Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias
Open accessAbstract
BACKGROUND: Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. METHODS: In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). RESULTS: Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response. CONCLUSIONS: Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).
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Ponatinib exposure of BaF3-BCR-ABL T315I cells reproduced the mass accumulation rate reduction seen with imatinib in wild-type BCR-ABL cells.
“However, exposure of these cells to the third-generation TKI ponatinib, which retains activity against BCR-ABL T315I, recapitulated the same reduction in MAR observed upon imatinib treatment of BaF3-BCR-ABL cells (Fig. 2b)20.”
From Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate (2016) · cites this paper as [20]
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- Authors
- Cortes, J. E., Kantarjian, H., Shah, N. P., Bixby, D., Mauro, M. J., Flinn, I., O'Hare, T., Hu, S., Narasimhan, N. I., Rivera, V. M., Clackson, T., Turner, C. D., Haluska, F. G., Druker, B. J., Deininger, M. W. N., & Talpaz, M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of California, San Francisco (US)
- U-M Rogel Cancer Center (US)
- Oregon Health & Science University (US)
- ARIAD Pharmaceuticals (United States) (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-11-29
- Volume
- 367
- Issue
- 22
- Pages
- 2075-2088
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3777383
- OpenAlex
- W2104694028
- Cited by
- 769
- References
- 47
- Citations by year
- 2026: 14 · 2025: 33 · 2024: 32 · 2023: 38 · 2022: 38 · 2021: 45 · 2020: 53 · 2019: 50 · 2018: 53 · 2017: 73 · 2016: 69 · 2015: 68 · 2014: 93 · 2013: 99 · 2012: 10
- FWCI
- 57.70
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (CA 016672, P01CA049639, R37CA065823, P30CA016672, P30CA069533)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- ponatinib, Philadelphia chromosome-positive leukemia, chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, T315I mutation, tyrosine kinase inhibitor resistance, BCR-ABL kinase domain mutations, dose-limiting toxicity, pancreatitis, hematologic response, cytogenetic response, molecular response
- MeSH terms
- Adult, Aged, Aged, 80 and over, Amylases, Antineoplastic Agents, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, Imidazoles, Lipase, Male, Middle Aged, Mutation, Pancreatitis, Protein-Tyrosine Kinases, Pyridazines, Structure-Activity Relationship, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, Drug Resistance, Neoplasm, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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