Avaliação dos efeitos cardiovasculares e renais do imatinibe

Abstract

The introduction of imatinib mesylate has revolutionized the management of chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Imatinib is not only more effective in delaying disease progression and improving survival time, but it is also associated with fewer adverse effects compared with traditional chemotherapy. The drug safety profile has been questioned by evidence concerning imatinib-related cardiac and renal toxicity. The aims of this thesis were, through three studies, to assess the cardiac effects of imatinib in CML patients on long-term treatment, using sensitive measures of left ventricular function; to investigate whether there is a relation between imatinib dose and treatment time with left ventricle ejection fraction and BNP; to assess the incidence of acute kidney injury and chronic renal failure in CML patients using imatinib; and to elucidate whether there is a relation between imatinib treatment duration and decrease in estimated glomerular filtration rate (GFR). Patients were recruited at the outpatient clinic of the Hematology Service of the Universidade Federal de Minas Gerais (UFMG). In the first study, 12 CML patients (median age 40 [IQR 28-48] years) underwent cardiac screening at the baseline and follow-up visit, which was performed after a median treatment time of 12.4 months. No significant changes on the frequency of cardiovascular signs and symptoms, electrocardiographic abnormalities, echocardiographic measurements and BNP levels were observed. Median ejection fraction was 67% at baseline versus 68% at follow-up (median intra-patient change 0.5%). Median BNP levels were 8.3 versus 7.3 pg/mL (median intra-patient change 0.2 pg/mL). Troponin I measures were below the lower limit of detection, whereas strain measures were similar to healthy control. The second study included 90 CML patients (mean age 49 ± 15 years) under imatinib therapy for a median treatment time of 3.3 years. The mean ejection fraction was 68 ± 7% and the median BNP level was 9.6 pg/mL (IQR 5.7-17.0 pg/mL). Two patients had either an elevated BNP or a depressed ejection fraction (2.2% 90% CI 0.9-6.8%). Most of troponin I measurements were lower than the detection limit, except for two patients. Longitudinal strain was similar to measurements in healthy controls. A weak relation was observed between log BNP and imatinib treatment duration and dose. There was no relation between these variables and left ventricle ejection fraction. The third study enrolled 105 CML patients on imatinib therapy for a median treatment time of 4.5 years. During follow-up, 7% of patients developed acute kidney injury; creatinine levels returned to baseline in only one of them. According to the regression equation, the mean baseline value of the estimated GFR was 88.9 mL/min/1.73m2. Estimated GFR decreased significantly with imatinib treatment duration; the mean decrease per year was 2.77 mL/min/1.73m2 (p<0.001); 12% of patients developed chronic renal failure. Age, hypertension and history of chronic renal failure or previous interferon usage were not significantly related to the mean decrease in the estimated GFR over time. In conclusion, imatinib-related cardiotoxicity is an uncommon event in CML patients, even during long-term treatment. Its clinical relevance and the usefulness of regular cardiac monitoring are both questionable. Conversely, the introduction of imatinib therapy in non-clinical trial CML patients is associated with potentially irreversible acute renal injury, and the long-term treatment may cause a clinically relevant decrease in the estimated GFR. Therefore, it is important to monitor renal function of CML patients under imatinib therapy by measuring the creatinine levels and estimating GFR. Attention must be paid to concomitant administration of other potentially nephrotoxic agents, to avoid additive nephrotoxicity in these patients. Furthermore, there is urgent need for further research on this subject.