Hematopoietic Stem Cell Transplantation in Patients with Hemoglobinopathies.

Hemoglobinopathies are the most common single-gene diseases and are estimated to affect millions of people worldwide. Thalassemia and sickle cell disease are the most prevalent diseases of this group. Today, despite the decreasing number of newborns diagnosed with a hemoglobinopathy, it remains an important health problem for many countries. Although regular red blood cell (RBC) transfusions, advanced iron chelation, and supportive therapy alternatives have improved life expectancy, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with hemoglobinopathies to prevent irreversible organ damage. Modern transplantation approaches and careful posttransplantation follow-up of patients have improved survival outcomes, and HSCT has now been performed in several patients with hemoglobinopathies worldwide. Considering current experiences, hematopoietic stem cell transplantation is recommended in cases of ß-thalassemia (ß-thal) in the presence of a matched family or unrelated donor, without secondary organ damage due to transfusion. In patients with sickle cell anemia, transplantation indications include transfusion dependence and cases of secondary organ damage. Recently, gene therapy as a possible treatment option has yielded promising results, though it is not in routine clinical use at its current stage.

Race and socioeconomic status in pediatric allogeneic hematopoietic cell transplantation for nonmalignant conditions.

BACKGROUND: Survival disparities by race/ethnicity and socioeconomic status (SES) are observed in a wide range of pediatric treatment settings including oncology and solid organ transplantation. To date, few studies have examined the effects of race and SES on outcomes in pediatric allogeneic hematopoietic cell transplantation (HCT). We explored whether survival differed by race/ethnicity or SES in children receiving HCT for nonmalignant conditions at a single institution serving a diverse patient population. PROCEDURES: The Kaplan-Meier method was used to estimate overall survival (OS) with the log-rank test for between-group comparisons. Cox proportional hazards models were used to identify risk factors for OS, adjusting for treatment- and disease-related factors. RESULTS: Of 133 subjects, 0 to 21 years, 19% were non-Hispanic (NH) white, 34% were NH black, 40% were Hispanic, and 7% were Asian. Sixty-seven percent of the subjects had public insurance; 49% lived in neighborhoods with poverty rate ≥20%. Primary diagnoses included hemoglobinopathies (56%), bone marrow failure (22%), and other conditions (22%). Median follow-up was 5.8 years (range 0.1-14.5). Analysis revealed no difference in OS by race, insurance type, or neighborhood SES. CONCLUSIONS: Findings from this single-institution study suggest that in pediatric patients undergoing HCT for nonmalignant conditions, treatment at a tertiary care center with a multidisciplinary approach may mitigate drivers of disparities observed in other settings. Additional studies are now needed to further elucidate the complex interrelationships among race, SES, and clinical outcomes for children undergoing HCT.

Non-myeloablative matched sibling stem cell transplantation with the optional reinforced stem cell infusion for patients with hemoglobinopathies.

BACKGROUND: The NIH protocol for non-myeloablative (NMA) conditioning allogeneic stem cell transplantation (alloSCT) with alemtuzumab and low-dose total body irradiation corrected the abnormal sickle cell disease (SCD) phenotype without the risk of graft-versus-host disease. However, alloSCT using NMA conditioning had been rarely applied to ß-thalassemia major (ß-TM) patients. METHODS: To avoid prolonged immunosuppression, we developed a two-stage strategy. Mixed donor chimerism was initially achieved using the protocol developed by the NIH protocol. Thereafter, we facilitated donor chimerism using the optional reinforced stem cell (SC) infusion in cases requiring protracted immunosuppression or experiencing impending graft failure. RESULTS: In this study, ß-TM (n = 9) and SCD (n = 4) patients were equally effectively treated with eradicating the abnormal hemoglobin phenotype. Five patients, including four ß-TM, achieved stable mixed chimerism without receiving optional reinforced SC infusion. All patients that received optional reinforced infusion achieved complete (n = 4) or mixed chimerism (n = 1). The overall survival rate and event-free survival at 4 years were 91.7% (95% CI; 53.9-98.8) in both groups, with a thalassemia-free survival rate in ß-TM patients of 87.5% (95% CI; 38.7-98.1). CONCLUSION: This study is the first to report successful NMA conditioning alloSCT to achieve stable mixed chimerism correcting the abnormal hemoglobin phenotype in adult ß-TM patients.

Haploidentical HSCT for hemoglobinopathies: improved outcomes with TCRαß+/CD19+-depleted grafts.

We examined outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) using T-cell receptor αß+ (TCRαß+)/CD19+-depleted grafts (TCR group, 14 patients) in children with hemoglobinopathies. Patients received a preparative regimen consisting of busulfan, thiotepa, cyclophosphamide, and antithymocyte globulin preceded by fludarabine, hydroxyurea, and azathioprine. The median follow-up among surviving patients was 3.9 years. The 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 84% and 69%, respectively. The incidence of graft failure was 14%. We compared outcomes to a historical group of 40 patients with hemoglobinopathies who received CD34+-selected grafts (CD34 group). The median follow-up of surviving patients for the CD34 group was 7.5 years. The 5-year probabilities of OS and DFS were 78% and 39%, respectively. The CD34 group had a significantly higher incidence of graft failure (45%) than the TCR group (14%) (P = .048). The incidences of grades 2 to 4 acute graft-versus-host disease (GVHD) in the TCR and CD34 groups were 28% and 29%, respectively, and 21% and 10% (P = .1), respectively, for extensive chronic GVHD. Viral reactivation was common in both groups. The overall incidence of posttransplant lymphoproliferative disorders for the entire group was 16%. Among all patients, 5 developed autoimmune hemolytic anemia or thrombocytopenia, with the overall cumulative incidence of 11%. The 2 groups showed suboptimal CD4+ recovery within the first 6 months of transplantation with no significant difference between groups. These data demonstrate that TCRαß+/CD19+-depleted grafts are associated with a reduced incidence of graft failure, but delayed immune reconstitution and associated morbidity and mortality remain a significant challenge.

Kuwait bone marrow transplantation activities.

Kuwait is located in the Arabian Gulf and has a population of 3.5million. The stem cell transplantation program started in 2000. Autologous peripheral blood stem cell transplantation started first, as it was easier technically to establish. In 2011, the allogeneic program started with focus on acute leukemia and hemoglobinopathies. The success of both programs required teamwork and support of health planners. The Kuwait National Bone Marrow Registry was established in 2012. The issue of donor availability and drug shortage remain the two main obstacles for expanding the bone marrow transplantation program.

Long-Term Follow-Up after Reduced-Intensity Conditioning and Stem Cell Transplantation for Childhood Nonmalignant Disorders.

Reduced-intensity conditioning (RIC) before hematopoietic stem cell transplantation (HCT) in children could result in fewer complications during follow-up compared with myeloablative regimens. Hence, many RIC regimens are under investigation, but long-term follow-up is essential. We describe late follow-up beyond 2 years post-HCT in 43 children with nonmalignant disorders who underwent related or unrelated donor (56%) HCT on a multicenter study using a RIC regimen (alemtuzumab, fludarabine, and melphalan) followed by bone marrow (n = 30), peripheral blood (n = 3), or umbilical cord blood (n = 10) HCT for immune dysfunction, bone marrow failure, metabolic disorders, or hemoglobinopathy. Recipients (median age, 7.5 years; range, 3 to 26) underwent HCT 2 to 8 years (median, 3.1 years) before this report. Full donor (67%) or stable mixed chimerism (33%) was noted without late graft rejection. Five patients (12%) required systemic immunosuppression therapy (IST) beyond 2 years post-HCT for graft-versus-host disease (GVHD); 2 patients died 38 and 79 months later, whereas the others improved, enabling an IST wean. Overall, 17 complications were documented in 10 patients (23%). Complications not related to GVHD included hypothyroidism (n = 2), low grade neoplasms (n = 2), and delayed puberty (n = 1). One patient with GVHD had ovarian failure; all other postpubertal females resumed normal ovarian function. Twenty-seven of 28 school-age recipients were functioning at grade level. RIC HCT recipients thus had few regimen-related toxicities during long-term follow-up. However, objective long-term follow-up is still necessary to identify complications so timely intervention may be planned.

Allogeneic Stem Cell Transplantation in Congenital Hemoglobinopathies Using a Tailored Busulfan-Based Conditioning Regimen: Single-Center Experience.

Hematopoietic stem cell transplantation (HSCT) is the only proven curative option for patients with hemoglobinopathies, both thalassemia and sickle cell anemia (SCA). A busulfan-based myeloablative conditioning regimen is the standard of care for HSCT in these patients, although increased treatment-related morbidity, including veno-occlusive disease (VOD), has been demonstrated. Thirty-eight pediatric patients, median age 8 years (range, 6 months to 22 years), suffering from hemoglobinopathy were treated at Rambam Medical Center in Haifa, Israel, between 1998 and 2011. Thirty-four patients had thalassemia major and 4 had SCA. The 38 patients underwent 40 HSCTs, 34 of which were first transplants and 6 second transplants. Most transplants (32/40) were from matched sibling donors. Sources of stem cells were peripheral blood in 30 transplants, bone marrow in 7 transplants, and cord blood in 3 transplants. All received different customized busulfan-based conditioning regimens tailored by pharmacokinetic analysis of busulfan levels. Primary engraftment occurred in 37 of 40 transplants. Neutrophil engraftment (>.5 × 10(9)/L) occurred at a median of 15.3 days post-transplantation (range, 10 to 45). Platelet transfusion independence (>20 × 10(9)/L) occurred at a median of 22.3 days (range, 11 to 60). The rate of 5-year overall survival for thalassemia patients after first transplantation was 90.5% ± 5.3%. The rate of 5-year thalassemia-free survival was 81.7% ± 6.8%. Cumulative incidence of acute graft-versus-host disease (GVHD) was 17.6%. Rate of grades III to IV GVHD was 8.8%. Cumulative incidence of chronic GVHD was 23.5%, with 11.8% incidence of extensive chronic GVHD. One patient developed VOD. Full donor chimerism occurred in 36.4% of patients with class 1 + 2 thalassemia, compared with 78.6% in class 3 thalassemia (P = .049). Overall survival above 90% in patients undergoing their first transplant was demonstrated using busulfan-based conditioning regimens. The low incidence of VOD was probably due to busulfan area under the curve measurements and dose adjustment.

Burden of Hemoglobinopathies (Thalassemia, Sickle Cell Disorders and G6PD Deficiency) in Iran, 1990-2010: findings from the Global Burden of Disease Study 2010.

BACKGROUND: Hemoglobinopathies are known as the most common genetic disorders in Iran. The paper aims to provide global estimates of deaths and disability adjusted life years (DALYs) due to hemoglobinopathies in Iran by sex and age during 1990 to 2010 and describe the challenges due to limitations of the Global Burden of Disease Study 2010 (GBD 2010). METHODS: GBD 2010 estimates of the numbers of deaths and years of life lost (YLLs) due to premature mortality were calculated using the Cause of Death Ensemble model (CODEm). Years of life lost due to disability (YLDs) were computed by multiplication of prevalence, the disability weight for occurrence of sequelae, and the duration of symptoms. Prevalence was estimated through a systematic search of published and available unpublished data sources, with a Bayesian meta-regression model developed for GBD 2010. Disability weights were produced using collected data from population-based surveys. Uncertainty from all inputs was incorporated into the computations of DALYs using simulation methods. We aim to prepare and criticize the results of GBD 2010 and provide some recommendations for reaching better conclusions about the burden of hemoglobinopathies in Iran. RESULTS: Between 1990 and 2010, the overall deaths attributed to hemoglobinopathies decreased from 0.51% to 0.36% of total deaths, with the corresponding burden declining from 1% to 0.82% of total DALYs. There was a reduction in deaths and DALYs rates for all ages and the rates attributed to all ages followed the same pattern in Iranian men and women. The highest DALYs for hemoglobinopathies, thalassemia, sickle cell disorder, and glucose-6-phosphate dehydrogenase deficiency (G6PD-D) were found in those aged less than 5 years. The collective burden of all of these hemoglobin disorder was lower in 2010 than in 1990. CONCLUSION: Although the screening programs in Iran have been very successful in reducing the number of thalassemia patients between 1990 to 2010, in order to provide a better estimation of the burden of hemoglobin disorders, it is necessary to perform a national and sub-national study of hemoglobinopathies using multiple national and sub-national surveys.

Morbilidad y mortalidad de la hemoglobinopatía sc en el Instituto de Hematología e Inmunología: Experiencia de 36 años / Morbility and mortality of hemoglobinopathy sc at the Institute of Hematology and Immunology: Experience of 36 years

Introducción: la hemoglobinopatía SC es la segunda variante de la drepanocitosis más frecuente en Cuba; sin embargo, existen pocos trabajos dirigidos a su estudio. Objetivo: realizar una caracterización de la historia natural de lahemoglobinopatía HSC, Métodos: se realizó un estudio observacional, descriptivo, retrospectivo y longitudinal en 148 pacientes con hemoglobinopatía HSC seguidos al menos 2 años en el Instituto de Hematología e Inmunología (1973-2009). Se definieron los eventos hematológicos según las normas cubanas de la drepanocitosis y los exámenes complementarios se realizaron en condiciones basales del paciente. Se utilizó la prueba de Chi Cuadrado para determinar asociación entre variables. Los parámetros de laboratorio se compararon mediante la prueba t Student. Para la estimación de la sobrevida global (SG) se empleó el método de Kaplan Meier. Resultados: predominó el sexo femenino (56,1 por ciento). La crisis vasoclusiva dolorosa (91,2 por ciento) y el síndrome torácico agudo (35,1 por ciento) fueron las manifestaciones clínicas más frecuentes. El 10,8 por ciento presentó afecciones oftalmológicas (hemovítreo, retinopatía, desprendimiento de retina y catarata). La esplenomegalia predominó en los pacientes menores de 40 años y la hepatomegalia se encontró en todas las edades. Hubo 36 mujeres con embarazos sin mortalidad materna ni perinatal y 26 abortos (65,4 por ciento fueron espontáneos). La anemia fue ligera pero más acentuada en el sexo femenino. Las funciones hepática y renal, mostraron deterioro con la edad. La supervivencia global a los 50 años fue del 79 por ciento. La causa de muerte más frecuente fue la insuficiencia renal crónica. Conclusiones: el aumento de la calidad y expectativa de vida de la HSC en Cuba es el resultado de la atención médica multidisciplinaria y el fácil acceso a los servicios de urgencia

Introduction: hemoglobinophatySC (HSC) is the second most common variant of sickle cell disease in Cuba and the world; nevertheless, there are few studies aimed in this field. Objective: to make the characterization of the natural history of HSC. Methods: an observational, descriptive, retrospective and longitudinal study was performed in 148 patients with HSC followed for at least two years at the Institute of Hematology and Immunology in the period 1973-2009. Hematological events according to Cuban procedures in sickle cell disease were determined and complementary studies were performed. Results: there was a predominance of females (56.1 percent). Vasocclusive painful crises (91.2 percent) and acute chest syndrome (35.1 percent) were the most frequent clinical events. Ophthalmology affections were present in 10,8 percent (hemovitreous, retinopathy, retinal detachment and cataract). Splenomegaly was predominant in patients under 40 years and hepatomegaly was found in all ages. There were 36 women with pregnancies without maternal or perinatal mortality. From 26 abortions (65.4 percent were spontaneous). Anemia was mild but more pronounced in females. Liver and kidney functions showed deterioration with age. Overall survival at 50 years was 79 percent. The main cause of death was chronic renal failure. Conclusions: increasing the quality of life and life expectancy of HSC in Cuba is the result of multidisciplinary comprehensive care and easy access to emergency services

Morbilidad y mortalidad de la hemoglobinopatía sc en el Instituto de Hematología e Inmunología: Experiencia de 36 años / Morbility and mortality of hemoglobinopathy sc at the Institute of Hematology and Immunology: Experience of 36 years

Introducción: la hemoglobinopatía SC es la segunda variante de la drepanocitosis más frecuente en Cuba; sin embargo, existen pocos trabajos dirigidos a su estudio. Objetivo: realizar una caracterización de la historia natural de lahemoglobinopatía HSC, Métodos: se realizó un estudio observacional, descriptivo, retrospectivo y longitudinal en 148 pacientes con hemoglobinopatía HSC seguidos al menos 2 años en el Instituto de Hematología e Inmunología (1973-2009). Se definieron los eventos hematológicos según las normas cubanas de la drepanocitosis y los exámenes complementarios se realizaron en condiciones basales del paciente. Se utilizó la prueba de Chi Cuadrado para determinar asociación entre variables. Los parámetros de laboratorio se compararon mediante la prueba t Student. Para la estimación de la sobrevida global (SG) se empleó el método de Kaplan Meier. Resultados: predominó el sexo femenino (56,1 por ciento). La crisis vasoclusiva dolorosa (91,2 por ciento) y el síndrome torácico agudo (35,1 por ciento) fueron las manifestaciones clínicas más frecuentes. El 10,8 por ciento presentó afecciones oftalmológicas (hemovítreo, retinopatía, desprendimiento de retina y catarata). La esplenomegalia predominó en los pacientes menores de 40 años y la hepatomegalia se encontró en todas las edades. Hubo 36 mujeres con embarazos sin mortalidad materna ni perinatal y 26 abortos (65,4 por ciento fueron espontáneos). La anemia fue ligera pero más acentuada en el sexo femenino. Las funciones hepática y renal, mostraron deterioro con la edad. La supervivencia global a los 50 años fue del 79 por ciento. La causa de muerte más frecuente fue la insuficiencia renal crónica. Conclusiones: el aumento de la calidad y expectativa de vida de la HSC en Cuba es el resultado de la atención médica multidisciplinaria y el fácil acceso a los servicios de urgencia(AU)

Introduction: hemoglobinophatySC (HSC) is the second most common variant of sickle cell disease in Cuba and the world; nevertheless, there are few studies aimed in this field. Objective: to make the characterization of the natural history of HSC. Methods: an observational, descriptive, retrospective and longitudinal study was performed in 148 patients with HSC followed for at least two years at the Institute of Hematology and Immunology in the period 1973-2009. Hematological events according to Cuban procedures in sickle cell disease were determined and complementary studies were performed. Results: there was a predominance of females (56.1 percent). Vasocclusive painful crises (91.2 percent) and acute chest syndrome (35.1 percent) were the most frequent clinical events. Ophthalmology affections were present in 10,8 percent (hemovitreous, retinopathy, retinal detachment and cataract). Splenomegaly was predominant in patients under 40 years and hepatomegaly was found in all ages. There were 36 women with pregnancies without maternal or perinatal mortality. From 26 abortions (65.4 percent were spontaneous). Anemia was mild but more pronounced in females. Liver and kidney functions showed deterioration with age. Overall survival at 50 years was 79 percent. The main cause of death was chronic renal failure. Conclusions: increasing the quality of life and life expectancy of HSC in Cuba is the result of multidisciplinary comprehensive care and easy access to emergency services(AU)

Combined umbilical cord blood and bone marrow from HLA-identical sibling donors for hematopoietic stem cell transplantation in children with hemoglobinopathies.

BACKGROUND: It is well established that umbilical cord blood and bone marrow are biologically different stem cell sources. PATIENTS AND METHODS: We analyzed the feasibility and outcome of hematopoietic stem cell transplantation (HSCT) in 13 children (median age 5.9 years) with hemoglobinopathies after the co- infusion of cord blood (CB) and bone marrow (BM) from the same human leucocyte antigen (HLA) identical sibling donor. We also compared outcomes of children with co-transplantation to outcomes in children with hemoglobinopathies who had received a BM (n = 21) or CB (n = 22) transplant alone. RESULTS: Compared to CB transplant (CBT) recipients, the co-transplant group had more rapid neutrophil (17 vs. 25 days, P = 0.013) and platelet (29 vs. 48 days, P = 0.009) recovery and less transplant related mortality. Patients who received a co-transplant had a lower incidence of ≥ grade II acute (0% vs. 26.3%) and chronic (0% vs. 21%) graft versus host disease (GVHD) compared to BM transplant (BMT) recipients (P = 0.055 and 0.045, respectively). With a median follow-up of >60 months in each treatment group, the 5-year probability of event free survival (EFS) was 100% in the co-transplant group, 90% after BMT and 86% after CBT (P = 0.42). CONCLUSION: Co-transplantation of CB and BM from HLA-identical sibling donors appears to be a feasible and effective strategy to further optimize outcomes of HSCT for hemoglobinopathies.

A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.

Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).

Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.

Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobinopathies. These genetic traits--including hemoglobin S (HbS), hemoglobin C (HbC), and α-thalassemia--are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait). Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. These hemoglobin variants thus represent a "natural experiment" to identify the cellular and molecular mechanisms by which P. falciparum produces clinical morbidity, which remain partially obscured due to the complexity of interactions between this parasite and its human host. Multiple lines of evidence support a restriction of parasite growth by various hemoglobinopathies, and recent data suggest this phenomenon may result from host microRNA interference with parasite metabolism. Multiple hemoglobinopathies mitigate the pathogenic potential of parasites by interfering with the export of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of the host red blood cell. Few studies have investigated their effects upon the activation of the innate and adaptive immune systems, although recent murine studies suggest a role for heme oxygenase-1 in protection. Ultimately, the identification of mechanisms of protection and pathogenesis can inform future therapeutics and preventive measures. Hemoglobinopathies slice the "Gordian knot" of host and parasite interactions to confer malaria protection, and offer a translational model to identify the most critical mechanisms of P. falciparum pathogenesis.

A national registry of haemoglobinopathies in Greece: deducted demographics, trends in mortality and affected births.

Haemoglobinopathies are the most common hereditary disorders in Greece. Although there is a successful national prevention program, established 35 years ago, there is lack of an official registry and collection of epidemiological data for haemoglobinopathies. This paper reports the results of the first National Registry for Haemoglobinopathies in Greece (NRHG), recently organized by the Greek Society of Haematology. NRHG records all patients affected by thalassaemia major (TM), thalassaemia intermedia (TI), "H" Haemoglobinopathy (HH) and sickle cell disease (SCD). Moreover, data about the annual rate of new affected births along with deaths, between 2000 and 2010, are reported. A total of 4,506 patients are registered all over the country while the number of affected newborns was significantly decreased during the last 3 years. Main causes for still having affected births are: (1) lack of medical care due to financial reasons or low educational level; (2) unawareness of time limitations for prenatal diagnosis (PD); due either to obstetricians' malpractice or to delayed demand of medical care of couples at risk; and (3) religious, social or bioethical reasons. Cardiac and liver disorders consist main causes for deaths while life expectancy of patients lengthened after 2005 (p < 0.01). The NRHG of patients affected by haemoglobinopathies in Greece provides useful data about the haemoglobinopathies in the Greek population and confirms the efficacy of the National Thalassaemia Prevention Program on impressively decreasing the incidence of TM and sickle cell syndromes.

Long-term follow-up of children with confirmed newborn screening disorders using record linkage.

BACKGROUND: Long-term follow-up of children identified through newborn screening is a critical process of data collection and analysis for advancing the public health understanding of the health outcomes and service uptake of the affected children. This article describes first steps toward the long-term follow-up of newborn screening children with confirmed disorders through records linkage using population-based administrative data. METHODS: The study cohort consisted of children born in 2006-2007 with confirmed disorders identified through newborn screening. Deterministic data linkage methods were used for record matching. RESULTS: The cohort was followed up to 2 years after birth by matching to data sources including vital records, hospital discharges, the Congenital Malformations Registry, and Early Intervention to monitor service utilization, comorbidities, and mortality of the affected children. Of 1215 children with confirmed conditions identified through newborn screening, 25 deaths (2.1%) were identified, 86.1% used hospital (in- or outpatient) services, 36.1% were enrolled in the Congenital Malformations Registry, and 19.9% used the services of the Early Intervention program during the 2-year follow-up period. CONCLUSIONS: Long-term follow-up of children with disorders identified through newborn screening can be initiated by using existing administrative data. This method is an inexpensive, cost-effective. and efficient approach for periodical assessment of services utilization, the efficiency of service delivery, and health outcomes for affected individuals.

Recent advances in bone marrow transplantation in hemoglobinopathies.

Allogeneic hematopoietic cell transplantation (HCT) is currently the only treatment with curative potential for sickle cell disease (SCD) and beta-thalassemia. HCT was first used to treat SCD and thalassemia more than two decades ago, and with increasing experience this treatment modality has shifted from being an experimental intervention to one in which selected patient populations are targeted for treatment. Recent multicenter clinical studies show an event-free survival (EFS) of 85% after human leukocyte antigen (HLA)-identical sibling transplantation for SCD, using conventional myeloablative conditioning with a backbone of busulfan (BU) and cyclophosphamide (CY) [1-3]. Results of HCT for thalassemia show very similar outcomes, with EFS probabilities that range from 81%-87% [4,5]. However, the risk of graft failure, recurrent disease, graft-versus-host-disease (GVHD), infections, and long-term sequelae of chronic GVHD and endocrinopathies related to Fe overload and myeloablative BU limit broader application of this therapy. Non-myeloablative conditioning regimens may offer a lower risk of toxicity, and investigations to identify a regimen that is sufficiently immunosuppressive to ensure stable engraftment of donor cells are ongoing. Alternative sources of donor hematopoietic cells that include HLA-matched unrelated donor (URD) and umbilical cord blood (UCB), are being pursued for hemoglobinopathies, with promising initial results. This review discusses the successes, challenges and future direction of HCT for SCD and thalassemia.

Infant mortality and reproductive wastage associated with different genotypes of haemoglobinopathies in Orissa, India.

BACKGROUND: Haemoglobinopathies, including sickle-cell disease and thalassaemia syndrome, are a group of blood diseases mostly confined to tropical and subtropical regions of the world. The spectrum of haemoglobin variants is a group of commonly encountered genetic conditions, with an average frequency of 19.32% in Orissa, varying from region to region and from community to community depending upon the type of mating practices. AIM: For the first time, the infant mortality rate (IMR), i.e. the number of deaths under 1 year of age (in a given year) per thousand live births in a particular area, was studied to find the cause of the high IMR and to relate it to different genotypes of haemoglobinopathies. RESULTS: IMR was found to be higher in couples with sickle-cell trait (75.9), beta-thalassaemia (184.2), and sickle cell/beta-thalassaemia (70.2) compared to normal couples (26.3). The reproductive wastage (abortions, stillbirths and neonatal deaths) and the number of deaths of offspring below 1 year of age (infant mortality) and below 10 years of age (childhood mortality) among affected couples in such families were also statistically significantly higher compared to normal parents. CONCLUSIONS: The progeny of sickle-cell trait, beta-thalassaemia trait, and sickle cell/beta-thalassaemia couples contributes substantially to the high neonatal/IMR in the coastal state of Orissa in Central-Eastern India. This study has revealed that in comparison to normal couples, couples who were carriers of haemoglobinopathies had a greater reproductive wastage. Screening and genetic counselling could be an important factor in reducing IMR in rural India. The traits/carriers of haemoglobinopathies should, specifically, avoid marriages and mating for the better health of subsequent generations.

Ventajas de la esplenectomía en hemoglobinopatía infantil / Splenectomy advantages in infantile hemoglobinopathy

Se realiza un estudio retrospectivo, descriptivo y longitudinal donde se revisan 10 expedientes clínicos correspondientes a pacientes con afecciones hematológicas, a los cuales se les había realizado la esplenectomía parcial como parte de su tratamiento, en los archivos del Hospital Pediátrico Docente ¨Pedro Agustín Pérez” de Guantánamo, durante el período de tiempo comprendido desde el 1ro. de enero de 2000 hasta el 30 de junio de 2003. Se exponen los resultados en cuadros estadísticos, haciendo énfasis en los aspectos quirúrgicos. Se resalta la importancia del Levine, las transfusiones sanguíneas cuando son necesarias y los análisis complementarios, como el hemograma completo, glicemia, grupo y Rh, coagulograma completo, conteo de plaquetas y conteo de reticulocitos, en la preparación preoperatoria de los pacientes. Se efectúan comparaciones con estudios nacionales y extranjeros. En la presente serie se significan lasenfermedades hematológicas de base que presentaron los pacientes estudiados, la morbilidad, la mortalidad y la evolución postoperatoria, así como los beneficios del tratamiento quirúrgico. Se formulan conclusiones y recomendaciones al respecto.(AU)