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1.  Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone 
Background
Established heart failure in thalassaemia major has a poor prognosis and optimal management remains unclear.
Methods
A 1 year prospective study comparing deferoxamine (DFO) monotherapy or when combined with deferiprone (DFP) for patients with left ventricular ejection fraction (LVEF) <56% was conducted by the Thalassemia Clinical Research Network (TCRN). All patients received DFO at 50–60 mg/kg 12–24 hr/day sc or iv 7 times weekly, combined with either DFP 75 at mg/kg/day (combination arm) or placebo (DFO monotherapy arm). The primary endpoint was the change in LVEF by CMR.
Results
Improvement in LVEF was significant in both study arms at 6 and 12 months (p = 0.04), normalizing ventricular function in 9/16 evaluable patients. With combination therapy, the LVEF increased from 49.9% to 55.2% (+5.3% p = 0.04; n = 10) at 6 months and to 58.3% at 12 months (+8.4% p = 0.04; n = 7). With DFO monotherapy, the LVEF increased from 52.8% to 55.7% (+2.9% p = 0.04; n = 6) at 6 months and to 56.9% at 12 months (+4.1% p = 0.04; n = 4). The LVEF trend did not reach statistical difference between study arms (p = 0.89). In 2 patients on DFO monotherapy during the study and in 1 patient on combined therapy during follow up, heart failure deteriorated fatally. The study was originally powered for 86 participants to determine a 5% difference in LVEF improvement between treatments. The study was prematurely terminated due to slow recruitment and with the achieved sample size of 20 patients there was 80% power to detect an 8.6% difference in EF, which was not demonstrated. Myocardial T2* improved in both arms (combination +1.9 ± 1.6 ms p = 0.04; and DFO monotherapy +1.9 ± 1.4 ms p = 0.04), but with no significant difference between treatments (p = 0.65). Liver iron (p = 0.03) and ferritin (p < 0.001) both decreased significantly in only the combination group.
Conclusions
Both treatments significantly improved LVEF and myocardial T2*. Although this is the largest and only randomized study in patients with LV decompensation, further prospective evaluation is needed to identify optimal chelation management in these high-risk patients.
doi:10.1186/1532-429X-15-38
PMCID: PMC3669105  PMID: 23688265
Thalassemia; Heart failure; Deferoxamine; Deferiprone; Combination
2.  Beliefs about chelation among thalassemia patients 
Background
Understanding patients’ views about medication is crucial to maximize adherence. Thalassemia is a congenital blood disorder requiring chronic blood transfusions and daily iron chelation therapy.
Methods
The Beliefs in Medicine Questionnaire (BMQ) was used to assess beliefs in chelation in thalassemia patients from North America and London in the Thalassemia Longitudinal Cohort (TLC) of the Thalassemia Clinical Research Network (TCRN). Chelation adherence was based on patient report of doses administered out of those prescribed in the last four weeks.
Results
Of 371 patients (ages 5-58y, mean 24y), 93% were transfused and 92% receiving chelation (26% deferoxamine (DFO; a slow subcutaneous infusion via portable pump), 63% oral, 11% combination). Patients expressed high “necessity” for transfusion (96%), DFO chelation (92%) and oral chelation (89%), with lower “concern” about treatment (48%, 39%, 19% respectively). Concern about oral chelation was significantly lower than that of DFO (p<0.001). Self-reported adherence to chelation was not associated with views about necessity or concerns, but negatively correlated with perceived sensitivity to DFO (Sensitive Soma scale; r=−0.23, p=0.01) and side effects of oral chelation (r=−0.14, p=0.04). High ferritin iron levels, potentially indicating lower adherence, were found in 41% of patients reporting low necessity of oral chelation compared to 24% reporting high necessity (p=0.048). Concerns about treatment were associated with lower quality of life and more symptoms of anxiety and depression.
Conclusions
Despite their requirement for multimodal therapy, thalassemia patients have positive views about medicine, more so than in other disease populations. Patients may benefit from education about the tolerability of chelation and strategies to effectively cope with side effects, both of which might be beneficial in lowering body iron burden.
Clinicaltrials.gov identifier
NCT00661804
doi:10.1186/1477-7525-10-148
PMCID: PMC3545841  PMID: 23216870
Thalassemia; Necessity; Concerns; Chelation; Adherence
3.  Education and Employment Status of Children and Adults with Thalassemia in North America 
Pediatric blood & cancer  2010;55(4):678-683.
Background
Advances in the management of thalassemia have resulted in increased life expectancy and new challenges. We conducted the first survey of education and employment status of people with thalassemia in North America.
Procedures
A total of 633 patients (349 adults and 284 school age children) enrolled in the Thalassemia Clinical Research Network (TCRN) registry in Canada and the US were included in the data analysis. Predictors considered for analysis were age, gender, race/ethnicity, site of treatment (Canada vs. United States), transfusion and chelation status, serum ferritin, and clinical complications.
Results
Seventy percent of adults were employed of which 67 percent reported working full-time. Sixty percent had a college degree and 14% had achieved some post college education. Eighty-two percent of school age children were at expected grade level. In a multivariate analysis for adults, Whites (OR=2.76, 95% CI: 1.50-5.06) were more likely to be employed compared to Asians. Higher education in adults was associated with older age (OR=1.67, 95% CI: 1.29-2.15), female gender (OR=2.08, 95% CI: 1.32-3.23) and absence of lung disease (OR=14.3, 95% CI: 2.04-100). Younger children (OR=5.7 for 10 year increments, 95% CI: 2.0 – 16.7) and Canadian patients (OR=5.6, 95% CI: 1.5-20) were more likely to be at the expected education level. Neither transfusion nor chelation was associated with lower employment or educational achievement.
Conclusions
Individuals with thalassemia in North America can achieve higher education; however, full-time employment remains a problem. Transfusion and chelation do not affect employment or education status of this patient population.
doi:10.1002/pbc.22565
PMCID: PMC2932798  PMID: 20535817
Employment; Education; Thalassemia
4.  Relationship between Chronic Transfusion Therapy and Body Composition in Subjects with Thalassemia 
The Journal of pediatrics  2010;157(4):641-647.e2.
Objective
To measure body composition in patients with thalassemia and explore its relationship to abnormal growth and bone mass.
Study design
Cross-sectional, multi-center study. Fat, lean, and bone mineral density (BMD) were assessed by DXA. Medical history, food frequency and physical activity questionnaires were conducted in 257 transfused thalassemia patients (23.7 ± 11 yr, Mean±SD, 51% male) compared with 113 non-transfused patients (21.3 ± 13 yr, 44% male).
Results
Subjects with thalassemia were leaner compared with healthy Americans from NHANES III data. Transfused subjects had higher percentage body fat compared with non- transfused after controlling for age, sex and ethnicity; 11.8% of non-transfused pediatric subjects were considered underweight, significantly lower than NHANES data (p=0.03). Hemoglobin level was positively related to lean mass (p=0.008). Body fat and lean mass were positive predictors for both height and BMD Z-scores after adjustment for transfusion status, age, sex, ethnicity, calcium intake and physical activity (all p<0.001).
Conclusions
Though the majority of adult patients with thalassemia had healthy body composition with rare obesity, young, non-transfused patients appear at risk for being underweight. Optimizing physical activity and appropriate use of transfusion therapy may improve growth and bone health in these at risk patients.
doi:10.1016/j.jpeds.2010.04.064
PMCID: PMC2936667  PMID: 20547400
DXA; lean mass; fat mass; body mass index (BMI); calcium
5.  Hb E/beta-thalassaemia: a common & clinically diverse disorder 
Haemoglobin E-beta thalassaemia (Hb E/β-thalassaemia) is the genotype responsible for approximately one-half of all severe beta-thalassaemia worldwide. The disorder is characterized by marked clinical variability, ranging from a mild and asymptomatic anaemia to a life-threatening disorder requiring transfusions from infancy. The phenotypic variability of Hb E/β-thalassaemia and the paucity of long-term clinical data, present challenges in providing definitive recommendations for the optimal management of patients. Genetic factors influencing the severity of this disorder include the type of beta-thalassaemia mutation, the co-inheritance of alpha-thalassaemia, and polymorphisms associated with increased production of foetal haemoglobin. Other factors, including a variable increase in serum erythropoietin in response to anaemia, previous or ongoing infection with malaria, previous splenectomy and other environmental influences, may be involved. The remarkable variation, and the instability, of the clinical phenotype of Hb E beta-thalassaemia suggests that careful tailoring of treatment is required for each patient, and that therapeutic approaches should be re-assessed over-time.
PMCID: PMC3237252  PMID: 22089616
Disease modifiers; genotype; haemoglobin E/β-thalassaemia; phenotye
6.  Bone Disease in Thalassemia: A Frequent and Still Unresolved Problem 
Adults with β thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, ≥6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1–75 yr), were studied. Spine and femur BMD Z-scores < −2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.
doi:10.1359/jbmr.080505
PMCID: PMC3276604  PMID: 18505376
DXA; BMD; fractures; vertebral morphometry; thalassemia
7.  Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study 
European Journal of Haematology  2008;80(2):168-176.
Objectives/methods
This 1-yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3–81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond–Blackfan anaemia (DBA; n = 30), other rare anaemias (n = 22) or β-thalassaemia (n = 85). Dosage was determined by baseline liver iron concentration (LIC).
Results
In patients with baseline LIC ≥7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC (P < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 ± 0.14 mg/kg/d; greatest in DBA: 0.4 ± 0.11 mg/kg/d). Overall, LIC changes were dependent on dose (P < 0.001) and transfusional iron intake (P < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group (r = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases.
Conclusions
Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups.
doi:10.1111/j.1600-0609.2007.00985.x
PMCID: PMC2268958  PMID: 18028431
iron chelation; deferasirox; Exjade, ICL670; myelodysplastic syndromes; thalassaemia; Diamond–Blackfan anaemia
8.  A response from Dr. Nancy Olivieri 
doi:10.1503/cmaj.1060039
PMCID: PMC1389830
9.  I beg to differ 
PMCID: PMC116622  PMID: 12137065

Results 1-9 (9)