Genotoxicidade e mutagenicidade em pacientes com leucemia mieloide crônica tratados com inibidores de tirosino-quinase

Abstract

Chronic myelogenous leukemia (CML) is a myeloproliferative disease of hematopoietic stem cells, characterized by the presence of the Philadelphia (Ph) chromosome, originating from a reciprocal translocation between the long arms of chromosomes 9 and 22, forming the gene BCR-ABL, which encodes a BCR-ABL oncoprotein with constitutive tyrosine kinase activity. The clinical course of CML is often divided into three phases: chronic, accelerated, and blast. The treatment of choice for the chronic phase is the first-generation tyrosine kinase inhibitor (TKI), imatinib mesylate, and for refractory patients, second-generation TKIs (dasatinib or nilotinib) are used. Studies have shown that residual leukemia may persist even in the best responders to TKI, since therapy is not curative. In this context, the present study aimed to evaluate the genotoxicity and mutagenicity of TKI in patients with CML followed at the hematology clinic of the Walter Cantídio University Hospital (HUWC). It is a cross-sectional study with 44 patients with clinical and molecular diagnosis of CML. Patients were stratified into three groups: diagnosis (CML D) (n = 5), use of first generation TKI (CML) (n = 31) and use of second generation TKI (CML) (n = 8). The control group (CG) consisted of apparently healthy individuals. Genotoxicity and mutagenicity were analyzed by the comet assay and micronucleus test. Statistical analysis of the data was performed using the GraphPad Prism 6.0 program using the Kruskal-Wallis or ANOVA, Mann Whitney or T-student tests, depending on the normality of the data and the level of significance was 5% (p < 0.05). Patients with CML had a statistically higher ADN damage index (DI) compared to CG (p < 0.0001). When the patients were stratified, a progressive increase of the DNA ID was verified in the groups: CML D, CML G1 and CML G2, respectively, relative to GC (p < 0.05). Patients with CML had a statistically higher micronucleus index (NMI), nucleoplasmic bridge index (NPI) and nuclear bud index (NBI) compared to the CG (p < 0.05). By stratifying patients with CML, it was found that patients in the G1 and G2 CML groups had statistically higher NMI and NPI compared to CG (p <0.001). NMI was also elevated in the CML G2 group in relation to the patients in the CML D group (p <0.01). The nuclear bud index (NBI) did not present statistical difference in the analyzes performed after the stratification of the groups. The TKI revolutionized CML therapy, improving patient survival. However, these results point to the relevance of studies that evaluate the possible genotoxic and mutagenic effects of this therapy in the long term. The mechanisms involved should be elucidated for the purpose of improving treatment as well as assessing the clinical impact this harm may cause.