A Hematopoietic Stem Cell Transplantation Startup in Iraqi Kurdistan: Results in Thalassemia Patients and Analysis of the Methodology.

In hemoglobinopathy-prone regions, like the Middle East, thalassemia is the most prevalent noncommunicable life-threatening disorder of children and is highly curable by hematopoietic stem cell transplantation (HSCT). Moreover, transplantation is very cost-effective, and HSCT programs can be established directly in middle-income countries (MICs) at a reduced cost while maintaining quality standards and outcomes consistent with international ones. The aim of the present study was to review and verify the efficacy of the applied methodology through the analysis of 47 consecutive matched-related HSCTs in children with thalassemia. In 2016, the first HSCT unit for adults and children with both malignant and nonmalignant diseases was developed in Iraqi Kurdistan, thanks to a capacity building project funded by the Italian Agency for Development Cooperation. Data on clinical activity were obtained from a cohort of patients treated in the newly established HSCT unit. Primary endpoints were overall survival (OS) and thalassemia-free survival (TFS). Startup of the HSCT unit was completed over a 3-year period. Assessing and meeting minimum requirements were crucial for the startup; moreover, a team of international health care professionals (HCPs), all experts in the field of HSCT, conducted the education and training phase, involving all the clinical and nonclinical professionals in the program. At a median follow-up of 2.6 years, the 3-year TFS and OS were 82.8% (SE, 5.5%) and 87.1% (SE, 4.9%), respectively. TFS and graft-versus-host-disease-free composite survival was 80.6% (SE, 5.8%). At present, the HSCT service is completely autonomous, and more than 250 transplants have been done in both adults and children. The minimal essential requirements for an HSCT startup may be affordable in many MICs. Our results for thalassemia are comparable with international data. A twinning program with an international group of experts and a capacity-building approach is crucial for the success of the program, a strategy that allows for rapid development of HSCT units.

An update on the US adult thalassaemia population: a report from the CDC thalassaemia treatment centres.

Thalassaemia is caused by genetic globin defects leading to anaemia, transfusion-dependence and comorbidities. Reduced survival and systemic organ disease affect transfusion-dependent thalassaemia major and thalassaemia intermedia. Recent improvements in clinical management have reduced thalassaemia mortality. The therapeutic landscape of thalassaemia may soon include gene therapies as functional cures. An analysis of the adult US thalassaemia population has not been performed since the Thalassemia Clinical Research Network cohort study from 2000 to 2006. The Centers for Disease Control and Prevention supported US thalassaemia treatment centres (TTCs) to compile longitudinal information on individuals with thalassaemia. This dataset provided an opportunity to evaluate iron balance, chelation, comorbidities and demographics of adults with thalassaemia receiving care at TTCs. Two adult cohorts were compared: those over 40 years old (n = 75) and younger adults ages 18-39 (n = 201). The older adult cohort was characterized by higher numbers of iron-related comorbidities and transfusion-related complications. By contrast, younger adults had excess hepatic and cardiac iron and were receiving combination chelation therapy. The ethnic composition of the younger cohort was predominantly of Asian origin, reflecting the demographics of immigration. These findings demonstrate that comprehensive care and periodic surveys are needed to ensure optimal health and access to emerging therapies.

Application of an optimized interpretation model in capillary hemoglobin electrophoresis for newborn thalassemia screening.

INTRODUCTION: Newborn screening is an important supplement to thalassemia control and prevention. Capillary electrophoresis (CE) technology has several advantages for thalassemia screening but with low sensitivity, especially for thalassemia carriers. This study aims to illustrate the application of an optimized interpretation model in newborn thalassemia screening by capillary hemoglobin electrophoresis. METHODS: Two thousand, two hundred fifty-eight neonates selected from four regions in China were enrolled and were screened for α-thalassemia and ß-thalassemia by capillary electrophoresis. Results were interpreted based on an optimized model integrated with multiple parameters. Molecular analysis was carried out in synchrony and used as the gold standard for the screening performance assessment. The consistency among different regions and thalassemia genotypes were also investigated. RESULTS: Among the 2258 neonates, 485 were identified to have a likely diagnosis of thalassemia, and 422 α-thalassemia, 80 ß-thalassemia, and 21 α/ß-thalassemia cases were confirmed by molecular analysis, including 277 α-thalassemia silent carriers, 135 α-thalassemia trait carriers, 10 Hemoglobin H disease, and 80 ß-thalassemia trait carriers. The screening sensitivity, specificity, positive, and negative predictive value for α-thalassemia and ß-thalassemia were 84.83%, 99.14%, 95.98%, 96.41%, and 88.75%, 98.73%, 76.34%, and 99.48%, respectively. The optimized interpretation model showed higher performance for thalassemia carriers, though some neonates with silent α-thalassemia genotypes (-α3.7 /αα, -α4.2 /αα, and αWS α/αα) and ß-28 /ßN genotype were still missed. The screening performance among different regions was comparable. CONCLUSIONS: Capillary hemoglobin electrophoresis with the optimized interpretation model shows reliable performance for newborn thalassemia screening. It is applicable to large-scale population screening.

Increased susceptibility to dextran sulfate-induced mucositis of iron-overload ß-thalassemia mice, another endogenous cause of septicemia in thalassemia.

Enterocyte damage and gut dysbiosis are caused by iron-overload in thalassemia (Thl), possibly making the gut vulnerable to additional injury. Hence, iron-overload in the heterozygous ß-globin deficient (Hbbth3/+) mice were tested with 3% dextran sulfate solution (DSS). With 4 months of iron-gavage, iron accumulation, gut-leakage (fluorescein isothiocyanate dextran (FITC-dextran), endotoxemia, and tight junction injury) in Thl mice were more prominent than WT mice. Additionally, DSS-induced mucositis in iron-overloaded mice from Thl group was also more severe than the WT group as indicated by mortality, liver enzyme, colon injury (histology and tissue cytokines), serum cytokines, and gut-leakage (FITC-dextran, endotoxemia, bacteremia, and the detection of Green-Fluorescent Producing Escherichia coli in the internal organs after an oral administration). However, Lactobacillus rhamnosus GG attenuated the disease severity of DSS in iron-overloaded Thl mice as indicated by mortality, cytokines (colon tissue and serum), gut-leakage (FITC-dextran, endotoxemia, and bacteremia) and fecal dysbiosis (microbiome analysis). Likewise, Lactobacillus conditioned media (LCM) decreased inflammation (supernatant IL-8 and cell expression of TLR-4, nuclear factor κB (NFκB), and cyclooxygenase-2 (COX-2)) and increased transepithelial electrical resistance (TEER) in enterocytes (Caco-2 cells) stimulated by lipopolysaccharide (LPS) and LPS plus ferric ion. In conclusion, in the case of iron-overloaded Thl, there was a pre-existing intestinal injury that wask more vulnerable to DSS-induced bacteremia (gut translocation). Hence, the prevention of gut-derived bacteremia and the monitoring on gut-leakage might be beneficial in patients with thalassemia.

A complication risk score to evaluate clinical severity of thalassaemia syndromes.

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients' treatment.

Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia.

Transfusion-dependent thalassaemia (TDT) requires red blood cell concentrates (RBCC) to prevent complications of anaemia, but carries risk of infection. Pathogen reduction of RBCC offers potential to reduce infectious risk. We evaluated the efficacy and safety of pathogen-reduced (PR) Amustaline-Glutathione (A-GSH) RBCC for TDT. Patients were randomized to a blinded 2-period crossover treatment sequence for six transfusions over 8-10 months with Control and A-GSH-RBCC. The efficacy outcome utilized non-inferiority analysis with 90% power to detect a 15% difference in transfused haemoglobin (Hb), and the safety outcome was the incidence of antibodies to A-GSH-PR-RBCC. By intent to treat (80 patients), 12·5 ± 1·9 RBCC were transfused in each period. Storage durations of A-GSH and C-RBCC were similar (8·9 days). Mean A-GSH-RBCC transfused Hb (g/kg/day) was not inferior to Control (0·113 ± 0·04 vs. 0·111 ± 0·04, P = 0·373, paired t-test). The upper bound of the one-sided 95% confidence interval for the treatment difference from the mixed effects model was 0·005 g/kg/day, within a non-inferiority margin of 0·017 g/kg/day. A-GSH-RBCC mean pre-transfusion Hb levels declined by 6·0 g/l. No antibodies to A-GSH-RBCC were detected, and there were no differences in adverse events. A-GSH-RBCCs offer potential to reduce infectious risk in TDT with a tolerable safety profile.

Increased sympathovagal imbalance evaluated by heart rate variability is associated with decreased T2* MRI and left ventricular function in transfusion-dependent thalassemia patients.

Early detection of iron overload cardiomyopathy is an important strategy for decreasing the mortality rate of patients with transfusion-dependent thalassemia (TDT). Although cardiac magnetic resonance (CMR) T2* is effective in detecting cardiac iron deposition, it is costly and not generally available. We investigated whether heart rate variability (HRV) can be used as a screening method of iron overload cardiomyopathy in TDT patients. HRV, evaluated by 24-h Holter monitoring, non-transferrin bound iron (NTBI), serum ferritin, left ventricular (LV) ejection fraction (LVEF), and CMR-T2* were determined. Patients with a cardiac iron overload condition had a significantly higher low frequency/high frequency (LF/HF) ratio than patients without a cardiac iron overload condition. Log-serum ferritin (r = -0.41, P=0.008), serum NTBI (r = -0.313, P=0.029), and LF/HF ratio (r = -0.286, P=0.043) showed a significant correlation with CMR-T2*, however only the LF/HF ratio was significantly correlated with LVEF (r = -0.264, P=0.043). These significant correlations between HRV and CMR-T2* and LVEF in TDT confirmed the beneficial role of HRV as a potential early screening tool of cardiac iron overload in thalassemia patients, especially in a medical center in which CMR T2* is not available. A larger number of TDT patients with cardiac iron overload are needed to confirm this finding.

What can we learn from ineffective erythropoiesis in thalassemia?

Erythropoiesis is a dynamic process regulated at multiple levels to balance proliferation, differentiation and survival of erythroid progenitors. Ineffective erythropoiesis is a key feature of various diseases, including ß-thalassemia. The pathogenic mechanisms leading to ineffective erythropoiesis are complex and still not fully understood. Altered survival and decreased differentiation of erythroid progenitors are both critical processes contributing to reduced production of mature red blood cells. Recent studies have identified novel important players and provided major advances in the development of targeted therapeutic approaches. In this review, ß-thalassemia is used as a paradigmatic example to describe our current knowledge on the mechanisms leading to ineffective erythropoiesis and novel treatments that may have the potential to improve the clinical phenotype of associated diseases in the future.

Is the Benefit-Risk Ratio for Patients with Transfusion-Dependent Thalassemia Treated by Unrelated Cord Blood Transplantation Favorable?

Transfusion-dependent thalassemia (TDT) is an inherited disorder characterized by absent or defective production of α- or ß-hemoglobin chains. If untreated, the disease invariably culminates in death in early infancy due to cardiac failure or overwhelming infection. Although there is clear evidence of good health-related quality of life and return to normal life style, the choice to undergo hematopoietic stem cell transplantation (HSCT) remains a challenge because of the potential risk of transplant-related mortality (TRM) in TDT. Successful hematopoietic stem cell transplantation may cure the hematological manifestations of TDT, but introduces risks of TRM and morbidity. The low incidence of graft-versus-host disease (GVHD) provides the major rationale for pursuing unrelated cord blood transplantation (CBT). Considerable evidence suggests a lower rate of recurrence after CBT than after transplantation from adult donors. As the TRM, overall survival, and thalassemia-free survival for CBT improve, the utility of this stem cell source will expand to indications that have hitherto rarely used unrelated CBT. This paper summarizes the current progress in understanding the advances in unrelated CBT for thalassemia. Although as yet only in a limited number of patients, the results of unrelated CBT for thalassemia are encouraging.

[Thalassaemia and pregnancy].

Global migration has resulted in a larger geographical spread of people with risk of hereditary anaemias. This leads to an increased incidence of pregnant women with rare diseases, including thalassaemia also in Scandinavia. Thalassaemia can cause severe anaemia and other complications during pregnancy, like risk of miscarriage, intrauterine fetal death, abruptio, intrauterine growth retardation, hypertension, gestational diabetes and pre-eclampsia. In this article, we focus on the aetiology, assessment, antenatal care and treatment of pregnant women with thalassaemia.

Progress Toward the Control and Management of the Thalassemias.

Because of the particularly high frequency of different severe forms of both α and ß thalassemia in Asia, the development of approaches for their prevention and management is particularly challenging. However, because of earlier partnerships with richer countries, so-called North/South partnerships, and help from their governments, considerable progress toward the better control of the thalassemias has been achieved in some countries. It is vital that the global health importance of the thalassemias and related disorders, by far the commonest genetic diseases, is emphasized to the appropriate international health agencies.

EVALUATION OF RED BLOOD CELL INDICES RELATED DISORDERS AMONG ELIGIBLE BLOOD DONORS AT THE UNIVERSITI PUTRA MALAYSIA (UPM).

Pre-donation screening declarations and hemoglobin (Hb) testing are measures used to determine the quality of donated blood. The copper sulphate (CuSo4) method used to screen for blood abnormalities can give inaccurate results if strict quality control is not applied. Blood donors who are carriers of thalassemia and those with mild iron deficiency anemia (IDA) are usually asymptomatic and frequently missed at blood donation. The aim of this study was to evaluate the red blood cell (RBC) indices related disorders among blood donors who were deemed qualified to donate blood after screening with CuSo4 method. One hundred fifty-eight volunteer blood donors at the Universiti Putra Malaysia (UPM), who had passed the CuSo4 screening method, were recruited for this study. Their bloods specimens were examined with a complete blood count. Subjects with a low mean corpuscular hemoglobin (MCH) level were examined further by checking a serum ferritin level, Hb quantification, and molecular analysis to examine for common RBC disorders. Fourteen point six percent of subjects had a low Hb level, two (1.3%) had IDA and four (2.5%) had thalassemia or some other hemoglobinopathy. Using a MCH level < 27 pg as a cut-off point, 58 subjects (36.7%) had suspected IDA, thalassemia or some other hemoglobinopathy. Eight point nine percent of subjects with a normal Hb level had thalassemia, and 3.8% had IDA. Malaysia has a high prevalence of thalassemia and other hemoglobinopathies. Pre-donation accurate screening is crucial to protect the quality of blood transfusion products. Public education regarding RBC disorders especially among blood donors is important.

Thalassemia bone disease: a 19-year longitudinal analysis.

Thalassemia is an inherited disorder of alpha or beta globin chain synthesis leading to ineffective erythropoiesis requiring chronic transfusion therapy in its most severe form. This leads to iron overload, marrow expansion, and hormonal complications, which are implicated in bone deformity and loss of bone mineral density (BMD). In this 19-year retrospective longitudinal study, the relationships between BMD (determined by dual-energy X-ray absorptiometry) and risk factors for osteoporosis in 277 subjects with transfusion-dependent thalassemia were examined. The mean age at first review was 23.2 ± 11.9 years and 43.7% were male. Hypogonadism was present in 28.9%. Fractures were confirmed in 11.6% of subjects and were more frequent in males (16.5%) compared with females (7.7%). Lumbar spine (LS), femoral neck (FN), and total body (TB) Z-scores were derived. Patients with transfusion-dependent thalassemia had a significant longitudinal decline in BMD at the FN and TB. In the linear mixed-model analysis of BMD and risk factors for bone loss, FN Z-score was more significantly associated with risk factors compared with the LS and TB. The rate of decline at the FN was 0.02 Z-score per year and was 3.85-fold greater in males. The decline in FN Z-score over the last 5 years (years 15 to 19) was 2.5-fold that of the previous 7 years (years 8 to 14) and coincided with a change in iron chelator therapy from desferrioxamine to deferasirox. Hemoglobin (Hb) levels positively correlated with higher TB and LS Z-scores. In conclusion, the FN is the preferred site for follow-up of BMD. Male patients with ß-thalassemia experienced a greater loss of BMD and had a higher prevalence of fractures compared with females. Transfusing patients (particularly males) to a higher Hb target may reduce the decline in BMD. Whether deferasirox is implicated in bone loss warrants further study.

Sobrecarga de hierro en enfermedades hematológicas y no hematológicas: una bomba de tiempo / Iron overload in hematological and no hematological disease: a time bomb

La sobrecarga de hierro es una complicación frecuente en un número importante de enfermedades hematológicas que cursan con anemia y requieren transfusiones sanguíneas como parte de su terapia. Entre ellas se destacan la talasemia, la drepanocitosis, los síndromes mielodisplásicos, la anemia de Blackfan-Diamond, la anemia de Fanconi y la deficiencia de piruvato quinasa, La sobrecarga de hieroo tambiún se presenta en otras enfermedades tales como la hemocromatosis hereditaria, la hepatitis viral, el síndrome metabólico y determinados trastornos neurovegetativos. El diagnóstico de sobrecarga suele hacerse mediante la determinación del hierro sérico no unido a la transferrina, la ferritina sérica y un aumento de la concentración hepática de hierro. Las consecuencias más importantes del efecto tóxico de un exceso de hierro son las disfunciones cardíacas y endocrinas, debidas al efecto oxidante del hierro sobre las membranas celulares, con el consiguiente daño celular. Tales alteraciones contribuyen al incremento de la morbilidad y la mortalidad en estos pacientes. El tratamiento consiste básicamente en el usode agentes quelantes de hierro que facilitan la excreción del exceso del metal y reducen su efecto tóxico, Entre tales agentes se cuentan la deferrioxamina (de uso intravenoso). y móa recientemente el deferiprone (ambos de uso orak)

Iron overload is a frequent complication in patients with hematological diseases which develop anemía and require blood transfusion as a therapeutic measure. Thalassemia, drepanocytosis, myelodisplastic syndromes, Blackfan-Diamond anemia, Franconi anemia and pyruvate kinase deficiency are the most common of these diseases. Iron overload is the hallmark of hereditary hemochromatosis, and also complicates diseases such as viral hepatitis, the metabolic syndrome, and certain neurovegetative disfunctions. The diagnosis of iron overload is commonly established through the evaluation of serum iron, transferrin saturation, serum ferritin and liver iron concentration. Cardiac and endocrine dysfunctions are the most important consequences of the toxic efffect of iron accumulation; these are due to the oxidixing effect of iron upon the cellular membranes, followed by cellular damage. Such alterations contribute to the increased morbility and mortality rates in these patients. The treatment of iron overload is based mainly on the use of iron chelators which facilitate the excretion of iron excess and reduce its toxic effect. Deferrioxamine (for intravenous use), and more recently deferiprone and deferasirox (both for oral administration) are the drugs of choice

Non-transfusion-dependent thalassemias.

Non-transfusion-dependent thalassemias include a variety of phenotypes that, unlike patients with beta (ß)-thalassemia major, do not require regular transfusion therapy for survival. The most commonly investigated forms are ß-thalassemia intermedia, hemoglobin E/ß-thalassemia, and α-thalassemia intermedia (hemoglobin H disease). However, transfusion-independence in such patients is not without side effects. Ineffective erythropoiesis and peripheral hemolysis, the hallmarks of disease process, lead to a variety of subsequent pathophysiologies including iron overload and hypercoagulability that ultimately lead to a number of serious clinical morbidities. Thus, prompt and accurate diagnosis of non-transfusion-dependent thalassemia is essential to ensure early intervention. Although several management options are currently available, the need to develop more novel therapeutics is justified by recent advances in our understanding of the mechanisms of disease. Such efforts require wide international collaboration, especially since non-transfusion-dependent thalassemias are no longer bound to low- and middle-income countries but have spread to large multiethnic cities in Europe and the Americas due to continued migration.

How I treat thalassemia.

The purpose of this article is to set forth our approach to diagnosing and managing the thalassemias, including ß-thalassemia intermedia and ß-thalassemia major. The article begins by briefly describing recent advances in our understanding of the pathophysiology of thalassemia. In the discussion on diagnosing the condition, we cover the development of improved diagnostic tools, including the use of very small fetal DNA samples to detect single point mutations with great reliability for prenatal diagnosis of homozygous thalassemia. In our description of treatment strategies, we focus on how we deal with clinical manifestations and long-term complications using the most effective current treatment methods for ß-thalassemia. The discussion of disease management focuses on our use of transfusion therapy and the newly developed oral iron chelators, deferiprone and deferasirox. We also deal with splenectomy and how we manage endocrinopathies and cardiac complications. In addition, we describe our use of hematopoietic stem cell transplantation, which has produced cure rates as high as 97%, and the use of cord blood transplantation. Finally, we briefly touch on therapies that might be effective in the near future, including new fetal hemoglobin inducers and gene therapy.

Prevalence, incidence and types of mild anemia in the elderly: the "Health and Anemia" population-based study.

BACKGROUND: Hemoglobin concentrations slightly below the lower limit of normal are a common laboratory finding in the elderly, but scant evidence is available on the actual occurrence of mild anemia despite its potential effect on health. The objectives of this study were to estimate the prevalence and incidence of mild grade anemia and to assess the frequency of anemia types in the elderly. DESIGN AND METHODS: This was a prospective, population-based study in all residents 65 years or older in Biella, Italy. RESULTS: Blood test results were available for analysis from 8,744 elderly. Hemoglobin concentration decreased and mild anemia increased steadily with increasing age. Mild anemia (defined as a hemoglobin concentration of 10.0-11.9 g/dL in women and 10.0-12.9 g/dL in men) affected 11.8% of the elderly included in the analysis, while the estimated prevalence in the entire population was 11.1%. Before hemoglobin determination, most mildly anemic individuals perceived themselves as non-anemic. Chronic disease anemia, thalassemia trait, and renal insufficiency were the most frequent types of mild anemia. The underlying cause of mild anemia remained unexplained in 26.4% of the cases, almost one third of which might be accounted for by myelodysplastic syndromes. In a random sample of non-anemic elderly at baseline (n=529), after about 2 years, the annual incidence rate of mild anemia was 22.5 per 1000 person-years and increased with increasing age. CONCLUSIONS: The prevalence and incidence of mild anemia increase with age and mild anemia affects more than one out of ten elderly individuals. Unexplained anemia is common and may be due to myelodysplastic syndromes in some cases.

[Vibrio vulnificus infection outside of the fish ponds in northern Israel: acquisition in the "Einot Tzukim" springs near the Dead Sea].

Vibrio vulnificus is a Gram-negative bacterium that may cause severe skin and systemic infection after exposure of open wounds to contaminated water, especially in patients with underlying disease such as immune-deficiency, iron overload or end stage liver or renal disease. The V. vulnificus infection has been reported in Israel almost exclusively after exposure to Tilapia fish cultivated in fresh water fish ponds in northern Israel. The authors report the first case of V. vulnificus infection acquired in a nature reserve in southeastern Israel, with no connection to fish handling. A 14.5-years-old girl with transfusion-dependant thalassemia major presented with high fever and a rapidly progressive bullous cellulitis of the ankle. The infection occurred around a cut on the left lateral malleolus, after bathing in the fresh water ponds of Einot Tzukim (Ein Feshcha) in south-eastern Israel, and progressed despite the use of broad-spectrum antibiotics. Blood and wound cultures eventually yielded Vibrio vulnificus and appropriate treatment was commenced. The fever subsided after a few days but resolution of the local findings was very gradual and lasted for weeks. The presence of V. vulnificus in natural springs far from the northern artificial fish ponds broadens the danger of this infection. We find it prudent to advise people at risk for V. vulnificus infection, such as those suffering from immunedeficiency, iron overload and end stage liver or renal disease, to refrain from bathing in natural ponds whilst injured.

Northern California Comprehensive Thalassemia Center

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