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Hydroxyurea (hydroxycarbamide) for sickle cell disease
Rankine-Mullings AE, Nevitt SJ
The Cochrane database of systematic reviews. 2022;9(9):Cd002202
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Editor's Choice
Abstract
BACKGROUND Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising foetal haemoglobin (HbF). This is an update of a previously published Cochrane Review. OBJECTIVES The aims of this review are to determine through a review of randomised or quasi-randomised studies whether the use of hydroxyurea in people with SCD alters the pattern of acute events, including pain; prevents, delays or reverses organ dysfunction; alters mortality and quality of life; or is associated with adverse effects. In addition, we hoped to assess whether the response to hydroxyurea in SCD varies with the type of SCD, age of the individual, duration and dose of treatment, and healthcare setting. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. The date of the most recent search was 17 February 2022. SELECTION CRITERIA Randomised and quasi-randomised controlled trials (RCTs and quasi-RCTs), of one month or longer, comparing hydroxyurea with placebo or standard therapy in people with SCD. DATA COLLECTION AND ANALYSIS Authors independently assessed studies for inclusion, carried out data extraction, assessed the risk of bias and assessed the quality of the evidence using GRADE. MAIN RESULTS We included nine RCTs recruiting 1104 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months. We judged the quality of the evidence for the first two comparisons below as moderate to low as the studies contributing to these comparisons were mostly large and well-designed (and at low risk of bias); however, the evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events, and the results are applicable only to individuals with HbSS and HbSβºthal genotypes. We judged the quality of the evidence for the third and fourth comparisons to be very low due to the limited number of participants, the lack of statistical power (both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes. Hydroxyurea versus placebo Five studies (784 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; four recruited individuals with only severe disease and one recruited individuals with all disease severities. Hydroxyurea probably improves pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use) and life-threatening illness, but we found no difference in death rates (10 deaths occurred during the studies, but the rates did not differ by treatment group) (all moderate-quality evidence). Hydroxyurea may improve measures of HbF (low-quality evidence) and probably decreases neutrophil counts (moderate-quality evidence). There were no consistent differences in terms of quality of life and adverse events (including serious or life-threatening events) (low-quality evidence). There were fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. Hydroxyurea and phlebotomy versus transfusion and chelation Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) contributed to this comparison. There were no consistent differences in terms of pain alteration, death or adverse events (low-quality evidence) or life-threatening illness (moderate-quality evidence). Hydroxyurea with phlebotomy probably increased HbF and decreased neutrophil counts (moderate-quality evidence), but there were more occurrences of acute chest syndrome and infections. Quality of life was not reported. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early. Hydroxyurea versus observation One study (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation. Pain alteration and quality of life were not reported. There were no differences in life-threatening illness, death (no deaths reported in either group) or adverse events (very low-quality evidence). We are uncertain if hydroxyurea improves HbF or decreases neutrophil counts (very low-quality evidence). Treatment regimens with and without hydroxyurea One study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea. Pain alteration, life-threatening illness and quality of life were not reported. There were no differences in death rates (no deaths reported in either group), adverse events or neutrophil levels (very low-quality evidence). We are uncertain if hydroxyurea improves HbF (very low-quality evidence). AUTHORS' CONCLUSIONS There is evidence to suggest that hydroxyurea may be effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial Doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly with regard to preventing chronic complications of SCD, or recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with the HbSC genotype. Future studies should be designed to address such uncertainties.
PICO Summary
Population
Adults and children with sickle cell disease (9 studies, n= 1,104).
Intervention
Hydroxyurea.
Comparison
Standard therapy. Placebo.
Outcome
Hydroxyurea vs. placebo: Hydroxyurea probably improved pain alteration and life-threatening illness, but there was no difference in death rates. Hydroxyurea may improve measures of raising foetal haemoglobin (HbF) and probably decreased neutrophil counts. There were no consistent differences in terms of quality of life and adverse events. There were fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. Hydroxyurea and phlebotomy vs. transfusion and chelation: There were no consistent differences in terms of pain alteration, death or adverse events or life-threatening illness. Hydroxyurea with phlebotomy probably increased HbF and decreased neutrophil counts, but there were more occurrences of acute chest syndrome and infections. Hydroxyurea vs. observation: There were no differences in life-threatening illness, death or adverse events. The authors were uncertain if hydroxyurea improved HbF or decreased neutrophil counts. Treatment regimens with and without hydroxyurea: There were no differences in death rates, adverse events or neutrophil levels. The authors were uncertain if hydroxyurea improved HbF.
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Luspatercept for the treatment of anaemia in non-transfusion-dependent β-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial
Taher AT, Cappellini MD, Kattamis A, Voskaridou E, Perrotta S, Piga AG, Filosa A, Porter JB, Coates TD, Forni GL, et al
The Lancet. Haematology. 2022
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Editor's Choice
Abstract
BACKGROUND In patients with non-transfusion-dependent β-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent β-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent β-thalassaemia. METHODS We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of β-thalassaemia or haemoglobin E/β-thalassaemia (concomitant α-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10·0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (≥8·5 g/dL vs <8·5 g/dL) and baseline Non-Transfusion-Dependent β-thalassaemia-Patient-Reported Outcome Tiredness/Weakness domain score (≥3 vs <3). All patients, study site staff, and sponsor representatives (who reviewed the data), except for designated individuals, were masked to drug assignment until the time the study was unblinded. Luspatercept or placebo was given once subcutaneously every 3 weeks for 48 weeks in the double-blind treatment period. Luspatercept was started at 1·0 mg/kg with titration up to 1·25 mg/kg, or reduction in the event of toxicity or excessive haemoglobin concentration increase. The primary endpoint was achievement of an increase from baseline of 1·0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03342404, and is ongoing. FINDINGS Between Feb 5, 2018, and Oct 14, 2019, 160 patients were screened for eligiblity, of whom 145 were randomly assigned to luspatercept (n=96) or placebo (n=49). 82 (57%) patients were female and 63 (43%) were male. 44 (30%) patients were Asian, 87 (60%) were White, and 14 (10%) identified as another race. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1·0 g/dL in haemoglobin concentration (common risk difference 77·1 [95% CI 68·7-85·5]; p<0·0001). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported during the study. INTERPRETATION Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent β-thalassaemia, for whom effective approved treatment options are scarce. FUNDING Celgene and Acceleron Pharma.
PICO Summary
Population
Patients with non-transfusion-dependent β-thalassaemia enrolled in the BEYOND trial, in Thailand, Lebanon, Greece, Italy, UK, and USA (n= 145).
Intervention
Luspatercept (n= 96).
Comparison
Placebo (n= 49).
Outcome
The primary endpoint was achievement of an increase from baseline of 1.0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1.0 g/dL in haemoglobin concentration (common risk difference 77.1 [95% Confidence Interval: 68.7-85.5]). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs. 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported.
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Contemporary Management and Prevention of Vaso-Occlusive Crises (VOCs) in Adults With Sickle Cell Disease
Weaver SB, Rungkitwattanakul D, Singh D
Journal of pharmacy practice. 2021;:8971900211026644
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Editor's Choice
Abstract
Sickle cell disease (SCD) is a hematological disorder that primarily affects individuals of African descent from sub-Saharan Africa and along the mediterranean. The main complications leading to hospitalizations include vaso-occlusive crises (VOCs) and acute chest syndrome (ACS). Therefore, the main objective of this paper was to identify and evaluate evidence-based management and prevention of VOCs in patients with SCD. A literature search of PubMed, Medline Cochrane and Google Scholar database (January 1985 to April 2020) was performed using the following search terms "vaso-occlusive crises", "sickle cell disease", "hydroxyurea", "L-glutamine", "voxelotor", "crizanlizumab", "treatment" and "prevention" as well as a combination of these terms. All English-language interventional studies assessing the efficacy and safety of VOC outcomes were evaluated. Literature was excluded if published in a language other than English or if it was a review article. A total of 69 articles were identified and there were 7 articles that met the search criteria. Majority of the studies focused on mean and median annual rates of VOCs as primary outcomes while median time to first sickle cell crises, median rates of hospitalizations etc were evaluated as secondary outcomes. After reviewing the literature, many patients with VOCs will still benefit from hydroxyurea therapy since long term efficacy data and cost is still a concern for the newer agents including L-glutamine, voxelotor and crizanlizumab. Other factors such as cost or compliance may also be taken into consideration when making recommendations for therapy.
PICO Summary
Population
Adult patients with sickle cell disease (7 studies).
Intervention
Hydroxyurea.
Comparison
Several comparators, including: L-glutamine, voxelotor and crizanlizumab.
Outcome
The majority of the studies focused on mean and median annual rates of vaso-occlusive crises (VOCs) as primary outcomes while median time to first sickle cell crises and median rates of hospitalizations were evaluated as secondary outcomes. The literature suggested that many patients with VOCs were still benefitting from hydroxyurea therapy since long term efficacy data and cost was still a concern for newer agents such as: L-glutamine, voxelotor and crizanlizumab.
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A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent beta-Thalassemia
Cappellini MD, Viprakasit V, Taher AT, Georgiev P, Kuo KHM, Coates T, Voskaridou E, Liew HK, Pazgal-Kobrowski I, Forni GL, et al
N Engl J Med. 2020;382(13):1219-1231
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Editor's Choice
Abstract
BACKGROUND Patients with transfusion-dependent beta-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor beta superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent beta-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 mug per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS The percentage of patients with transfusion-dependent beta-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).
PICO Summary
Population
Adults with transfusion-dependent beta-thalassemia (n= 336).
Intervention
Luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) for at least 48 weeks (n=224).
Comparison
Placebo for at least 48 weeks (n= 112).
Outcome
The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group, as was the percentage of those who had a reduction of at least 50%. The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 mug per liter in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo.
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Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa
John CC, Opoka RO, Latham TS, Hume HA, Nabaggala C, Kasirye P, Ndugwa CM, Lane A, Ware RE
N Engl J Med. 2020;382(26):2524-2533
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Editor's Choice
Abstract
BACKGROUND Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown. METHODS In a randomized, double-blind trial, we compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events. RESULTS Children received hydroxyurea at a fixed dose (94 children; mean [+/-SD] age, 4.6+/-1.0 years) or with dose escalation (93 children; mean age, 4.8+/-0.9 years); the mean doses were 19.2+/-1.8 mg per kilogram per day and 29.5+/-3.6 mg per kilogram per day, respectively. The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose. At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group (P<0.001). Children in the dose-escalation group had fewer sickle cell-related adverse events (incidence rate ratio, 0.43; 95% confidence interval [CI], 0.34 to 0.54), vaso-occlusive pain crises (incidence rate ratio, 0.43; 95% CI, 0.34 to 0.56), cases of acute chest syndrome or pneumonia (incidence rate ratio, 0.27; 95% CI, 0.11 to 0.56), transfusions (incidence rate ratio, 0.30; 95% CI, 0.20 to 0.43), and hospitalizations (incidence rate ratio, 0.21; 95% CI, 0.13 to 0.34). Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia. CONCLUSIONS Among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety. (Funded by the Doris Duke Charitable Foundation and the Cincinnati Children's Research Foundation; NOHARM MTD http://clinicaltrials.gov/ ClinicalTrials.gov number, NCT03128515.).
PICO Summary
Population
Children with sickle cell anaemia in Sub-Saharan Africa (n= 187).
Intervention
Hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day), (n= 94).
Comparison
Hydroxyurea with dose escalation (approximately 30 mg per kilogram per day), (n= 93).
Outcome
86% of the children in the dose-escalation group reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group. Children in the dose-escalation group had fewer sickle cell-related adverse events, vaso-occlusive pain crises, cases of acute chest syndrome or pneumonia, transfusions, and hospitalizations.