Extramedullary haematopoiesis in patients with thalassemia: a cross-sectional description of its prevalence, clinical features and survival.

INTRODUCTION: Despite knowledge advances on extramedullary haematopoiesis (EMH) in thalassemic patients, the real picture remains an open issue. OBJECTIVES: To assess EMH prevalence in patients with thalassemia major (TM) and intermedia (TI), to describe magnetic resonance imaging (MRI) findings and to explore clinical risk factors. METHODS: In this cross-sectional study, images and clinical records of 184 consecutive patients with thalassemia who underwent T2* MRI between 2004 and 2011 were reviewed. Association of EMH with survival was investigated for patients with available follow-up charts. RESULTS: EMH was detected in 16/168 (9.5%) patients with TM (aged 19-49 years) and in 3/16 (18.8%) with TI (aged 36-41 years). Most (88%) had paravertebral thoracic and/or abdominal masses. Age was significantly associated with EMH risk (hazard ratio, [HR] 1.10/year; confidence interval [CI]: 1.03-1.18; p-value < 0.001), while lower pancreatic iron content by T2*MRI (HR: 0.94/ms; CI: 0.89-0.99; p-value = 0.049) was a protective factor. Estimated survival rate was superior for EMH-positive (n = 19) when compared to EMH-negative patients (n = 75) (p-value = 0.013). CONCLUSIONS: The prevalence of EMH was 10.3% (19/184), presented mainly as tumoral masses of 3 to 10 cm. Age was a risk factor for EMH development, while lower pancreatic iron might be a protective factor in this cohort.

Cardiac iron overload evaluation in thalassaemic patients using T2* magnetic resonance imaging following chelation therapy: a multicentre cross-sectional study

Abstract Introduction Magnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. Methods We evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. Results We evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59-14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. Conclusions Chelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis.

Cardiac iron overload evaluation in thalassaemic patients using T2* magnetic resonance imaging following chelation therapy: a multicentre cross-sectional study.

INTRODUCTION: Magnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. METHODS: We evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. RESULTS: We evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59-14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. CONCLUSIONS: Chelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis.

Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study.

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, -0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

Sobrecarga de ferro em pacientes talassêmicos brasileiros / Iron overload in Brazilian thalassemic patients

Objectives: To evaluate the use of magnetic resonance imaging in patients with Beta-thalassemia and to compare T2* magnetic resonance imaging results with serum ferritin levels and the redox active fraction of labile plasma iron. Methods: We have retrospectively evaluated 115 chronically transfused patients (65 women). We tested serum ferritin with chemiluminescence, fraction of labile plasma iron by cellular fluorescence and used T2* MRI to assess iron content in the heart, liver, and pancreas. Hepatic iron concentration was determined in liver biopsies of 11 patients and the results were compared with liver T2* magnetic resonance imaging. Results: The mean serum ferritin was 2,676.5+/- 2,051.7ng/mL. A fraction of labile plasma iron was abnormal (> 0,6 Units/mL) in 48/83 patients (57%). The mean liver T2* value was 3.91 ± 3.95 ms, suggesting liver siderosis in most patients (92.1%). The mean myocardial T2* value was 24.96 ± 14.17 ms and the incidence of cardiac siderosis (T2* < 20 ms) was 36%, of which 19% (22/115) were severe cases (T2* < 10 ms). The mean pancreas T2* value was 11.12 ± 11.20 ms, and 83.5% of patients had pancreatic iron deposition (T2* < 21 ms). There was significant curvilinear and inverse correlation between liver T2* magnetic resonance imaging and hepatic iron concentration (r= -0.878; p < 0.001) and moderate correlation between pancreas and myocardial T2* MRI (r = 0.546; p < 0.0001). Conclusion: A high rate of hepatic, pancreatic and cardiac impairment by iron overload was demonstrated. Ferritin levels could not predict liver, heart or pancreas iron overload as measured by T2* magnetic resonance imaging. Therewas no correlation between liver, pancreas, liver and myocardial iron overload, neither between ferritin and fraction of labile plasma iron with liver, heart and pancreas T2* values.

Objetivo: Avaliar o acúmulo de ferro em diferentes órgãos por meio da ressonância nuclear magnética T2* e correlacionar os resultados aos níveis de ferritina sérica, ferro plasmático lábil e outros órgãos envolvidos. Métodos: Foram avaliados retrospectivamente 115 pacientes talassêmicos (sendo 65 mulheres). A concentração hepática de ferro foi determinada em biópsia de 11 pacientes; os resultados foram comparados com os valores de T2* fígado. Resultados: a ferritina sérica média foi de 2.676,5 +/- 2.051,7 ng/mL. O ferro plasmático lábil foi anormal (> 0,6 Unidades/mL) em 48/83 pacientes (57%). A média dos valores de T2* no fígado foi 3,91 ± 3,95 ms, sugerindo siderose hepática em 92,1% pacientes. A média do T2* cardíaco foi de 24,96 ± 14,17 ms e 36% dos pacientes apresentavam siderose cardíaca (T2* < 20ms), dos quais 19% (22/115) já apresentavam sobrecarga cardíaca grave (T2* < 10 ms). A média de T2* no pâncreas foi de 11,12 ± 11,20 ms, perfazendo um total de 83,5% de pacientes com sobrecarga de ferro pancreático (T2* < 21 ms). Houve correlação significativa, curvilínea e inversa entre T2* fígado e a concentração de ferro hepática (r = -0,878; p <0,001) e correlação moderada entre T2* pâncreas e T2* miocárdio (r = 0,546; p<0,0001). Conclusão: Uma elevada taxa de acometimento hepático, pancreático e cardíaco por sobrecarga férrica foi demonstrada. Os níveis de ferritina não puderam prever sobrecarga de ferro hepático, cardíaco ou pancreáticos medidos por meio da ressonância nuclear magnética T2*. Não houve correlação entre a sobrecarga de ferro no fígado, pâncreas e miocárdio, nem entre a ferritina e os níveis plasmáticos de ferro sérico e os valores de T2* no fígado, coração e pâncreas.

Iron overload in Brazilian thalassemic patients.

UNLABELLED: ABSTRACTObjectives:To evaluate the use of magnetic resonance imaging in patients with ß-thalassemia and to compare T2* magnetic resonance imaging results with serum ferritin levels and the redox active fraction of labile plasma iron. METHODS: We have retrospectively evaluated 115 chronically transfused patients (65 women). We tested serum ferritin with chemiluminescence, fraction of labile plasma iron by cellular fluorescence and used T2* MRI to assess iron content in the heart, liver, and pancreas. Hepatic iron concentration was determined in liver biopsies of 11 patients and the results were compared with liver T2* magnetic resonance imaging. RESULTS: The mean serum ferritin was 2,676.5 +/- 2,051.7 ng/mL. A fraction of labile plasma iron was abnormal (> 0,6 Units/mL) in 48/83 patients (57%). The mean liver T2* value was 3.91 ± 3.95 ms, suggesting liver siderosis in most patients (92.1%). The mean myocardial T2* value was 24.96 ± 14.17 ms and the incidence of cardiac siderosis (T2* < 20 ms) was 36%, of which 19% (22/115) were severe cases (T2* < 10 ms). The mean pancreas T2* value was 11.12 ± 11.20 ms, and 83.5% of patients had pancreatic iron deposition (T2* < 21 ms). There was significant curvilinear and inverse correlation between liver T2* magnetic resonance imaging and hepatic iron concentration (r= -0.878; p < 0.001) and moderate correlation between pancreas and myocardial T2* MRI (r = 0.546; p < 0.0001). CONCLUSION: A high rate of hepatic, pancreatic and cardiac impairment by iron overload was demonstrated. Ferritin levels could not predict liver, heart or pancreas iron overload as measured by T2* magnetic resonance imaging. There was no correlation between liver, pancreas, liver and myocardial iron overload, neither between ferritin and fraction of labile plasma iron with liver, heart and pancreas T2* values.

Terapia quelante oral com deferiprona em pacientes com sobrecarga de ferro / Oral iron chelator therapy with deferiprone in patients with overloaded iron

Apesar da introdução da quelação parenteral de ferro com desferoxamina há mais de trinta anos, 50 por cento dos pacientes com talassemia major morrem antes dos 35 anos de idade, predominantemente por insuficiência cardíaca secundária a sobrecarga de ferro. Embora a desferrioxamina, possa reduzir ou estabilizar o acúmulo de ferro no corpo, um grande número de pacientes não recebe terapia adequada com este quelante devido principalmente à intolerância a um regime que requer administração parenteral prolongada, cinco a sete dias por semana. Para esses pacientes, a deferiprona, um quelante oralmente ativo, surge com uma alternativa de tratamento para o controle da sobrecarga de ferro. Um grande número de estudos clínicos demonstraram a segurança e eficácia da deferiprona. Estima-se que mais de 6 mil pacientes com sobrecarga de ferro já tenham sido tratados com este quelante, com alguns pacientes tomando a droga por mais de dez anos. A quantidade de ferro excretada induzida pela deferiprona é diretamente influenciada pela dose da droga e pelo grau de sobrecarga de ferro do paciente. Recentemente, demonstrou-se que desferrioxamina e deferiprona exibem capacidades quelantes diversas e que, usados simultaneamente ou numa terapia sequencial, promovem uma excreção de ferro adicional ou sinérgica com rápida redução na carga de ferro do corpo. Pela primeira vez é possível considerar esquemas de quelação individualizados baseados nas necessidades individuais de cada paciente

mode of administration which impairs the compliancewith the regime of repeatedly subcutaneous infusions.For these patients, the orally active iron chelatordeferiprone is an attractive alternative to control theoverloaded iron. It has been estimated that more thansix thousands patients have already been treated withdeferiprone, with some of them taking the chelator for10 years or more. The deferiprone-induced ironexcretion is directly related to the dose of deferiproneand the patient’s iron load. In most of transfusiondependentpatients, a dose of 75 mg/kg/day is sufficientto offset the transfusional iron-load. Recently, it hasbeen demonstrated that desferrioxamine anddeferiprone exhibit different chelating capabilities forthe removal of iron from the various body iron poolsand that the use of both chelators promote an additiveor synergistic iron excretion with rapid reduction inthe body iron load. It now is possible to consider tailormadechelation regimens based on individual patientneeds.

Diagnóstico pré-natal da talassemia beta / Prenatal diagnosis of beta thalassemia

Demosntramos nossa recente experiência na realizaçäo de diagnóstico pré-natal da talassemia beta no Hospital Universitário da Faculdade de Ciências Médicas da UNICAMP. O casal estudado tem um filho homozigoto para a talassemia beta e está em curso a segunda gestaçäo. A análise molecular mostra que o feto é heterozigoto para o alelo beta (C-T)