RT Journal Article
SR Electronic
T1 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
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 7374
OP 7379
DO 10.1158/1078-0432.CCR-06-1516
VO 12
IS 24
A1 Soverini, Simona
A1 Colarossi, Sabrina
A1 Gnani, Alessandra
A1 Rosti, Gianantonio
A1 Castagnetti, Fausto
A1 Poerio, Angela
A1 Iacobucci, Ilaria
A1 Amabile, Marilina
A1 Abruzzese, Elisabetta
A1 Orlandi, Ester
A1 Radaelli, Franca
A1 Ciccone, Fabrizio
A1 Tiribelli, Mario
A1 di Lorenzo, Roberto
A1 Caracciolo, Clementina
A1 Izzo, Barbara
A1 Pane, Fabrizio
A1 Saglio, Giuseppe
A1 Baccarani, Michele
A1 Martinelli, Giovanni
YR 2006
UL http://clincancerres.aacrjournals.org/content/12/24/7374.abstract
AB 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.