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

Simona Soverini, Sabrina Colarossi, Alessandra Gnani, Gianantonio Rosti, Fausto Castagnetti, Angela Poerio, Ilaria Iacobucci, Marilina Amabile, Elisabetta Abruzzese, Ester Orlandi, Franca Radaelli, Fabrizio Ciccone, Mario Tiribelli, Roberto Di Lorenzo, Clementina Caracciolo, Barbara Izzo, Fabrizio Pane, Giuseppe Saglio, Michele Baccarani, Giovanni Martinelli

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)7374-7379
Number of pages6
JournalClinical Cancer Research
Volume12
Issue number24
DOIs
Publication statusPublished - Dec 15 2006

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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