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Contribution of ABL Kinase Domain Mutations to Imatinib Resistance in Different Subsets of Philadelphia-Positive Patients: By the GIMEMA Working Party on Chronic Myeloid Leukemia

Authors' Affiliations: ¹ Department of Hematology/Oncology "L. and A. Seràgnoli," University of Bologna, Bologna, Italy; ² Department of Hematology, University of Rome "Tor Vergata," Rome, Italy; ³ Division of Hematology, Policlinico S. Matteo, Pavia, Italy; ⁴ Department of Hematology, Institute of Medical Sciences, Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; ⁵ Division of Hematology, Ospedale Civile, Latina, Italy; ⁶ Division of Hematology, University of Udine, Udine, Italy; ⁷ Division of Hematology, Ospedale Civile, Pescara, Italy; ⁸ Department of Hematology and Bone Marrow Transplant Unit, Palermo, Italy; ⁹ CEINGE Advanced Biotechnologies and Department of Biochemistry and Medical Biotechnology, University of Naples "Federico II," Naples, Italy; and ¹⁰ Division of Hematology and Internal Medicine, Department of Clinical and Biological Science, University of Turin, Orbassano, Italy

Requests for reprints: Giovanni Martinelli, Department of Hematology/Oncology, University of Bologna, "L. and A. Seràgnoli," S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy. Phone: 39-051-6363829; Fax: 39-051-6364037; E-mail: gmartino{at}kaiser.alma.unibo.it.

Purpose: ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients.

Experimental Design: Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib.

Results: Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated with imatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis.

Conclusions: We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.

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