The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era Among the cohort of 661 patients in this study, 125 were retrospectively selected for mutation analyses using direct sequencing, according to their timing of cytogenetic and molecular response achievement and extent of molecular response. Point mutations involving 17 different amino acids were detected in 25 patients. A double mutation was observed in three patients. Table 1 depicts position and frequency of BCR-ABL mutations found in IM treated patients. No published report of the V268M mutation was found in the literature. Different increments in BCR-ABL levels (2 fold, 0.5-log and 1-log) assessed in at least two different samples were defined as parameters for mutation screening. Screening for mutant variants of BCR-ABL is frequently performed by Sanger's direct sequencing. The sensitivity of this method is of approximately 10-20% of total BCR-ABL+ cells; this sensitivity is assumed to be effective for detecting and characterizing mutations throughout the kinase domain. There may be a role for more sensitive mutation analysis, particularly when considering the lack of TKI effectiveness against T315I mutated clones(27) and when considering therapeutic options after IM resistance. However this has not yet been established. Due to the existence of different mechanisms accounting for the resistant phenotype, different point mutations will differentially impact specific TKIs. Mutation analysis is always recommended before changing to another inhibitor after resistance. The use of dasatinib will be preferred for CML patients resistant to IM carrying a Y253H, E255V/K or F359C/V mutation, while Rev Bras Hematol Hemoter. 2011;33(6):455-60 nilotinib should be indicated in the presence of the V299L or F317L mutations.(28,29) To date, the T315I mutation confers resistance to all available TKIs. Conclusions Detection of biomarkers that allow early prediction of response to TKIs is a major challenge. In an era of targeted TKI therapy, the key point is to select the appropriate agent at the appropriate juncture for each patient, with the aim of achieving long-term, durable responses with minimal toxicity. The rapidity of responses obtained by 2nd generation TKIs as compared to IM will most likely modify the management of patients with newly diagnosed CP-CML, but economic factors may influence treatment decisions. Acknowledgement Role of the funding source: This work was supported by the Brazilian public agencies Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ-PPSUS) and INCT para Controle do Câncer (Grants CNPq 573806/2008-0 and FAPERJ E26/170.026/2008). The funding sources have had no involvement neither in the study design, collection, analysis and interpretation of data; nor in the writing of the manuscript or in the decision to submit the manuscript for publication. References 1. Lucas CM, Harris RJ, Giannoudis A, Davies A, Knight K., Watmough SJ, et al. Chronic myeloid leukemia patients with the e13a2 BCR- ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript. Haematologica. 2009;94 (10):1362-7. Comment in: Haematologica. 2010;95(5):852-3. 2. Druker BJ. Translation of the Philadelphia chromosome into therapy for CML. Blood. 2008;112(13):4808-17. 3. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low- dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. Comment in: Curr Hematol Rep. 2004;3(1):37-8. N Engl J Med. 2003;348 (11):1048-50. Clin Lab Haematol. 2005;27(6):416-7. 4. Deininger M, O'Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP et al. International Randomized Study of Interferon Vs STI571 (IRIS) 8-Year Follow up: Sustained Survival and Low Risk for Progression or Events in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. ASH Annual Meeting Abstracts 2009;114:1126. 5. Hochhaus A, O'Brien SG, Guilhot F, BJ Druker, S Branford, L Foroni, et al. Six-year follow- up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009; 23(6):1054-61. 6. Alvarado Y, Kantarjian H, O'Brien S, Faderl S, Borthakur G, Burger J, et al. Significance of suboptimal response to imatinib, as defined by the European LeukemiaNet, in the long-term outcome of patients with early chronic myeloid leukemia in chronic phase Cancer. 2009;115(16):3709-18 7. Kantarjian HM, O'Brien S, Cortes JE, Shan J, Giles FJ, Rios MB, et al. Complete cytogenetic and molecular responses to interferon- alpha-based therapy for chronic myelogenous leukemia are 459