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.

R2* magnetic resonance imaging (R2*-MRI) can quantify hepatic iron content (HIC) by noninvasive means but is not fully investigated. Patients with iron overload completed 1.5T R2*-MRI examination and liver biopsy within 30 days. Fortythree patients (sickle cell anemia, n ‫؍‬ 32; ␤-thalassemia major, n ‫؍‬ 6; and bone marrow failure, n ‫؍‬ 5) were analyzed: median age, 14 years, median transfusion duration, 15 months, average (؎SD) serum ferritin 2718 plus or minus 1994 ng/mL, and average HIC 10.9 plus or minus 6.8 mg Fe/g dry weight liver. Regions of interest were drawn and analyzed by 3 independent reviewers with excellent agreement of their measurements (intraclass correlation coefficient ‫؍‬ 0.98). Ferritin and R2*-MRI were weakly but significantly associated (range of correlation coefficients among the 3 reviewers, 0.41-0.48; all P < .01). R2*-MRI was strongly associated with HIC for all 3 reviewers (correlation coefficients, 0.96-0.98; all P < .001). This high correlation confirms prior reports, calibrates R2*-MRI measurements, and suggests its clinical utility for predicting HIC using R2*-MRI. This study was registered at www.clinicaltrials.gov as #NCT00675038. IntroductionMonitoring body iron content is critical for clinical management of patients with iron overload. Prior reports of iron measurements by R2 magnetic resonance imaging (MRI) and R2*-MRI relaxometry in the liver have shown good correlations with hepatic iron content (HIC). 1-3 However, MRI calibration varies according to instrumentation and technique. To calibrate the R2*-MRI technique for noninvasive HIC assessment, we conducted a study to estimate the correlation of R2*-MRI with liver biopsy-proven HIC determination in patients with iron overload. Methods PatientsPatients 7 years of age and older with iron overload (ferritin Ͼ 1000 ng/mL within 3 months of enrollment or Ն 18 erythrocyte transfusions) were eligible. All participants underwent nonsedated liver MRI examination and ferritin measurement, followed within 30 days by liver biopsy with HIC determination. The St Jude Children's Research Hospital Institutional Review Board provided continuing approval, and all participants or legal guardians signed informed consent in accordance with the Declaration of Helsinki. Liver biopsiesTwo liver specimens were obtained, the first for liver iron quantitation (Mayo Laboratories, Rochester MN) and the second for pathology review. All histology was reviewed by a single pathologist blinded to clinical status and HIC values. Liver fibrosis was scored from zero (absent fibrosis) to 6 (cirrhosis). 4 MRI techniqueThe single breath-hold R2*-MRI used a 1.5T MRI scanner (Siemens Symphony, Siemens; Malvern, PA) using a multiecho gradient echo sequence to acquire 20 images with increasing echo times (range, 1.1-17.3 ms). Liver images were obtained in transversal slice orientation through the center at the main portal vein origin. Slice thickness measured 10 mm with in-plane resolution of 3.125 mm. Quantitative T2* maps were calculated offline using custom-...

Three easily identifiable manifestations of sickle cell disease that may appear in the first two years of life (dactylitis, severe anemia, and leukocytosis) can help to predict the possibility of severe sickle cell disease later in life.

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin ( = .007), lower indirect bilirubin ( = .005), and missense mutations ( = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

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