{"doi":"10.1056/nejmoa1205127","title":"Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias","abstract":null,"journal":"New England Journal of Medicine","year":2012,"id":605576,"datarank":0.9977357810384593,"base_score":6.651571873589727,"endowment":6.651571873589727,"self_citation_contribution":0.9977357810384593,"citation_network_contribution":0.0,"self_endowment_contribution":0.9977357810384593,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":773,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1056715,"name":"Hagop Kantarjian","orcid":null,"position":1,"is_corresponding":false},{"id":714326,"name":"Neil P. Shah","orcid":"0000-0003-4398-3388","position":2,"is_corresponding":false},{"id":1554187,"name":"Dale Bixby","orcid":null,"position":3,"is_corresponding":false},{"id":471568,"name":"Michael J. Mauro","orcid":"0000-0002-2251-4032","position":4,"is_corresponding":false},{"id":1554188,"name":"Ian Flinn","orcid":null,"position":5,"is_corresponding":false},{"id":217037,"name":"Thomas O'Hare","orcid":null,"position":6,"is_corresponding":false},{"id":1554189,"name":"Simin Hu","orcid":null,"position":7,"is_corresponding":false},{"id":1554190,"name":"Narayana I. Narasimhan","orcid":null,"position":8,"is_corresponding":false},{"id":473697,"name":"Victor M. Rivera","orcid":"0000-0002-7258-3001","position":9,"is_corresponding":false},{"id":1053310,"name":"Tim Clackson","orcid":null,"position":10,"is_corresponding":false},{"id":616265,"name":"Christopher D. Turner","orcid":"0000-0003-2348-5373","position":11,"is_corresponding":false},{"id":174186,"name":"Frank G. Haluska","orcid":null,"position":12,"is_corresponding":false},{"id":51804,"name":"Brian J. Druker","orcid":null,"position":13,"is_corresponding":false},{"id":1554191,"name":"Michael W.N. Deininger","orcid":null,"position":14,"is_corresponding":false},{"id":284124,"name":"Moshe Talpaz","orcid":"0000-0003-3361-3981","position":15,"is_corresponding":false},{"id":1554186,"name":"Jorge E. Cortes","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias","abstract":"<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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.<h4>Conclusions</h4>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. 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