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Journal publications

Journal publications
N Engl J Med. 2016 Dec 3. [Epub ahead of print]
Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease.
Ataga KI1, Kutlar A1, Kanter J1, Liles D1, Cancado R1, Friedrisch J1, Guthrie TH1, Knight-Madden J1, Alvarez OA1, Gordeuk VR1, Gualandro S1, Colella MP1, Smith WR1, Rollins SA1, Stocker JW1, Rother RP1.
Author information
Abstract
Background The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. Methods In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed. Results A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. Conclusions In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).

N Engl J Med. 2016 Feb 18;374(7):625-35.
A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events.
Heeney MM1, Hoppe CC, Abboud MR, Inusa B, Kanter J, Ogutu B, Brown PB, Heath LE, Jakubowski JA, Zhou C, Zamoryakhin D, Agbenyega T, Colombatti R, Hassab HM, Nduba VN, Oyieko JN, Robitaille N, Segbefia CI, Rees DC; DOVE Investigators.
Abstract
BACKGROUND:
Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events.
METHODS:
Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries.
RESULTS:
A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups.
CONCLUSIONS:
Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).

Haematologica. 2016 Dec 1.[Epub ahead of print]
Cure for thalassemia major: from allogeneic hematopoietic stem cell transplantation to gene therapy.
Srivastava A1, Shaji RV2.
Abstract
Allogeneic hematopoietic stem cell transplantation has been established for several decades as a gene replacement therapy for patients with thalassemia major and now offers very high rates of cure to those who are able to access this therapy. Outcomes have improved tremendously over the last decade even in high-risk patients. The limited data available suggests that the long-term outcome is also excellent with >90% survival but for best results, hematopoietic stem cell transplantation should be offered early before any end organ damage occurs. However, access to this therapy is limited by lack of suitable donors in more than half the patients. Inadequate hematopoietic stem cell transplantation services and the cost of therapy are other reasons for the same, particularly in those parts of the world which have a high prevalence of this condition. As a result <10% of eligible patients are actuallyable to avail this therapy. Other options for curative therapies are therefore needed. Recently, gene correction in autologous hematopoietic stem cells has been successfully established using lentiviral vectors, and several clinical trials have been initiated. A gene editing approach to correct the β globin mutation or disrupt BCL11A to increase fetal hemoglobin production has also been reported and is expected to be introduced in clinical trials soon. Curative possibilities for the major hemoglobin disorders are expanding. Providing access to these therapies around the world would be the challenge.
Blood. 2016 Sep 22;128(12):1555-61.
A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major.
Fernandes JL1, Loggetto SR2, Veríssimo MP3, Fertrin KY4, Baldanzi GR5, Fioravante LA1, Tan DM6, Higa T7, Mashima DA8, Piga A9, Coelho OR4, Costa FF4, Saad ST4.
Abstract
Cardiovascular disease resulting from iron accumulation is still a major cause of death in patients with thalassemia major (TM). Voltage-gated calcium-channel blockade prevents iron entry into cardiomyocytes and may provide an adjuvant treatment to chelation, reducing myocardial iron uptake. We evaluated whether addition of amlodipine to chelation strategies would reduce myocardial iron overload in TM patients compared with placebo. In a multicenter, double-blind, randomized, placebo-controlled trial, 62 patients were allocated to receive oral amlodipine 5 mg/day or placebo in addition to their current chelation regimen. The main outcome was change in myocardial iron concentration (MIC) determined by magnetic resonance imaging at 12 months, with patients stratified into reduction or prevention groups according to their initial T2* below or above the normal human threshold of 35 ms (MIC, 0.59 mg/g dry weight). At 12 months, patients in the reduction group receiving amlodipine (n = 15) had a significant decrease in MIC compared with patients receiving placebo (n = 15) with a median of -0.26 mg/g (95% confidence interval, -1.02 to -0.01) vs 0.01 mg/g (95% confidence interval, -0.13 to 0.23), P = .02. No significant changes were observed in the prevention group (treatment-effect interaction with P = .005). The same findings were observed in the subgroup of patients with T2* <20 ms. Amlodipine treatment did not cause any serious adverse events. Thus, in TM patients with cardiac siderosis, amlodipine combined with chelation therapy reduced cardiac iron more effectively than chelation therapy alone. Because this conclusion is based on subgroup analyses, it needs to be confirmed in ad hoc clinical trials. This trial was registered at www.clinicaltrials.gov identifier as #NCT01395199.
Blood. 2016 Jul 14;128(2):265-76.
Minihepcidin peptides as disease modifiers in mice affected by β-thalassemia and polycythemia vera.
Casu C1, Oikonomidou PR1, Chen H2, Nandi V3, Ginzburg Y2, Prasad P4, Fleming RE5, Shah YM6, Valore EV7, Nemeth E7, Ganz T8, MacDonald B9, Rivella S10.
Abstract
In β-thalassemia and polycythemia vera (PV), disordered erythropoiesis triggers severe pathophysiological manifestations. β-Thalassemia is characterized by ineffective erythropoiesis, reduced production of erythrocytes, anemia, and iron overload and PV by erythrocytosis and thrombosis. Minihepcidins are hepcidin agonists that have been previously shown to prevent iron overload in murine models of hemochromatosis and induce iron-restricted erythropoiesis at higher doses. Here, we show that in young Hbb(th3/+) mice, which serve as a model of untransfused β-thalassemia, minihepcidin ameliorates ineffective erythropoiesis, anemia, and iron overload. In older mice with untransfused β-thalassemia, minihepcidin improves erythropoiesis and does not alter the beneficial effect of the iron chelator deferiprone on iron overload. In PV mice that express the orthologous JAK2 mutation causing human PV, administration of minihepcidin significantly reduces splenomegaly and normalizes hematocrit levels. These studies indicate that drug-like minihepcidins have a potential as future therapeutics for untransfused β-thalassemia and PV.
Lancet. 2016 Jun 18;387(10037):2565-74.
Cardiovascular complications and risk of death in sickle-cell disease.
Gladwin MT1.
Abstract
In sickle-cell disease, a point mutation in the β-globin chain causes haemoglobin to polymerise within erythrocytes during deoxygenation, altering red blood cell rheology and causing haemolysis. Improvements in health infrastructure, preventive care, and clinical treatments have reduced the morbidity and mortality of sickle-cell disease in developed countries. However, as these patients live longer, the chronic effects of sustained haemolytic anaemia and episodic vaso-occlusive events drive the development of end-organ complications. Cardiopulmonary organ dysfunction and chronic kidney injury have a large effect on morbidity and premature mortality, and typically accelerate in the second decade of life. These processes culminate in the development of pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, and sudden death. In this Series paper, we review the mechanisms, clinical features, and epidemiology of major cardiovascular complications in patients with sickle-cell disease and discuss how screening and intervention could reduce their incidence.

Lancet. 2016 Feb 13;387(10019):661-70.
Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.
Ware RE1, Davis BR2, Schultz WH3, Brown RC4, Aygun B5, Sarnaik S6, Odame I7, Fuh B8, George A9, Owen W10, Luchtman-Jones L11, Rogers ZR12, Hilliard L13, Gauger C14, Piccone C15, Lee MT16, Kwiatkowski JL17, Jackson S18, Miller ST19, Roberts C20, Heeney MM21, Kalfa TA3, Nelson S22, Imran H23, Nottage K24, Alvarez O25, Rhodes M26, Thompson AA27, Rothman JA28, Helton KJ24, Roberts D18, Coleman J24, Bonner MJ28, Kutlar A29, Patel N29, Wood J30, Piller L2, Wei P2, Luden J18, Mortier NA3, Stuber SE3, Luban NL11, Cohen AR17, Pressel S2, Adams RJ18.
Abstract
BACKGROUND:
For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions.
METHODS:
TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant’s maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307.
FINDINGS:
Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions).
INTERPRETATION:
For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke.

Haematologica. 2015 Apr;100(4):452-7.
A genetic score for the prediction of beta-thalassemia severity.
Danjou F1, Francavilla M2, Anni F2, Satta S2, Demartis FR2, Perseu L3, Manca M3, Sollaino MC3, Manunza L2, Mereu E2, Marceddu G2, Pissard S4, Joly P5, Thuret I6, Origa R2, Borg J7, Forni GL8, Piga A9, Lai ME3, Badens C10, Moi P11, Galanello R11.
Abstract
Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.-158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We characterized 54 genetic variants at these five loci robustly associated with the amelioration of beta-thalassemia phenotype, to build a predictive score of severity using a representative cohort of 890 β-thalassemic patients. Using Cox proportional hazard analysis on a training set, we assessed the effect of these loci on the age at which patient started regular transfusions, built a Thalassemia Severity Score, and validated it on a testing set. Discriminatory power of the model was high (C-index=0.705; R(2)=0.343) and the validation conducted on the testing set confirmed its predictive accuracy with transfusion-free survival probability (P<0.001) and with transfusion dependency status (Area Under the Receiver Operating Characteristic Curve=0.774; P<0.001). Finally, an automatized on-line calculation of the score was made available at http://tss.unica.it. Besides the accurate assessment of genetic predictors effect, the present results could be helpful in the management of patients, both as a predictive score for screening and a standardized scale of severity to overcome the major-intermedia dichotomy and support clinical decisions.

N Engl J Med. 2014 Aug 21;371(8):699-710.
Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia.
DeBaun MR1, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, Meier ER, Howard TH, Majumdar S, Inusa BP, Telfer PT, Kirby-Allen M, McCavit TL, Kamdem A, Airewele G, Woods GM, Berman B, Panepinto JA, Fuh BR, Kwiatkowski JL, King AA, Fixler JM, Rhodes MM, Thompson AA, Heiny ME, Redding-Lallinger RC, Kirkham FJ, Dixon N, Gonzalez CE, Kalinyak KA, Quinn CT, Strouse JJ, Miller JP, Lehmann H, Kraut MA, Ball WS Jr, Hirtz D, Casella JF.
BACKGROUND:
Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.
METHODS:
In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.
RESULTS:
A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04).
CONCLUSIONS:
Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).
Blood. 2014 May 15;123(20):3089-94; quiz 3210. doi: 10.1182/blood-2013-01-435776. Epub 2014 Feb 7.
Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia.
King A1, Shenoy S1.
Blood. 2014 Mar 6;123(10):1447-54.
A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA).
Pennell DJ1, Porter JB, Piga A, Lai Y, El-Beshlawy A, Belhoul KM, Elalfy M, Yesilipek A, Kilinç Y, Lawniczek T, Habr D, Weisskopf M, Zhang Y, Aydinok Y; CORDELIA study investigators.
Abstract
Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.
Haematologica. 2014 May;99(5):811-20. doi: 10.3324/haematol.2013.099747.
Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel.
Angelucci E1, Matthes-Martin S, Baronciani D, Bernaudin F, Bonanomi S, Cappellini MD, Dalle JH, Di Bartolomeo P, de Heredia CD, Dickerhoff R, Giardini C, Gluckman E, Hussein AA, Kamani N, Minkov M, Locatelli F, Rocha V, Sedlacek P, Smiers F, Thuret I, Yaniv I, Cavazzana M, Peters C; EBMT Inborn Error and EBMT Paediatric Working Parties.
Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management.

Haematologica. 2014 Mar;99(3):e38-40.
A decisional algorithm to start iron chelation in patients with beta thalassemia.
Danjou F1, Cabantchik ZI, Origa R, Moi P, Marcias M, Barella S, Defraia E, Dessì C, Foschini ML, Giagu N, Leoni GB, Morittu M, Galanello R.
Haematologica. 2013 Sep;98(9):1368-74.
International survey of T2* cardiovascular magnetic resonance in β-thalassemia major.
Carpenter JP1, Roughton M, Pennell DJ; Myocardial Iron in Thalassemia (MINT) Investigators.
Abstract
Accumulation of myocardial iron is the cause of heart failure and early death in most transfused thalassemia major patients. T2* cardiovascular magnetic resonance provides calibrated, reproducible measurements of myocardial iron. However, there are few data regarding myocardial iron loading and its relation to outcome across the world. A survey is reported of 3,095 patients in 27 worldwide centers using T2* cardiovascular magnetic resonance. Data on baseline T2* and numbers of patients with symptoms of heart failure at first scan (defined as symptoms and signs of heart failure with objective evidence of left ventricular dysfunction) were requested together with more detailed information about patients who subsequently developed heart failure or died. At first scan, 20.6% had severe myocardial iron (T2*≤ 10 ms), 22.8% had moderate myocardial iron (T2* 10-20 ms) and 56.6% of patients had no iron loading (T2*>20 ms). There was significant geographical variation in myocardial iron loading (24.8-52.6%; P<0.001). At first scan, 85 (2.9%) of 2,915 patients were reported to have heart failure (81.2% had T2* <10 ms; 98.8% had T2* <20 ms). During follow up, 108 (3.8%) of 2,830 patients developed new heart failure. Of these, T2* at first scan had been less than 10 ms in 96.3% and less than 20 ms in 100%. There were 35 (1.1%) cardiac deaths. Of these patients, myocardial T2* at first scan had been less than 10 ms in 85.7% and less than 20 ms in 97.1%. Therefore, in this worldwide cohort of thalassemia major patients, over 43% had moderate/severe myocardial iron loading with significant geographical differences, and myocardial T2* values less than 10 ms were strongly associated with heart failure and death.

Lancet Glob Health. 2014 Feb;2(2):e80-9.
Global migration and the changing distribution of sickle haemoglobin: a quantitative study of temporal trends between 1960 and 2000.
Piel FB, Tatem AJ, Huang Z, Gupta S, Williams TN, Weatherall DJ.
Abstract
BACKGROUND:
Changes in the geographical distribution of genetic disorders are often thought to happen slowly, especially when compared with infectious diseases. Whereas mutations, genetic drift, and natural selection take place over many generations, epidemics can spread through large populations within a few days or weeks. Nevertheless, population movements can interfere with these processes, and few studies have been done of their eff ect on genetic disorders. We aimed to investigate the eff ect of global migration on the distribution of the sickle-cell gene-the most common and clinically significant haemoglobin structural variant.
METHODS:
For each country, we extracted data from the World Bank’s Global Bilateral Migration Database about international human migrations between 1960 and 2000. We combined this information with evidence-based estimates of national HbS allele frequencies, generated within a Bayesian geostatistical framework, to analyse temporal changes in the net numbers of migrants, and classified countries with an index summarising these temporal trends.
FINDINGS:
The number of international migrants increased from 92.6 million in 1960, to 165.2 million in 2000. The estimated global number of migrants with HbS increased from about 1.6 million in 1960, to 3.6 million in 2000. This increase was largely due to an increase in the number of migrants from countries with HbS allele frequencies higher than 10%, from 3.1 million in 1960, to 14.2 million in 2000. Additionally, the mean number of countries of origin for each destination country increased from 70 (SE 46) in 1960, to 98 (48) in 2000, showing an increasing diversity in the network of international migrations between countries. Our index of change map shows a patchy distribution of the magnitude of temporal changes, with the highest positive and negative values scattered across all continents.
INTERPRETATION:
Global human population movements have had a substantial eff ect on the distribution of the HbS gene. Population movements can create a long-term burden on health-care systems. Our findings, which emphasise countries in which migration fluxes are changing the most, should increase awareness about the global burden of haemoglobinopathies and encourage policy makers to implement specific public health interventions, such as screening programmes and genetic counselling.
FUNDING:
Wellcome Trust, European Research Council, Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases-National Institutes of Health, the Research and Policy for Infectious Disease Dynamics program, Fogarty International Center.
Lancet. 2013 Jan 12;381(9861):142-51. doi: 10.1016/S0140-6736(12)61229-X. Epub 2012 Oct 25.
Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates.
Piel FB1, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, Temperley WH, Williams TN, Weatherall DJ, Hay SI.
Abstract
BACKGROUND:
Reliable estimates of populations affected by diseases are necessary to guide efficient allocation of public health resources. Sickle haemoglobin (HbS) is the most common and clinically significant haemoglobin structural variant, but no contemporary estimates exist of the global populations affected. Moreover, the precision of available national estimates of heterozygous (AS) and homozygous (SS) neonates is unknown. We aimed to provide evidence-based estimates at various scales, with uncertainty measures.
METHODS:
Using a database of sickle haemoglobin surveys, we created a contemporary global map of HbS allele frequency distribution within a Bayesian geostatistical model. The pairing of this map with demographic data enabled calculation of global, regional, and national estimates of the annual number of AS and SS neonates. Subnational estimates were also calculated in data-rich areas.
FINDINGS:
Our map shows subnational spatial heterogeneities and high allele frequencies across most of sub-Saharan Africa, the Middle East, and India, as well as gene flow following migrations to western Europe and the eastern coast of the Americas. Accounting for local heterogeneities and demographic factors, we estimated that the global number of neonates affected by HbS in 2010 included 5,476,000 (IQR 5,291,000-5,679,000) AS neonates and 312,000 (294,000-330,000) SS neonates. These global estimates are higher than previous conservative estimates. Important differences predicted at the national level are discussed.
INTERPRETATION:
HbS will have an increasing effect on public health systems. Our estimates can help countries and the international community gauge the need for appropriate diagnoses and genetic counselling to reduce the number of neonates affected. Similar mapping and modelling methods could be used for other inherited disorders.

Blood. 2012 Aug 2;120(5):970-7.
Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study.
Taher AT1, Porter J, Viprakasit V, Kattamis A, Chuncharunee S, Sutcharitchan P, Siritanaratkul N, Galanello R, Karakas Z, Lawniczek T, Ros J, Zhang Y, Habr D, Cappellini MD.
Abstract
Nontransfusion-dependent thalassemia (NTDT) patients may develop iron overload and its associated complications despite receiving only occasional or no transfusions. The present 1-year, randomized, double-blind, placebo-controlled THALASSA (Assessment of Exjade in Nontransfusion-Dependent Thalassemia) trial assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients. A total of 166 patients were randomized in a 2:1:2:1 ratio to starting doses of 5 or 10 mg/kg/d of deferasirox or placebo. The means ± SD of the actual deferasirox doses received over the duration of the study in the 5 and 10 mg/kg/d starting dose cohorts were 5.7 ± 1.4 and 11.5 ± 2.9 mg/kg/d, respectively. At 1 year, the liver iron concentration (LIC) decreased significantly compared with placebo (least-squares mean [LSM] ± SEM, -2.33 ± 0.7 mg Fe/g dry weight [dw], P = .001, and -4.18 ± 0.69 mg Fe/g dw, P < .001) for the 5 and 10 mg/kg/d deferasirox groups, respectively (baseline values [means ± SD], 13.11 ± 7.29 and 14.56 ± 7.92 mg Fe/g dw, respectively). Similarly, serum ferritin decreased significantly compared with placebo by LSM -235 and -337 ng/mL for the deferasirox 5 and 10 mg/kg/d groups, respectively (P < .001). In the placebo patients, LIC and serum ferritin increased from baseline by 0.38 mg Fe/g dw and 115 ng/mL (LSM), respectively. The most common drug-related adverse events were nausea (n = 11; 6.6%), rash (n = 8; 4.8%), and diarrhea (n = 6; 3.6%). This is the first randomized study showing that iron chelation with deferasirox significantly reduces iron overload in NTDT patients with a frequency of overall adverse events similar to placebo.

Blood. 2012 Mar 22;119(12):2746-53.
Chelation use and iron burden in North American and British thalassemia patients: a report from the Thalassemia Longitudinal Cohort.
Kwiatkowski JL1, Kim HY, Thompson AA, Quinn CT, Mueller BU, Odame I, Giardina PJ, Vichinsky EP, Boudreaux JM, Cohen AR, Porter JB, Coates T, Olivieri NF, Neufeld EJ; Thalassemia Clinical Research Network.
Abstract
Morbidity and mortality in thalassemia are associated with iron burden. Recent advances in organ-specific iron imaging and the availability of oral deferasirox are expected to improve clinical care, but the extent of use of these resources and current chelation practices have not been well described. In the present study, we studied chelation use and the change in iron measurements in 327 subjects with transfusion-dependent thalassemia (mean entry age, 22.1 ± 2.5 years) from 2002-2011, with a mean follow-up of 8.0 years (range, 4.4-9.0 years). The predominant chelator currently used is deferasirox, followed by deferoxamine and then combination therapies. The use of both hepatic and cardiac magnetic resonance imaging increased more than 5-fold (P < .001) during the study period, leading to an 80% increase in the number of subjects undergoing liver iron concentration (LIC) measurements. Overall, LIC significantly improved (median, 10.7 to 5.1 mg/g dry weight, P < .001) with a nonsignificant improvement in cardiac T2* (median, 23.55 to 34.50 ms, P = .23). The percentage of patients with markers of inadequate chelation (ferritin > 2500 ng/mL, LIC > 15 mg/g dry weight, and/or cardiac T2* < 10 ms) also declined from 33% to 26%. In summary, increasing use of magnetic resonance imaging and oral chelation in thalassemia management has likely contributed to improved iron burden.

N Engl J Med. 2011 Jul 7;365(1):44-53.
A hemodynamic study of pulmonary hypertension in sickle cell disease.
Parent F1, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, Habibi A, Bennani S, Savale L, Adnot S, Maitre B, Yaïci A, Hajji L, O’Callaghan DS, Clerson P, Girot R, Galacteros F, Simonneau G.
Abstract
BACKGROUND:
The prevalence and characteristics of pulmonary hypertension in adults with sickle cell disease have not been clearly established.
METHODS:
In this prospective study, we evaluated 398 outpatients with sickle cell disease (mean age, 34 years) at referral centers in France. All patients underwent Doppler echocardiography, with measurement of tricuspid-valve regurgitant jet velocity. Right heart catheterization was performed in 96 patients in whom pulmonary hypertension was suspected on the basis of a tricuspid regurgitant jet velocity of at least 2.5 m per second. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of at least 25 mm Hg.
RESULTS:
The prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second was 27%. In contrast, the prevalence of pulmonary hypertension as confirmed on catheterization was 6%. The positive predictive value of echocardiography for the detection of pulmonary hypertension was 25%. Among the 24 patients with confirmed pulmonary hypertension, the pulmonary-capillary wedge pressure was 15 mm Hg or less (indicating precapillary pulmonary hypertension) in 11 patients. Patients with confirmed pulmonary hypertension were older and had poorer functional capacity and higher levels of N-terminal pro-brain natriuretic peptide than other patients. In contrast, patients who had a tricuspid regurgitant jet velocity of at least 2.5 m per second without pulmonary hypertension and patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second had similar clinical characteristics.
CONCLUSIONS:
In this study of adults with sickle cell disease, the prevalence of pulmonary hypertension as confirmed on right heart catheterization was 6%. Echocardiographic evaluation alone had a low positive predictive value for pulmonary hypertension. (Funded by the French Ministry of Health and Assistance Publique-Hôpitaux de Paris; ClinicalTrials.gov number, NCT00434902.).

Circulation. 2011 Mar 22;123(11):1227-32.
Pulmonary hypertension associated with hemoglobinopathies: prevalent but overlooked.
Farmakis D, Aessopos A.
Circulation. 2011 Nov 15;124(20):2253-63.
Iron overload cardiomyopathy in clinical practice.
Kremastinos DT, Farmakis D.
Blood. 2011 Sep 29;118(13):3479-88.
How I treat thalassemia.
Rachmilewitz EA1, Giardina PJ.
Abstract
The purpose of this article is to set forth our approach to diagnosing and managing the thalassemias, including β-thalassemia intermedia and β-thalassemia major. The article begins by briefly describing recent advances in our understanding of the pathophysiology of thalassemia. In the discussion on diagnosing the condition, we cover the development of improved diagnostic tools, including the use of very small fetal DNA samples to detect single point mutations with great reliability for prenatal diagnosis of homozygous thalassemia. In our description of treatment strategies, we focus on how we deal with clinical manifestations and long-term complications using the most effective current treatment methods for β-thalassemia. The discussion of disease management focuses on our use of transfusion therapy and the newly developed oral iron chelators, deferiprone and deferasirox. We also deal with splenectomy and how we manage endocrinopathies and cardiac complications. In addition, we describe our use of hematopoietic stem cell transplantation, which has produced cure rates as high as 97%, and the use of cord blood transplantation. Finally, we briefly touch on therapies that might be effective in the near future, including new fetal hemoglobin inducers and gene therapy.

Blood. 2011 Jul 28;118(4):884-93.
Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up.
Cappellini MD1, Bejaoui M, Agaoglu L, Canatan D, Capra M, Cohen A, Drelichman G, Economou M, Fattoum S, Kattamis A, Kilinc Y, Perrotta S, Piga A, Porter JB, Griffel L, Dong V, Clark J, Aydinok Y.
Abstract
Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years’ deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years’ exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

Haematologica. 2011 Apr;96(4):515-20.
Cardiac iron and cardiac disease in males and females with transfusion-dependent thalassemia major: a T2* magnetic resonance imaging study.
Marsella M1, Borgna-Pignatti C, Meloni A, Caldarelli V, Dell’Amico MC, Spasiano A, Pitrolo L, Cracolici E, Valeri G, Positano V, Lombardi M, Pepe A.
Abstract
BACKGROUND:
It has been repeatedly reported that female patients with thalassemia major survive longer than males and that the difference is due to a lower rate of cardiac disease in females.
DESIGN AND METHODS:
We compared the cardiac iron load as measured by T2* magnetic resonance imaging in 776 patients (370 males) examined at the National Research Council as part of an Italian cooperative study. We also established normal left ventricular ejection fraction values for our population.
RESULTS:
The prevalence of cardiac disease was higher in males than in females (105 males versus 69 females; P < 0.0001). Cardiac T2* was significantly lower in patients with heart dysfunction (P < 0.0001), but no difference was observed according to sex. Twenty males and five females had a history of cardiac arrhythmias. Their cardiac T2* was not significantly lower than that of patients without arrhythmias (24 ms versus 26 ms; P = 0.381), nor was there a difference between sexes. Liver T2* was significantly lower in males and females with heart dysfunction compared to those without. Ferritin levels were higher in patients of both sexes with heart dysfunction without significant differences between males and females. Conclusions Males and females are at the same risk of accumulating iron in their hearts, but females tolerate iron toxicity better, possibly as an effect of reduced sensitivity to chronic oxidative stress.

Haematologica. 2011 Jan;96(1):41-7.
Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging.
Pepe A1, Meloni A, Capra M, Cianciulli P, Prossomariti L, Malaventura C, Putti MC, Lippi A, Romeo MA, Bisconte MG, Filosa A, Caruso V, Quarta A, Pitrolo L, Missere M, Midiri M, Rossi G, Positano V, Lombardi M, Maggio A.
Abstract
BACKGROUND:
Oral deferiprone was suggested to be more effective than subcutaneous desferrioxamine for removing heart iron. Oral once-daily chelator deferasirox has recently been made commercially available but its long-term efficacy on cardiac iron and function has not yet been established. Our study aimed to compare the effectiveness of deferasirox, deferiprone and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function in thalassemia major patients by means of quantitative magnetic resonance imaging.
DESIGN AND METHODS:
From the first 550 thalassemia subjects enrolled in the Myocardial Iron Overload in Thalassemia network, we retrospectively selected thalassemia major patients who had been receiving one chelator alone for longer than one year. We identified three groups of patients: 24 treated with deferasirox, 42 treated with deferiprone and 89 treated with desferrioxamine. Myocardial iron concentrations were measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Liver iron concentrations were measured by T2* multiecho technique.
RESULTS:
The global heart T2* value was significantly higher in the deferiprone (34 ± 11 ms) than in the deferasirox (21 ± 12 ms) and the desferrioxamine groups (27 ± 11 ms) (P = 0.0001). We found higher left ventricular ejection fractions in the deferiprone and the desferrioxamine versus the deferasirox group (P = 0.010). Liver iron concentration, measured as T2* signal, was significantly lower in the desferrioxamine versus the deferiprone and the deferasirox group (P = 0.004).
CONCLUSIONS:
The cohort of patients treated with oral deferiprone showed less myocardial iron burden and better global systolic ventricular function compared to the patients treated with oral deferasirox or subcutaneous desferrioxamine.