Is chronic use of hydroxyurea safe for patients with sickle cell anemia? An account of genotoxicity and mutagenicity

Abstract

Sickle cell anemia (SCA) is a hereditary hematological disease that is characterized by a point mutation in the beta globin S gene and has no specific treatment; hydroxyurea (HU) is the only therapeutic agent used in clinical practice. In the present study, we evaluated the deoxyribonucleic acid (DNA) damage index (DI) and chromosomal damage in leukocytes of adult patients with SCA with and without HU. The DI was assessed by the comet assay and chromosomal damage by the leukocyte micronucleus test of adult patients treated with HU (SCA‐HU) and without the use of HU (SCA‐NoHU). This is a cross‐sectional study with 77 patients with SCA who attended a referral hospital in Fortaleza, Brazil. The control group (CG) consisted of 58 reportedly healthy individuals. The comparisons of means were performed by analysis of variance and Tukey's post‐test. Values of P < 0.05 were considered statistically significant. SCA‐NoHU patients had statistically higher DI values and a statistically significantly higher frequency of micronuclei compared to the CG. In addition, HU treatment accentuated DNA lesions by significantly increasing both parameters in treated patients (SCA‐HU). HU potentiates DNA damage and the occurrence of chromosomal damage, which may promote genomic instability, mutation occurrence, and carcinogenesis. Studies are needed to evaluate the involved pathways, repair mechanisms, and the clinical impact that such damage can cause. Environ. Mol. Mutagen. 60:302–304, 2019. © 2018 Wiley Periodicals, Inc.

Hematological Malignancies in Sickle Cell Disease Patients: Report of Four Cases in Togo and Literature Review

“…The leukemogenic risk could theoretically increase with the duration of drug exposure. The DNA damage index in peripheral blood leukocytes of HU-treated sickle cell patients was found to be higher than in controls, and this phenomenon was confirmed to be influenced by the duration and dose of HU treatment, as well as by HbS genotype [17] [18]. The leukemic risk of HU has never been confirmed in major sickle cell patients with chronic myeloproliferative diseases [19] [20], and no increased risk of malignancy has been reported in large studies of myeloproliferative syndromes in major sickle cell patients [21] [22] [23].…”

Sickle cell disease and acute leukemia: one case report and an extensive review

“…The leukemogenic risk could theoretically increase with the duration of drug exposure. The index of DNA damage in peripheral blood leukocytes from HU-treated patients with SCD was demonstrated higher than in controls and was confirmed influenced by the duration and the dose of HU treatment, and by the HbS genotype [ 45 , 46 ]. The leukemic risk of HU has never been confirmed in patients with chronic myeloproliferative diseases [ 47 , 48 ], and no increased risks of malignancy were reported in large series of SCD patients [ 49 – 51 ].…”

Case Report of Myelodysplastic Syndrome in a Sickle-Cell Disease Patient Treated with Hydroxyurea and Literature Review

“…A chronic inflammatory state, free radicals induced by free hemoglobin or heme, chronic hematopoietic stress, and premature “aging” of hematopoiesis with accrued genetic, epigenetic, and functional alteration of hematopoietic cells were suggested as possible explanations for this finding. HU may carry itself an intrinsic risk of oncogenic potential due to the increased frequency of acquired DNA mutations in SCD patients [ 9 ]. Nevertheless, no significant increase in myeloid malignancies occurred in a large population-based cohort following introduction of HU therapy in SCD patients.…”