Originally published as JCO Early Release 10.1200/JCO.2008.16.9953 on July 21 2008

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Finding of Kinase Domain Mutations in Patients With Chronic Phase Chronic Myeloid Leukemia Responding to Imatinib May Identify Those at High Risk of Disease Progression

Jamshid S. Khorashad, Hugues de Lavallade, Jane F. Apperley, Dragana Milojkovic, Alistair G. Reid, Marco Bua, Richard Szydlo, Eduardo Olavarria, Jaspal Kaeda, John M. Goldman, David Marin

From the Department of Haematology, Hammersmith Hospitals Trust, Imperial College London, London, United Kingdom

Corresponding author: David Marin, MD, Department of Haematology, Imperial College London, Du Cane Rd, London W12 0NN, United Kingdom; e-mail: d.marin{at}imperial.ac.uk

Purpose Kinase domain (KD) mutations in the BCR-ABL gene are associated with resistance to imatinib in chronic myeloid leukemia (CML) but their incidence and prognostic significance in chronic phase (CP) patients without resistance are unclear.

Patients and Methods We analyzed outcome for 319 patients with CML-CP who were treated with imatinib; 171 were in early CP (ECP) and 148 were in late CP (LCP). Patients were screened routinely for mutations using direct sequencing regardless of response status. The 5-year cumulative incidence of mutations was 6.6% for ECP and 17% for LCP patients.

Results Of the 319 patients, 214 (67%) achieved complete cytogenetic responses (CCyR). The identification of a mutation without other evidence of imatinib resistance was highly predictive for loss of CCyR (RR, 3.8; P = .005) and for progression to advanced phase (RR, 2.3; P = .01), though the intervals from first identification to loss of CCyR and disease progression were relatively long (median, 21 and 16 months, respectively). Mutations in the P-loop (excluding residue 244) were associated with a higher risk of progression than mutations elsewhere.

Conclusion We conclude that routine mutation screening of patients who appear to be responding to imatinib may identify those at high risk of disease progression.

published online ahead of print at www.jco.org on July 21, 2008

Supported by the NIHR Biomedical Research Centre Funding Scheme; and by a grant from the Fondation de France (Paris, France; H.d.L.).

J.S.K. and H.d.L. contributed equally to this article.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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