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https://hdl.handle.net/2440/127119
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Type: | Journal article |
Title: | A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias |
Author: | Cortes, J.E. Kim, D.W. Pinilla-Ibarz, J. Le Coutre, P. Paquette, R. Chuah, C. Nicolini, F.E. Apperley, J.F. Khoury, H.J. Talpaz, M. DiPersio, J. DeAngelo, D.J. Abruzzese, E. Rea, D. Baccarani, M. Müller, M.C. Gambacorti-Passerini, C. Wong, S. Lustgarten, S. Rivera, V.M. et al. |
Citation: | New England Journal of Medicine, 2013; 369(19):1783-1796 |
Publisher: | Massachusetts Medical Society |
Issue Date: | 2013 |
ISSN: | 0028-4793 1533-4406 |
Statement of Responsibility: | J.E. Cortes, D.-W. Kim, J. Pinilla-Ibarz, P. le Coutre, R. Paquette ... Timothy Hughes ... et al. |
Abstract: | Background: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonineto- isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph-positive ALL). Methods: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. Results: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. Conclusions: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440.) |
Keywords: | PACE Investigators Humans Thrombosis Thrombocytopenia Imidazoles Pyridazines Protein Kinase Inhibitors Adolescent Adult Aged Aged, 80 and over Middle Aged Female Male Leukemia, Myelogenous, Chronic, BCR-ABL Positive Precursor Cell Lymphoblastic Leukemia-Lymphoma Young Adult |
Rights: | © 2013 Massachusetts Medical Society. All rights reserved. |
DOI: | 10.1056/NEJMoa1306494 |
Published version: | http://dx.doi.org/10.1056/nejmoa1306494 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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