Hydroxyurea has many characteristics of an ideal drug for sickle cell anemia (SCA) and provides therapeutic benefit through multiple mechanisms of action. Over the past 25 years, substantial ...experience has accumulated regarding its safety and efficacy for patients with SCA. Early proof-of-principle studies were followed by prospective phase 1/2 trials demonstrating efficacy in affected adults, then adolescents and children, and more recently infants and toddlers. The phase 3 National Heart, Lung and Blood Institute–sponsored Multicenter Study of Hydroxyurea trial proved clinical efficacy for preventing acute vaso-occlusive events in severely affected adults. Based on this cumulative experience, hydroxyurea has emerged as an important therapeutic option for children and adolescents with recurrent vaso-occlusive events; recent evidence documents sustained long-term benefits with prevention or reversal of chronic organ damage. Despite abundant evidence for its efficacy, however, hydroxyurea has not yet translated into effective therapy for SCA. Because many healthcare providers have inadequate knowledge about hydroxyurea, patients and families are not offered treatment or decline because of unrealistic fears. Limited support for hydroxyurea by lay organizations and inconsistent medical delivery systems also contribute to underuse. Although questions remain regarding its long-term risks and benefits, current evidence suggests that many young patients with SCA should receive hydroxyurea treatment.
Sickle cell disease Ware, Russell E, Dr Prof; de Montalembert, Mariane, MD PhD; Tshilolo, Léon, Prof ...
The Lancet (British edition),
07/2017, Letnik:
390, Številka:
10091
Journal Article
Recenzirano
Summary Sickle cell disease is a common and life-threatening haematological disorder that affects millions of people worldwide. Abnormal sickle-shaped erythrocytes disrupt blood flow in small ...vessels, and this vaso-occlusion leads to distal tissue ischaemia and inflammation, with symptoms defining the acute painful sickle-cell crisis. Repeated sickling and ongoing haemolytic anaemia, even when subclinical, lead to parenchymal injury and chronic organ damage, causing substantial morbidity and early mortality. Currently available treatments are limited to transfusions and hydroxycarbamide, although stem cell transplantation might be a potentially curative therapy. Several new therapeutic options are in development, including gene therapy and gene editing. Recent advances include systematic universal screening for stroke risk, improved management of iron overload using oral chelators and non-invasive MRI measurements, and point-of-care diagnostic devices. Controversies include the role of haemolysis in sickle cell disease pathophysiology, optimal management of pregnancy, and strategies to prevent cerebrovascular disease.
In a trial evaluating two daily-dose levels of voxelotor, which binds to sickle hemoglobin and prevents polymerization under hypoxic conditions, hemoglobin levels increased by more than 1 g per ...deciliter in approximately half the patients who received the drug, and markers of hemolysis decreased. Toxic effects were mainly low grade and not different from those with placebo.
PURPOSE OF REVIEWOver the past several decades, hydroxyurea has emerged as a well tolerated and potent disease-modifying therapy for children and adults with sickle cell anemia (SCA). Strong, ...evidence-based recommendations from the National Institutes of Health, American Society of Hematology, and British Society of Haematology document that hydroxyurea is now standard of care treatment for SCA. In low-resource settings, however, hydroxyurea is rarely utilized due to lack of availability, inadequate treatment guidance, and excessive costs.
RECENT FINDINGSResearch trials conducted within the Caribbean and sub-Saharan Africa confirm the efficacy of hydroxyurea as a well tolerated, feasible, and beneficial treatment in low-resource countries. Hydroxyurea is therefore vital to reaching the targets for control of SCA outlined by the WHO. To maximize its utilization toward real-world effectiveness, specific attention must be given to healthcare provider education and training, public and institutional awareness, and medication access and affordability.
SUMMARYEfforts to introduce hydroxyurea effectively into low-resource countries should urgently address the lack of treatment guidelines, gaps in knowledge and clinical infrastructure, and medication inaccessibility. Partnerships among governmental, academic, pharmaceutical, and charitable organizations must tackle these barriers so that all individuals living with SCA worldwide can benefit from hydroxyurea.
Red blood cell transfusions have reduced morbidity and mortality for patients with sickle cell disease. Transfusions can lead to erythrocyte alloimmunization, however, with serious complications for ...the patient including life-threatening delayed hemolytic transfusion reactions and difficulty in finding compatible units, which can cause transfusion delays. In this review, we discuss the risk factors associated with alloimmunization with emphasis on possible mechanisms that can trigger delayed hemolytic transfusion reactions in sickle cell disease, and we describe the challenges in transfusion management of these patients, including opportunities and emerging approaches for minimizing this life-threatening complication.
Stroke is a devastating complication of sickle cell anemia (SCA) with high recurrence if untreated. Chronic transfusions reduce recurrent strokes but have associated morbidities including iron ...overload. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) was a multicenter phase 3 randomized trial comparing standard treatment (transfusions/chelation) to alternative treatment (hydroxyurea/phlebotomy) for children with SCA, stroke, and iron overload. SWiTCH was a noninferiority trial with a composite primary end point, allowing an increased stroke risk but requiring superiority for removing iron. Subjects on standard treatment received monthly transfusions plus daily deferasirox iron chelation. Subjects on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose (MTD), followed by monthly phlebotomy. Subjects on standard treatment (N = 66) maintained 30% sickle hemoglobin (HbS) and tolerated deferasirox at 28.2 ± 6.0 mg/kg/d. Subjects on alternative treatment (N = 67) initiated hydroxyurea and 60 (90%) reached MTD at 26.2 ± 4.9 mg/kg/d with 29.1% ± 6.7% fetal hemoglobin (HbF). Adjudication documented no strokes on transfusions/chelation but 7 (10%) on hydroxyurea/phlebotomy, still within the noninferiority stroke margin. The National Heart, Lung, and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content, indicating futility for the composite primary end point. Transfusions and chelation remain a better way to manage children with SCA, stroke, and iron overload. This clinical trial was registered at ClinicalTrials.gov NCT00122980.
Introduction: Sickle cell anemia (SCA) is a severe, inherited hemoglobin disorder affecting 100,000 persons in the US and millions worldwide. Hydroxyurea, a once daily oral medication, has emerged as ...the primary disease-modifying therapy for SCA. The accumulated body of evidence over 30 years demonstrates that hydroxyurea is a safe and effective therapy for SCA, but hydroxyurea remains underutilized for a variety of reasons.
Areas covered: In this review, we summarize the available evidence regarding the pharmacology, clinical, and laboratory benefits, and safety of hydroxyurea therapy for the treatment of SCA. The purpose of this review is to provide the reader a comprehensive understanding of hydroxyurea and to reinforce the fact that hydroxyurea is a safe and effective medication for the treatment of SCA.
Expert opinion: In our opinion, hydroxyurea therapy should be considered standard-of-care for SCA, representing an essential component of patient management. Early initiation and broader use of hydroxyurea will alter the natural history of SCA, so affected children can live longer and healthier lives. In addition, hydroxyurea use should be extended to low-resource settings such as sub-Saharan Africa, where the burden of SCA and the need for hydroxyurea is arguably the greatest.
Summary
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 SCA — treatment significantly reduces disease manifestations and prolongs survival. Despite these recognised benefits, long‐standing 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.
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