Transfusion-dependent Thalassemia Major Patients Research Articles

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.

Role of cardiac magnetic resonance T1 mapping in comparison to T2* for cardiac iron overload assessment in transfusion-dependent thalassemia major patients

BackgroundCardiac complications are the leading cause of death in transfusion-dependent thalassemia major (TDT) patients due to increased cardiac iron overload (CIO), so this study’s purpose is to assess the diagnostic utility of cardiac magnetic resonance T1 mapping in correlation to T2* for the assessment of CIO in TDT patients. This prospective case–control study involved 55 TDT patients and 30 age- and gender-matched healthy controls. All the patients underwent assessment of myocardial T2*, and native T1 values by conventional cardiac magnetic resonance imaging, and native T1 mapping technique to assess the CIO. Comparison and association between T2*, and native T1 values among TDT patients were studied.ResultsA statistically significant difference is noted between control and patient groups in regard to mean T2* and native T1 values (P = 0.03 and 0.01, respectively). The mean native T1 value in TDT patients was lower than in the control group (992 ± 54 vs. 1234 ± 42), respectively, with a statistically significant P value of 0.04. The study evoked a statistically significant strong positive association, and correlation was noted between measured T2* and native T1 values (r = 0.84, P value = 0.001), while a moderate negative association was observed between native T1 values and S. ferritin levels (r = − 0.53, P value = 0.02).ConclusionsNative T1 mapping is a non-invasive promising complementary technique to T2* that helps to detect cardiac iron overload in TDT patients, as it is strongly associated with T2*. Also, native T1 value can differentiate mild, moderate, severe, and no cardiac iron overload.

Health-related Quality of Life in Pediatric and Adolescent Patients with Transfusion Dependent ß-Thalassemia

Objective: To evaluate the impact of disease on physical, educational, psychological and social wellbeing of transfusion dependent thalassemia major patients. Study Design and Setting: A case control study conducted in Thalassemia Centre of Pediatric Ward, PNS Shifa Hospital Karachi for a duration of six months from March 2019 till August 2019. Methodology: Seventy cases of thalassemia major patients were enrolled along with a control group of hundred patients. The enrolled cases were registered thalassemia patients of pediatric hematology clinic. The controls are healthy, age and sex matched participants and their history was taken to compare with the diseased participants. Peds QL4.0 generic core scale proforma was filled to assess health related quality of life (HRQoL) in these patients. Results: Mean age of patients was 8.56 ± 4.526 and 7.94 ± 4.528 for controls. The greatest level of difficulty was seen in thalassemia patients in physical functioning, health activities and emotional functioning domains with a score of 9.4 ± 6.85, 9.186 ± 5.724 and 6.4 ± 3.5 respectively. The total score in terms of increasing difficulty was 51.84 ± 21.26 in patients while it was 15.06 ± 10.26 in control group with a significant difference (p = 0.05). There was also significant association of splenectomy with health-related scores. Conclusion: This study reiterated the impact of blood transfusion, iron chelation and other clinical dependencies of thalassemia major patients on their quality of life. The questionnaire data provided valuable information regarding impact on daily life activities and its difference in comparison to controls.

The relationship of myocardial and liver T2* values with cardiac function and laboratory findings in transfusion-dependent thalassemia major patients: A retrospective cardiac MRI study.

Cardiac complications are the leading cause of death in thalassemia patients. It is assumed that progressive iron accumulation results in myocyte damage. Myocardial T2* measurement by cardiac MRI quantifies iron overload. We aimed to study the association between left and right ventricular (LV and RV) function and iron deposition estimation by cardiac MRI T2* in a sample of Iranian patients. Cardiac MRI exams of 118 transfusion-dependent thalassemia major patients were evaluated retrospectively. Biventricular function and volume and myocardial and liver T2* values were measured. The demographic and lab data were registered. Poisson and chi-square regression analyses investigated the correlation between the T2* value and ventricular dysfunction. The study participants' mean (SD) age was 32.7y (9.02), and 47.46% were female. Forty-nine cases (41.52%) revealed at least uni-ventricular dysfunction. LV dysfunction was noted in 20 cases, whereas 47 patients revealed RV dysfunction. The risk of LV dysfunction was 5.3-fold higher in patients with cardiac T2* value less than 10msec (RR=5.3, 95% CI=1.6, 17.1, P<0.05). No association was found between age, liver T2* value, serum ferritin level, and chelation therapy with the risk of LV and RV dysfunction. Cardiac MRI T2* measure is a good indicator of LV dysfunction. Moreover, MRI parameters, especially RV functional measures, may have a substantial role in patient management. Therefore, cardiac MRI should be included in beta-thalassemia patients' management strategies.

Incidence of impaired glucose tolerance and diabetes mellitus in transfusion dependent thalassemia patients of rural Bengal - An institutional study

: Thalassemia is the world’s commonest monogenic disorder. Molecular biology and genetics have revealed more than 200 mutations of thalassemia syndrome. These children become symptomatic from progressive haemolytic anaemia. They have to take lifelong treatments with regular packed red blood cell transfusion. Our body has no effective means of iron excretion and this leads to progressive iron accumulation in various organs after prolonged blood transfusion. This results in dysfunction of liver, heart and endocrine system and increased mortality. Iron toxicity to pancreatic beta cell leads to impairment in glucose metabolism. : Our study aims to find out the incidence of impaired glucose tolerance (IGT) and diabetes mellitus (DM) in transfusion dependent thalassemia major patients. This is an observational descriptive study carried out from January 2017 to June 2018. The study included 48 samples. There post-prandial blood sugar level and glycated haemoglobin (HbA1c) was analysed. Any proved case of juvenile diabetes mellitus was excluded from the study. We found that the incidence of IGT and DM were 12.5% and 4.16% respectively in our study population. The blood sugar level was significantly high in study group (p=&amp;#60;0.0001) as compared to the control group. The present study showed strong correlation between units of blood transfusion and blood sugar level as well as HbA1C percentage (in both cases p= &amp;#60;0.00001.)Thalassemia patients receiving regular blood transfusion are at increased risk of developing IGT and DM. Early initiation of chelation and judicious use of blood transfusion must be considered for these patients to prevent such complications.

Epidemiological and Clinical Profile of Iraqi Patients with β-Thalassemia Major

Thalassemia is an autosomal recessive inherited blood disorder due to hemoglobin-production abnormalities. Over the past three decades, hyper-transfusion therapy in these patients has shown significant increase in life expectancy and quality of life. unfortunately, this type of therapy also increased the frequency of complications due to iron overload. The study aims to identify the Sociodemographic and clinical characteristics of patients with thalassemia, and to assess transfusion related complication among them. A descriptive, cross-sectional study was conducted in Thalassemia Center in Al-Najaf province in Iraq, during the period from the 1st of April to the 31st of August 2018. Data were collected through direct interview with patients/parents using a specially designed questionnaire form. A total of 175 transfusion dependent thalassemia major patients were included, the mean age 10. 5 years ranging from 5 m to 34years. Patients under 10 years of age represented the highest rate with Male: Female ratio 1.2:1. 60% were from rural area with high percentage of parental consanguinity (70%). The study documented the relationship between iron over load and appearance of complications. Development of preventive measures as genetic counseling, prenatal diagnosis, pre-marital screening are the best ways to decrease the incidence of disease, in addition to regular blood transfusion with optimum chelation therapy.

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.

A randomized controlled trial evaluating the effects of amlodipine on myocardial iron deposition in pediatric patients with thalassemia major.

BackgroundMortality rates increase due to iron deposition in the cardiac muscles of thalassemia major (TM) patients. Iron overload cardiomyopathy could be treated with a combination therapy of an iron chelator and an L-type calcium channel blocker. We designed a randomized controlled study to assess the potential of amlodipine, alongside chelation, in reducing myocardial iron concentration in TM patients compared with a placebo.ObjectivesThis study aims to estimate the change in myocardial iron concentration (MIC) determined by magnetic resonance imaging after 6 months of treatment with amlodipine, as well as measuring the changes in the secondary outcomes (liver iron concentration (LIC), serum ferritin level (SF), and left ventricle ejection fraction (LVEF)) of study participants.MethodsA single, randomized, placebo-controlled trial was performed in 40 β-Thalassemia major patients aged between 6 and 20 years old, who received either oral amlodipine 2.5–5 mg/day or a placebo, in addition to a Deferasirox chelation regimen in a 1:1 allocation ratio.ResultsAfter 6 months, a significant reduction was noted in the MIC of patients receiving amlodipine (n=20), compared with the patients receiving the placebo (n=20). At baseline, the mean was 0.76±0.11 mg/g dry weight, while at 6 months, the mean was 0.51±0.07 mg/g dry weight (p<0.001). Also, there was a significant change in the myocardial T2* after 6 months; the amlodipine increased the myocardial T2* from 40.63±5.45 ms at baseline to 43.25±5.35 ms (p<0.001). However, amlodipine did not significantly affect the secondary outcomes by the end of the study.ConclusionThe addition of amlodipine to the standard chelation therapy in transfusion-dependent thalassemia major patients improves myocardial iron overload without increasing the adverse effects.

Study of Anxiety among Thalassemia Major Adolescent Patients

Background: Beta (β) thalassemia major is most common monogenic disorder in the world. Transfusion dependent thalassemia major patients are at risk of iron overload and hence its associated complications. Thalassemia is a major sanitary problem not only for the patients and their families but also for each country’s public health systems with regard to treatment expenses including regular injections, iron chelating agents, frequent hospitalizations and other medical consistencies and they are vulnerable to, social and psychological problems. Objectives: To determine prevalence and severity of anxiety in transfusion dependent Beta thalassemia major patients attending a tertiary care hospital. Materials and Methods: The study was done at a tertiary care teaching hospital in a tertiary care hospital. Thalassemia major patients who received blood transfusions at 2 to 4 weeks interval in the hospital were included in this study. Clinical assessment of each child was done and psychiatric illness was diagnosed using ICD-10 DCR. Hamilton Anxiety rating scale (HAM-A) were used. Result: Males (80%) outnumbered females (20%) with male to female ratio of 4:1. Nearly half of the study population was aged between 10 to 12 years. Majority of the patients had one blood transfusion per month (91.43%). Out of 31 patients, 25 were males and 6 were females. Age range was 10 -18 years with mean age of 12.45 ± 2.41 years..The prevalence of anxiety was 38.71 % with majority showing mild severity followed by mild to moderate severity. Conclusion: This study help to know the severity of the anxiety in β thalassemia patients who are chronically ill and have prolonged treatment. Early assessment and treatment by psychiatrist will surely help to have good psychological condition.

A Study of Severity of Depression in Thalassemia Patients

Background: Beta Thalassemia major is most common monogenic disorder in the world.. Transfusion dependent thalassemia major patients are at risk of iron overload and hence its associated complications. Thalassemia is a major sanitary problem not only for the patients and their families but also for each country’s public health systems with regard to treatment expenses including regular injections, iron chelating agents, frequent hospitalizations and other medical consistencies and they are vulnerable to, social and psychological problems. Objectives: To determine prevalence and severity of depression in transfusion dependent Beta thalassemia major patients attending a tertiary care hospital. Materials and Methods: The study was done in a tertiary care hospital. Thalassemia major patients who received blood transfusions for 2 to 4 weeks interval in the hospital were included in this study. Clinical assessment of each child was done and psychiatric illness was diagnosed using ICD-10 DCR. Hamilton Depression rating scale (HAM-D) were used. Result: Males (80%) outnumbered females (20%) with male to female ratio of 4:1. Nearly half of the study population was aged between 10 to 12 years. Majority of the patients had one blood transfusion per month (91.43%). Out of 31 patients, 25 were males and 6 were females. Age range was 10 -18 years with mean age of 12.45 ± 2.41 years. The prevalence of depression was 41.94 % with majority showing mild depression. Conclusion: This study helps to know the severity of the depression in β thalassemia patients who are chronically ill and have prolonged treatment. Early assessment and treatment by psychiatrist will surely help to have good psychological condition.

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.

Association of Liver Iron Concentration Levels with Myocardial T2* Responses in Transfusion-Dependent Thalassemia Major Patients Treated with Deferasirox and Deferoxamine- Extension of Cordelia Study

Background: Beta thalassemia major patients (pts) are at an increased risk of heart failure, due to the deposition of iron in the heart causing myocardial siderosis. Intensive long-term iron chelation therapy (ICT) is required to obtain a normal myocardial T2* (mT2* >20 ms). Previously published studies suggested that cardiac iron removal lags changes in liver iron, and liver iron concentration (LIC) may affect the rate of removal of cardiac iron (Porter et al, ASH 2013). The objective of these analyses was to evaluate the association of the severity of LIC levels with the change in mT2* responses in pts with myocardial siderosis when treated with deferasirox (DFX) and deferoxamine (DFO) for up to 24 months (mo) in the CORDELIA study. Due to the very low pt numbers in the DFO arm, the results for these pts are not presented here. Methods: The study design, inclusion, and exclusion criteria have been reported previously (Pennell et al, Am J Hematol. 2015). Pts were categorized into LIC Results: Of 197 pts, 160 (81.2%) completed 12 mo of treatment and 146 (74.1%) entered into the extension study whereas 103 pts continued on initially assigned treatment. Pts completing 24 mo of treatment included 65 (87.8%) of 74 pts (mean age 20.1±6.9 years, 59.5% male) on DFX and the results for these pts are presented as follows. Average actual doses (mg/kg/d) were 26.7±8.9, 31.5±7.4, 38.0±2.9 for LIC The LIC levels for pts categorized by LIC For pts with BL LIC The mT2* responses for pts categorized according to visit specific LIC levels (LIC Discussion: Overall, DFX treatment resulted in a substantial decrease in LIC and improved mT2*. These results suggest a greater difference in mT2* improvement and CIC reduction in pts who achieved lower LIC during treatment with DFX. This divergence was progressive with time, being maximal at Mo 24. Thus, a therapeutic response in LIC with DFX may be associated with a greater likelihood of improving mT2*. Pts with high LIC ≥15 may require an effective long-term treatment with higher doses of ICT to have an improvement in mT2*, suggesting that cardiac iron removal is likely to be slow in heavily iron overloaded pts. These results are consistent with the previous report which showed a significant decrease in LIC and increased mT2* responses at Mo 36 in pts who attained lower end-of-year LIC levels when treated with DFX (Porter et al, ASH 2013) and highlight the potential value of monitoring the liver and cardiac responses during ICT. To further understand the kinetics between liver and cardiac iron removal, prospective investigation is warranted. Disclosures Pennell:Novartis: Consultancy, Research Funding; Apotex: Consultancy, Research Funding. Porter:Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. Piga:Acceleron: Research Funding; Cerus: Research Funding; Apopharma: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene Corporation: Honoraria. Han:Novartis: Employment. Vorog:Novartis: Employment. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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.

Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications

Combined chelation treatment may be a better approach for transfusion-dependent thalassemia major patients with iron overload complications because of increased efficacy. Combination therapy with desferrioxamine and deferiprone has already been reported to improve survival dramatically by reversing cardiac dysfunction and other endocrine complications. Some patients have intolerance or inconvenience to parenteral desferrioxamine. The hypothesis of this study was that combining two oral chelators, deferiprone and deferasirox, might lead to similar results. Following approval by the hospital ethical committee and a written informed consent from each patient, 16 patients who fulfilled the criteria participated in a study protocol for a period of up to 2 years. Efficacy measures analysis demonstrated a statistically significant decrease of total body iron load as estimated by serum ferritin, LIC and MRI T2* indices. Regarding the safety assessment, the incidence of adverse events was minor compared to the associated toxicity of monotherapy of each drug. No new onset of iron overload-related complications was demonstrated. A reversal of cardiac dysfunction was observed in 2/4 patients, while the mean LVEF increased significantly. Regarding endocrine assessment, in 2/8 patients with impaired glucose tolerance, we noted a significant decrease in the mean 2 h glucose in OGTT. Additionally an improvement in gonadal function was observed and one male and one female gave birth to two healthy children without hormonal stimulation. Combined oral chelation in thalassemia offers the promise of easier administration, better compliance and may lead to an improvement of patient quality of life by preventing or even reversing iron overload complications.

-Thalassemia Mutations among Transfusion-Dependent Thalassemia Major Patients in Northern Iraq

Molecular defects responsible for β-thalassemias (thal) were investigated among 254 chromosomes from 127 transfusion-dependent unrelated thalassemic patients from two provinces in Northern Iraq. Among fourteen identified mutations, the seven most common found in 88.2% of the thal chromosomes were: IVS-II-1 (G → A), IVS-I-1 (G → A), codon 8 (−AA), codon 39 (G → T), codon 8/9 (+G), codon 44 (−C), and codon 5 (−CT). There were some notable differences in frequencies of various mutations in comparison to other Eastern Mediterranean populations, as well as between the two provinces studied. The latter illustrates the relative heterogeneity of the mutations distribution in Iraq, and the need to screen other areas of the country, to ensure establishing an effective prenatal program.

Bone Marrow Transplantation in Thalassemia Major Patients Using “Short” Anti-Thymocyte Globulin Therapy in Shiraz, Southern Iran

Allogeneic bone marrow transplantation (BMT) was performed on 113 Iranian transfusion-dependent thalassemia major patients from May 1993 through September 2003. To have at least 2 years follow-up, we report BMT on 90 patients transplanted up to December 2001. The donors were human leukocyte antigen (HLA)-identical, mixed lymphocyte culture (MLC)-nonreactive siblings ( n = 74) on parents ( n = 6); HLA-identical MLC-reactive siblings ( n = 5) or parents ( n = 1); and one HLA antigen-mismatched sibling ( n = 4). The induction regimen in 11 patients was oral busulfan (BU) (14 mg/kg) and IV cyclophosphamide (CY; 200 mg/kg); in fifteen patients it was BU (15 mg/kg) and cyclophosphamide (CY; 200 mg/kg); in 47 patients, BU (15 mg/kg), CY (200 mg/kg), and short course of anti-thymocyte globulin (ATG, horse; 40 mg/kg including 10 mg/kg on days −2, −1, +1, +2); and in 15 patients, BU (15 mg/kg) CY (200 mg/kg), and ATG (60 to 100 mg/kg; 10 mg/kg at 3 to 5 days before and after BMT). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and prednisolone. The group who received BU (14 mg/kg) and CY (200 mg/kg), as compared to the group receiving BU (15 mg/kg) and CY (200 mg/kg), was of younger age and lower risk; median age 7 versus 10 years, and 46% versus 7% in Lucarelli’s risk group class I (the best prognostic group), respectively. These patients showed a lower disease-free survival (DFS), namely 64% versus 73%, with a follow up of 2 to 10.5 years. Thus from 9.5 years ago, our standard protocol for BU has been 15 mg/kg. The group who received “short” ATG (40 mg/kg), BU (15 mg/kg), and CY (200 mg/kg) showed almost the same outcome as the group who received a higher dose of ATG (60 to 100 mg/kg), namely DFS 72% versus 73%, respectively, despite the fact that half of both groups were included in the Lucarelli’s risk group class III (the worst prognostic group) 49% versus 53%. We showed the same DFS for the patients who received BU (15 mg/kg), CY (200 mg/kg), and no ATG compared with the ATG group (73% vs 72%), but 27% of the group without ATG developed grade IV acute GVHD and 54% developed chronic GVHD. In the group with short ATG, 15% and 17% of patients developed grade IV acute and chronic GVHD, respectively. There was no significant difference for falls in platelets and white blood cell or engraftment days and the number of packed red blood cell transfusions among the groups. The median hospital stay was longer for the group with BU (15 mg/kg), CY (200 mg/kg) namely 81 versus 61 to 65 days. Second bone marrow infusions were needed in 6% and 20% of patients who received ATG doses of (40 versus 60 to 100 mg/kg; respectively (1 to 2 month post-BMT). BU at a dose of 15 mg/kg was more effective than 14 mg/kg BU for its myeloablative properties. By adding “short” ATG course to the conditioning regimen, the incidence of grade IV acute and chronic GVHD was reduced in thalassemic patients, especially when an HLA disparity was present.

Iron status and oxidative stress in beta-thalassemia patients in Jakarta.

A study on thalassemia intermedia and major patients in Jakarta was initiated to obtain a comprehensive picture of metabolic dysregulation, iron overload, oxidative stress, and cell damage. Data are presented from a group of 14 transfusion-dependent patients in an age range of 11-25 years (T) and another group of 9 frequently transfused (for at least 15 years) patients aged 17-30 years (L). A third group comprised 6 patients (aged 7 to 14 years) who had not yet obtained transfusions (N). The 21 controls (C) were voluntary students without diagnosis or clinical signs of thalassemia up to 30 years of age. The study was approved by the Ethical Clearance Board of the Medical Faculty and all blood samples from controls and patients were obtained on fully informed consent. Levels of antioxidants (vitamins A, C, E and beta-carotene) and reactive thiols are considerably decreased in transfused patients, whereas signs of iron overload and cell damage are increased (serum iron, ferritin, transferrin saturation, SGOT, SGPT, gamma-GT, bilirubin). Results can be summarized that non-transfused thalassemia intermedia patients exert slight signs of oxidative stress, and increased hemoglobin degradation but no significant indication of tissue or cell damage. This picture differs considerably from transfusion-dependent thalassemia major patients: highly significant decrease in antioxidants and thiols and tremendous iron overload and cell damage. The picture is even worsened in long-term transfused patients. Iron chelation after transfusion is not sufficient in Indonesia, because it is normally (with few exceptions) applied only once together with transfusion. Hence, one major reason of the bad condition of transfusion-dependent thalassemia patients in Indonesia appears to be frequent transfusions (on the average one per month) and insufficient chelation of one treatment per month together with transfusion.

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.

Chronic liver disease in transfusion-dependent thalassemia: liver iron quantitation and distribution.

The quantitative and/or qualitative distribution of liver iron was assessed in 81 transfusion-dependent thalassemia major patients with chronic liver disease (36 with chronic active hepatitis, 23 with chronic persistent hepatitis, 22 with siderosis). Viral marker studies showed only 3 cases with both HBsAg and anti-HBc positivity in the serum, while the others had anti-HBc and anti-HBs or only anti-HBs or no B viral markers. A significantly higher iron overload was found in chronic hepatitis, particularly chronic active hepatitis, than in siderosis. The increased iron overload may be due to less intensive chelation treatment, higher intestinal absorption secondary to lower mean Hb levels, and/or to liver inflammation-dependent iron deposition. The liver iron overload in turn amy facilitate the development or persistence of chronic progressive liver disease.