Clinical outcome of chronic myeloid leukemia imatinib-resistant patients: do BCR–ABL kinase domain mutations affect patient survival? First multicenter Argentinean study

Abstract

In imatinib-treated patients with chronic myeloid leukemia (CML), BCR–ABL mutations are the most common mechanism of resistance. Here we report the first multicenter Argentinean study investigating mutations in those patients with CML who fail or lose response to imatinib, with or without previous interferon treatment. Point mutations were detected in 36 of 154 patients by direct sequencing. In our series, the single most common mutations were G250E, E255K/V, and M351T. The presence of mutations correlated significantly with accelerated phase, lack of molecular response, and lower cytogenetic and hematological responses. While overall survival did not differ between patients with or without mutations, the probability of progression was higher in patients with mutations. Cases with non-P-loop mutations showed a significantly better overall survival from diagnosis. Multivariate analysis showed that the most significant variables related to the development of mutations were accelerated phase, duration of imatinib treatment, and time delay to starting imatinib. Our results demonstrated that mutation frequency increased with the progression of disease, and suggest that imatinib treatment should be started early.

Keywords:

• CML
• imatinib
• mutations
• BCR–ABL
• P-loop
• resistance

Acknowledgements

The study was funded by the National Academy of Medicine in Buenos Aires and a Novartis research grant.

The authors thank biochemist M. T. Cuello for her technical assistance.

We acknowledge the memory of Santiago Pavlovsky, Director of Fundaleu, for his support of this project.

Other contributions were from:

Marta Dragosky, Institute Henri Moore; Alejandra Kurchan, Hospital de Neuquén; Gabriela Flores, Hospital Durand; Rafael Calahonra, Hospital Nacional de Clínicas, Buenos Aires; Francisca Rojas, Hospital Nacional de Clínicas, Buenos Aires; Fernando Pagani, Clinica Colón, Mar Del Plata; Alejandra Miño, Hospital Naval; Jose Luis Saavedra, Hospital Rio Gallegos; Maria Jose Lopez, Hospital Córdoba, Córdoba; Mariel Perez, Hospital Rossi, La Plata; Ricardo Aguirre, Centro Privado Salta; Alicia Enrico, Hospital Italiano, La Plata; Alicia Magariños, Hospital Maciel, Uruguay; Paula Rocca, Hospital Alvarez; Victoria Canessa, Hospital Gonet; Patrícia Gargallo, Cemic; Leandro Riera, Cemic; Dardo Riveros, Cemic; Rosita Santarelli, Hospital Pirovano; Fernando Bezares, Hospital Alvarez.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.