Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure Journal Article


Authors: 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.; le Coutre, P.; Ottmann, O.; Heinrich, M. C.; Steegmann, J. L.; Deininger, M. W. N.; Janssen, J. J. W. M.; Mahon, F. X.; Minami, Y.; Yeung, D.; Ross, D. M.; Tallman, M. S.; Park, J. H.; Druker, B. J.; Hynds, D.; Duan, Y.; Meille, C.; Hourcade-Potelleret, F.; Vanasse, K. G.; Lang, F.; Kim, D. W.
Article Title: Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure
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. Copyright © 2019 Massachusetts Medical Society.
Journal Title: New England Journal of Medicine
Volume: 381
Issue: 24
ISSN: 0028-4793
Publisher: Massachusetts Medical Society  
Date Published: 2019-12-12
Start Page: 2315
End Page: 2326
Language: English
DOI: 10.1056/NEJMoa1902328
PUBMED: 31826340
PROVIDER: scopus
DOI/URL:
Notes: Article -- Source: Scopus
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MSK Authors
  1. Martin Stuart Tallman
    494 Tallman
  2. Jae Hong Park
    178 Park
  3. Michael John Mauro
    144 Mauro