1. ¹Hematology Department, E. Herriot Hospital, Lyon, France
2. ²Hematology Department, CHRU, Lille, France
3. ³INSERM U817, Institut de Recherche contre le Cancer, Lille, France
4. ⁴Laboratory for Hematology and Molecular Biology, Hospital J Bernard, Poitiers, France
5. ⁵Laboratory for Hematology and Cytogenetics, CHLS, Pierre-Bénite, France
6. ⁶Laboratory for Hematology, Henri Mondor Hospital, Créteil, France
7. ⁷Hematology Department, Hospital Haut-Lévêque, Pessac, France
8. ⁸Oncology, Cellular Therapy and Hematology Department, Hospital J Bernard, Poitiers, France
9. ⁹Laboratory for Molecular Biology, Saint Louis Hospital, Paris, France
10. ¹⁰Hematology Department, CHU, Versailles, France

Correspondence: Dr C Roche-Lestienne, U817 et CHRU de Lille 1, place de Verdun, 59045 Lille Cedex, France. E-mail: croche@lille.inserm.fr

¹¹These authors contributed equally to this work.

Received 12 July 2005; Revised 2 March 2006; Accepted 17 March 2006; Published online 27 April 2006.

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.