Chronic myeloid leukemia treatment guidelines: Brazilian Association of Hematology, Hemotherapy and Cell Therapy. Brazilian Medical Association Guidelines Project – 2012 The 5-year disease-free survival in chronic phase CML patients who adhere to imatinib treatment is 16.9% higher than for non-adherent patients. Non-compliance reduces the possibility of complete cytogenetic response by 18% (NNH: 6). The greatest cause of cessation of imatinib treatment (29.6%) is related to noncompliance. Complete cytogenetic response is correlated to adherence to treatment, with a reduction in the response in noncompliant patients by 20%(72)(B). Recommendation: adherence to imatinib treatment is directly correlated to the probability of molecular and cytogenetic responses and disease-free survival. Are prior cytogenetic response to imatinib and performance status prognostic factors for response to second-line tyrosine kinase inhibitors in imatinib- resistant patients? The best cytogenetic response (0% positive Philadelphia chromosome) during treatment with imatinib is predictive of response to dasatinib and nilotinib, with an increase in cytogenetic response by 21% when compared to no cytogenetic response during treatment with imatinib, i.e. Philadelphia ≥ 95% (52)(B). The response to second-line TKI of Imatinib-resistant CML patients is associated with some other prognostic factors such as: 1. low-risk Sokal: 25.5% increase in cytogenetic response and 27.0% in disease-free survival; 2. percentage of positive Philadelphia chromosome at the beginning of treatment < 95%: 43.8% increase in the cytogenetic response and 27.3% in disease-free survival; 3. time to therapeutic failure of imatinib ≤ 6 months: 37.2% increase in cytogenetic response, 24.3% increase in overall survival rate and 13.8% increase in progression-free survival(52)(B). The prognosis of treatment using second-line TKIs (nilotinib or dasatinib) in Imatinib-resistant CML patients can be predicted by prior cytogenetic response (imatinib), giving an estimated 37% increase in disease-free survival at 3 years and in the cytogenetic response at 1 year. A performance status (European Cooperative Oncology Group - ECOG) of “0” at the beginning of treatment with second-line TKIs, predicts an 18% increase in disease-free survival and a 32% increase in overall survival at 3 years(73)(B). Other prognostic factors may be associated with response to treatment with nilotinib or dasatinib such as: age greater than 55 years with a 24% reduction in cytogenetic response at 1 year, a 20% reduction in disease-free survival at 3 years and a 6% reduction in overall survival at 3 years; ≥ 90% Philadelphia chromosome- positive metaphases at start of treatment with second-line TKIs with a 30% reduction in the cytogenetic response and a 21% reduction in disease-free survival(73)(B). Recommendation: Information related to cytogenetic response and performance status (ECOG) should be used to assess prognosis on starting second-line treatment with TKIs such as nilotinib or dasatinib in Imatinib-resistant CML patients. Additionally age and cytogenetic response prior to treatment with second-generation TKIs should be taken into account. When is it necessary to make an analysis of BCR- ABL mutations in CML patients under treatment with tyrosine kinase inhibitors? BCR-ABL mutations are associated to 100% resistance to imatinib treatment in accelerated-phase CML patients and in 79% of chronic-phase patients(74)(C). The presence of BCR-ABL mutations increases the risk by 52% of chronic-phase CML patients evolving to the accelerated or blast crisis phases within 9 months (NNH: 2). These mutations, especially P-loop mutations, also reduce the time free of disease progression and survival of these patients(75)(B). In the follow-up of CML, BCR-ABL mutations occur at different times in patients under treatment with imatinib and are correlated with lower survival rates. For patients in the early phase of the disease, mutations are associated with increases in transformation to the accelerated (32%) and blast crisis phases (16%) and a reduction in the complete cytogenetic response (24%). Regardless of the stage of the disease, mutations reduce hematologic response(76)(B). BCR-ABL mutations in CML patients under imatinib treatment predict, within about 20 months, loss of complete cytogenetic response and progression to the advanced stages of the disease(77)(B). Hematologic and cytogenetic responses are similar in patients with and without BCR-ABL mutations under treatment with second-generation TKIs (dasatinib and nilotinib). Moreover disease-free survival and overall survival are not significantly different between these two groups of patients(78)(B). In the four-year follow-up of chronic phase CML patients, the time from the beginning of imatinib treatment to the progression of the disease to the accelerated or blast crisis phases is worse in patients with mutations than those without mutations. The overall survival of patients without mutations and those with mutations is 51 and 10 months, respectively but this varies according to the type of mutation (P-loop type - 13 months and T315I - 9 months)(79)(B). Among chronic phase CML patients under nilotinib treatment, the two-year overall survival is reduced by 38% in the presence of BCR-ABL mutations. In addition, the presence of mutations is associated with a 34% reduction in the cytogenetic response(80)(B). T315I mutations occur more often in patients treated with dasatinib. The presence of mutations during nilotinib or dasatinib treatment is predictive of a worse prognosis in these patients(21)(B). Recommendation: BCR-ABL mutations should be investigated in CML patients resistant to TKIs (suboptimal response or failure) regardless of the stage, because their presence predicts the greater risk of resistance and shorter survival. Rev Bras Hematol Hemoter. 2012;34(5):367-82 373