The aim of this prospective study was to evaluate the long-term efficacy and safety of hydroxyurea (HU) in patients with sickle cell disease (SCD). Thirty-four patients with sickle cell anemia (hemoglobin S [HbS]/HbS), 131 with HbS/␤ 0 -thal, and 165 with HbS/␤ ؉ -thal participated in this trial. HU was administered to 131 patients, whereas 199 patients were conventionally treated. The median follow-up period was 8 years for HU patients and 5 years for non-HU patients. HU produced a dramatic reduction in the frequency of severe painful crises, transfusion requirements, hospital admissions, and incidence of acute chest syndrome. The probability of 10-year survival was 86% and 65% for HU and non-HU patients, respectively (P ‫؍‬ .001), although HU patients had more severe forms of SCD. The 10-year probability of survival for HbS/ HbS, HbS/␤ 0 -thal, and HbS/IVSI-110 patients was 100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and 66%, for non-HU patients. The multivariate analysis showed that fetal hemoglobin values at baseline and percentage change of lactate dehydrogenase between baseline and 6 months were independently predicted for survival in the HU group. These results highlight the beneficial effect of HU, which seems to modify the natural history of SCD and raise the issue of expanding its use in all SCD patients. (Blood.

Cardiac complications in 110 patients (mean age, 32.5 ؎ 11.4 years) with thalassemia intermedia (TI) were studied. Sixtyseven (60.9%) of them had not been transfused or were minimally transfused (group A). The rest had started transfusions after the age of 5 years (mean, 15.1 ؎ 10.1 years), initially on demand and later more frequently (group B). Overall mean hemoglobin and ferritin levels were 9.1 ؎ 1.1 g/dL and 1657 ؎ 1477 ng/mL, respectively. Seventy-six healthy controls were also studied. The investigation included thorough history taking, clinical examination, electrocardiography, chest radiograph, and full resting echocardiography. Of 110 patients, 6 (5.4%) had congestive heart failure (CHF), and 9 (8.1%) had a history of acute pericarditis. Echocardiography showed pericardial thickening, with or without effusion, in 34.5% of the patients.

BACKGROUND Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β 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 β-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 μg 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 β-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.)

SummaryOsteoporosis represents an important cause of morbidity in adult patients with thalassaemia major (TM). The pathogenesis of osteoporosis in TM is multifactorial, and includes bone marrow expansion, endocrine dysfunction and iron overload. Additional genetic factors, such as the COLIA 1 gene polymorphism, seem to play an important role in the development of low bone mass in these patients. However, the mechanisms through which these factors lead to bone loss have not been completely clarified. The diminished osteoblast function is accompanied by a comparable or even greater increase in osteoclast activity. The receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway has been recently recognized as the final, dominant mediator of osteoclast proliferation and activation. There is increased evidence that this pathway interferes in the pathogenesis of thalassaemiainduced osteoporosis. Currently, bisphosphonates that are potent inhibitors of osteoclast function have been used in TM patients with encouraging results. This review attempts to summarize all the novel data for the biology of bone damage in TM. It also describes the results of all major studies that have investigated the effects of different treatment modalities for TM-induced osteoporosis, their mode of action, and the future implications of their use.

Summary Magnetic resonance imaging (MRI) appears to be useful for monitoring iron overload in thalassaemia. We studied 106 patients with beta‐thalassaemia: 80 with thalassaemia major (TM) and 26 with thalassaemia intermedia (TI). Thirty‐five patients with sickle cell disease (SCD) were also evaluated. Serum ferritin, liver and myocardial T2‐relaxation time and liver iron concentration (LIC) were measured. LIC values, based on biopsies from 29 patients, showed a close inverse correlation with the respective liver T2‐values, along with a strong positive correlation with ferritin levels in all patients. Heart T2‐values correlated with left ventricular ejection fraction in TM and SCD, but not in TI patients. Both liver and heart T2‐values were significantly lower in TM patients than those of TI, and SCD patients. Ferritin levels showed a strong correlation with liver T2‐values in all three groups of patients. Similarly, a negative correlation was found between serum ferritin levels and heart T2‐values in TM, but not in TI and SCD patients. Heart and liver T2‐values showed a significant correlation only in TM patients. These results suggest that the MRI technique (T2 relaxation time) used in our study, is a reliable, safe and non‐invasive method for the assessment of the deposition of iron in the liver; results for the heart become reliable only when there is heavy iron deposition.

Summary. Bone disease in patients with thalassaemia major is a multifactorial and still poorly understood process. The present study evaluated 45 thalassaemic patients using dual X-ray absorptiometry at three sites (lumbar spine, head of femur and forearm) to assess bone mineral density, in parallel with a series of biochemical markers to measure bone formation and bone resorption. To identify possible interfering factors, our patients were grouped according to whether or not they needed transfusion therapy; the presence of hypogonadism was also considered. Our results showed that patients on regular transfusions had a markedly low bone mineral density in contrast to those not requiring blood support and that this finding was more pronounced in the hypogonadic group, irrespectively of sex. The decrease of bone mineral density values was more prominent in the forearm, thus making this site particularly interesting for such studies. Bone formation, as evidenced by the levels of serum alkaline phosphatase and osteocalcin, did not appear to be impaired, while bone resorption was grossly increased in all patient groups. The latter process was clearly evident using the recently introduced measurement of the urinary N-terminal peptides of collagen type I, the sensitivity of which has already been established in other groups of osteoporotic patients. Our conclusion is that, in spite of the severe bone destruction that occurs in thalassaemia major, the fact that bone formation remains intact calls for a more intensive treatment comprising hormonal replacement, bisphosphonates and other agents.

K E Y P O I N T S l A high percentage of patients with b-thalassemia had improvement in hemoglobin or transfusion burden after receiving luspatercept. l Findings support a randomized clinical trial to assess the efficacy and safety of luspatercept for treatment of b-thalassemia. b-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with b-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent ( ‡4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ‡5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ‡1.5 g/dL from baseline for ‡14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ‡20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ‡1.5 g/dL over ‡14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ‡20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of b-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as

Haemoglobinopathies are the most common hereditary disorders in Greece. Although there is a successful national prevention program, established 35 years ago, there is lack of an official registry and collection of epidemiological data for haemoglobinopathies. This paper reports the results of the first National Registry for Haemoglobinopathies in Greece (NRHG), recently organized by the Greek Society of Haematology. NRHG records all patients affected by thalassaemia major (TM), thalassaemia intermedia (TI), "H" Haemoglobinopathy (HH) and sickle cell disease (SCD). Moreover, data about the annual rate of new affected births along with deaths, between 2000 and 2010, are reported. A total of 4,506 patients are registered all over the country while the number of affected newborns was significantly decreased during the last 3 years. Main causes for still having affected births are: (1) lack of medical care due to financial reasons or low educational level; (2) unawareness of time limitations for prenatal diagnosis (PD); due either to obstetricians' malpractice or to delayed demand of medical care of couples at risk; and (3) religious, social or bioethical reasons. Cardiac and liver disorders consist main causes for deaths while life expectancy of patients lengthened after 2005 (p < 0.01). The NRHG of patients affected by haemoglobinopathies in Greece provides useful data about the haemoglobinopathies in the Greek population and confirms the efficacy of the National Thalassaemia Prevention Program on impressively decreasing the incidence of TM and sickle cell syndromes.