Real-life experience with hydroxyurea in sickle cell disease: A multicenter study in a cohort of patients with heterogeneous descent

Abstract

We conducted the first nation-wide cohort study of sickle cell disease (SCD) in Italy, a Southern European country exposed to intense recent flux migration from endemic areas for SCD. We evaluate the impact of hydroxyurea on a total of 652 pediatric and adult patients from 33 Reference Centers for SCD (mean age 24.5 ± 15 years, 51.4% males). Hydroxyurea median treatment duration was 7 years (range: < 1 year to 29 years) at a mean therapeutic dose of 18 ± 4.7 mg/kg/day. Hydroxyurea was associated with a significant increase in mean total and fetal hemoglobin and a significant decrease in mean hemoglobin S, white blood and platelet counts, and lactate dehydrogenase levels. Hydroxyurea was associated with a significant reduction in the incidence of acute chest syndrome (− 29.3%, p < 0.001), vaso-occlusive crisis (− 34.1%, p < 0.001), hospitalization (− 53.2%, p < 0.001), and bone necrosis (− 6.9%, p < 0.001). New silent cerebral infarction (SCI) occurred during treatment (+ 42.4%, p < 0.001) but not stroke (+ 0.5%, p = 0.572). These observations were generally consistent upon stratification for age, descent (Caucasian or African), genotype (βS/βS, βS/β⁰ or βS/β⁺) and duration of treatment (< or ≥ 10 years). There were no new safety concerns observed compared to those commonly reported in the literature. Our study, conducted on a large population of patients with different descent and compound state supports the benefits of hydroxyurea therapy as a treatment option. Registered at clinical trials.gov (NCT02709681).

Introduction

With the ongoing search for targeted and curative therapeutics for sickle cell disease (SCD) and its manifestations, hydroxyurea remains a cornerstone of conventional management owing to its oral efficacy and low toxicity [1], [2]. The disease modifying properties of hydroxyurea were initially attributed to its ability to induce fetal hemoglobin and decrease hemoglobin S polymerization [3], [4] which should theoretically ameliorate downstream pathophysiologic mechanisms, acute and long-term clinical morbidity. Other beneficial effects have subsequently emerged including increasing total hemoglobin levels, decreasing platelet and white blood cell counts, changing expression of adhesion molecules, and nitric oxide generation [1], [5], [6]. Thirty years of clinical experience through randomized clinical trials and large observational studies established that hydroxyurea is safe and effective in decreasing the frequency of acute complications like painful vaso-occlusive crisis and acute chest syndrome, while also decreasing the need for blood transfusion and hospitalization in SCD adults and children as young 9 months of age [7], [8], [9], [10], [11], [12], [13]. Long-term follow-up studies have also established continued benefit as well as reduction in mortality [14], [15], [16], [17]. In addition, the initial concerns on HU effects on fertility and carcinogenic potential have not been fully established in patients with SCD and require a long-term follow-up on large cohorts of SCD patients [7], [8], [9], [10], [11], [12], [13]. Despite such substantial body of evidence, hydroxyurea is considered an underutilized medication in SCD [1], [13], [18]. Thus, data from real-life experiences with hydroxyurea remain essential to further illustrate the role of this intervention to practicing clinicians.

Until the last decade, SCD was endemic in Southern Italy (Sicily and Calabria) with limited number of patients spread all over the country due to internal migration. Thus, data on the epidemiology and clinical profile of SCD in Italy, as Southern European country exposed to intense migration fluxes from areas endemic for SCD, such as the Sub-Saharian countries [19], have been deeply changed. Such current and future mobility and migration flows, pose considerable new challenges that have to be taken into consideration by member states and EU authorities primarily through collection of data from existing patients.

With this background, the aim of this study was to report the first, real-life experience with the use of hydroxyurea in a large cohort of SCD patients with heterogeneous descent and different compound state.