Absence of hydroxyurea‐induced mutational effects supports higher utilisation for the treatment of sickle cell anaemia

Abstract

Hydroxyurea (hydroxycarbamide) is approved for treating both children and adults with sickle cell anaemia (SCA). Fetal haemoglobin (HbF) induction is the primary treatment response, along with improved anaemia, reduced haemolysis, myelosuppression and decreased endothelial inflammation. Hydroxyurea has proven clinical efficacy for SCAtreatment significantly reduces disease manifestations and prolongs survival. Despite these recognised benefits, longstanding concerns regarding the risks of mutagenic and potentially carcinogenic drug exposure have hampered efforts for broad hydroxyurea use in SCA, although these are based largely on outdated experimental models and treatment experiences with myeloproliferative neoplasms. Consequently, many patients with SCA are not receiving this highly effective disease-modifying therapy. In this review, we describe the concept of genotoxicity and its laboratory measurements, summarise hydroxyurea-associated data from both preclinical and clinical studies, and discuss carcinogenic potential. The genotoxicity results clearly demonstrate that hydroxyurea does not directly bind DNA and is not mutagenic. Rather, its genotoxic effects are limited to indirect clastogenicity occurring in select cell types, and only when high dose and time thresholds are exceeded. This absence of mutagenic activity is consistent with the observed lack of any compelling carcinogenic potential. Since hydroxyurea therapy for SCA carries minimal carcinogenic risks, the current drug labelling should be modified accordingly, and prescribing practices should be broadened to allow better access and increased utilisation of this highly effective drug.

Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy

“…151 The relationship between SCD and malignancy has been closely considered, including long-standing concerns of possible mutagenic risk of hydroxyurea (although reassuringly no clinical evidence of carcinogenic potential has been observed despite widespread use), and especially with recent reports of two patients developing MDS/AML on lentiviral b-globin gene addition trials (ClinicalTrials.gov: NCT04293185). 152,153 Based on retrospective analyses, individuals with SCD have been reported to have an increased risk of hematological malignancy, especially MDS and AML. [154][155][156] Although the mechanism is unknown, those with a more severe course of disease are 4-fold more likely to develop leukemia.…”

How I approach disease‐modifying therapy in children with sickle cell disease in an era of novel therapies

“…11 While the labeling of hydroxyurea as a chemotherapy agent due to its historical use to treat cancer and data from early in vitro and animal studies using extreme concentrations of hydroxyurea has resulted in significant notoriety, there is now sufficient real-world clinical evidence to strongly support our belief that the benefits significantly outweigh any putative risk. [16][17][18] However, further studies investigating the long-term effects of hydroxyurea upon reproductive and other organs are needed, particularly in children who began hydroxyurea at an early age. 19 Importantly, as we have demonstrated, the conversation about hydroxyurea must begin early with its introduction as a medication prescribed to prevent acute and chronic complications of SCA and to allow for a high quality of life.…”

Clonal hematopoiesis in sickle cell disease

“…Hydroxyurea (HU) has been shown to have a significantly positive clinical impact in individuals with SCD and is thought to primarily influence disease severity by increasing levels of fetal hemoglobin (HbF) [18]. Given its cytotoxic effects and evidence from animal models, it has been posited that HU may be mutagenic and potentially carcinogenic, despite demonstrated safety profiles in vivo [19]. We therefore reasoned that while the overall SCD cohort may not exhibit an elevated risk of developing CH, those treated with HU may.…”