A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease

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

Evaluation of Chronic Transfusion (Tx) Practices in Children with Sickle Cell Disease (SCD): A Survey of STOP II Investigators

The follow-up Stroke Prevention Trial (STOP II) attempts to optimize tx therapy for primary stroke prevention in children with SCD who are at increased risk due to an abnormal Doppler ultrasound. A survey of participating investigators (PIs) was performed in order to assess tx practices; 12 PIs out of 26 responded. To begin chronic tx, 42 % of the PIs preferred erythrocytapheresis (ECP), partial or total exchange to bring hemoglobin (Hb) S 30%. Most PIs had a post-tx target hematocrit (Hct) 35–36%, but a third of them did not have one. Pre-tx Hct and/or Hb S (but not post-tx values) were used to predict the timing of the next tx by 83% of the group. When performing ECP, the PIs participated in the decision of how much to exchange pts only 33% of the time; generally ECP was planned by a blood bank physician and/or by machine programming. Chelation began either after 12–30 months of tx (median 18 months), or after serum ferritin 1000–2500 ng/ml (median 2000). 67% of the PIs obtained liver biopsies in all or some of the STOP II pts. Indications for liver biopsies were cited as routine for transfused pts (5 PIs) or depending on ferritin values (6 PIs). Deferoxamine 25–50 mg/kg was infused subcutaneously over 8–10 hours 5–7 nights a week in all pts. Eight PIs reported the use of central venous lines (ports) in some pts to facilitate IV access. Barriers cited to effective chronic tx were: pt compliance with chelation (7 reported it as most important), IV access, pt compliance with tx schedule, hypersplenism, and alloimmunization. We conclude that hematologists :(1) Administer leucoreduced Rh and Kell compatible, S negative PRBC to keep pre-tx Hb S levels <30%, (2) use pre-tx Hb S and Hct to predict next tx, usually every 3–4 weeks, (3) monitor and treat iron overload, and (4) report that poor compliance with chelation is a key barrier to an effective tx program. Although liver biopsy to monitor iron stores and partial/total exchange to limit iron overload are accepted interventions, medical practice still varies

Pharmacokinetics of Hydroxyurea in Young Children with Sickle Cell Anemia: A Report from the BABY HUG Trial

Abstract There is a paucity of pharmacokinetic (PK) data about hydroxyurea (HU) in persons with sickle cell anemia (SCA) and none in very young children. HU clearance is predominantly renal. The kidney may be damaged during infancy in SCA, but the first abnormality is usually hyperfiltration which may lead to enhanced HU clearance. Following a 15 mg/kg oral dose of commercially available HU capsules, PKs in 7 adults with SCA and normal renal function have been reported to be a mean±SD half-life (T1/2) of 3.14±0.9 hrs, a maximal concentration (Cmax) of 28.32±11.0 ug/mL, and an area under the curve (AUC) of 81.66±15.5 ug•hr/mL. The Phase II Study of HU in adults concluded that initial 2 hour clearance of HU was not associated with either the maximum tolerated dose or fetal hemoglobin response to treatment. However, the AUC did predict HU toxicity and, in another study, the need for dose adjustment in adults with SCA and renal insufficiency. BABY HUG is an NHLBI-NICHD sponsored Pediatric Phase III Clinical Trial designed to critically assess the efficacy of a novel liquid HU preparation in preventing organ damage in young children with SCA. Forty-five African-American infants, 12 to 18 months (mo) of age (mean 14.7 mo) were recruited without regard to disease severity to the just completed randomized, double-blind, placebo-controlled BABY HUG Feasibility and Safety Pilot Trial. First dose PKs were obtained 0, 1, 2, and 4 hours after oral administration of 20 mg/kg of HU in 22 consecutive patients (mean age 14.5 mo), coincident with measurement of glomerular filtration rate (GFR) by nuclear medicine DTPA clearance. An additional PK sample was obtained between 4 and 8 hours in 15 of the 22 (68%). Samples were frozen at −70°C, shipped, and assayed by high resolution gas chromatography with mass spectrometric detection (limit of detection 0.5 ug/mL). The T1/2 (2.36±0.99 hrs), Cmax (19.81±5.8 ug/mL; 0.26±0.8 uM/L), and AUC (68.82±11.5 ug•hr/mL) were somewhat lower in BABY HUG patients than in the small group of adults with SCA from the literature. There were no apparent relationships between PKs and baseline GFR measured by DTPA or calculated from the Schwartz equation. Younger patients ≤15 mo (n=15) had a trend toward a shorter T1/2 (2.1 vs 2.8 hours; p=0.118) and a lower predicted measurable HU concentration at 8 hours (1.2 vs 2.1 ug/mL; p=0.056) than those 16–18 mo (n=7). There were no age related differences in AUC (67.4 vs 71.8 ug•hr/mL; p=0.421) or Cmax (20.5 vs 18.2 ug/mL; p=0.409). PKs of this novel liquid preparation of HU in young children with SCA may be different than that of adults with the standard capsule formulation. The BABY HUG Trial will continue to refine the PK model by additional evaluations including samples from patients as young as 9 mo of age, the new lower age of eligibility for the open study currently accruing patients

Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG)

Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects. This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ 0thalassaemia, were aged 9–18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2–4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400. 96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m 2, p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia. On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia. The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development

Impact of hydroxyurea on clinical events in the BABY HUG trial

The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled 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 ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov)

Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury

Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% ± 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% ± 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% ± 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% ± 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182