., DeAngelo, D. J., Breccia, M., Goh, Y. T., Talpaz, M., Hochhaus, A., Coutre, P. L., Ottmann, O., Heinrich, M. C., Steegmann, J. L., Deininger, M. W. N., Janssen, J. J. W. M., Mahon, F. X., Minami, Y., Yeung, D., ... Kim, D. W. (2019). Asciminib in chronic myeloid leukemia after Abl kinase inhibitor failure. New England Journal of Medicine, 381(24), 2315-2326. https://doi.org/10.1056/NEJMoa1902328