Search

Introduction: Ineffective erythropoiesis and subsequent anemia as well as primary and secondary (transfusional) iron overload are key drivers for morbidity and mortality outcomes in patients with β-thalassemia., Areas Covered: In this review, we highlight evidence from observational studies evaluating the association between measures of anemia and iron overload versus outcomes in both non-transfusion-dependent and transfusion-dependent forms of β-thalassemia., Expert Opinion: Several prognostic thresholds have been identified with implications for patient management. These have also formed the basis for the design of novel therapy clinical trials by informing eligibility and target endpoints. Still, several data gaps persist in view of the challenge of assessing prospective long-term outcomes in a chronic disease. Pooling insights on the prognostic value of different measures of disease mechanism will be key to design future scoring systems that can help optimize patient management.

Data on iron overload status and change thresholds that can predict mortality in patients with transfusion-dependent β-thalassemia (TDT) are limited. This was a retrospective cohort study of 912 TDT patients followed for up to 10 years at treatment centers in Italy (median age 32 years, 51.6% female). The crude mortality rate was 2.9%. Following best-predictive threshold identification through receiver operating characteristic curve analyses, data from multivariate Cox-regression models showed that patients with Period Average Serum Ferritin (SF) > 2145 vs ≤ 2145 ng/mL were 7.1-fold (P < 0.001) or with Absolute Change SF > 1330 vs ≤ 1330 ng/mL increase were 21.5-fold (P < 0.001) more likely to die from any cause. Patients with Period Average Liver Iron Concentration (LIC) > 8 vs ≤ 8 mg/g were 20.2-fold (P < 0.001) or with Absolute Change LIC > 1.4 vs ≤ 1.4 mg/g increase were 27.6-fold (P < 0.001) more likely to die from any cause. Patients with Index (first) cardiac T2* (cT2*) < 27 vs ≥ 27 ms were 8.6-fold (P < 0.001) more likely to die from any cause. Similarly, results at varying thresholds were identified for death from cardiovascular disease. These findings should support decisions on iron chelation therapy by establishing treatment targets, including safe iron levels and clinically meaningful changes over time., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency., Competing Interests: Declaration of competing interest K.M.M. reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos; and research funding from Agios Pharmaceuticals and Pharmacosmos. M.D.C. reports consultancy fees from Novartis, Celgene/Bristol Myers Squibb, Vifor Pharma, and Ionis Pharmaceuticals; and research funding from Novartis, Celgene/Bristol Myers Squibb, La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and CRISPR Therapeutics. T.D.C. provides advisory support to Agios Pharma, Bristol Meyers Squibb, and Chiesi. K.H.M.K. reports consultancy fees from Agios Pharmaceuticals, Alexion Pharmaceuticals, Bristol Myers Squibb, Forma Therapeutics, Pfizer, NovoNordisk, and Vertex Pharmaceuticals; honoraria from Agios Pharmaceuticals and Bristol Myers Squibb; membership on an advisory committee for Bioverativ/Sanofi/Sangamo; and research funding from Agios Pharmaceuticals and Pfizer. H.A-S. reports consultancy fees from Novartis, Forma Therapeutics, Agios Pharmaceuticals, argenx, Moderna, Pharmacosmos, and Sobi; and research funding from Agios Pharmaceuticals, Amgen, Sobi, Novartis, and Vaderis Therapeutics. S.S. reports consultancy fees from Agios Pharmaceuticals, bluebird bio, Fulcrum Therapeutics, Chiesi, Celgene Corp (Bristol Myers Squibb), and Vertex; honoraria for CME activities from Plexus, CCO, and Physicians' Education Resource; advisory board travel from Agios Pharmaceuticals, Celgene Corp (Bristol Myers Squibb), and bluebird bio; research funding from Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, and Forma Therapeutics; and serving on a clinical trial steering committee for CRISPR/Vertex CTX001 for thalassemia. V.V. reports consultancy fees from Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Novartis, Vifor Pharma, Pharmacosmos, IONIS Pharmaceuticals, Inc., and DisperSol Technologies, LLC; and research funding from Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Novartis, Vifor Pharma, Pharmacosmos, IONIS Pharmaceuticals, Inc., DisperSol Technologies, LLC, and The Government Pharmaceutical Organization (GPO). A.T.T. reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Vifor Pharma, and Pharmacosmos; and research funding from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, Vifor Pharma, and Pharmacosmos., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The intricate interplay of anemia and iron overload under the pathophysiological umbrella of ineffective erythropoiesis in non-transfusion-dependent β-thalassemia (NTDT) results in a complex variety of clinical phenotypes that are challenging to diagnose and manage. In this article, we use a clinical framework rooted in pathophysiology to present 4 common scenarios of patients with NTDT. Starting from practical considerations in the diagnosis of NTDT, we delineate our strategy for the longitudinal care of patients who exhibit different constellations of symptoms and complications. We highlight the use of transfusion therapy and novel agents, such as luspatercept, in the patient with anemia-related complications. We also describe our approach to chelation therapy in the patient with iron overload. Although tackling every specific complication of NTDT is beyond the scope of this article, we touch on the management of the various morbidities and multisystem manifestations of the disease., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The management of iron overload in thalassemia has changed dramatically since the implementation of magnetic resonance imaging, which allows detection of preclinical iron overload and prevention of clinical complications. This study evaluated the effect of deferasirox (DFX), the newest once-daily oral chelator, on cardiac function, iron overload and cardiovascular events over a longer follow up in a "real world" setting. Longitudinal changes in cardiac magnetic resonance T2*, cardiac function parameters and cardiovascular clinical events were assessed in a cohort of 98 TM patients exposed to DFX for a mean of 6.9 years (range 1.8-11.6 years). No cardiac death or incident heart failure occurred. Cardiac T2* significantly increased (+2.6 ± 11.9 msec; P = 0.035) in the whole population, with a significantly greater increase (+11.6 ± 15.5 msec, P = 0.019) in patients with cardiac iron overload (T2* <20 ms). A significant improvement in left-ventricular ejection fraction (LVEF) (from 50.6 ± 6 to 60.2 ± 5; P = 0.001) was observed in 11 (84.6%) out of 13 patients who normalized cardiac function (LVEF >56%). Arrhythmias were the most frequent cardiac adverse event noted but none led to DFX discontinuation. Our data indicate that DFX is effective in maintaining cardiac iron level in the normal range and in improving cardiac iron overload. No heart failure or cardiac death was reported over this longer observation up to 12 years. For the first time, a DFX-induced improvement in LVEF was observed in a subgroup of patients with abnormal cardiac function at baseline, a preliminary observation which deserves further evaluation., (© 2018 Wiley Periodicals, Inc.)

Stress erythropoiesis (SE) is characterized by an imbalance in erythroid proliferation and differentiation under increased demands of erythrocyte generation and tissue oxygenation. β-thalassemia represents a chronic state of SE, called ineffective erythropoiesis (IE), exhibiting an expansion of erythroid-progenitor pool and deposition of alpha chains on erythrocyte membranes, causing cell death and anemia. Concurrently, there is a decrease in hepcidin expression and a subsequent state of iron overload. There are substantial investigative efforts to target increased iron absorption under IE. There are also avenues for targeting cell contact and signaling within erythroblastic islands under SE, for therapeutic benefits., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Non-transfusion-dependent thalassaemias (NTDT) encompass a spectrum of anaemias rarely requiring blood transfusions. Increased iron absorption, driven by hepcidin suppression secondary to erythron expansion, initially causes intrahepatic iron overload. We examined iron metabolism biomarkers in 166 NTDT patients with β thalassaemia intermedia (n = 95), haemoglobin (Hb) E/β thalassaemia (n = 49) and Hb H syndromes (n = 22). Liver iron concentration (LIC), serum ferritin (SF), transferrin saturation (TfSat) and non-transferrin-bound iron (NTBI) were elevated and correlated across diagnostic subgroups. NTBI correlated with soluble transferrin receptor (sTfR), labile plasma iron (LPI) and nucleated red blood cells (NRBCs), with elevations generally confined to previously transfused patients. Splenectomised patients had higher NTBI, TfSat, NRBCs and SF relative to LIC, than non-splenectomised patients. LPI elevations were confined to patients with saturated transferrin. Erythron expansion biomarkers (sTfR, growth differentiation factor-15, NRBCs) correlated with each other and with iron overload biomarkers, particularly in Hb H patients. Plasma hepcidin was similar across subgroups, increased with >20 prior transfusions, and correlated inversely with TfSat, NTBI, LPI and NRBCs. Hepcidin/SF ratios were low, consistent with hepcidin suppression relative to iron overload. Increased NTBI and, by implication, risk of extra-hepatic iron distribution are more likely in previously transfused, splenectomised and iron-overloaded NTDT patients with TfSat >70%., (© 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions., Procedure: This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT., Results: Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy., Conclusions: Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile., (© 2016 Wiley Periodicals, Inc.)

Long-term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion-dependent beta thalassemia patients. In a 1-year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [Gmean ] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; Gmean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long-term safety profile of deferasirox or DFO was consistent with previous reports; serious drug-related AEs were reported in 6.8% of deferasirox and 6.9% of DFO patients. Continued treatment of severely iron-overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron (Clinicaltrials.gov identifier: NCT00600938)., (© 2014 Wiley Periodicals, Inc.)

Iron overload may still occur in transfusion-independent patients with β-thalassemia intermedia due to increased intestinal iron absorption. In this study, we evaluated the association between iron overload, using a liver iron concentration threshold of therapeutic significance (≥5mg/g), and morbidity in 168 chelation naive patients with β-thalassemia intermedia. We demonstrated that patients with a liver iron concentration ≥5mg/g have a significantly higher prevalence of several serious vascular and endocrine/bone morbidities than do patients with <5mg/g, and we established absolute morbidity risk values differentiating both groups. We also demonstrated that the association between iron overload and morbidity in such patients is independent of the effects of advancing age and disease severity. These findings suggest that treating iron burden in β-thalassemia intermedia may be associated with reduction in serious morbidity risk., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We conducted a cross-sectional study on 924 β-thalassaemia major patients (mean age 30·1 years) treated at nine Italian centres using the WEBTHAL software, to evaluate real-life application of iron overload assessment and management standards. Serum ferritin <2500 ng/ml was a risk factor for never having liver iron concentration (LIC) measurement, while absence of cardiac disease and siderosis were risk factors for a delay in LIC measurement >2 years. Patients who never had a cardiac MRI (CMR) T2* measurement were <18 years, had iron intake ≤0·4 mg/kg per day, or a serum ferritin <2500 ng/ml. A history of normal CMR T2* was the main risk factor for a delay in subsequent assessment of >2 years. Deferoxamine (22·8%) was more commonly used in patients with Hepatitis C Virus or high serum creatinine. Deferiprone (20·6%) was less commonly prescribed in patients with elevated alanine aminotransferase; while a deferoxamine + deferiprone combination (17·9%) was more commonly used in patients with serum ferritin >2500 ng/ml or CMR T2* <20 ms. Deferasirox (38·3%) was more commonly prescribed in patients <18 years, but less commonly used in those with heart disease or high iron intake. These observations largely echoed guidelines at the time, although some practices are expected to change in light of evolving evidence., (© 2013 John Wiley & Sons Ltd.)

Purpose of Review: The aim is to overview recent evidence on consequences, assessment, and management of iron overload in transfusion-independent patients with β-thalassemia intermedia., Recent Findings: Despite their transfusion-independence, β-thalassemia intermedia patients can still accumulate iron due to increased intestinal absorption. Recent observational studies show that iron burden in this group of patients can ultimately reach considerably high thresholds, and leads to a variety of serious morbidities involving the liver, endocrine glands, and arguably the vascular system. The diagnosis of iron overload in this patient population can follow established guidelines from β-thalassemia major patients, although with careful interpretation of spot serum ferritin levels. Data from a recent randomized clinical trial demonstrated the efficacy and safety of iron chelation therapy in decreasing liver iron concentration in this group of patients, which may ultimately help in reducing morbidity risk., Summary: Iron overload in transfusion-independent patients with β-thalassemia intermedia deserves careful attention, and prompt diagnosis and management are recommended.

Despite receiving no or only occasional blood transfusions, patients with non-transfusion-dependent thalassemia (NTDT) have increased intestinal iron absorption and can accumulate iron to levels comparable with transfusion-dependent patients. This iron accumulation occurs more slowly in NTDT patients compared to transfusion-dependent thalassemia patients, and complications do not arise until later in life. It remains crucial for these patients' health to monitor and appropriately treat their iron burden. Based on recent data, including a randomized clinical trial on iron chelation in NTDT, a simple iron chelation treatment algorithm is presented to assist physicians with monitoring iron burden and initiating chelation therapy in this group of patients., (Copyright © 2013 Wiley Periodicals, Inc.)

Despite evidence of considerable iron overload in transfusion-independent patients with β-thalassemia intermedia, data on hepatic outcomes remain scarce. We analyzed data from a cohort of 42 β-thalassemia intermedia adults followed for four years (median age 38years), and evaluated the association between longitudinal changes in serum ferritin levels and transient elastography values, a measure of hepatic stiffness predictive of fibrosis. We observed a significant increase in both serum ferritin levels (+81.2 [μg/l]/year) and transient elastography values in non-chelated patients (n=28) (+0.3kPa/year), with two patients worsening their fibrosis stage. Chelated patients (n=14) had a significant decrease in both measures (-42.0 [μg/l]/year and -0.9kPa/year, respectively), with two patients improving their fibrosis stage. There was a strong correlation between the rate of change in serum ferritin level and the rate of change in transient elastography value (R(2): 0.836, p<0.001) noted in both non-chelated and chelated patients. An association between iron overload status and hepatic disease merits further evaluation in this subset of transfusion-independent patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Our understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with β-thalassemia intermedia has substantially increased over the past decade. Earlier studies observed that patients with β-thalassemia intermedia experience a clinical-complications profile that is different from that in patients with β-thalassemia major. In this article, a variety of clinical morbidities are explored, and their associations with the underlying disease pathophysiology and risk factors are examined. These involve several organs and organ systems including the vasculature, heart, liver, endocrine glands, bone, and the extramedullary hematopoietic system. The effects of some therapeutic interventions on the development of clinical complications are also discussed.

Iron overload due to increased intestinal iron absorption represents an important clinical problem in patients with non-transfusion-dependent thalassemia (NTDT), particularly as they advance in age. Current models for iron metabolism in patients with beta (β)-thalassemia intermedia (TI) suggest that suppression of serum hepcidin results in increased iron absorption and release of iron from the reticuloendothelial system, leading to depletion of macrophage iron, relatively low levels of serum ferritin, and liver iron loading. The clinical consequences of iron overload in patients with NTDT are multifactorial and include endocrinopathy, bone disease, thromboembolism, pulmonary hypertension, cerebrovascular and neuronal damage, liver fibrosis or cirrhosis, and increased risk of hepatocellular carcinoma. Although serum ferritin levels correlate with liver iron concentration (LIC), they underestimate iron load in these patients compared with transfusion-dependent patients with equivalent LIC. Therefore, direct measurement of LIC is recommended with chelation therapy as indicated., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background/aims: Renal manifestations have been described in β-thalassemia major and were attributed to transfusional iron overload and chelation therapy. Patients with the milder phenotype, β-thalassemia intermedia (TI), remain largely transfusion and iron chelation independent while enduring a chronic hemolytic anemia and primary iron overload. Data on renal function in patients with TI is lacking., Methods: In this cross-sectional study of 50 TI patients, we evaluated the association of estimated glomerular filtration rate (eGFR) and urinary protein to creatinine (UPr/UCr) ratio with relevant patient, disease and laboratory indices., Results: The median age of patients was 28 years (44% males). The eGFR was >90 ml/min/1.73 m(2) in all patients, with a median value of 142.3 ml/min/1.73 m(2). The median UPr/UCr ratio was 213.2 mg/g. There was a negative correlation between age and eGFR, while the UPr/UCr ratio correlated positively with markers of anemia, hemolysis and iron overload. A total of 24 (48%) patients had evidence of glomerular hyperfiltration, while 7 (14%) had proteinuria (UPr/UCr ratio >500 mg/g). Patients with proteinuria were characterized by elevated liver iron concentration (>7 mg Fe/g dry weight), non-transferrin-bound iron levels and nucleated red blood cell counts., Conclusions: A considerable proportion of TI patients show evidence of abnormally elevated eGFR, with a declining trend towards advancing age. The occurrence of proteinuria is associated with anemia, hemolysis and iron toxicity., (Copyright © 2012 S. Karger AG, Basel.)

Over the last four decades, monumental advances have been made in the understanding, assessment, and management of transfusion-dependent patients, which have translated into significant improvements in patient morbidity and mortality. Important lessons have been learned from extensive clinical experience of iron management in the thalassemias, but greater knowledge of key differences in the sickle-cell disease (SCD) population may impact on our approach to patient assessment and management. The unique pathophysiology of SCD is reflected in a distinct pattern of iron loading with minimal organ-specific injury. An appreciation and understanding of these differences should allow us to develop tailored management approaches that optimize patient outcomes., (Copyright © 2010 Wiley-Liss, Inc.)

Chronic transfusional iron overload leads to significant morbidity and mortality. While deferoxamine (DFO) is an effective iron chelator with over four decades of experience, it requires tedious subcutaneous infusions that reflect negatively on patient compliance. The novel oral iron chelators deferiprone (L1) and deferasirox (DFRA) opened new horizons for the management of transfusional siderosis. A large body of evidence is now available regarding their efficacy and safety in various populations and settings. Nevertheless, experience with both drugs witnessed some drawbacks, and the search for an ideal and cost-effective iron chelator continues.

Increased survival in patients with β thalassaemia major (TM) allowed for several morbidities to manifest. Renal manifestations of the disease and its treatment have been poorly evaluated. There is evidence, mainly from studies in the paediatric population, of tubular dysfunction and glomerular filtration rate abnormalities in this patient population. Long-term outcomes of these changes, however, have not been prospectively investigated. The pathogenesis of these abnormalities could be attributed to iron overload, too aggressive iron removal, and/or the underlying anaemia. These changes seem to be nonprogressive, resolve spontaneously in most part, or may require iron chelator dose modifications. Relative iron depletion may explain renal function changes attributed to chelation therapy; thus, sudden removal of iron or overchelation should be avoided. Future studies should aim to evaluate the natural history of kidney function in TM patients to help understand the mechanisms and long-term sequelae of the observed renal changes., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Cardiac involvement in patients with thalassemia intermedia (TI) is characterized by a high-output state and pulmonary hypertension, with systolic left ventricle function usually being preserved. Myocardial iron overload in patients with TI has not been extensively studied. We conducted a cross-sectional study of 49 Italian patients with TI. Patient charts were reviewed and data collected for transfusion and iron chelation history, status of the spleen, and comorbid illnesses or infections. Blood samples were obtained for assessment of hemoglobin, serum ferritin, and liver enzyme levels. Doppler echocardiography was done for all patients. Cardiac and hepatic iron levels were measured by magnetic resonance imaging T2*. The mean age was 40.5 +/- 8.3 years, with a male to female ratio of 29:20. A total of 34 (69.4%) patients were splenectomized, and four patients had evidence of hepatitis C infection. Around 45% of patients were transfusion naïve while the rest received infrequent (47%) or regular (8%) transfusions. A total of 31 (63.3%) patients were maintained on iron chelation therapy. None of the patients had evidence of heart failure. Mean serum ferritin and liver iron concentration were 1,060.2 ng/ml and 8.2 mg Fe per gram dry weight, respectively. None of the patients had evidence of cardiac iron overload (mean cardiac T2* = 38.7 +/- 11.0 ms). There were no statistically significant correlation between cardiac T2* values and liver iron concentration, serum ferritin, or any patient, disease, or treatment-related parameters. Patients with TI show absence of cardiac iron overload even if hepatic iron accumulation is significant.

Background: The use of magnetic resonance imaging (MRI) to detect organ-specific iron overload is becoming increasingly common. Although hepatic iron overload has been recognized in patients with sickle cell disease (SCD), cardiac iron deposition has only been examined in a few reports., Methods: This was a cross-sectional study of 23 patients with SCD. Patient charts were reviewed and data collected for drug use, total lifetime transfusions (TLT), transfusion rate (TR), status of the spleen, and comorbid illnesses or infections. Blood samples were obtained for assessment of hemoglobin, serum ferritin, non-transferrin-bound iron (NTBI), and liver enzyme levels. Doppler echocardiography was performed to detect pulmonary hypertension (PHT) and assess left ventricular ejection fraction. Cardiac iron levels were measured by MRI T2*. Direct determination of liver iron concentration (LIC) was performed using R2 MRI. In this study, cardiac T2* >20 ms was considered normal., Results: The mean age was 24.4 +/- 9.7 yr, with a male to female ratio of 15:8. A total of 9 (49.9%) patients were splenectomized. The mean TR was 14.1 +/- 13.2 Units/yr, and the mean hemoglobin level was 9.0 g/dL. PHT was detected in 6 (27.3%) patients, but none had evidence of heart failure. The mean serum ferritin, LIC, and NTBI levels were 997.7 ng/mL, 4.6 mg Fe/g dw, and 1.1 +/- 2.2, respectively. TR was a much better predictor of iron burden (LIC, ferritin, NTBI) than TLT. In fact, TR less than 10 Units/yr did not produce significant iron overload reflecting spontaneous losses as high as 0.11 mg/kg/d. None of the patients had evidence of cardiac iron overload (mean cardiac T2* = 37.3 +/- 6.2 ms; range: 21.9-46.8 ms). There was also no statistically significant correlation between cardiac T2* values and any of the study variables., Conclusion: Our study demonstrates that TR is a stronger predictor of iron overload than TLT. It also confirms cardiac sparing in patients with SCD, even in subjects with significant transfusion burden, systemic and hepatic iron overload.

Non-transferrin-bound iron (NTBI) was evaluated as an index of iron overload in a cross-sectional randomised study in 74 non-transfused patients with thalassaemia intermedia (TI). Mean NTBI (2.92 +/- 3.43 micromol/l), serum ferritin (1023 +/- 780 ng/ml) and liver iron concentration (LIC; 9.0 +/- 7.4 mg Fe/g dry weight) were increased above reference-range levels. Significant positive correlations occurred between mean NTBI and LIC (Pearson correlation 0.36; P = 0.002) and serum ferritin (Pearson correlation 0.421; P < 0.0001); with higher levels observed in splenectomised patients. NTBI assessment has potential as a simple reliable approach to determining iron status in TI.

In patients suffering from transfusion-dependent anemia, excess iron secondary to regular transfusions cannot be physiologically excreted. This leads to a state of chronic iron overload with iron accumulating in the liver, heart, and endocrine organs, and ultimately results in significant morbidity and mortality. Historically, iron overload was assessed through measurement of serum ferritin or direct determination of liver iron concentration (LIC) by means of biopsy. Although both correlate well with iron overload severity, several limitations pertinent to both are of concern. This has led to the identification of novel noninvasive iron assessment measures, namely magnetic resonance imaging (MRI) R2 and T2*. Moreover, investigations of other potential indices like nontransferrin-bound iron (NTBI) and labile plasma iron (LPI) are yielding promising results. Optimal iron overload assessment and monitoring is a key element in the development of improved strategies of iron chelation therapy that can be tailored to meet the patient's specific needs.

We conducted a retrospective cohort study on 663 transfusion-dependent β-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: −170.7 ng/mL, P = 0.049, deferiprone: −236.7 ng/mL, P = 0.001; deferasirox: −323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload. [ABSTRACT FROM AUTHOR]

In this work, we aimed to establish subgroups of clinical severity in a global cohort of β-thalassemia through unsupervised random forest (RF) clustering. We used a large global dataset of 7910 β-thalassemia patients and evaluated 19 indicators of phenotype severity (IPhS) to determine their contribution and relatedness in grouping β-thalassemia patients into clusters using RF analysis. RF clustering suggested that three clusters with minimal overlapping exist (classification error rate: 4.3%), and six important IPhS were identified: the current age of the patient, the mean serum ferritin level, the age at diagnosis, the age at first transfusion, the age at first iron chelation, and the number of complications. Cluster 3 represented patients with early initiation of transfusion and iron chelation, considerable iron overload, and early mortality from heart failure. Patients in Cluster 2 had lower serum ferritin levels, although they had a higher number of complications manifesting overtime. Patients in Cluster 1 represented a subgroup with delayed or absent transfusion and iron chelation, but with a high morbidity rate. Hepatic disease and cancer were dominant causes of death in patients in Cluster 1 and 2. Our findings established that patients with β-thalassemia can be clustered into three groups based on six parameters of phenotype severity. [ABSTRACT FROM AUTHOR]

Efforts to optimize the management of patients with β-thalassemia major (TM) continue to expand. Evidence from biomedical research evaluating safe and careful processing measures of blood products, the efficacy and safety of oral iron chelators, and noninvasive techniques for the assessment of iron overload are translated into better patient outcomes. The construction of TM management guidelines facilitated the incorporation of such evidence into practice. However, as several aspects of the management of TM remain controversial or governed by resource availability, a concern regarding potential variations in recommendations made by the different guidelines becomes rational, especially for physicians treating TM patients outside countries where the guidelines were constructed. In this work, we overview currently available guidelines for the management of TM and explore apparent similarities and differences between them. The evaluated guidelines included the Thalassaemia International Federation, US, Canadian, UK, Italian and Australian guidelines. We noted a general consensus for most aspects of management, although some guidelines provided more comprehensive and contemporary recommendations than others. We did not identify differences warranting concern, although minor differences in iron overload assessment strategy and more notable variations in the recommendations for iron chelation therapy were observed. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Renal manifestations have been described in β-thalassemia major and were attributed to transfusional iron overload and chelation therapy. Patients with the milder phenotype, β-thalassemia intermedia (TI), remain largely transfusion and iron chelation independent while enduring a chronic hemolytic anemia and primary iron overload. Data on renal function in patients with TI is lacking. Methods: In this cross-sectional study of 50 TI patients, we evaluated the association of estimated glomerular filtration rate (eGFR) and urinary protein to creatinine (UPr/UCr) ratio with relevant patient, disease and laboratory indices. Results: The median age of patients was 28 years (44% males). The eGFR was >90 ml/min/1.73 m2 in all patients, with a median value of 142.3 ml/min/1.73 m2. The median UPr/UCr ratio was 213.2 mg/g. There was a negative correlation between age and eGFR, while the UPr/UCr ratio correlated positively with markers of anemia, hemolysis and iron overload. A total of 24 (48%) patients had evidence of glomerular hyperfiltration, while 7 (14%) had proteinuria (UPr/UCr ratio >500 mg/g). Patients with proteinuria were characterized by elevated liver iron concentration (>7 mg Fe/g dry weight), non-transferrin-bound iron levels and nucleated red blood cell counts. Conclusions: A considerable proportion of TI patients show evidence of abnormally elevated eGFR, with a declining trend towards advancing age. The occurrence of proteinuria is associated with anemia, hemolysis and iron toxicity. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In patients suffering from transfusion-dependent anemias such as thalassemia major, aplastic anemia, myelodysplasia, and myelofibrosis, excess iron secondary to regular transfusions cannot be physiologically excreted. This leads to a state of chronic iron overload with iron accumulating in the liver, heart, and endocrine organs. This ultimately results in significant morbidity and mortality. Historically, iron overload has been assessed by measurement of serum ferritin or direct determination of liver iron concentration by means of biopsy. However, although useful for serial monitoring of iron burden, recent studies show that they give a poor indication of cardiac iron status and it is this that mainly determines survival. The search for better and more direct measures of cardiac and hepatic iron has led to the identification of novel, noninvasive iron assessment techniques, namely, magnetic resonance imaging R2 and T2*. Moreover, investigations of other potential indices, especially nontransferrin-bound iron and labile plasma iron, are giving additional useful information. Optimal iron overload assessment and monitoring is a key element in the development of improved strategies of iron chelation therapy that can be tailored to meet the individual patient's needs. [ABSTRACT FROM AUTHOR]

In patients suffering from transfusion-dependent anemias such as thalassemia major, aplastic anemia, myelodysplasia, and myelofibrosis, excess iron secondary to regular transfusions cannot be physiologically excreted. This leads to a state of chronic iron overload with iron accumulating in the liver, heart, and endocrine organs. This ultimately results in significant morbidity and mortality. Historically, iron overload has been assessed by measurement of serum ferritin or direct determination of liver iron concentration by means of biopsy. However, although useful for serial monitoring of iron burden, recent studies show that they give a poor indication of cardiac iron status and it is this that mainly determines survival. The search for better and more direct measures of cardiac and hepatic iron has led to the identification of novel, noninvasive iron assessment techniques, namely, magnetic resonance imaging R2 and T2*. Moreover, investigations of other potential indices, especially nontransferrin-bound iron and labile plasma iron, are giving additional useful information. Optimal iron overload assessment and monitoring is a key element in the development of improved strategies of iron chelation therapy that can be tailored to meet the individual patient's needs. [ABSTRACT FROM AUTHOR]

The article focuses on the relationship between age and complications in thalassaemia intermedia (TI) patients. It discusses the factors behind the problems which include, ineffective erythropoiesis, chronic hemolytic anemia, and iron overload. It indicates a relationship between advancing age and serum ferritin (SF) levels. It also points towards the fact that patients with TI require close clinical follow up since they run the risk of develop serious complications with the passage of time.

Chronic iron overload from frequent blood transfusions to treat patients with severe anemias leads to significant morbidity and mortality. Although desferrioxamine, the current standard of care, is an effective iron chelator with long-term evidence, it requires tedious subcutaneous infusion that reflects negatively on patient compliance. Deferiprone opened the horizon for an era of oral iron chelators. Although collective evidence proved its efficacy, safety issues are still of high concern and require regular monitoring. The experience with these two drugs helps better delineate the optimal goals of iron chelation therapy and the ideal iron chelator. [ABSTRACT FROM AUTHOR]

Objectives: Patients with beta-thalassemia intermedia tend to present later in life with milder anemia than beta-thalassemia major patients. The incidence of mortality and its causes in this patient population remains unknown. We aim to reveal the incidence and most common causes of death in this population. Methods and results:We reviewed the charts of all of the beta-thalassemia intermedia patients who had been followed at the Chronic Care Center in Hazmieh, Lebanon during a 10-year period. A total of 18 patients out of 127 had died during the follow-up period giving a cumulative 10-year mortality incidence of 14%. The most common causes of cardiac deaths were due to renal and cardiac causes. Discussion: Most causes of death have been linked to the high levels of iron coupled with anemia present in this patient population. Many of deaths could be prevented by adequate treatment. Conclusion: Larger studies with more comprehensive data capture on risk factors of mortality in this patient population are called for. [ABSTRACT FROM AUTHOR]

Iron overload due to increased intestinal iron absorption remains a concern in patients with non-transfusion-dependent thalassemia (NTDT). A dynamic regulation between ineffective erythropiesis and iron metabolism in these disorders has been recently elucidated. Although the rate of iron loading in NTDT is slower than that observed in regularly transfused patients, the process is cumulative and patients may reach considerably high liver iron concentration levels. The clinical con- sequences of iron overload in patients with NTDT are various and include hepatic disease, endocrinopathy, bone disease, and vascular outcomes; while cardiac siderosis is less frequently observed. Although serum fer- ritin levels correlate with LIC in NTDT, they underestimate iron load when compared with transfusion-dependent patients with equivalent LIC. Therefore, direct measurement of LIC is recommended to identify patients at risk and guide iron chelation decisions. [ABSTRACT FROM AUTHOR]