In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants.
Thomas O'Hare,Denise K. Walters,Eric P. Stoffregen,Taiping Jia,Paul W. Manley,Jürgen Mestan,Sandra W. Cowan-Jacob,Francis Y. Lee,Michael Heinrich,Michael W. Deininger,Brian J. Druker,Brian J. Druker +11 more
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TLDR
It is reported that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for allImatinib-resistant mutants tested, with the exception of T315I.Abstract:
Imatinib, a Bcr-Abl tyrosine kinase inhibitor, is a highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most chronic phase patients, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired imatinib resistance has been traced to Bcr-Abl kinase domain mutations with decreased imatinib sensitivity. Thus, alternate Bcr-Abl kinase inhibitors that have activity against imatinib-resistant mutants would be useful for patients who relapse on imatinib therapy. Two such Bcr-Abl inhibitors are currently being evaluated in clinical trials: the improved potency, selective Abl inhibitor AMN107 and the highly potent dual Src/Abl inhibitor BMS-354825. In the current article, we compared imatinib, AMN107, and BMS-354825 in cellular and biochemical assays against a panel of 16 kinase domain mutants representing >90% of clinical isolates. We report that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors hold promise for treating imatinib-refractory CML.read more
Citations
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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
Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.
Hagop M. Kantarjian,Neil P. Shah,Andreas Hochhaus,Jorge E. Cortes,Sandip Shah,Manuel Ayala,Beatriz Moiraghi,Zhixiang Shen,Jiri Mayer,Ricardo Pasquini,Hirohisa Nakamae,Françoise Huguet,Concepción Boqué,Charles Chuah,Eric Bleickardt,M. Brigid Bradley-Garelik,Chao Zhu,Ted Szatrowski,David Shapiro,Michele Baccarani +19 more
TL;DR: Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long- term outcomes among patients with newly diagnosed chronic-phase CML.
Journal ArticleDOI
Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.
Hagop M. Kantarjian,Francis J. Giles,Lydia Wunderle,Kapil N. Bhalla,Susan O'Brien,Barbara Wassmann,Chiaki Tanaka,Paul W. Manley,Patricia Rae,William Mietlowski,Kathy Bochinski,Andreas Hochhaus,James D. Griffin,Dieter Hoelzer,Maher Albitar,Margaret Dugan,Jorge E. Cortes,Leila Alland,Oliver G. Ottmann +18 more
TL;DR: Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML, and common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes.
Journal ArticleDOI
Chronic Myeloid Leukemia: An Update of Concepts and Management Recommendations of European LeukemiaNet
Michele Baccarani,Jorge E. Cortes,Fabrizio Pane,Dietger Niederwieser,Giuseppe Saglio,Jane F. Apperley,Francisco Cervantes,Michael W. Deininger,Alois Gratwohl,François Guilhot,Andreas Hochhaus,Mary M. Horowitz,Timothy P. Hughes,Hagop M. Kantarjian,Richard A. Larson,Jerald P. Radich,Bengt Simonsson,Richard T. Silver,John M. Goldman,Rüdiger Hehlmann +19 more
TL;DR: Imatinib should be continued indefinitely in optimal responders and second-generation TKIs are recommended, followed by allogeneic hematopoietic stem-cell transplantation only in instances of failure and, sometimes, suboptimal response, depending on transplantation risk.
References
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Brian J. Druker,Moshe Talpaz,Debra Resta,Bin Peng,Elisabeth Buchdunger,John Ford,Nicholas B. Lydon,Hagop M. Kantarjian,Renaud Capdeville,Sayuri Ohno-Jones,Charles L. Sawyers +10 more
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TL;DR: The results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.
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