Determination of serum levels of imatinib mesylate in patients with chronic myeloid leukemia: validation and application of a new analytical method to monitor treatment compliance

OBJECTIVE: The goal of this study was to monitor imatinib mesylate therapeutically in the Tumor Biology Laboratory, Department of Hematology and Hemotherapy, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (USP). A simple and sensitive method to quantify imatinib and its metabolite (CGP74588) in human serum was developed and fully validated in order to monitor treatment compliance. METHODS: The method used to quantify these compounds in serum included protein precipitation extraction followed by instrumental analysis using high performance liquid chromatography coupled with mass spectrometry. The method was validated for several parameters, including selectivity, precision, accuracy, recovery and linearity. RESULTS: The parameters evaluated during the validation stage exhibited satisfactory results based on the Food and Drug Administration and the Brazilian Health Surveillance Agency (ANVISA) guidelines for validating bioanalytical methods. These parameters also showed a linear correlation greater than 0.99 for the concentration range between 0.500 µg/mL and 10.0 µg/mL and a total analysis time of 13 minutes per sample. This study includes results (imatinib serum concentrations) for 308 samples from patients being treated with imatinib mesylate. CONCLUSION: The method developed in this study was successfully validated and is being efficiently used to measure imatinib concentrations in samples from chronic myeloid leukemia patients to check treatment compliance. The imatinib serum levels of patients achieving a major molecular response were significantly higher than those of patients who did not achieve this result. These results are thus consistent with published reports concerning other populations

Pretherapeutic Expression of the hOCT1 Gene Predicts a Complete Molecular Response to Imatinib Mesylate in Chronic-Phase Chronic Myeloid Leukemia

In this retrospective study we evaluated the pretherapeutic mRNA expression of the hOCT1 (human organic cation transporter 1) gene in patients with chronic-phase (CP) chronic myeloid leukemia (CML) who varied in terms of their response to imatinib (IM). hOCT1 mRNA was quantified by real-time PCR. Patients were classified as expressing either high (n = 44) or low hOCT1 mRNA (n = 44). the complete cytogenetic response rates observed at 6, 12 and 18 months were 47.7, 84.1 and 91%, respectively, in patients with high hOCT1 mRNA and 47.5, 81.8 and 86.3%, respectively, in patients with low hOCT1 transcripts. the major molecular response rates were not significantly different between patients with high and low hOCT1 mRNA after 6 months of therapy (22.7 vs. 9.1%; p = 0.07), but they were significantly different after 12 months (54.5 vs. 31.8%; p = 0.026) and 18 months (77.2 vs. 56.8%; p = 0.034). Complete molecular responses were observed in 5 patients with low and 17 patients with high hOCT1 mRNA (p = 0.003). the 5-year event-free and overall survival analyses revealed no significant differences between the groups. These data imply that knowledge of the pretherapeutic level of hOCT1 could be a useful marker to predict IM therapy outcome in treatment-naive CP CML patients. Copyright (C) 2012 S. Karger AG, BaselMaria Cecilia Souto Vidigal Foundation, São Paulo, BrazilUniv São Paulo, Dept Hematol, Sch Med, Tumor Biol Lab,Fac Med, BR-05403000 São Paulo, BrazilUniv São Paulo, Cytogenet Lab, Fac Med, BR-05403000 São Paulo, BrazilUniv São Paulo, Discipline Hematol, Fac Med, BR-05403000 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Translat Med, São Paulo, BrazilSão Paulo Inst Trop Med, São Paulo, BrazilSão Paulo Inst Canc, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Translat Med, São Paulo, BrazilWeb of Scienc

Evaluation of Long-Term Outcomes, Cytogenetic and Molecular Responses with Imatinib Mesylate in Early and Late Chronic-Phase Chronic Myeloid Leukemia: A Report from a Single Institute

Here we compare the management and survival outcomes of chronic myeloid leukemia (CML) patients who had early or late imatinib mesylate (IM) therapy. the cytogenetic and molecular responses of 189 CML patients were analyzed. of this group, 121 patients were classified as the early chronic phase (ECP) group and started IM within 12 months of diagnosis. the other 68 patients were classified as the late chronic phase (LCP) group who had been treated with interferon (IFN)-alpha-2 and crossed over to IM more than 12 months after diagnosis. the overall rates of complete cytogenetic response (CCyR) and major molecular response (MMR) at last follow-up were 83.6 and 78.1% in the ECP and LCP groups, respectively. the CCyR rates were 89.3 (for ECP patients) versus 73.5% (for LCP patients; p < 0.0001). At last follow-up, 82.4% ECP and 64.2% LCP patients had achieved an MMR (p < 0.0001). No significant differences were noted between the two groups with regard to survival outcomes. Our experience reveals that IM is an effective rescue therapy in most CML LCP patients who are intolerant or in whom IFN-alpha therapy fails. Such therapeutic options should be considered in LCP patients, particularly in countries where IM may not be available. Copyright (C) 2012 S. Karger AG, BaselFoundation Maria Cecilia Souto Vidigal, São Paulo, BrazilUniv São Paulo, Sch Med, Dept Hematol, Tumor Biol Lab,Fac Med, BR-05403000 São Paulo, BrazilUniv São Paulo, Fac Med, Cytogenet Lab, BR-05403000 São Paulo, BrazilUniv São Paulo, Fac Med, Discipline Hematol, BR-05403000 São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo Inst Canc, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Translat Med, São Paulo, BrazilSão Paulo Inst Trop Med, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo Inst Canc, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Translat Med, São Paulo, BrazilWeb of Scienc