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Chronic Myeloproliferative Disorders

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)

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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