Abstract
The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P=0.003). With a median follow-up of 39.2 months (6.3–67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P=0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P=0.014), and a worse progression-free survival (PFS) for T315I mutations (P=0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.
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Acknowledgements
We thank the various clinical and technical teams from the different centers participating in this study. We are grateful to Professor Tessa L Holyoake (University of Glasgow, Scotland, UK) for critically reviewing this manuscript, and Mrs Barbara White-Meunier for valuable advise. This study has been partially funded by grants from Cancéropôle Rhône-Alpes 2003 and Nord-Ouest, the Association Cent pour Sang la Vie and Ligue contre le cancer Rhône 2005 (to FE-N, SH) and Nord-Pas de Calais 2005 (to CP, CR-L) committees and Fondation de France (to CP, CR-L).
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Nicolini, F., Corm, S., Lê, QH. et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(ϕ)-LMC GROUP). Leukemia 20, 1061–1066 (2006). https://doi.org/10.1038/sj.leu.2404236
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DOI: https://doi.org/10.1038/sj.leu.2404236
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