BCR-ABL Mutations in Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors and Impact on Survival

Abstract

This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.

Keywords::

• Chronic myeloid leukemia
• BCR-ABL mutations
• Imatinib
• Resistance
• Tyrosine kinase inhibitors

AUTHOR CONTRIBUTIONS

KBP designed the research, treated patients, collected, analyzed and interpreted the data, wrote, and approved the manuscript; I.B. analyzed and interpreted the data, wrote and approved the manuscript; CB, LF, VF, RP, VH, NC, MC, EBM, JLL CP, MP, EEC, LAM, BS, NH, AHM, and EF treated patients, collected data, and approved the manuscript; RAS, LN, and IZ performed the mutation analysis, collected data, and approved the manuscript; CAS and NS treated patients, analyzed and interpreted the data, reviewed, and approved the manuscript; ECMM participated in the statistical analysis, analyzed and interpreted the data, reviewed, and approved the manuscript; JC analyzed and interpreted the data and approved the manuscript; RB performed mutation analysis, collected the data, analyzed and interpreted the data, wrote, and approved the manuscript.

ACKNOWLEDGMENTS

This study was supported in part by research funding from FAPESP (Fundação de Amparo à Pesquisa de Estado de São Paulo) (grants 03/12605-2R; 03/09054-4; and 05/59708-6) to KBP, from Fundação Maria Cecília de Souto Vidigal to IB, and from Novartis Argentina’ grants to RB. The authors would like to thank the data managers, physicians, and laboratory staff of the participant centers, in particular Luz Marina Majsa (from United States), Oscar Ballester (English review) and to doctors Riva ME; Lanari E; Milone J; Ventriglia V; Bullorsky E (for the contribution with their patients from Argentina); Anderson Tavares (Unicamp); Paola Cappelletti; and Simone Bonecker (INCA) (from Brazil).

DECLARATION OF INTEREST

KBP, VF, LF, MC, CB, BS, CP, EBM are members of the speakers’ Bureau of Bristol Myers Squibb (BMS) and Novartis. IZ received research grants from Novartis and BMS. JC received research support from Ariad, BMS, Novartis, Pfizer and Teva and is a consultant for Ariad, BMS, Pfizer and Teva. NS and RP: Novartis: Membership on an entity's Board of Directors or advisory committees. The other authors report no potential conflicts of interest.