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Originally published as JCO Early Release 10.1200/JCO.2005.05.531 on May 2 2005

Journal of Clinical Oncology, Vol 23, No 18 (June 20), 2005: pp. 4100-4109
© 2005 American Society of Clinical Oncology.
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ABL Mutations in Late Chronic Phase Chronic Myeloid Leukemia Patients With Up-Front Cytogenetic Resistance to Imatinib Are Associated With a Greater Likelihood of Progression to Blast Crisis and Shorter Survival: A Study by the GIMEMA Working Party on Chronic Myeloid Leukemia

Simona Soverini, Giovanni Martinelli, Gianantonio Rosti, Simona Bassi, Marilina Amabile, Angela Poerio, Barbara Giannini, Elena Trabacchi, Fausto Castagnetti, Nicoletta Testoni, Simona Luatti, Antonio de Vivo, Daniela Cilloni, Barbara Izzo, Milena Fava, Elisabetta Abruzzese, Daniele Alberti, Fabrizio Pane, Giuseppe Saglio, Michele Baccarani

From the Institute of Hematology and Medical Oncology "Seràgnoli," University of Bologna, Bologna; CEINGE Advanced Biotechnologies and Department of Biochemistry and Medical Biotechnology, University of Naples "Federico II," Naples; Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, Turin; and Novartis Pharma, Origgio, Italy

Address reprint requests to Giovanni Martinelli, MD, Institute of Hematology and Medical Oncology "Seràgnoli," University of Bologna, Via Massarenti 9-40138 Bologna, Italy; e-mail: gmartino{at}kaiser.alma.unibo.it

PURPOSE: Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib.

PATIENTS AND METHODS: Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months.

RESULTS: Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045).

CONCLUSION: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.

Supported by European LeukemiaNet, Cofin 2003 (M.B.), Associazione Italiana Contro le Leucemie-Linfomi e Mieloma, Associazione Italiana per la Ricerca sul Cancro, Fondazione Del Monte di Bologna e Ravenna, Fondo per Gli Investimenti della Ricerca di Base, and Ateneo 60% grants.

No previous article reporting the same set of data has been published.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


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