Background Sickle cell anaemia (SCA) is associated with significant morbidity from acute complications and organ dysfunction beginning in the first year of life. In the first multicenter randomised double-blinded trial in very young children with SCA, the impact of hydroxyurea (hydroxycarbamide) therapy on organ dysfunction, clinical complications, and laboratory findings, and its toxicity, were examined. Methods Eligible subjects had HbSS or Sβ0thalassaemia, were age 9–18 months at randomisation, and were not selected for clinical severity. Subjects received liquid hydroxyurea, 20 mg/kg/day, or placebo for two years. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional evaluations included: blood counts, HbF, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every two to four weeks. Findings Ninety-six subjects received hydroxyurea and 97 placebo; 86% completed the study. Significant differences were not seen for the primary endpoints, but suggestive benefit was noted in quantitative measures of spleen function. Hydroxyurea significantly decreased pain and dactylitis with trends for decreased acute chest syndrome, hospitalisation and transfusion. Hydroxyurea increased haemoglobin and HbF and decreased WBC count. Toxicity was limited to mild-moderate neutropaenia. Interpretation Although hydroxyurea treatment did not reduce splenic and renal dysfunction assessed by primary endpoint measures, it resulted in major clinical benefit because of diminished acute complications, favorable haematologic results, and a lack of unexpected toxicities. Based on the safety and efficacy data from this trial, hydroxyurea can now be considered for all very young children with SCA.
Summary Deferasirox is a once‐daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open‐label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non‐progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1 year, similar dose‐dependent LIC reductions were observed with deferasirox and deferoxamine. Once‐daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.
The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebocontrolled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninetythree subjects were randomized to hy- Continuing Medical Education onlineThis activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) ™ . Physicians should claim only the credit commensurate with the extent of their participationin the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 4448. Disclosures The authors, the Associate Editor Narla Mohandas, and CME questions author Laurie Barclay, freelance writer and reviewer, Medscape, LLC, declare no competing financial interests. Learning objectivesUpon completion of this activity, participants will be able to:1. Describe the effect of hydroxyurea on rates of sickle cell complications for infants with sickle cell anemia (SCA) on the basis of a phase 3, multicenter, randomized trial.2. Describe the effect of hydroxyurea on rates of hospitalizations and transfusions for infants with SCA on the basis of a phase 3, multicenter, randomized trial.3. Describe the safety of hydroxyurea for infants with SCA on the basis of a phase 3, multicenter, randomized trial.
A decrease in the duration of painful episodes and an increase in the proportion of patients who achieved resolution of the symptoms were observed when the purified poloxamer 188-treated patients were compared with the patients receiving placebo. However, the difference between these groups was significant but relatively small. In subgroup analysis, a more significant effect on both parameters was observed in children and in patients who were receiving concomitant hydroxyurea. It is important to confirm both of these observations in further prospective trials.
We evaluated spleen function in 193 children with sickle cell anemia 8 to 18 months of age by 99m Tc sulfur-colloid liver-spleen scan and correlated results with clinical and laboratory parameters, including 2 splenic biomarkers: pitted cell counts (PIT) and quantitative Howell-Jolly bodies (HJB) enumerated by flow cytometry. Loss of splenic function began before 12 months of age in 86% of infants in association with lower total or fetal hemoglobin and higher white blood cell or reticulocyte counts, reinforcing the need for early diagnosis and diligent preventive care. PIT and HJB correlated well with each other and liver-spleen scan results. Previously described biomarker threshold values did define patients with abnormal splenic function, but our data suggest that normal spleen function is better predicted by PIT of < 1.2% or HJB < 55/10 6 red blood cells and absent function by PIT > 4.5% or HJB > 665/10 6 . HJB is methodologically advantageous compared with PIT, but both are valid biomarkers of splenic function. This trial was registered at www.clinicaltrials.gov as #NCT00006400. (Blood. 2011;117(9): 2614-2617) IntroductionThe spleen is one of the first organs damaged in sickle cell anemia (SCA). Consequences of this damage, increased risk of invasive pneumococcal infection and splenic sequestration, are difficult to predict for a given child. The "gold standard" for assessment of splenic filtrative function is a 99m Tc sulfur-colloid liver-spleen (LS) scan. However, LS scans yield qualitative results and require low-dose radiation exposure.BABY HUG, the Pediatric Hydroxyurea phase 3 Clinical Trial, is an National Heart, Lung, and Blood Institute and National Institute of Child Health and Human Development-sponsored 14-center, randomized double-blind placebo-controlled trial of the efficacy of hydroxyurea in preventing chronic organ damage in infants with SCA. The trial was approved by the institutional review boards of all participating centers. Prevention of loss of splenic function is a primary endpoint. 1 After written informed consent in accordance with the Declaration of Helsinki, splenic filtrative function of children in BABY HUG was assessed by LS scan and compared with 2 surrogate biomarkers: pitted erythrocyte (PIT) counts by Nomarski optics and Howell-Jolly Bodies (HJBs) quantitated by flow cytometry. These pretreatment baseline data form the largest reported assessment of spleen function in young children with SCA by LS scan, define parameters of loss of function, and validate both biomarkers as accurate noninvasive measures of splenic function. Methods LS scanA standardized dose of 0.05 mCi/kg (minimum 0.5 mCi, 1 mCi if local practice) of 99m Tc sulfur-colloid was injected into a peripheral vein. Liver and spleen were imaged 30 minutes later in the posterior, anterior, left anterior oblique, and right posterior oblique planes. Splenic uptake was qualitatively interpreted on de-identified films by structured consensus of 3 pediatric nuclear medicine physicians as normal (spleen uptake equal to li...
Cerebrovascular disease is a common cause of morbidity in sickle cell anemia (HbSS): approximately 10% of patients have a clinical stroke before 20 years of age, and another 22% have silent infarction on magnetic resonance imaging. The phenotypic variation among patients with HbSS suggests a role for modifier genes and/or environmental influences. To assess the familial component of clinical stroke in HbSS, we estimated the prevalence of clinical stroke among all patients and among HbSS sibling pairs at 9 pediatric centers. The sample included 3425 patients with sickle cell disease who were younger than 21 years, including 2353 patients with HbSS. The stroke prevalence was 4.9% for all genotypes; 7.1% for patients with HbSS; 1.1% for patients with HbS o thalassemia; 0.6% for patients with S ؉ thalassemia; and 0% for patients with HbSC. In 207 sibships, more than 1 child had HbSS. There were 42 sibships in which at least 1 sibling had a stroke, and in 10 of the 42, 2 siblings had a stroke. A permutation test indicated that the number of families in which 2 children had strokes was larger than the number expected if strokes were randomly distributed among children in sibships (P ؍ .0012). There was no difference in stroke prevalence based on sex, nor was the mean age at stroke presentation significantly different between singletons and sibships with stroke. We conclude that there is a familial predisposition to stroke in HbSS. Attempts to identify genetic modifiers should be initiated with familybased studies. IntroductionCerebrovascular disease is the second leading cause of mortality and a common cause of morbidity in sickle cell anemia (HbSS): approximately 10% of patients will have a clinical stroke by age 20 years, and another 22% have evidence of silent infarction on magnetic resonance imaging (MRI). 1,2 The pathophysiology of cerebrovascular disease in sickle cell anemia may involve stenosis of large arteries of the circle of Willis, intracranial hemorrhage, and/or microvascular disease. 3,4 The histology of these vascular lesions demonstrates intimal hyperplasia and smooth muscle proliferation compatible with endothelial damage. 5 A moyamoya pattern of lenticulostriate collateral vessels develops around the areas of stenosis in about 30% of patients. 6 Patients with moyamoya also have a higher risk for recurrent stroke. 7 Features of sickle cell disease that predispose patients to endothelial damage include adhesive properties of sickle reticulocytes (promoted by adhesion proteins, von Willebrand factor, and thrombospondin), leukocyte adhesion, and biomechanical disturbances of fluid shear stresses generated by increased blood flow secondary to anemia. [8][9][10] The propensity for stroke is associated with abnormal blood flow velocity in large arteries that can be detected presymptomatically by transcranial Doppler (TCD). 11 A familial predisposition to stroke in sickle cell anemia has been suggested by the observation that the prevalence of stroke among siblings with HbSS appears to be increased. 12...
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