Chromosome damage and repair in children with sickle cell anaemia and long-term hydroxycarbamide exposure

Hydroxycarbamide (hydroxyurea) provides laboratory and clinical benefits for adults and children with sickle cell anaemia (SCA). Given its mechanism of action and prior reports of genotoxicity, concern exists regarding long-term toxicities and possible carcinogenicity. We performed cross-sectional analyses of chromosome stability using peripheral blood mononuclear cells (PBMC) from 51 children with SCA and 3-12 years of hydroxycarbamide exposure (mean age 13.2 +/- 4.1 years), compared to 28 children before treatment (9.4 +/- 4.7 years). Chromosome damage was less for children receiving hydroxycarbamide than untreated patients (0.8 +/- 1.2 vs. 1.9 +/- 1.5 breaks per 100 cells, P = 0 004). There were no differences in repairing chromosome breaks after in vitro radiation; PBMC from children taking hydroxycarbamide had equivalent 2 Gy-induced chromosome breaks compared to untreated patients (30.8 +/- 16.1 vs. 31.7 +/- 8.9 per 100 cells, P = not significant). Radiation plus hydroxycarbamide resulted in similar numbers of unrepaired breaks in cells from children on hydroxycarbamide compared to untreated patients (95.8 +/- 44.2 vs. 76.1 +/- 23.1 per 100 cells, P = 0.08), but no differences were noted with longer exposure (97.9 +/- 42.8 breaks per 100 cells for 3-6 years of hydroxycarbamide exposure vs. 91.2 +/- 48.4 for 9-12 years of exposure). These observations provide important safety data regarding long-term risks of hydroxycarbamide exposure for children with SCA, and suggest low in vivo mutagenicity and carcinogenicity.