A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias
Jorge E. Cortes,Dong-Kee Kim,Javier Pinilla-Ibarz,P. le Coutre,Ronald Paquette,Charles Chuah,F. E. Nicolini,Jane F. Apperley,Hanna Jean Khoury,Moshe Talpaz,John F. DiPersio,Daniel J. DeAngelo,Elisabetta Abruzzese,Delphine Rea,Michele Baccarani,Martin C. Müller,Carlo Gambacorti-Passerini,Stephane Wong,Stephanie Lustgarten,Victor M. Rivera,Timothy P. Clackson,Christopher D. Turner,Frank G. Haluska,François Guilhot,Michael W. Deininger,Andreas Hochhaus,Timothy P. Hughes,J. M. Goldman,Neil P. Shah,Hagop M. Kantarjian +29 more
TLDR
Ponatinib had significant antileukemic activity across categories of disease stage and mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%.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.read more
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A view on drug resistance in cancer
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Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia
Andreas Hochhaus,Richard A. Larson,François Guilhot,Jerald P. Radich,Susan Branford,Timothy P. Hughes,Michele Baccarani,Michael W. Deininger,Francisco Cervantes,Satoko Fujihara,Christine Elke Ortmann,Hans D. Menssen,Hagop M. Kantarjian,Stephen G. O'Brien,Brian J. Druker +14 more
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European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia
Andreas Hochhaus,Michele Baccarani,Richard T. Silver,Charles A. Schiffer,Jane F. Apperley,Francisco Cervantes,Richard E. Clark,Jorge E. Cortes,Michael W. Deininger,François Guilhot,Henrik Hjorth-Hansen,Timothy P. Hughes,Jeroen Janssen,Hagop M. Kantarjian,Dong-Wook Kim,Richard A. Larson,Jeffrey H. Lipton,Francois-Xavier Mahon,Jiří Mayer,Franck E. Nicolini,Dietger Niederwieser,Fabrizio Pane,Jerald P. Radich,Delphine Rea,Johan Richter,Gianantonio Rosti,Philippe Rousselot,Giuseppe Saglio,Susanne Saußele,Simona Soverini,Juan Luis Steegmann,Anna G. Turkina,Andrey Zaritskey,Ruediger Hehlmann +33 more
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References
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European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013
Michele Baccarani,Michael W. Deininger,Gianantonio Rosti,Andreas Hochhaus,Simona Soverini,Jane F. Apperley,Francisco Cervantes,Richard E. Clark,Jorge E. Cortes,François Guilhot,Henrik Hjorth-Hansen,Timothy P. Hughes,Hagop M. Kantarjian,Dong-Wook Kim,Richard A. Larson,Jeffrey H. Lipton,François Xavier Mahon,Giovanni Martinelli,Jiri Mayer,Martin C. Müller,Dietger Niederwieser,Fabrizio Pane,Jerald P. Radich,Philippe Rousselot,Giuseppe Saglio,Susanne Saußele,Charles A. Schiffer,Richard T. Silver,Bengt Simonsson,Juan Luis Steegmann,John M. Goldman,Rüdiger Hehlmann +31 more
TL;DR: Optimal responders to chronic myeloid leukemia treatment should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.
Journal ArticleDOI
Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive Leukemias
Moshe Talpaz,Neil P. Shah,Hagop M. Kantarjian,Nicholas J. Donato,John Nicoll,Ron Paquette,Jorge E. Cortes,Susan O'Brien,Claude Nicaise,Eric Bleickardt,M. Anne Blackwood-Chirchir,Vishwanath Iyer,Tai-Tsang Chen,Fei Huang,Arthur P. DeCillis,Charles L. Sawyers,Charles L. Sawyers +16 more
TL;DR: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib, which is effective in Philadelphia chromosome-positive leukemias but relapse occurs.
Journal ArticleDOI
AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance
Thomas O'Hare,Thomas O'Hare,William C. Shakespeare,Xiaotian Zhu,Christopher A. Eide,Christopher A. Eide,Victor M. Rivera,Frank Wang,Lauren T. Adrian,Lauren T. Adrian,Tianjun Zhou,Huang Wei Sheng,Qihong Xu,Chester A. Metcalf,Jeffrey W. Tyner,Marc M. Loriaux,Amie S. Corbin,Amie S. Corbin,Scott Wardwell,Yaoyu Ning,Jeffrey A. Keats,Yihan Wang,Raji Sundaramoorthi,Mathew Thomas,Dong Zhou,Joseph Snodgrass,Lois Commodore,Tomi K. Sawyer,David C. Dalgarno,Michael W. Deininger,Brian J. Druker,Brian J. Druker,Tim Clackson +32 more
TL;DR: Design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants, and clinical evaluation ofAP24534 as a pan-BCR-ABl inhibitor for treatment of CML are reported.
Journal ArticleDOI
Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia.
Andreas Hochhaus,Stephen G. O'Brien,François Guilhot,B. J. Druker,Susan Branford,Letizia Foroni,JohnM. Goldman,Martin C. Müller,Jerald P. Radich,Marc Rudoltz,Manisha Mone,Insa Gathmann,Timothy P. Hughes,Richard A. Larson +13 more
TL;DR: During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC), and the toxicity profile was unchanged.
Journal ArticleDOI
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance
Hagop M. Kantarjian,Francis J. Giles,Norbert Gattermann,Kapil N. Bhalla,Giuliana Alimena,Francesca Palandri,Gert J. Ossenkoppele,Franck E. Nicolini,Stephen G. O'Brien,Mark R. Litzow,Ravi Bhatia,Francisco Cervantes,Ariful Haque,Yaping Shou,Debra Resta,Aaron Weitzman,Andreas Hochhaus,Philipp le Coutre +17 more
TL;DR: Nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance and was effective in patients harboring BCR-ABL mutations associated with imatinIB resistance (except T315I), and also in Patients with a resistance mechanism independent of B CR-ABl mutations.
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