Real-life experience with hydroxyurea in sickle cell disease: A multicenter study in a cohort of patients with heterogeneous descent
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.
Section snippets
Methods
This was a retrospective cohort study of SCD patients attending treatment centers across Italy. All Italian Hematology Centers part of the Italian Society of Thalassemia and Hemoglobinopathies (SITE) and all Pediatric Hematology Oncology Units part of the Italian Association of Pediatric Hematology Oncology (AIEOP) were invited to participate in the study. Invitation was expressed during two meetings of the Working Groups and by a letter. All large Regional Reference Centers (pediatric and
Patients' characteristics
A total of 652 SCD patients who had received hydroxyurea were included in this analysis. The mean age at the time of hydroxyurea initiation was 24.5 ± 15.0 years (range: 1.0–67.0), with 32.7% of patients being in the pediatric age group (< 18 years). There was an equal gender distribution with 51.4% of patients being men. The majority of patients were of Caucasian (64.4%) or African (35.6%) origin; Supplementary Fig. 1 illustrates the origins of patients analyzed in this study. Around half of the
Discussion
This is the first large multicenter study in Southern European country, involving a large number of patients with different descent (Caucasian and Africans), referring to national comprehensive centers for hemoglobinopathies.
Our data indicate that hydroxyurea therapy lowers the incidence and annual frequency of acute chest syndrome, painful vaso-occlusive crisis, and hospitalization through a large cohort of SCD patients with either Caucasian or African descent.
Although established as a
Acknowledgements
The authors thank Khaled Musallam MD PhD (President, International Network of Hematology, London, UK) for statistical and medical editorial assistance.
*CENTERS AND INVESTIGATORS OF THE ITALIAN MULTICENTER STUDY OF HYDROXURYEA IN SICKLE CELL ANEMIA
The study was conducted by centers from the Italian Society of Thalassemia and Hemoglobinopathies (SITE) and the Sickle Cell Disease Working Group of the Italian Association of Pediatric Hematology Oncology (AIEOP). Clinic of Pediatric
Authors' contributions
All authors participated in study concept and design, data collection and assembly, data analysis and interpretation, manuscript drafting, and critical revision for intellectual content.
Disclosure of conflicts of interest
All authors have approved the final article. The authors declare no competing financial interests.
Sources of funding
None.
References (35)
- et al.
Sickle-cell disease
Lancet
(2010) - et al.
Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia
Blood
(1992) - et al.
Erythroid adhesion molecules in sickle cell disease: effect of hydroxyurea
Transfusion clinique et biologique: journal de la Societe francaise de transfusion sanguine.
(2008) - et al.
Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG)
Lancet
(2011) - et al.
Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group
Blood
(1999) - et al.
The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS)
Blood
(2010) - et al.
Stroke With Transfusions Changing to Hydroxyurea (SWiTCH)
Blood
(2012) - et al.
Central nervous system complications and management in sickle cell disease
Blood
(2016) - et al.
Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members
JAMA
(2014) - et al.
Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia
J. Clin. Invest.
(1984)
Hydroxyurea generates nitric oxide in human erythroid cells: mechanisms for gamma-globin gene activation
Exp. Biol. Med. (Maywood).
Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
N. Engl. J. Med.
Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children
Pediatrics
Systematic review: hydroxyurea for the treatment of adults with sickle cell disease
Ann. Intern. Med.
Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment
JAMA
Hydroxyurea therapy for sickle cell anemia
Expert Opin. Drug Saf.
The effect of hydroxcarbamide therapy on survival of children with sickle cell disease
Br. J. Haematol.
Cited by (33)
Platelet counts on peripheral blood and Mean Platelet Volume as markers of clinical severity in Sickle Cell Disease
2021, Blood Cells, Molecules, and DiseasesAdvances in neuroimaging to improve care in sickle cell disease
2021, The Lancet NeurologyCitation Excerpt :Importantly, in sickle cell anaemia, silent cerebral infarcts are not silent but are associated with statistically significant cognitive impairment,24 as outlined later. As in the general population,28 the presence of silent cerebral infarcts in children and adults with sickle cell anaemia increases the risk of future cerebral infarcts.19–21 Finally, large artery stenosis, believed to be caused by intimal hyperplasia29 and frequently associated with moyamoya syndrome, is an important cause of stroke in sickle cell anaemia, yet in one study, only eight (16%) of 50 adults with sickle cell anaemia (mean age 27 years) had intracranial stenosis of a major cerebral artery of greater than 50%.30
American Society of Hematology 2020 guidelines for sickle cell disease: Prevention, diagnosis, and treatment of cerebrovascular disease in children and adults
2020, Blood AdvancesCitation Excerpt :The traditional definition of stroke endorsed by the World Health Organization (WHO) requires clinical symptoms for >24 hours and has been in use since the 1970s.24 Our panel affirmed the importance of silent cerebral infarcts given the known impact on cognition and an established biomarker for infarct recurrence in children and adults with HbSS or HbSβ0 thalassemia25-27 and in the general population.28 However, we recognize that the MRI-based definition is challenging in low-middle–income settings where MRI is not widely available.
Sickle Cell Disease and Stroke
2019, Pediatric NeurologyHydroxyurea reduces cerebral metabolic stress in patients with sickle cell anemia
2019, BloodCitation Excerpt :The HUSTLE study found patients treated with HU had slower SCI accumulation than untreated patients,26 which was corroborated by Rushton et al's retrospective study.27 In contrast, Rigano et al reported an increase in detection and progression of SCIs in a cohort treated with HU when compared with the cohort's pretreatment period in a multicenter, retrospective study evaluating clinical consequences of SCD in participants who were treated with HU.28 Our data provide physiologic evidence that patients with SCA treated with HU have lower OEF when compared with those not receiving disease-modifying therapy.