Transfusion-dependent Thalassemia Major Research Articles

Correlation of anthropometric measurements with pretransfusion haemoglobin in transfusion dependent thalassemia major children

Background: The etio-pathogenesis of growth failure in transfusion dependent thalassemia major (TDTM) children is mainly because of chronic anemia, iron overload and endocrine complications. Aim was to determine the association between anthropometric measurements with pre-transfusion haemoglobin in TDTM children. Methods: Present cross-sectional study included total 55 children between 5-18 years of age who were diagnosed as TDTM. Mean pre transfusion hemoglobin of last 1 year was obtained from previous medical records. Anthropometric measurements like weight in kg and height in cm measured while body mass index (BMI) was calculated using standard formula in each patient. Weight for age, height for age, and BMI were plotted on WHO 2006 and Indian academy of paediatrics 2015 combined growth charts in terms of percentile. Data was analysed statistically. Results: Total 55 children of TDTM between 5-18 years of age were studied. The mean age was 10.42(4.07) years. The mean weight (kg), height (cm) and BMI was 23.76 (7.5), 123.94 (18.13) and 15.24 (1.76) respectively. Fifty-one (92.73%) children were having BMI less than 3rd centile (Underweight). Forty (93.02%) and 11 (91.66%) children between age group of 5-10 years and more than 10 years were underweight and was statistically significant (p<0.05). Total 50 (94.33%) children were having mean pre transfusion hemoglobin below 9 gm/dl who were underweight which was statistically significant. Conclusions: Low pre-transfusion hemoglobin is one of the risk factors for growth failure in children with TDTM and it should be maintained above 9 gm/dl may for normal growth in children with TDTM.

Clinical utility of circulating TWEAK and CD163 as biomarkers of iron-induced cardiac decompensation in transfusion dependent thalassemia major

Background and aimTumor necrosis factor-like weak inducer of apoptosis (TWEAK) affects most of the cells involved in cardiac fibrosis like inflammatory cells, cardiomyocytes and fibroblasts. CD163, the receptor of TWEAK on the surface of type 2 macrophages, is shed into plasma upon macrophages activation. This work aimed to evaluate serum TWEAK and its decoy receptor CD163 as probable biomarkers to monitor myocardial iron overload (MIO) in transfusion dependent thalassemia major (TDTM) patients and to predict iron-induced cardiac decompensation (IICD). MethodsA total of 140 TDTM patients were enrolled. Patients were categorized into two groups; group I (n = 70) diagnosed with IICD while group II (n = 70) had no evidence of IICD. sTWEAK and sCD163 were quantitated utilizing Enzyme-linked-immunosorbent- assay. ResultssTWEAK was evidently lower in group I than group II (medians, 412 and 1052 pg/mL respectively). sCD163 was higher in group I than group II (medians, 615.5 and 323.5 ng/mL respectively). sTWEAK positively correlated with cardiac MRI-T2 mapping and ventricular ejection fractions and negatively correlated with B-Natriuretic peptide and cardiac troponin. An inverse relationship between TWEAK and CD163 was documented throughout the study. sTWEAK, sCD163 and TWEAK/CD163 ratio proved to be significant predictors of IICD in TDTM patients. TWEAK/CD163 ratio < 1.04 discriminated IICD in TDTM patients with 100 % clinical sensitivity and specificity. ConclusionCirculating TWEAK and CD163 appears to be promising biomarkers for monitoring MIO and predicting IICD in TDTM patients.

Alloimmunization and Autoimmunization in Adult Transfusion Dependent Beta Thalassemia Major Patients: Report from a Comprehensive Center in Israel

BACKROUND: Survival of patients with transfusion dependent (TD) beta thalassemia major (TM) has improved significantly over the past few decades as better treatment became available. However, due to ineffective erythropoiesis, reduced red blood cell (RBC) survival, and subsequent continuous hemolytic anemia, these patients are regularly and heavily transfused since early childhood. Exposure to multi transfusions is associated with significant risks including development of antibodies against RBC antigens, both alloantibodies and autoantibodies, which in turn complicate RBC cross matching, shorten in vivo survival of transfused RBC, and may accelerate tissue iron loading. Anti-K, anti-E and other Rh blood group system alloantibodies are the most frequently detected.AIMS: Assessment of RBC alloimmunization and autoimmunization rate in adult patients with TD TM followed and treated in our center.PATIENTS and METHODS: The study included a total of 40 patients with TD TM, >18 years of age. Clinical and transfusion records, including age, gender, ethnicity, history of pregnancies, blood group, history of splenectomy, age at first transfusion and lifelong cumulative number of blood units transfused, were retrieved from patients' files and from the blood bank database.RESULTS: Twenty one (52.5%) patients were males, 19 (47.5%) were females, the mean ±SD (range) age was 31.8 ± 6.9 (20-47) years, 29 patients (72.5%) were of Muslim Arab origin, 11 (27.5%) were Jewish. Thirty (75.0%) of the patients were splenectomized (SPX). The median (mean) ±SD (range) age at first transfusion was 0.71 (1.07) ± 0.93 (0.25-4.0) years, and the mean ±SD (range) of lifelong cumulative number of blood units transfused was 828.5 ± 239.3 (439-1363).Alloimmunization was demonstrated in 17 (42.5%) patients; 10 of 21 (47.6%) males and 7 of 19 (36.8%) females; 11 of 29 (37.9%) of Muslim Arab origin, 6 of 11 (54.5%) of Jewish origin; 11 (64.7%) had >1 alloantibody. Among female patients, alloimmunization was demonstrated in 4 (31.0%) of 13 with no history of pregnancy and in 3 (50.0%) of 6 with history of pregnancy. Twelve (40.0%) of 30 SPX patients had alloantibodies, compared to 5 (50.0%) of 10 patients with intact spleen.Anti-Rh antibodies were the most prevalent, detected in 10/17 (58.8%) patients having 12 alloantibodies (8 anti-E, 2 anti-D, 1 anti-C and 1 anti-Cw), followed by Anti-Kell antibodies detected in 7/17 (41.2%) patients having 8 alloantibodies (6 anti-K, 2 anti-Kpa). One patient had anti-Jkb, and 3 patients had alloantibodies against low frequency antigens. Autoimmunization was demonstrated in 2 (5.0%) patients (Figure 1).Significant inverse correlation was found between age at first transfusion and rate of alloimmunization. Thirty (75.0%) patients started blood transfusions before 1 year; 9 (30.0%) of them had alloantibodies. Ten (25.0%) patients started blood transfusions after the first year; 8 (80.0%) of them had alloantibodies (p=0.009).There was no significant association between alloimmunization and patients' age, gender, ethnicity, history of pregnancies, blood group, splenectomy status, and lifelong cumulative number of blood units transfused (p >0.05).CONCLUSIONS: We have found a high rate (42.5%) of alloimmunization in adult TD TM patients, which might be attributed to multi transfusions over many years without RBC antigen matching beyond ABO and Rh. Alloimmunization rate was lower in those who began transfusions before 1 year of age, similar to previous studies, supporting the concept of immune tolerance developing in young children who begin transfusions before 1 year of age. Based on our study results, transfusion policies, especially extended antigen matching for Rh and K, should be considered in order to reduce alloimmunization. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Alloimmunization and autoimmunization in adult transfusion-dependent thalassemia patients: a report from a comprehensive center in Israel.

Patients with beta thalassemia major (TM) are transfusion-dependent (TD) since early childhood and for life. Development of alloantibodies and autoantibodies against red blood cell (RBC) antigens is increasingly recognized as a significant transfusion hazard, especially among heavily transfused patients. The aim of this study is to assess RBC alloimmunization and autoimmunization rates in TD TM patients treated in our Comprehensive Center of Adult Thalassemia, Hemoglobinopathies and Rare Anemias. TD TM patients, regularly transfused every 2-3 weeks, were included in the study. Clinical and RBC transfusion records, including RBC antibodies, since diagnosis in early childhood, were retrieved from patients' files and from the blood bank database. Forty TD TM patients, > 18 years of age, were included in the study. Alloimmunization was demonstrated in 17 (42.5%) patients. Thirty-four alloantibodies were detected, with the most frequent being RH related (12 of 34, 35.3%) followed by those of the Kell system (8 of 34, 23.5%). Age at first transfusion was positively related to the probability of developing alloantibodies (p = 0.02). Splenectomy was found to be correlated with developing alloantibodies (p = 0.016). Logistic regression analysis of the lifelong probability of developing alloantibodies on the age at first transfusion and splenectomy demonstrates a strong positive relationship (p = 0.002). A substantially high rate of alloimmunization was found among adult TD TM patients. Early initiation of RBC transfusions, avoidance of splenectomy and extended Rh and K antigen matching, can reduce the incidence of alloimmunization in TD TM patients.

Indicators of male fertility potential in adult patients with beta-thalassemia major: a comparative study between patients undergone allogeneic stem cell transplantation and transfusion-dependent patients

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment for thalassemia major (TM). Infertility and its indicators have been assessed in transfusion dependent TM men, but in this study, we sought to compare the fertility indicators of TM patients after HSCT with those in patients treated conventionally. The possible influential factors on reproductive capacity in TM patients undergone allogeneic HSCT were also evaluated.Patients and methodsIn this cross-sectional study, we compared the gonadal hormones level, testicular volume, Tanner stage and sperm analysis in transfusion-dependent thalassemia major (TDTM) patients who survived matched sibling HSCT (n = 43) with patients conventionally treated by transfusion and iron chelation (n = 52).ResultsThe patients’ age range was between 16 to 41 years. Tanner stage 4–5 was seen in 39 patients (41%). The prevalence of hypogonadism in our patients was 32.63% but its frequency was not significantly different between the two groups (p = 0.35). Azospermia, oligospermia, astenospermia, teratospermia and even having dry and low volume ejaculate were all significantly more frequent in the post-transplant patients compared to TDTM group. In the post-HSCT group, neither patients’ age at transplantation nor the conditioning regimen used in their transplant process did significantly affect their hormonal status and sperm parameters. Chronic graft versus host disease (GVHD) occurred in 14 (40%) patients. No significant difference was observed between the grade of chronic GVHD and hypogonadism (P = 0.853).ConclusionsThalassemia patients undergone allogeneic HSCT have lower fertility potential, mainly in sperm parameters compared with patients treated with blood transfusion and chelation. This information is important for thalassemic patients considering HSCT.

Clinical utility of endocrine markers predicting myocardial siderosis in transfusion dependent thalassemia major.

Endocrinopathy due to iron overload is the most common morbidity whereas myocardial siderosis causing toxic cardiomyopathy is the leading cause of mortality among patients with transfusion dependent thalassemia major (TDTM). If detected early, this can be treated with aggressive chelation. T2* cardiac magnetic resonance imaging (CMR) guided chelation protocols are now the gold standard but have limited availability in low and middle-income countries. We hypothesized that markers of endocrine dysfunction would correlate with T2* CMR and can be used to predict the severity of myocardial siderosis and guide chelation therapy. We undertook a multicenter retrospective study of 280 patients with TDTM to assess the prevalence of endocrinopathies and the predictive value of a number of individual and composite markers of endocrinopathy with T2* CMR. The prevalence of hypogonadism, stunting, hypoparathyroidism, and hypothyroidism was 82%, 69%, 40%, and 30%, respectively. The sensitivity of hypogonadism and stunting predicting severe myocardial siderosis was 90% and 80%, respectively. We conclude that clinical markers of endocrine dysfunction, especially hypogonadism (positive likelihood ratio [LR+]=1.4, 95% confidence interval [CI]=1.0-1.9; positive predictive value [PPV]=77%, 95% CI=70-82; negative predictive value [NPV]=57%, 95% CI=34-77] and stunting (LR+=1.3, 95% CI=1.1-1.6; PPV=64%, 95% CI=60-69; NPV=55%, 95% CI=45-64) in TDTM can predict severe myocardial siderosis and can potentially guide chelation therapy, especially where access to T2* CMR is limited.

Abstract 21067: Improvements in Regional Myocardial Function on 2D STE With Optimized Chelation in Patients With Thalassemia Major (TM)

Intro: Thalassemia Major (TM) is characterized by recurrent blood transfusions leading to myocardial siderosis and complications including arrhythmias and heart failure. These can be reversible with adequate chelation. We explored the effect of improved chelation and subsequent cardiac T2* MRI (CMR) values on regional myocardial function assessed by 2D STE in setting of normal LVEF. Methods: Data was derived from TM patients recruited for the AMIT study (efficacy of amlodipine with chelation in reducing myocardial iron). All patients underwent echocardiographic imaging at baseline, 6 and 12 months. LSsys was extracted from basal, mid, and apical segments of the LV medial and lateral wall by 2D STE technique. A linear regression model was run to determine the effect of improved T2* in the setting of improved chelation on regional LSsys strain parameters. Results: Nineteen TM patients (11 males), median age 16 (8-21) yrs. All participants were transfused every 2-3 weeks. (median pre-transfusional Hb of 9.3 (8.3-10.8) mg/dL). T2* based chelation regimen was initiated at baseline and compliance to this regimen was gauged at regular clinical visits. 25 data points were available from interval 2D STE imaging for analysis. Medial basal LSsys (-17.3% ± 2.2) and lateral basal LSsys (-16.7% ± 4.4) strains were significantly lower than mean apical LSsys strains (-24.9% ± 4.0) (p &lt;0.01). With optimized improved chelation, we determined up to a 6.3% improvement was seen in LSsys basal septal and 6.7% improvement in LSsys apical septal for each 1 ms improvement in T2* (p values &lt; 0.05). Conclusion: 2D STE can help identify regional myocardial dysfunction prior to development of overt cardiac dysfunction. In patients with transfusion dependent TM, compliance to an optimized chelation regimen can help improve regional myocardial function prior to progression to systolic dysfunction and clinically symptomatic sideroblastic complications.

Burden of Cardiac Siderosis in a Thalassemia-Major Endemic Population: A Preliminary Report From Pakistan.

To describe the initial experience and demographics of T2* cardiac magnetic resonance-based myocardial-iron quantification of transfusion-dependent thalassemia-major (TM) patients from Pakistan and the correlation with serum ferritin. Eligible TM patients presenting between April 2014 and April 2015 to Aga Khan University Hospital, Pakistan, for T2*CMR were included. The severity of myocardial-iron deposition was defined as follows: normal T2*>20 ms, mild-moderate T2*10 to 20 ms, and severe T2*<10 ms. Cardiac symptoms were classified using the NYHA functional classification. Echocardiographic systolic and diastolic functions were performed. Continuous variables were presented as the median (minimum-maximum value). Correlation was measured using the Spearman rank correlation. Multivariate logistic regression was used to determine factors associated with the NYHA functional class. A total of 83 patients (49 male and 34 female) with TM, age 19 (5 to 45) years at presentation for T2*CMR, were reviewed. At presentation, 70% of the patients were classified as NYHA class II or worse. T2*<20 ms was observed in 62.6% of the patients, with 47% showing severe iron deposition (T2<10 ms). No correlation of T2*<20 ms (r=-0.157, P=0.302) and T2*<10 ms (r=-0.128, P=0.464) was observed with serum ferritin. On multivariate analysis, lower T2* values correlated with a worsening NYHA functional class. There is a high prevalence of severe myocardial iron load in Pakistani TM patients. Serum ferritin did not correlate with T2* values. Lower T2* was the only clinical factor associated with the NYHA functional class.

Reproductive behavior in carrier couples for transfusion-dependent thalassemia major: evaluation of knowledge, attitude and practice

Background and Purpose: Despite extensive research on family planning and education, reproductive behavior of high-risk couples for thalassemia remains a major concern among medical professionals. This study aimed to evaluate the knowledge and attitude of carrier couples for transfusion-dependent thalassemia major (TDTM). Methods: This case-control study was conducted 327 carrier couples for thalassemia minor. Contact information of the couples was obtained from three healthcare centers randomly selected from the eastern, central and western parts of Mazandaran province, Iran. To match the socioeconomic status, two control families (right and left neighbors) were interviewed per each carrier couple. Epidemiological characteristics and knowledge of the carrier couples were assessed via 10 and 20 questions, respectively, and scores above 15 were interpreted as adequate knowledge. Moreover, attitude of the subjects was evaluated via 16 items scored based on a four-point Likert scale. Data analysis was performed in SPSS V.16 using Mann-Whitney U test and T-test for the comparison of study groups, and P value of less than 0.05 was considered significant. Results: In total, 327 high-risk couples for minor thalassemia and 660 control families were enrolled in this study. Among the subjects, 32.6% and 22.3% had adequate knowledge about thalassemia. In addition, attitude of the carrier couples was positive in 58% and 41% of the cases. Also, 30.5% and 31.2% of case and control subjects had favorable socioeconomic status, respectively. Conclusion: According to the results of this study, knowledge of carrier couples was adequate with regard to TDTM, and they had a positive attitude toward receiving prenatal diagnosis for this syndrome. However, reproductive practice of high-risk couples was relatively poor. Therefore, it is recommended that reproductive behavior of high-risk couples for TDTM be monitored regularly in order to improve their practice.

Neutrophil Gelatinase-Associated Lipocalin Levels in Patients with Thalassemia and Sickle Cell Disease: Correlation with Renal Injury

Background and Aims: Neutrophil gelatinase-associated lipocalin (NGAL) is a protein belonging to the lipocalin superfamily initially found in activated neutrophils, in accordance with its role as an innate antibacterial factor. However, it subsequently was shown that many other types of cells, including in the kidney tubule, may produce NGAL in response to various injuries. The increase in NGAL production and release from tubular cells after harmful stimuli of various kinds may have self-defensive intent based on the activation of specific iron-dependent pathways, which in all probability also represent the mechanism through which NGAL promotes kidney growth and differentiation. NGAL levels clearly correlate with severity of renal impairment, probably expressing the degree of active damage underlying the chronic condition. For all these reasons, NGAL may become one of the most promising next-generation biomarkers in clinical nephrology and beyond. We aimed to investigate the clinical significance of NGAL levels and its correlation with renal function in patients with hemoglobinopathies.Patients and Methods: 117 adult patients with hemoglobinopathies were included in the study divided in 3 groups. Group A: 30 patients with transfusion-dependent thalassemia major (TM); Group B: 29 patients with Non-Transfusion-Dependent Thalassemia (TI) and Group C: 58 patients with HbS/βthal disease, while 20 apparently healthy individuals served as controls (Group D). In patients and controls along with standard blood and urine chemistry. Measurements of serum Cystatin C and NGAL were performed by means of immunonephelometric and immunoenzymatic techniques, (Siemens Healthcare Diagnostics, Liederbach, Germany and R&D Systems, Minneapolis, MN, USA), respectively. Estimated Glomerular Filtration Rate (eGFR) values were calculated with an unadjusted for body surface Cystatin C based equation: eGFR (mL/min)=77.24(Cys C)-1.2623.Results: The main results of the study showed that: a) NGAL levels were significantly higher in all the groups of patients compared to controls: Group A 95.0±45.0µg/L, Group B 139.1±86.1µg/L, Group C 117.8±37.3µg/L vs Group D 50.3±11.3µg/L (p<0.001), b) Cystatin C levels were significantly higher in patients of Group A 0.94±0.34mg/L and Group C 1.04±0.50mg/L compared to controls 0.75±0.09mg/L (p<0.01), while no significant difference was found between Group B 0.72±0.13mg/L and controls (p>0.300), c) NGAL levels and eGFR values (Group A: 96.9±39.8, Group B: 117.0±26.0, Group C: 86.2±27.8 and group D: 109.6±15.0mL/min, respectively) correlated significantly in patients of Group A and Group C (r=-0.739, p<0.001 and r=-0.735, p<0.001, respectively), while NGAL values are independent from eGFR values in patients of Group B.Conclusions: These findings illustrate the tubular-glomerular activation feedback mirrored by NGAL in patients with transfusion-dependent thalassemia major and HbS/βthal disease, who suffer from renal injuries, indicating that tubular damage precedes GFR reduction. Upregulation of NGAL in patients with non-transfusion-dependent thalassemia independently of renal injuries may reflect the compensatory, protective role of NGAL in response to diverse cellular stresses, including inflammation and oxidative stress. However, recent reports have implicated NGAL upregulation as a mechanism that contributes to anemia in the setting of chronic low grade inflammation. In experimental models, systemic and medullary NGAL has been demonstrated to induce inhibition of erythropoiesis through induction of apoptosis and arrest of differentiation of erythroid progenitor cells. DisclosuresNo relevant conflicts of interest to declare.

Marriage and child bearing in patients with transfusion-dependent thalassemia major.

With good care, patients with transfusion-dependent thalassemia major (TDTM) can reach older ages, marry and reproduce. This study was conducted by the Thalassemia Research Center. Medical notes of all TDTM patients and all non-transfusion-dependent thalassemia major (NTDTM) patients were reviewed from July to December 2012. Also, patients were interviewed. The questionnaire was made in consultation with research methodology experts and reliability was achieved by a pilot study of 12 patients, by the test-retest method (r = 0.9). Epidemiologic characteristics of patients and the pregnancy outcomes were recorded. Descriptive statistics were used with SPSS 17. Four hundred and nineteen medical records were reviewed. Three hundred and forty-five (82.5%) were TDTM. One hundred and seventy-five (50.7%) were female with a mean age of 25.4 ± 7.05 years and 42 (25%) had been married. Mean age of menarche and marriage was 15.4 ± 1.6 and 21.8 ± 4.5 years, respectively. Total number of live children is nine so far. Mode of delivery in female patients was cesarean section. Almost 78% of newborns weighed 2500-4000 g. Almost 22% of pregnancies were assisted. Male patients consisted of 170 (49.3%) and 55 (32.3%) of them had been married. Mean age at marriage was 24.27 ± 3.5 years. With better management, patients with TDTM can reach the age of reproduction. Medical teams should be prepared for this possibility.

Correlation of NT-ProBNP Levels and Cardiac Iron Concentration in Patients with Transfusion-Dependent Thalassemia Major,

Abstract 3192 Background:Iron-induced cardiotoxicity remains the leading cause of morbidity and mortality in patients with transfusion-dependent thalassemia major (TM). Heart failure in these patients, which may be reversible but has a poor prognosis, is characterized by myocardial iron deposition-related early diastolic dysfunction. N-terminal-proBNP (amino-terminal) (NT-proBNP) is a sensitive biomarker for the detection of asymptomatic left ventricular (LV) dysfunction.Patients and Methods: In this study, we prospectively evaluated plasma NT-proBNP levels determined on the Roche cobas e411immunoassay analyzer using electrochemiluminescence technique in 187 adult patients aged 19–54 years with TM. Possible correlations with the proposed recently cardiac iron concentration [Fe] based on an equation derived from heart T2* assessment by MRI: [Fe] = 45.0 × [T2*]−1.22 with [Fe] in milligrams per gram dry weight and T2* in milliseconds (Carpenter et al Circulation 2011;123;1519–1528) were explored. Results:143 patients had low cardiac hemosiderosis, defined as [Fe] < 1.1 mg/g dry weight, corresponding to T2*>20 milliseconds and 44 patients with high cardiac hemosiderosis, defined as [Fe] >1.2 mg/g dry weight. The main results of the study showed that: a) NT-proBNP levels were markedly increased in thalassemic patients (152.2 26.4 pg/mL, ranged from 6.0 – 1336.0 pg/mL compared to normal control levels 40.1 19.7 pg/mL, p<0.001, b) NT-proBNP levels were significantly higher in high cardiac hemosiderosis patients compared to low cardiac hemosiderosis patients (185.1 78.2 vs 128.9 20.2 pg/mL, p<0.05), c) NT-proBNP levels correlated with [Fe] values (r= 0.387, p<0.001). This correlation was significant in patients with high cardiac hemosiderosis (r= 0.520, p<0.001), but not in patients with low cardiac hemosiderosis (p>0.1), and d) no significant correlation was found between NT-proBNP levels and left ventricular ejection fraction (LVEF) values, (p>0.3). Conclusions:Our study demonstrate for first time the significant association of NT-proBNP levels and cardiac iron concentration in patients with TM linking blood chemistry and imaging techniques. Multicenter studies of these parameters during iron chelation therapies are needed to validate their association and further exploit its clinical use. Disclosures:Kattamis:Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Wording to add.

Electrocardiographic consequences of cardiac iron overload in thalassemia major

Iron cardiomyopathy is a leading cause of death in transfusion-dependent thalassemia major (TM) patients and MRI (T2*) can recognize preclinical cardiac iron overload, but, is unavailable to many centers. We evaluated the ability of 12-lead electrocardiography to predict cardiac iron loading in TM. 12-lead electrocardiogram and cardiac T2* measurements were performed prospectively, with a detectable cardiac iron cutoff of T2*less than 20 ms. Patients with and without cardiac iron were compared using two-sample statistics and against population norms using age and gender-matched Z-scores. 45/78 patients had detectable cardiac iron. Patients having cardiac iron were older and more likely female but had comparable liver iron burdens and serum ferritin. Increased heart rate (HR) and prolonged corrected QT interval (QT(c)) were present, regardless of cardiac iron status. Repolarization abnormalities were the strongest predictors of cardiac iron, including QT/QT(c) prolongation, left shift of T-wave axis, and interpretation of ST/T-wave morphology. Recursive partitioning of the data for females using T-axis and HR and for males using QT, HR, and T-axis produced algorithms with AUROC's of 88.3 and 87.1, respectively. Bradycardia and repolarization abnormalities on 12-lead electrocardiography were the most specific markers for cardiac iron in thalassemia major. Changes in these variables may be helpful to stratify cardiac risk when cardiac MRI is unavailable. However, diagnostic algorithms need to be vetted on larger and more diverse patient populations and longitudinal studies are necessary to determine reversibility of the observed abnormalities.

Evaluation of Serum Insulin, Glucose, Lipid Profile, and Liver Function in β-Thalassemia Major Patients and Their Correlation With Iron Overload

labmedicine.com Thalassemias are a heterogeneous group of genetic disorders resulting from defects in genes producing α or β globin chains. β thalassemia results from a defect in β globulin chain production and ranges from clinically silent heterogeneous thalassemia minor to severe transfusion-dependent thalassemia major (TM). 1-6 Frequent blood transfusions have increased life expectancy and improved the quality of life for the patients with TM, but it causes progressive iron overload, which is a major clinical complication of the treatment. Some evidence shows that oxidative stress (caused by iron accumulation) is the most important factor in the pathogenesis of clinical complications of the disease. 7-9 A wide range of literature has documented multiple organ dysfunction among which the heart, liver, and endocrine system are the most common organs affected. 10,11 Glucose intolerance is a common consequence of transfusion therapy in patients with TM, but the relative contribution of pancreatic damage and insulin resistance to glucose intolerance is unclear. 12-15 The exact mechanism of iron

History of Hepatitis B or C Does Not Affect Safety and Efficacy of Deferasirox (Exjade®) in Thalassemia Major Patients: Sub-Analysis of the EPIC Trial.

Abstract 5107 BackgroundMany thalassemia major (TM) patients have concomitant hepatitis B and/or C infection and data suggest that iron overload in these patients increases the risk of liver fibrosis progression. Deferasirox (Exjade®), which has demonstrated efficacy and safety in reducing iron overload in a variety of transfusion dependent anemias, has been uncommonly associated with elevations of transaminases suggestive of hepatitis (0.3%). However, whether patients' viral hepatitis status affects the overall and liver safety of deferasirox remains unclear. The prospective, multicenter EPIC study of deferasirox enrolled some patients with a history of hepatitis B or C. This sub-analysis of EPIC assesses the overall and liver safety of deferasirox over 1 year of treatment in TM patients with and without a history of hepatitis B or C. MethodsPatients aged ≥2 years with transfusion-dependent TM and serum ferritin (SF) levels of ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg of red blood cells), or R2 MRI-confirmed liver iron concentration of >2 mg Fe/g dry weight were enrolled. Deferasirox starting dose was 10–30 mg/kg/day depending on the frequency of blood transfusions. Protocol-specified dose adjustments of 5–10 mg/kg/day (range 0–40) were performed every 3 months based on SF trends and safety markers. Safety was evaluated through continuous monitoring and recording of adverse events (AEs), as well as monthly blood chemistry assessments including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ResultsOf 937 enrolled patients with TM, 258 (27.5%) had a history of hepatitis B or C and 679 (72.5%) did not. Compared with patients with no viral hepatitis, patients with a history of hepatitis B or C were older (mean age 26.5 ± 9.9 vs 15.3 ± 9.5 years), more commonly splenectomized (50.4 vs 29.9%), received more transfusions (195 vs 188 mL/kg) and were chelated for longer prior to study entry (15.9 ± 10.5 vs 8.7 ± 7.4 years). In total, 212 (82.2%) and 636 (93.7%) of patients with and without viral hepatitis, respectively completed the study. The most common drug-related AEs were gastrointestinal disorders, such as diarrhea (14.7% vs 6.2%, respectively; P<0.0001), abdominal pain (7.4% vs 4.7%, respectively; P=0.110) and nausea (5.0% vs 3.5%, respectively; P=0.291), as well as skin rash (10.5% vs 13.5%, respectively; P=0.205). Three patients (1.2%) with hepatitis had two consecutive increases in ALT 10 x the upper limit of normal (ULN); all three patients had elevated baseline levels (mean 95.6 U/L). Two patients (0.3%) without hepatitis had similar increases, one of whom had elevated baseline levels (225 U/L). Mean ALT and AST levels decreased during deferasirox treatment in both groups; decreases were significant in patients without hepatitis (Figure). 12 (4.7%) and 25 (3.7%) patients with and without a history of viral hepatitis, respectively had serum creatinine >33% above baseline and ULN on two consecutive visits [Display omitted] Overall median SF decreased from baseline (3157 ng/mL) by 129 ng/mL after 1 year (P=0.0007) at a mean actual dose of 24.2 ± 5.6 mg/kg/day and mean transfusional iron intake of 0.43 ± 0.2 mg/kg/day. Reduction in SF was similar in patients with or without a history of viral hepatitis (–113 and –148 ng/mL, respectively). ConclusionsThis sub-analysis of EPIC demonstrates that once-daily deferasirox is well tolerated in patients with TM irrespective of viral hepatitis history with no significant difference in the incidence of abdominal pain, nausea and skin rash. Increases in ALT >10 x ULN were very low and occurred at a comparable frequency in patients with and without viral hepatitis. Mean liver transaminases, although higher at baseline in patients with a history of hepatitis B or C compared to those without, decreased in both groups, suggesting an overall improvement in liver function with deferasirox treatment. Reduction in SF was similar in both patient groups. Further confirmatory data are required to evaluate the effect of hepatitis viral load on the response to deferasirox therapy. DisclosuresCappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Chan:Novartis: Honoraria, Research Funding. Lin:Taiwan Pediatric Onclogy Group (TPOG): Consultancy; Novartis: Honoraria, Speakers Bureau. Sutcharitchan:Novartis: Honoraria, Research Funding; Novo Nordisk: Honoraria. Taher:Novartis: Honoraria, Research Funding. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees.

Cumulative Efficacy and Safety of 5-Year Deferasirox (Exjade®) Treatment in Pediatric Patients with Thalassemia Major: A Phase II Multicenter Prospective Trial

Background: Pediatric thalassemia major (TM) patients may begin lifelong iron chelation therapy (ICT) as early as 2 years to avoid potential complications of iron overload, such as impaired growth and the later development of cardiac dysfunction. Deferasirox (Exjade®), administered orally once daily, was developed to improve compliance to long-term ICT in patients with transfusion-dependent anemias. We report cumulative efficacy, safety and development data in pediatric patients with transfusion-dependent TM treated with deferasirox for 5 years (study 106).Methods: Pediatric TM patients stratified into two age groups (children 2-≤12 years; adolescents 12–17 years) were enrolled in study 106 and received deferasirox 10 mg/kg/day for 1 year. Patients completing the 1 year study were able to continue deferasirox treatment for an additional 4 years at adjusted doses, to evaluate long term safety and effect on liver iron concentration (LIC). Safety was assessed by the incidence and type of adverse events (AEs), laboratory parameters and growth/sexual development. Efficacy was evaluated by changes in LIC by SQUID.Results: 20 children (mean age 6.7±2.8 years) and 20 adolescents (mean age 14.1±1.6 years) were enrolled. Children had a greater mean iron intake (0.46–0.49 mg/kg/day) than adolescents (0.39–0.41 mg/kg/day). Median exposure to deferasirox was 5.0 years for children, 5.5 years for adolescents; mean dose in children and adolescents was 18.9±5.7 and 20.9±4.5 mg/kg/day, respectively. On average, 30% of children and 10% of adolescents received <15 mg/kg/day. Mean final dose was 26.3 mg/kg/day for children and 27.8 mg/kg/day for adolescents. Relative change in LIC over the treatment period is shown in Figure 1. [Display omitted] Overall, 24 patients (60.0%; 11 children and 13 adolescents) completed the 5-year study. Reasons for discontinuation were AEs (n=8), consent withdrawal (n=7), unsatisfactory therapeutic effect (n=1). Most common AEs were cough, pyrexia (n=34, 85%) and rhinitis (n=30, 75%); the annual frequency of reported AEs did not increase from year to year and generally occurred in similar proportions for children and adolescents. One child had a serious AE (increased transaminases) assessed as drug-related. Two other patients had an ALT increase >10 × ULN on at least one visit; baseline levels were >8 × ULN in one patient, and normal in the other. Both patients were restarted on deferasirox after 2 week interruptions without further incident. No patient had an increase in serum creatinine >33% above baseline and ULN at two consecutive visits. Neutropenia (neutrophil count <1.5×109/L at two consecutive visits), assessed unrelated to treatment, occurred in one child and two adolescents. There were no clinically significant visual defects and one child had a drug-related audiometric abnormality (hypoacusis). Physical development was normal in both groups; growth velocity was higher in children. Sexual development progressed normally in adolescents.Conclusions: Deferasirox dose-dependently reduced iron overload over 5 years of treatment in these heavily transfused pediatric patients with TM. Dose increases over time, with a stable iron intake, were associated with a decrease in LIC for both groups, but the reduction in LIC was greater in adolescents. Despite having a higher transfusional iron intake, more children than adolescents were on a dose <15 mg/kg/day, highlighting that transfusional iron intake should be considered when selecting deferasirox dose. Deferasirox was generally well tolerated. There was no evidence of progressive renal, hepatic or bone marrow dysfunction. Deferasirox treatment had no negative impact on growth and sexual development.

Switching from Deferoxamine (Desferal®, DFO) to Deferasirox (Exjade®) Maintains Effective Control of Iron Levels in Patients with Thalassemia Major (TM)

Background: The clinical outcome of transfusion-dependent TM patients with iron overload has been shown to depend on the dose and frequency of deferoxamine (DFO) use. However, the demanding regimen of slow subcutaneous infusions often leads to poor compliance. Deferasirox (Exjade®), a once-daily oral chelator, has potential compliance advantages. Doses of 20–30 mg/kg/day are non-inferior to DFO >35 mg/kg in TM patients with baseline liver iron concentration (LIC) >7 mg Fe/g dry weight (dw). This analysis reports efficacy and safety data from TM patients with iron overload who received DFO in a 1-year core trial (107), and then switched to deferasirox in an ongoing 4-year extension trial (107E).Methods: TM patients with iron overload ≥2 years of age were randomized to DFO or deferasirox in study 107. Patients with LIC <7 or ≥7 mg Fe/g dw received DFO <25–<35 or 35-≥50 mg/kg, respectively, but some patients with baseline LIC <7 mg Fe/g dw remained on their higher pre-study DFO doses since these were efficacious. Patients completing the 1-year core trial had a repeat LIC assessment by biopsy or SQUID, and were continued on or switched to deferasirox during 107E for long term efficacy and safety evaluation. Deferasirox dose was based on the end of 1-year LIC, and adjusted according to trends in serum ferritin (SF) level. Efficacy and safety data were analyzed annually for patients receiving DFO in study 107 who switched to deferasirox in 107E, to determine long-term outcome.Results: 259 patients, 129 children (2–<16 years) and 130 adults (≥16 years) are included. Average daily DFO dose during study 107 was 42.7±9.2 mg/kg; mean transfusional iron intake was 0.4±0.3 mg/kg/day (range 0.2–0.9). Baseline LIC was ≤7 and >7 mg Fe/g dw in 85 and 174 patients, respectively. Median SF change after 12 months of DFO was −264 ng/mL (baseline 2037 ng/mL). Patients crossed over to deferasirox and have received treatment for a median of 35.2 months. At month 42 of deferasirox, median SF had further decreased by −257 ng/mL (baseline 1843 ng/mL) in a dose-related manner (Figure 1). [Display omitted] During DFO treatment the most common drug-related AEs were injection-site reaction (n=6, 2.3%) and pain (n=6, 2.3%); no drug-related AEs led to discontinuation. One patient had a serious drug-related AE. Three patients (1.2%) had an alanine aminotransferase (ALT) increase >10 × ULN on at least one visit, where baseline ALT values were normal, ≥1–<5 × ULN and ≥5–<10 × ULN. Irrespective of relationship to DFO, deafness, tinnitus and hypoacusis were reported in five, four and three patients, while five and one had lenticular opacities and maculopathy, respectively.During year 1 of deferasirox treatment the most common drug-related AEs were rash (n=17, 6.6%), diarrhea (n=11, 4.2%) and nausea (n=7, 2.7%); the annual frequency of these drug-related AEs decreased to <1.5% thereafter. Five drug-related AEs led to discontinuation. Seven patients (2.7%) had a serious drug-related AE. In year 1, three patients (1.2%) had serum creatinine increases >33% above baseline and ULN on two consecutive visits, with a subsequent overall annual incidence of 2–3%. In year 1, four patients (1.5%) had an ALT increase >10×ULN on at least one visit (baseline values were ≥1–<5×ULN for three patients and ≥5–<10×ULN for the other), as did six patients in year 2 of deferasirox therapy; no ALT values >10×ULN were reported thereafter. Irrespective of relationship to deferasirox, hypoacusis, deafness and tinnitus were seen in four, two and one patients, respectively, and one had lenticular opacities.Conclusions: TM patients who have previously received chelation therapy with DFO can maintain effective chelation when switched to deferasirox, as demonstrated by a continued and dose-dependent decrease in SF. Over long-term deferasirox treatment with increased dose, there was no increased risk of toxicity, no evidence of progressive renal or liver dysfunction and an annual decrease in drug-related AEs.

The Changing Profile of Homozygous β-Thalassemia: Demography, Ethnicity, and Age Distribution of Current North American Patients and Changes in Two Decades

Background. The age of patients with homozygous β-thalassemia is increasing because of better treatment and decreased births. A countering influence is immigration of ethnic groups with a high prevalence of thalassemia. Methods. A questionnaire sent to 48 North American centers requested information about current patients with homozygous β-thalassemia: age, clinical severity, and ethnicity. An 83% response was obtained. Twelve reference hospitals that participated in similar surveys in 1972 and 1984 were included. Results. Five hundred eighteen patients with homozygous β-thalassemia represent most North American patients. Four hundred forty-three (86%) of these had transfusion-dependent thalassemia major (TM); 75 (14%) had thalassemia intermedia (TI). Sixty-two percent were of Greek and Italian ancestry. There were approximately equal numbers of patients with TM in 5-year intervals between 0 and 25 years of age. Thereafter, the number of patients fell sharply. The mean age (±SD) of the patients with TM was 16.1 ± 9.2 years. Striking differences were seen in Italian and Greek patients compared with those of other ancestries. Sixty-six percent of the 271 Italian and Greek patients with TM were older than 16 years of age, whereas 77% of the 172 patients of other ethnic groups with TM were younger than 15 years of age. The mean age of the 75 patients with TI was greater than that of the patients with TM. Seventy-three percent of African-American patients with thalassemia had TI, compared with 0% of Southeastern Asian patients. Comparisons of patients with TM from the 12 reference hospitals for two decades show increasing mean ages of TM patients (1973, 11.4 ± 6.7 years; 1985, 14.2 ± 7.3 years; and 1993, 16.1 ± 9.2 years). Conclusions. There are probably only 750 to 1000 patients with homozygous β-thalassemia in North America. Only about 15 to 20 new cases are diagnosed each year. The increasing mean age and age distribution indicate that modern therapies are effective, but immigration of non-Mediterranean ethnic groups with thalassemia has resulted in more, younger patients. TM is increasingly becoming a disease of young adults.