Treatment Of Thalassemia Research Articles

Current standards and the latest developments in the treatment of thalassaemia

AbstractThalassaemia syndrome is an autosomal recessive inherited disease caused by impaired productions of the globin chains leading to chronic anaemia. In the last few decades, red blood cell transfusion, iron chelation therapy and allogeneic haematopoietic stem cell transplantation are three main treatment modalities in this disease. Advances in understanding the underlying basis of the thalassaemia disease have introduced several new innovative therapeutic approaches including modulating of erythropoiesis, modulating of iron metabolism and gene therapy. Preclinical studies of several novel therapeutic agents showed promising results. Currently, there are multiple ongoing clinical studies of these novel therapies in patients with thalassaemia. This review aims to summarize the key points of current standard treatment and the latest developments in the treatment of thalassaemia.

Gene characteristics and changing trend of neonatal thalassemia in Dongguan, China

To study the gene distribution characteristics of neonatal thalassemia in Dongguan, China and the changing trend of the gene distribution characteristics of neonates with thalassemia in Dongguan in 2014-2018. A retrospective analysis was performed for the data on neonatal thalassemia screening from the Dongguan Neonatal Disease Screening System between January 2014 and December 2018. A total of 616 718 neonates were enrolled who were born in Dongguan. Among the 616 718 neonates, 52 308 were positive for primary screening, 10 366 were recalled, 8 576 underwent genetic diagnosis, and 6 432 were confirmed with thalassemia by genetic diagnosis. The carrying rates of thalassemia genes in 2014-2018 were 5.81%, 5.47%, 5.96%, 6.91%, and 7.90% respectively, and showed an upward trend (P<0.001). The positive rates of neonatal thalassemia screening in 2014-2018 were 9.12%, 8.34%, 7.54%, 8.13%, and 9.32% respectively (P<0.001). The positive rates of genetic diagnosis of neonatal thalassemia in 2014-2018 were 0.89%, 1.11%, 1.24%, 0.90%, and 1.09% respectively (P<0.001). In 2014-2018, 5 098 cases of α-thalassemia were detected, accounting for 79.26% of all cases, and 1 230 cases of β-thalassemia were detected, accounting for 19.12% of all cases. The detection rate of α-thalassemia was significantly higher than that of β-thalassemia in each year (P<0.001). In 2014-2018, static α-thalassemia, mild α-thalassemia, and mild β-thalassemia were the main types observed in neonates. Most of the neonates with thalassemia have α-thalassemia in Dongguan, with static α-thalassemia and mild α-thalassemia as the main types. The carrying rate of thalassemia genes keeps increasing in neonates in Dongguan, and the prevention and treatment of thalassemia is still challenging.

Beta Thalassemia Major: Overview of Molecular Etiology, Pathophysiology, Current and Novel Therapeutic Approaches

Major beta thalassemia is a severe form of thalassemia caused by the alteration of two beta globin genes resulting in a defective synthesis of hemoglobin.&#x0D; It is characterized by chronic severe anemia, ineffective erythropoiesis (IE) and iron overload. However although the thransfusion and chelation assosciated constitute the basis of the traitement curently recommended, they do not allow always to control the iron overload induced by pathology and repeated transfusions.&#x0D; Hematopoietic stem cell transplantation (HSCT) has proven to be a definitive treatment for beta thalassemia. However, this procedure is confronted to immunological complications and the small nomber of histocompatible donors. In the face of these therapeutic blocks, much research has been undertaken in recent years leading to the development of a number of promising therapeutic strategies in order to reduce the constraints linked to current chronic treatments, and to move towards an access to healing for all patients. Among other three approaches are envisaged and are in the experimental phase: Gene therapy to restore globin chain imbalance, Improve ineffective erythropoiesis and Improve iron dysregulation. In this article we give a view on the pathophysiology, clinical manifestations, genetic origin of beta-thalassaemia major. The second part presents the therapeutic arsenal currently used, and its limits leading to therapeutic impasse. The last part explores the scientific tracks that present a real therapeutic potential in β-Thalassemia.

Outcome of Treatment with Thalidomide in Transfusion Dependent Thalassemia Patients: A Prospective Study in a Thalassemia Center, Dhaka, Bangladesh

The aim of the study was to assess the outcome of thalidomide in patients with Thalassemia. Method: We identified the outcome of thalidomide in 51 patients with thalassemia needing blood transfusion. We enlisted thalassemia patients, who received treatment with thalidomide between 01 July 2017 and 29 Feb 2020 in Combined Military Hospital, Dhaka. Thalidomide was used in a reduced dose (2 mg/ kg to 5 mg/kg). Thalidomide had been stopped in those patients who developed complications. The following factors were recorded: age and sex, hemoglobin (Hb) levels, ferritin level, blood transfusion interval before and after treatment with thalidomide. Furthermore, we documented blood transfusion dependence and the complications subsequently. All data were studied using SPSS v 24.0 (SPSS Inc. Chicago, IL, U.S.A.). For patients, a paired sample t-test was used to compare the changes in the mean Hb level, ferritin level and the difference in blood transfusion interval before and after treatment with thalidomide. P < 0.05 was considered statistically significant. Results: The study included 51 patients comprised of 23 females (45.1%) and 28 males (54.9%) with an age ranging from 3 to 24 years (9.75±4.11 years). Amongst them 18% (n=9) were beta-thalassemia and 82% (n=42) were Hb E beta-thalassemia. Data of Hb and ferritin levels before and after treatment were recorded in all 51 patients. Ferritin levels reduced to 20.52% (3258.11±2291.91 ng/ml to 2589.65± 2072.74 ng/ml). Hb level increased by 19.26% (7.04±0.53 g/dL to 8.39±1.44g/dL). We found 18 (35.3%) patients with no requirement of blood transfusion after the treatment. 63% (n=32) of the patients showed no adverse effect of thalidomide after the treatment. 16% (n=8) of the patients showed high ALT (Alaline Aminotransferase) and 6% (n=3) showed excessive sleepiness. Other effects included- high TSH, acute urticaria, restlessness, edema, facial puffiness, palpitation, and vomiting. Conclusion: Treatment with thalidomide considerably improved Hb level, increased blood transfusion interval even resulted to non-dependence on blood transfusion and reduced ferritin levels. More studies are necessary to clarify the possible use of thalidomide in the treatment of thalassemia.

THE HISTORY OF DEFERIPRONE (L1) AND THE COMPLETE TREATMENT OF IRON OVERLOAD IN THALASSAEMIA

Deferiprone (L1) was originally designed, synthesised and screened in vitro and in vivo in 1981 by Kontoghiorghes G. J. following his discovery of the novel alpha-ketohydroxypyridine class of iron chelators (1978–1981), which were intended for clinical use. The journey through the years for the treatment of thalassaemia with L1 has been a very difficult one with an intriguing turn of events, which continue until today. Despite many complications, such as the extensive use of L1 suboptimal dose protocols, the aim of chelation therapy-namely, the complete removal of excess iron in thalassaemia major patients, has been achieved in most cases following the introduction of specific L1 and L1/deferoxamine combinations. Many such patients continue to maintain normal iron stores. Thalassemia has changed from a fatal to chronic disease; also thanks to L1 therapy and thalassaemia patients are active professional members in all sectors of society, have their own families with children and grandchildren and their lifespan is approaching that of normal individuals. No changes in the low toxicity profile of L1 have been observed in more than 30 years of clinical use and prophylaxis against the low incidence of agranulocytosis is maintained using mandatory monitoring of weekly white blood cells’ count. Thousands of thalassaemia patients are still denied the cardioprotective and other beneficial effects of L1 therapy. The safety of L1 in thalassaemia and other non-iron loaded diseases resulted in its selection as one of the leading therapeutics for the treatment of Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration and other similar cases. There are also increasing prospects for the application of L1 as a main, alternative or adjuvant therapy in many pathological conditions including cancer, infectious diseases and as a general antioxidant for diseases related to free radical pathology.

Pengalaman Ibu Merawat Anak Thalasemia di RSUD Dr.Slamet Garut

Thalasemia adalah kelainan darah yang diturunkan dari orangtuanya, anak dengan thalasemia harus melakukan tranfusi darah secara rutin yang mengakibatkan kelebihan zat besi, selain itu juga harus mengomsumsi obat kelasi besi untuk mengurangi kelebihan zat besi akibat keseringan tranfusi darah yang dilakukan seacra rutin dan jangka waktu lama. Adanya perawatan tranfusi dengan secara rutin. sehingga sangat perlu ibu mendampingi anaknya. Ibu tidak hanya melakukan aktivitas sehari-hari saja melainkan ibu sebagai perawat dimana merawat anak-anaknya yang sakit. sehingga sangat perlu ibu Selama perawatan dan Pengetahuan mengenai thalasemia sangat penting Metode yang digunakan pada penelitian ini adalah kualitatif dengan metode fenomologi dekriptif ini, bertujuan untuk mengeksplor pengalaman ibu merawat anak thalasemia. Hasil penelitian menunjukan 5 tema yaitu 1) Perasaan Ibu pertama mengetahui anaknya Thalasemia (kaget, syok, tidak menerima,menerima), 2) Upaya ibu Mengobati Anak, 3), kendala ibu merawat anak thalasemia, 4) Menerima kenyataan setelah melakukan pengobatan 5) Dukungan yang diperoleh ibu. Kesimpulan Diharapkan tenaga kesehatan termasuk perawat anak dapat memberikan pengetahuan dalam perawatan dan pengetahuan kepada keluarga terutama ibu yang mendampingi anaknya sealama perawatan.

Preclinical Evaluation of ALS20, a New and Improved Lentiviral Vector for Beta-Globinopathies

The ongoing clinical trials, based on the use of lenti-globin vectors for beta-globinopathies, indicate that current vectors require high number of integrations (~3-4 copies per genome) in a pancellular fashion to make a patient transfusion independent, regardless of the genotype. This increased VCN requirement could increase the risk of genome toxicity, limiting the application of these vectors and preventing their use in a reduced myeloablative regimen. To overcome this limitation we designed new vectors, using modification or inclusion of a variety of regulatory genomic elements aiming to increase expression of the beta-globin gene. We performed in vitro and in vivo studies to compare the ability of these constructs to express the therapeutic gene with a low number of integrations and reduced chimerism. We screened new constructs using a CRISPR-Cas9 modified clonal cell line, HUDEPM#13, which derives from the previously described erythroid HUDEP-2 cell line (Kurita, 2013). Upon differentiation, HUDEPM#13 cells produce a hemoglobin variant (HbMut) that can be discriminated by liquid chromatography from the adult hemoglobin (HbA) produced by the transgene in the lentiviruses. Among our candidates we identified a construct, indicated as ALS20, that synthesizes HbA at high level at a single integration (VCN). Moreover, ALS20 produced significantly more HbA per copy than constructs currently utilized in clinical trials, which were reproduced based on the literature (Negre, 2015; Miccio, 2008; and Boulad, 2014) and designated CV-1, CV-2, and CV-3, respectively. In erythroblasts differentiated in vitro from patients with SCD ALS20 produces, on average, 21% HbA at VCN=1(P&lt;0.001). CV1, which proved to be the most powerful among the clinical vectors tested in HUDEP#M13, produces, on average, 14.9% HbA at VCN=1 (P&lt;0.001). Overall, ALS20 expresses 40% more HbA per VCN in patients' cells, confirming results observed in the mutant HUDEP cell line. In a parallel potency assay, we tested ALS20 using beta0/beta0 thalassemic specimens, which represent the most severe phenotype to correct, due to complete absence of HbA production. Statistical analyses indicate that ALS20 produces, on average, 32.5% HbA at VCN=1 (P&lt;0.001). All results were obtained targeting a range between 0 and 3 integrations, using dilutions of the viral product. Our ongoing bone marrow transplantation studies, using a semi-myeloablative conditioning based on busulfan administration on the beta thalassemia Hbbth3/+mouse model, indicate that ALS20 is curative at VCN lower than 1. In fact, mice with an average of 0.8 copies per genome and 65% transgenic chimerism, present Hb levels of 13.6g/dL, reiterating the potential of this new lentivirus in vivo. In immunocompromised NSG mice, injection of human CD34+cells transduced with ALS20 did not trigger tumor formation or meaningful pathological changes. The safety of our vector has been further assessed using an in vitro immortalization assay on primary mouse BM cells, in which no clonal survival has been observed. Finally, genome integration analyses on human CD34+cells infected with ALS20 showed that none of the examined samples had clones that exceeded the 20% abundance threshold, in accordance with the expected level of safety for gene therapy-based approaches. In summary, we have identified a powerful new lentiviral vector with an enhanced ability to synthesize hemoglobin with a low number of integrations. ALS20's performance has been demonstrated in specimens from patients with hemoglobinopathies as well as in mice affected by thalassemia. Treatment of thalassemia and SCD with ALS20 could reduce the risk of cytotoxic events due to high levels of integration, and also lessen the intensity of the myeloablative regimen to correct anemia in patients. This, in addition with its confirmed safety features, makes this construct an outstanding candidate for clinical trial. Disclosures Kwiatkowski: Imara: Consultancy; Apopharma: Research Funding; Terumo: Research Funding; Novartis: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy. Rivella:Meira GTx, Ionis Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Disc medicine, Protagonist, LIPC, Meira GTx: Consultancy.

Complementary Base Editing Approaches for the Treatment of Sickle Cell Disease and Beta Thalassemia

Sickle cell disease (SCD) and Beta thalassemia are disorders of beta globin production and function that lead to severe anemia and significant disease complications across a multitude of organ systems. Autologous transplantation of hematopoietic stem cells engineered through the upregulation of fetal hemoglobin (HbF) or correction of the beta globin gene have the potential to reduce disease burden in patients with beta hemoglobinopathies. Base editing is a recently developed technology that enables precise modification of the genome without the introduction of double strand DNA breaks. Gamma globin gene promoters were comprehensively screened with cytosine and adenine base editors (ABE) for the identification of alterations that would derepress HbF. Three regions were identified that significantly upregulated HbF, and the most effective nucleotide residue conversions are supported by natural variation seen in patients with hereditary persistence of fetal hemoglobin (HPFH). ABEs have been developed that significantly increase the level of HbF following nucleotide conversion at key regulatory motifs within the HBG1 and HBG2 promoters. CD34+ hematopoietic stem and progenitor cells (HSPC) were purified at clinical scale and edited using a process designed to preserve self-renewal capacity. Editing at two independent sites with different ABEs reached 94 percent and resulted in up to 63 percent gamma globin by UPLC. The levels of HbF observed should afford protection to the majority of SCD and Beta thalassemia patients based on clinical observations of HPFH and non-interventional therapy that links higher HbF dosage with milder disease (Ngo et al, 2011 Brit J Hem; Musallam et al, 2012 Blood). Directly correcting the Glu6Val mutation of SCD has been a recent goal of genetic therapies designed for the SCD population. Current base editing technology cannot yet convert mutations like those that result from the A-T transversion in sickle beta globin; however, ABE variants have been designed to recognize and edit the opposite stranded adenine residue of valine. This results in the conversion of valine to alanine and the production of a naturally occurring variant known as Hb G-Makassar. Beta globin with alanine at this position does not contribute to polymer formation, and patients with Hb G-Makassar present with normal hematological parameters and red blood cell morphology. SCD patient fibroblasts edited with these ABE variants achieve up to 70 percent conversion of the target adenine. CD34 cells from healthy donors were then edited with a lead ABE variant, targeting a synonymous mutation in an adjacent proline that resides within the editing window and serves as a proxy for editing the SCD mutation. The average editing frequency was 40 percent. Donor myeloid chimerism documented at these levels in the allogeneic transplant setting exceeds the 20 percent that is required for reversing the sickle phenotype (Fitzhugh et al, 2017 Blood). These next generation editing approaches provide a promising new modality for treating patients with Beta thalassemia and SCD. Disclosures No relevant conflicts of interest to declare.

Complementary Transplantation with Unrelated Cord Blood Following Haploidentical Stem Cells for Juvenile Myelomonocytic Leukemia:Double-Centers Study from China

Background At present, allogeneic-HSCT is still the only proven potentially curative strategy for Juvenile myelomonocytic leukemia(JMML) children, being only able to cure about 50% of patients by either a relative donnor or an unrelated volunteer. Relapse represented the main causes of treatment failure. The data of HLA-haploidentical transplantation is poorly reported so far. But we have reported an encouraging result in the treatment of leukemia and Thalassemia with complementary transplantation(CT), i.e. unrelated umbilical cord blood(UCB) following haploidentical stem cells transplantation(see blood 2016 128:1235). The evidence of aberrant DNA methylation in JMML provided a rationale for the use of the DNA hypomethylating agent 5-azacytidine or Decitabine(DAC). Recent studies have indicated hypomethylating agent maybe reduce the disease burden in the pretransplant window with minimal toxicity and play an immunomodulatory role after transplantation. Therefore, we developed a novel CT strategy combinated with hypomethylation agent for children with JMML. Patients and method 48 patients received CT combined with DAC from December 2014 to April 2019 in two independent HSCT-centers. Of them, 44 patients had molecular genetics mutation(including NF1, PTPN11,Kras,Nras),and 6 patients had cytogenetic abnormalities with monosomy 7. The median age at diagnosis was 22 (1 to 90) ms. (Table.1). 47 of 48 patients received 2~6 courses of DAC therapy (20mg/m2/d ×5 days for each course with 4-weeks interval) and 1~2 courses of mild-moderate cytotoxic chemotherapy (according to the"A-triple-V"regimen from Korea or reduced-intensity FlAG regimen) as "Bridging therapy" in order to reduce the tumor burden prior to HSCT. There was only one patient who was accepted one course of DAC therapy prior to HSCT. In addition, low dose DAC was also administrated 2~6 courses (10mg/m2/day for 3 or 5 days for each course with the interval of 4~6 weeks) for all patients in order to overcome immune-escape of leukemia cells post HSCT. None of the patients underwent splenectomy. Conditioning regimen included DAC ,Cyclophosphamide(Cy) ,Busulfan,Fludarabine and Thiotepa (or replaced by Busulfan). GVHD prophylaxis consisted of Cy on day+3,+4, MMF and Tacrolimus from day+6. Noteworthily, UCB was infused on day+6 (Fig.1). Human leukocyte antigen of UCB-donor/recipient pairs had less than 3/10 loci incompatibility.The median number of infusion mononuclear cells from haploid-donor was 37.8×108/kg, and which of infusion nucleated cells from UCB was 8.8×107/kg(Table.1). Results The median and mean follow-up time was 13.5 and 16.2 (3 to 63)ms ,respectively. Full donor cells engrafted in all patients (donor cell engraftment in one case without any cytotoxic chemotherapy before HSCT, who was occurred in a salvaged HSCT from another haplo-donor and UCB-donor after primary failure of first CT ). 5-years OS, disease-free survival(DFS) and transplant-related mortality were 90.1%,86.9% and 4.4%, respectively(Fig.2). Haplo-cells and UCB-cells engrafted finally in 26 and 22 patients, respectively. The median times to neutrophil more than 0.5×109/L and platelet more than 20×109/L were 29 days and 24 days post-HSCT, respectively (Table.2). Platelets and neutrophi recovered earlier in patients with haplo-engrafted than those with UCB-engrafted (p=0.000)(Table.3). Five patients developed relapse after HSCT, who had PTPN11 mutation. 4 of them were Haplo-cells engraftment. The median time to relapse after HSCT was 5.5 (1.5 to 12 ) months. There ware no significant difference in the OS and DFS between UCB-engrafted group and Haplo-engrafted group(p=0.612 and p=0.227,respectively)(Fig.3).The cumulative incidences of grades Ⅱ-Ⅳ aGVHD was 38% (18 pts).The number of patients with grade III and Ⅳ aGVHD were 7 in total. Chronic GVHD occurred in 7 patients, and no chronic GVHD more than grade II (NIH criterion) occurred in all patients(Table.2).The most common complication associated CT was infection. The reactivation incidences of CMV, EBV and human herpes virus 6 were 27% ,13% and 5.0%, respectively. Recoverable serious pancytopenia occurred in four patients with DAC therapy post-HSCT. Summary CT have significantly improved the therapeutic effect in JMML-HSCT.Hypomethylation agent may play an important role in CT. Neither cord blood-engraftment nor haploid-engraftment demonstrated a clear superiority for CT. Disclosures No relevant conflicts of interest to declare.

Treatment of thalassaemia: a review of the new approaches on transfusion safety and the novel therapeutics

Lifetime red cell concentrate (RCC) transfusions still account for significant iron overload‐related morbidity and mortality despite chelation therapy in thalassaemia. The cumulative risk of transfusion‐transmitted infections is substantial for thalassaemia patients. Pathogen reduction technologies for RCC may imply a proactive approach against new/re‐emerging pathogens and may be an ultimate safeguard for transfusion safety in the developing countries. Red cell alloimmunization may become a significant clinical challenge in thalassaemia. The availability of high‐throughput molecular blood group antigen typing in the donors may allow perfect match transfusion, beyond ABO‐D and CEK antigen‐matched transfusions. Allogeneic stem cell transplantation (A‐SCT) is the only available curative therapy in thalassaemia, but carries a substantial risk of serious adverse events and mortality. Gene addition therapy for correction of the α‐globin chain imbalance overcomes the problems of donor availability and immunological complications of A‐SCT. Gene editing by either gene disruption or correction emerged as a potential alternative to gene addition therapy in beta‐thalassaemia. A new era of novel therapeutics targeting α/β imbalance, ineffective erythropoiesis or iron dysregulation is unfolding in thalassaemia management, and a number of those now have agents in preclinical and clinical development. Hydroxyurea (HU) may improve globin chain imbalance and be beneficial for reducing or omitting transfusion requirement. Ruxolitinib has allowed steady decrease in spleen volume that may serve for avoiding splenectomy in beta‐thalassaemia. Luspatercept may restore normal erythroid differentiation and improve anaemia. Hepcidin mimetics or TMPRSS6 inhibitors may modulate ineffective erythropoiesis by iron restriction and improve anaemia and organ iron loading.

CRISPR/Cas9 gene correction of HbH-CS thalassemia-induced pluripotent stem cells

Haemoglobin (Hb) H-constant spring (CS) alpha thalassaemia (- -/-αCS) is the most common type of nondeletional Hb H disease in southern China. The CRISPR/Cas9-based gene correction of patient-specific induced pluripotent stem cells (iPSCs) and cell transplantation now represent a therapeutic solution for this genetic disease. We designed primers for the target sites using CRISPR/Cas9 to specifically edit the HBA2 gene with an Hb-CS mutation. After applying a correction-specific PCR assay to purify the corrected clones followed by sequencing to confirm the mutation correction, we verified that the purified clones retained full pluripotency and exhibited a normal karyotype. This strategy may be promising in the future, although it is far from representing a solution for the treatment of HbH-CS thalassemia now.

What's new in diagnostics and treatment of hemoglobinopathies?

Improvement of care for thalassemia during previous decades focussed on the development of new diagnostic and treatment modalities concerning secondary hemochromatosis resulting from symptomatic treatment with regular transfusion. In addition, hematopoetic stem transplantation as the so far only curative approach had been developed and constantly improved. New approaches for the treatment of thalassemias already entering clinical practice include e. g. additive gene therapy and medical treatment with new drugs like luspatercept. For sickle cell disease, a variety of treatment approaches either to correct the genetic change by gene therapy, to affect the underlying mechanism of sickling e. g. by R-state- stabilising agents, or later the pathophysiology of vaso-occlusive complications e. g. by inhibiting selectins are currently thoroughly investigated and some of them will probably get approval very soon.

Innovative Curative Treatment of Beta Thalassemia: Cost-Efficacy Analysis of Gene Therapy Versus Allogenic Hematopoietic Stem-Cell Transplantation.

Seventy-five percent of patients with beta thalassemia (β-thalassemia) do not have human leukocyte antigen-matched siblings and until recently had no access to a curative treatment. Gene therapy is a promising treatment that can be proposed to these patients. This study estimates its cost and efficacy. In a monocentric retrospective study and cost-efficacy analysis, this study compared the two-year outcomes and costs of patients with β-thalassemia treated by gene therapy and hematopoietic stem-cell transplantation (HSCT). Grade III and grade IV complications, hospitalizations, and length of stay were extracted from the hospital discharge data. Costs were estimated from hospital accounting information and national cost studies. A total of seven patients with β-thalassemia treated between 2009 and 2016 were included, of whom four received gene therapy. Patients treated by gene therapy were older and had fewer complications and hospital admissions. Infectious complications were three times more frequent for patients treated with HSCT than for gene therapy. Average costs were €608,086 for patients treated by gene therapy and €215,571 for HSCT. The total cost of the vector was 48% of the total cost of gene therapy. Gene therapy as a curative alternative for patients lacking human leukocyte antigen-matched donors was costlier but resulted in fewer complications than HSCT.

Treatment of thalassemia among paediatric Syrian refugees in Lebanon: MSF experience

Treatment of thalassemia among paediatric Syrian refugees in Lebanon: MSF experience

Meeting Report: The Equality Project on Endocrine Complications in Thalassemia: Selected Highlights from the First Turkish Congress, Antalya, 10th-11th December 2018.

Major difficulties reported by endocrinologists /pediatricians/ hematologists in the care of thalassemic patients with endocrine complications were: lack of facilities, correct interpretation of tests, unfamiliarity with medical treatment and the cost of diagnostics and therapeutics. Therefore, there is a felt need to educate and train more endocrinologists/pediatricians/hematologists in this field in order to optimise growth and prevent endocrine complications. To achieve this goal, in 2015, a project called Equality was submitted by three countries (Turkey, Spain and Italy) and approved by the European Union (EU) with the aim to train doctors and nurses, taking care of youth and young adults TM patients, in the prevention, diagnosis, and management of endocrine disorders. The selected highlights of the First Turkish Congress held in Antalya (10th-11th December 2018) are reported. Overall the conference provided a wide coverage of conventional treatment of thalassemias and endocrine complications in patients with β-thalassemia major. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended.

Next-generation sequencing improves molecular epidemiological characterization of thalassemia in Chenzhou Region, P.R. China.

ObjectivesThalassemia is a highly prevalent monogenic inherited disease in southern China. It is important to collect epidemiological data comprehensively for proper prevention and treatment.MethodsIn this study, blood samples collected from 15 807 residents of Chenzhou were primarily screened by hematological tests. A total of 3973 samples of suspected thalassemia carriers were further characterized by combined next‐generation sequencing (NGS) and Gap‐PCR.ResultsIn total, 1704 subjects were diagnosed as thalassemia carriers with a total prevalence rate of 10.78%, including 943 α‐thalassemia carriers, 708 β‐thalassemia carriers, and 53 composite α and β‐thalassemia carriers. The prevalence rates of α‐thalassemia, β‐thalassemia, and composite α and β‐thalassemia were 5.97%, 4.48%, and 0.34%, respectively. Meanwhile, we characterized 19 α‐thalassemia variations and 21 β‐thalassemia variations in thalassemia carriers. Approximately 2.88% of thalassemia carriers would be missed by traditional genetic analysis. In addition, four novel thalassemia mutations and one novel abnormal hemoglobin mutation were identified.ConclusionsOur data suggest a high prevalence of thalassemia and a diverse spectrum of thalassemia‐associated variations in Chenzhou. Also, combined NGS and Gap‐PCR is an effective thalassemia screening method. Our findings might be helpful for prevention and treatment of thalassemia in this region.

Frequency and Risk Factors of Red Blood Cell Alloimmunization in Thalassemia Major Patients in Markazi province

Background: Thalassemia is one of the most common genetic disorders throughout the world. Blood transfusion plays an important role in the treatment of thalassemia but it leads to numerous complications such as iron overload and alloimmunization. This study evaluated the frequency and risk factors associated with alloimmunization in thalassemia major patients living in Markazi province, Iran. Materials and Methods: In this descriptive study, 48 thalassemia major patients who underwent blood transfusion at Amirkabir hospital were included. Patients' demographic data were recorded using a questionnaire. In order to perform alloimmunization screening and autoantibody assessment, patients were referred to Tehran Blood Transfusion Organization Laboratory. Results: The current study was performed on 48 patients with thalassemia major,. The mean age of patients was 12.5 ± 8.3 years. Among patients 26 (54.16%) were male and 22 (45.83%) were female, 13 patients (27.08%) had alloantibodies. Among 48 patients, 19 (39.58%) had undergone splenectomy. The patients' age of the first blood transfusion ranged from 1 month to 14 months and the mean age of the first blood transfusion was 9.5 ± 7.08 months. The blood transfusion intervals in patients were from 21 days to 40 days and the blood volume received at each transfusion session was 10-15 cc/kg of the body weight. In the current study, the data analysis indicated no significant correlation between alloantibodies and RH phenotype (P=0.43), patients' gender (P=0.9), or blood groups (P=0.4); whereas, a significant correlation was found between alloantibodies and splenectomy (P=0.02) as an increase in the prevalence of alloantibodies was reported in splenectomised patients. Conclusion: No significant difference was found between the patients with and without alloantibodies in terms of the prevalence of Rh phenotype, gender, and blood groups. However, there was a significant difference between the patients with and without alloantibodies in terms of splenectomy. Key words: Allo-immunization, Risk factors, Thalassemia major

Empowerment Pattern for Thalasemi Patients in Dr. Soetomo Hospital Surabaya (Study of the Association of Parents with Thalassemia Indonesia, Surabaya)

Thalassemia is a hereditary disease that until now there is no effective treatment for healing, this disease is not contagious and generally attacks children with a variety of typical symptoms that can be detected since the age of a toddler (under five years). In the city of Surabaya there were 520 sufferers, this number was based on data from the administrators gathered in the organization of the POPTI (Association of Indonesian thalassemia Parents) in the city of Surabaya. There is a pattern of empowerment carried out by the management of POPTI in Surabaya to parents whose children suffer from thalassemia, as well as to adult patients. The thing to do is to conduct routine assistance at Dr. Soetomo Surabaya hospital every Tuesday and Wednesday. The purpose of this study is to describe and analyze the pattern of empowerment carried out by POPTI (Association of Parents with thalassemia Indonesia) in Surabaya in the treatment of thalassemia in Surabaya. This study used a qualitative method with a descriptive approach, with the primary data of the study obtained through in-depth interviews with 9 (nine) parents whose children suffered from thalassemia as key informants, the details of which consisted of 3 (three) POPTI administrators in Surabaya and 6 (six) members POPTI city of Surabaya. Based on the results of the analysis and discussion, the conclusions of the study are: 1) The joining of parents in the POPTI city of Surabaya provides many benefits in the care of their children who suffer from thalassemia in Dr. Soetomo Hospital Surabaya; 2) The form of empowerment patterns carried out by parents of elderly patients who are members of the POPTI container in Surabaya starts with routine mentoring which results in a shared value for parents; 3) There is a tiered learning pattern from patients who are considered senior to teach other patients in terms of understanding and ability to understand the flow of care services to thalassemia patients

Effectiveness and Safety of Deferasirox in Thalassemia with Iron Overload: A Meta-Analysis

Deferasirox (DFX) has recently been used to treat thalassemia with iron overload; however, its long-term effectiveness and safety await multi-year studies. In this study, a systematic meta-analysis was performed to assess the effectiveness and safety of DFX in the treatment of thalassemia with iron overload. We performed a systematic electronic literature search for randomized controlled studies of DFX in the Embase, Medline, Cochrane, and Chinese Biomedical Literature (CBM) databases from January 1990 to May 2018. Particular attention was paid to mortality, serum ferritin (SF), liver iron concentration (LIC), myocardial iron concentration, and adverse events (AEs). Six studies comparing DFX with deferoxamine (DFO) and placebo were enrolled. DFX was not better than DFO in lowering SF and LIC, with an exception that high DFX dose (>30 mg/kg/day) was superior to DFO in LIC. Otherwise, AEs such as gastrointestinal problems appeared to be more common with DFX. DFX does not seem to be superior to DFO at low dose. Similar efficacy seems to be achievable depending on dose. However, the convenient oral administration of DFX has a higher compliance rate.

Iron Chelation Therapy of Thalassemia Patients Is Still a Challenge. Single Centre Experience from United Arab Emirates

Thalassemia is a group of complex haemoglobin disorders common in the Mediterranean countries, the Middle East and South East Asia1. Thalassemia is common in the United Arab Emirates (UAE) affecting indigenous population and the expatriates. The exact prevalence of thalassemia is not known.The management of thalassemia has improved significantly due to improvement in transfusion support and the management it's complications. This has led to the improvement of the overall survival and most patients reaching their adulthood2. Despite this some die at young age mainly due to poor access to health care2, proper management and lack of compliance to chelation therapy which leads to the development of otherwise preventable complications2.Blood transfusion is the corner stone of the management of patient with thalassemia major and intermediate3. Blood transfusion improves the anemia and its symptoms but also suppress the resultant ineffective erythropoiesis. This is usually started once the patient has signs and symptoms of anemia and unable to compensate for the low haemoglobin3. The aim of blood transfusion is to maintain good quality of life and to prevent the skeletal abnormalities2. Although blood transfusion is essential in the management of patients with thalassemia, it will ultimately lead to iron overload. In addition there is excess of gastrointestinal iron absorption in these patients, secondary to the ineffective erythropoiesis4. To reduce the iron absorption the target is to maintain the pre-transfusion hemoglobin level between 9 and 10 g/dl. Iron overload is major cause of mortality and morbidity in patient's thalassemia major and intermedia5.In this retrospective analysis we reviewed the ferritin levels over 1 year in 25 patients with thalassemia major or intermedia attending the adult hematology department at Tawam hospital The patients received regular blood transfusion once every three weeks. Of the 25 patients 16 were males and 9 were females. The age range was 15 years to 47 years. Nineteen patients had their chelation therapy changed during the year from Exjade (Deferasirox tablets for oral suspension) to Jadenu (Deferasirox tablets) which improved our patient's compliance. The remaining 6 patients continued on Exjade. In addition to this 17 patients received additional Desferral infusion in connection with their blood transfusion. None of the patient was on subcutaneous desferral infusion. During our observation two patients were lost to follow up and one patient died.The medium ferritin level for our evaluable patients was at start of the review 2488 mcg/l, with a range between 609 mcg/l to 5147 mcg/l. The medium ferritin level at the end was 1691 mcg/l with a range between 470 mcg/l to 3731 mcg/l. Figure 1 one shows the ferritin value a start and end of the review for each patient. Our patients with the highest ferritin levels are despite repeated counselling not compliant with their medications.Despite significant improvement in the management of thalassemia patients, iron overload remain a challenge. The main problems to achieving full control over the iron overload are lack of compliance. Hopefully the newest oral formulation will increase the compliance and at least we have seen a decrease in the ferritin levels over the last year in most patients.References.1 De Dreuzy E, Bhukhai K, Leboulch P, Payen E Current and future alternative therapies forBeta Thalassemia major. Biomedical Journal 39, 124-382 Modell, B., Khan, M., and Darlison, M. Survival in beta thalassaemia major in the UK:Data from the UK Thalassaemia Register. Lancet 355 [2000]: 2051-2052.3 Rebulla P, Modell B. Transfusion requirements and effects in patients with thalassaemiamajor. Cooleycare Programme. Lancet 1991;337:277-804 Gardenghi S, Marongiu MF, Ramos P, et al. - Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood 2007; 109:5027-355 Porter, J.B., and Davis, B.A. Monitoring chelation therapy to achieve optimaloutcome in the treatment of thalassaemia. Best Practice & Research: ClinicalHaematology 15 [2002]: 329-3686 Ayidinok Y, Kattamis A, Cappellini MD, et al. Deferasirox- Deferoxaminecombination therapy reduces cardiac iron with rapid liver iron removal after 24months in patients with severe transfusional iron overload (abstract).Haematologica 2014;99:229. DisclosuresNo relevant conflicts of interest to declare.