A randomized, controlled clinical trial established the efficacy and safety of short-term use of hydroxyurea in adult sickle cell anemia. To examine the risks and benefits of long-term hydroxyurea usage, patients in this trial were followed for 17.5 years during which they could start or stop hydroxyurea. The purpose of this follow-up was to search for adverse outcomes and estimate mortality. For each outcome and for mortality, exact 95% confidence intervals were calculated, or tests were conducted at a 5 0.05 level (P-value <0.05 for statistical significance). Although the death rate in the overall study cohort was high (43.1%; 4.4 per 100 person-years), mortality was reduced in individuals with long-term exposure to hydroxyurea. Survival curves demonstrated a significant reduction in deaths with long-term exposure. Twenty-four percent of deaths were due to pulmonary complications; 87.1% occurred in patients who never took hydroxyurea or took it for <5 years. Stroke, organ dysfunction, infection, and malignancy were similar in all groups. Our results, while no longer the product of a randomized study because of the ethical concerns of withholding an efficacious treatment, suggest that long-term use of hydroxyurea is safe and might decrease mortality. Am. J. Hematol. 85:403-408, 2010. V

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.

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV > 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P ‫؍‬ .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 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 participation in 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 1185.

BackgroundElevation of echocardiography-determined tricuspid regurgitant jet velocity predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell disease. The definition, prevalence and clinical correlates of elevated jet velocity have not been established in pediatric patients. The present study tested the hypotheses that elevated jet velocity affects 10% of pediatric patients, is associated with both hemolysis and hypoxia, and has clinical correlates with acute chest syndrome, stroke, transfusion requirement and abnormal 6-minute walk test results. Design and MethodsA prospective multicenter study of 310 patients aged 3-20 years old with sickle cell disease under basal conditions and 54 matched controls was conducted. A hemolytic index was generated by principal component analysis of the levels of lactate dehydrogenase, aspartate aminotransferase and bilirubin and reticulocyte count. ResultsElevated jet velocity (defined as ≥2.60 m/sec based on the mean±2 SD in controls) occurred in 32 patients (11.0%) including one child of 3 years old. After adjustment for hemoglobin concentration, systolic blood pressure and left ventricular diastolic function, a 2 SD increase in the hemolytic index was associated with a 4.5-fold increase in the odds of elevated jet velocity (p=0.009) and oxygen saturation ≤98% with a 3.2-fold increase (p=0.028). Two or more episodes of acute chest syndrome had occurred in 28% of children with elevated jet velocity compared to in 13% of other children (p=0.012), more than ten units of blood had been transfused in 39% versus 18% (p=0.017) and stroke had occurred in 19% versus 11% (p=0.2). The distance walked in 6-minute walk tests did not differ significantly, but oxygen saturation declined during the tests in 68% of children with elevated jet velocity compared to in 32% of other children (p=0.0002). ConclusionsAccording to a pediatric-specific definition the prevalence of elevated jet velocity in this population of young patients with sickle cell disease was 11%. The study provides evidence for independent associations of elevated jet velocity with hemolysis and oxygen desaturation. Further investigations should address whether elevated jet velocity may indicate future complications and whether early intervention is beneficial.Key words: sickle cell disease, pulmonary hypertension, hemolysis, oxygen saturation, tricuspid regurgitant jet velocity, children.Citation: Minniti CP, Sable C, Campbell A, Rana S, Ensing G, Dham N, Onyekwere O, Nouraie M, Kato GJ, Gladwin MT, Castro OL, and Gordeuk VR. Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica 2009; 94:340-347. doi:10.3324/haematol.13812 ©2009 Ferrata Storti Foundation.

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