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Aim To determine the proportion of non-compliance to iron chelation therapy (ICT) and its associated factors amongst patients with transfusion-dependent thalassaemia (TDT) in Malaysia. Methods A cross-sectional study was conducted amongst patients with TDT aged 9 years old and above, who were on iron chelation treatment, attending three tertiary hospitals in Kelantan and Terengganu. The socio-demographic, clinical and chelator history of patients were obtained. The compliance of patients to chelators was assessed using the Medication Compliance Questionnaire (MCQ). Social support was assessed using the Medical Outcome Study–Social Support Survey (MOS). Data was analysed using simple and multiple logistic regression. Results The proportion of non-compliance to ICT was 24.7%. Age, activity restriction and latest serum ferritin level of ≥1000 μg/L were significantly associated with non-compliance to ICT. Conclusion The non-compliance to ICT amongst patients with TDT in Kelantan and Terengganu is 24.7%. Providing motivational interview, enhanced self-empowerment of patients and psychological support are recommended to improve the non-compliance aspect amongst patients on ICT.

Patients with myelodysplastic syndromes (MDS) often experience chronic anemia and long-term red blood cell transfusion dependence associated with significant burden on clinical and health-related quality of life (HRQoL) outcomes. In the MEDALIST trial (NCT02631070), luspatercept significantly reduced transfusion burden in patients with lower-risk MDS who had ring sideroblasts and were refractory to, intolerant to, or ineligible for prior treatment with erythropoiesis-stimulating agents. We evaluated the effect of luspatercept on HRQoL in patients enrolled in MEDALIST using the EORTC QLQ-C30 and the QOL-E questionnaire. Change in HRQoL was assessed every 6 weeks in patients receiving luspatercept with best supportive care (+ BSC) and placebo + BSC from baseline through week 25. No clinically meaningful within-group changes and between-group differences across all domains of the EORTC QLQ-C30 and QOL-E were observed. On one item of the QOL-E MDS-specific disturbances domain, patients treated with luspatercept reported marked improvements in their daily life owing to the reduced transfusion burden, relative to placebo. Taken together with previous reports of luspatercept + BSC reducing transfusion burden in patients from baseline through week 25 in MEDALIST, these results suggest luspatercept may offer a treatment option for patients that reduces transfusion burden while providing stability in HRQoL.

Aims The current study evaluated the association of echocardiography, cardiac magnetic resonance (CMR), and ferritin data with 10-year survival in thalassemia patients. Methods Demographics, ferritin, echocardiography, and CMR parameters of stable consecutive thalassemia patients were prospectively collected. Results In total, 75 patients (mean age 37 ± 11 years, 45% male) with thalassemia were included and dichotomized based on their survival status after a median follow-up period of 10.3 [9.6-10.9] years. Older age (HR: 1.071, p = 0.001), ferritin ≥2000 ng/ml (HR: 4.682, p = 0.007) and ≥1700 ng/ml (HR: 7.817, p = 0.002), elevated LV end-diastolic pressure (HR: 1.019, p = 0.044), TR Vmax >2.8 m/s (HR: 6.845, p = 0.005), and CMR T2∗ ≤20 msec (HR: 3.602, p = 0.043) and ≤34 msec (HR: 5.854, p = 0.026) were associated with increased all-cause mortality (primary endpoint). A baseline model including age was created and became more predictive of worse survival by adding TR Vmax >2.8 m/s instead of elevated LV end-diastolic pressure (C index 0.767 vs. 0.760, respectively), ferritin ≥1700 ng/ml instead of ≥2000 ng/ml (C index 0.890 vs. 0.807, respectively), or CMR T2∗≤34 msec instead of ≤20 msec (C index 0.845 vs. 0.839, respectively). Parameters associated with the combined endpoint of cardiac mortality/cardiac hospitalization (secondary endpoint) after adjusting for age were ferritin ≥1700 ng/ml (HR 3.770, p = 0.014), ratio E/A wave >2 (HR 3.565, p = 0.04), TR Vmax >2.8 m/s (HR 4.541, p = 0.049), CMR T2∗ ≤20 ms (HR 9.462, p = 0.001), and CMR T2∗ ≤34 ms (HR 11.735, p = 0.002). The model including age and T2∗ ≤34 ms instead of T2∗ ≤20 ms was more predictive of the secondary endpoint (C-index 0.844 vs 0.838, respectively). Conclusions In thalassemia patients, TR Vmax >2.8 m/s, ferritin ≥2000 ng/ml, and CMR T2∗ ≤20 ms were associated with worse long-term survival. In the current era of advanced chelation therapy, aiming for ferritin ≤1700 ng/ml and CMR T2∗ ≥34 ms may improve their prognosis.

Haematopoietic insufficiency is the treatment target of lower-risk myelodysplastic syndrome (MDS). Although erythropoiesis-stimulating agents (ESAs) are generally effective for treating anaemia, resistance can develop. Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) improves renal anaemia by promoting endogenous erythropoietin production and normalizing iron metabolism. HIF-PH inhibitors could be used to treat MDS, but their efficacy and safety have not been studied. A 78-year-old female patient with essential thrombocythemia gradually developed anaemia and was diagnosed with therapy-related MDS 4 years later. The anaemia temporarily improved with ESAs, but the patient became transfusion dependent. At the same time, anaemia and chronic renal failure due to nephrosclerosis progressed, and the patient was diagnosed with MDS with renal anaemia. After switching from ESAs to roxadustat, an HIF-PH inhibitor, anaemia improved, and the patient was no longer transfusion dependent. No progression of the underlying disease or any adverse events was observed 4 months after initiating roxadustat.

The article presents retrospective data analysis of a cohort of patients with PKD (n = 41 patients, aged 4 months – 26,5 years, median of age – 5 years 1 month) who were examined at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology for unspecifid hereditary hemolytic anemia during the period 2013–2020. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. In all patients, the diagnosis was confimed by Next Generation sequencing (NGS). The homozygous mutations in the PKLR gene were found in 10 patients (24.39%), compound heterozygous mutations in 31 patients (75.61%), 77.78% of them were missense mutations. Gender distribution (male:female) was 1:1.73. At least once transfusion of erythrocyte suspension was required to 40 (97.56%) patients. The minimum age at the time of the debut of transfusion dependence was the fist day of life, the maximum was 4 years. Exchange blood transfusion was performed in 13 children, severe normocytic hyperregenerative anemia with transfusion of red blood cells in the fist days of life was noted in 12 children, at the 1st month of life – in 9 children, at the 2nd month of life – in 8 children, at the 3rd month – in 6 children, at the 5th month – in 2 children, at the 1st year – in 1 child, and 2 children underwent single transfusions on the background of infectious episodes at 3 and 4 years respectively. Splenectomy due to high transfusion dependence was performed in 10 patients: transfusion independence was achieved in 5 patients, in 5 – an increase in the interval between blood transfusions. Median of surgical intervention (9 patients): 7 years 4 months, minimum age – 1 year 4 months, maximum – 14 years 4 months. In total, 36 genotypes were described in 41 patients, among them were: c.1529G>A in 3 patients, c.1137_1139del / c.1456C>T – in 2 patients, c.1079G>A/c.1529G>A in 2 patients, c.1130T>C/c.1456C>T in 2 patients, other genotypes occurred once. Two mutations were the most frequent: c.1456C>T (16.67%) and c.1529G>A (16.67%). 19 (46,34%) of patients had previously not described mutations.

Luspatercept (Reblozyl®), a first-in-class erythroid maturation agent, is approved in several countries worldwide for the treatment of adults with transfusion-dependent anaemia due to myelodysplastic syndromes (MDS), who have failed prior erythropoiesis-stimulating therapy, or β-thalassaemia. In pivotal, placebo-controlled, phase III trials, subcutaneous luspatercept significantly reduced red blood cell (RBC) transfusion requirements in patients with MDS or β-thalassaemia. Luspatercept had a generally manageable tolerability profile in clinical trials. Adverse events of special interest include thromboembolic events, hypertension and bone pain. Thus, luspatercept is an emerging treatment option in adults with transfusion-dependent anaemia due to MDS or β-thalassaemia.

Hb E (HBB: c.79G>A)/β-thalassemia (Hb E/β-thal) is responsible for nearly half of all the different kinds of severe β-thal. This disorder is characterized by a wide range of clinical variability ranging from mild, asymptomatic non transfusion-dependent thalassemia (NTDT) to severe transfusion-dependent thalassemia (TDT). The aim of the present study was to determine the prevalence of different β-globin gene (HBB) mutations in Hb E/β-thal subjects and their potential role in transfusion dependence. One hundred and ten consecutive children with Hb E/β-thal attending the Pediatric Department of Burdwan Medical College, Burdwan, West Bengal, India were enrolled. Based on hemoglobin (Hb) electrophoresis or high-performance liquid chromatography (HPLC), patients were recruited and later β-globin gene sequencing was done to find out the prevalence of different HBB mutations. Transfusion-dependent thalassemia was seen in 42 children (38.2%), while NTDT was seen in 68 children (61.8%). A total of 10 different β-globin mutant alleles were characterized. The most frequent mutation on the β-globin gene was IVS-I-5 (G>C) (HBB: c0.92+5G>C) in both groups. The β-globin gene mutations alone cannot determine transfusion dependence among the Hb E/β-thal patients.

Thalassemia, derived from Thalassa [Greek: Sea] refers to a cluster of hereditary haemoglobinopathies initially reported in areas of Sub-Saharan Africa, the Indian subcontinent, Southeast Asia, and the Mediterranean where malaria was (or is) endemic. Currently, it is the most frequently recognized haemoglobinopathy, and has been correlated with a plethora of immune system changes such as neutropenia, natural killer cell dysfunctions, increased activity of CD8 suppressor cells, along with disturbances in macrophage function, chemotaxis, phagocytosis, and interferons INFγ production.1 The reduction in the alpha or beta chain that leads to the production of haemoglobin is the key pathophysiology behind thalassemia. Therefore, weakened red blood cells can contribute to inadequate erythropoiesis and haemolytic anaemia. Thalassemia diseases are known as transfusion-dependent or non-dependent according to either their beta-globin chain genotype or their clinical path. The most serious type of thalassemia is beta-thalassemia major, and it is transfusiondependent, presenting in early infancy.2 A diagnosis of β-thalassemia major (BTM) means lifelong, regular transfusions, supplemented with adequate iron chelation therapy for the patient.3 This also means that unless adequate blood screening and hygiene procedures are in place, patients with BTM are at a risk of transfusion transmitted infections (TTI).4 Many countries have been prompted by the spread of Covid-19 infection to shutter routine outpatient coronary health care units before the pandemic is over, which also extends to people with thalassemia, who require regular follow-ups. While Covid-19 infection rates remain high, patients with thalassemia with planned cardiovascular examinations are advised to delay their medical appointments for a minimum of 3 months.1 In addition, according to the statement published by the Thalassemia International Foundation on the 13th of July, 2020, patients with hemoglobinopathies are at a greater risk in acquiring the Covid-19 infection, posing an additional challenge to the patients, families, and medical staff managing these disorders.5 Thalassaemic patients have reduced levels of protein S and protein C; elevated aggregation of platelets; and recruitment of monocytes, granulocytes, and endothelial cells. Patients of thalassemia also show elevated markers of platelet and coagulation activation, even in the absence of major thromboembolic events. An increase in D-Dimer levels is also seen in most Covid-19 patients who are hospitalised, attributable to the underlying inflammatory process.1 A variety of questions have been raised during the ongoing Covid-19 pandemic with respect to diagnostic and clinical approaches towards this particular population. The precise path of infection with Covid-19 in those patients has yet to be elucidated.2 The progression of Covid-19 infection in patients with hemoglobinopathy in general and thalassemia in particular is not fully known and is still an area of discussion and under review. We report a case of a 30-year-old male patient, a known case of beta thalassemia major on maintenance transfusion and iron chelation therapy who acquired Covid-19 infection.

To study vitamin C levels in children with transfusion-dependent β-thalassemia and correlate with age, transfusions received and iron overload; and to study the effect of administering vitamin C on its levels and Malondialdehyde (MDA) in deficient patients. This case-control study enrolled 100 children with transfusion-dependent β-thalassemia and 30 healthy controls. MDA levels before and after administration of vitamin C were performed randomly in 36 children with low vitamin C levels. 81/95 (85.3%) study subjects vs none in control group, had low plasma vitamin C levels (P

Some studies have indicated that the use of luspatercept may be a novel and efficient treatment for β-thalassemia patients. In this article, we aimed to review the current evidence related to luspatercept prescription and its clinical effectiveness in patients with β-thalassemia. PubMed, Web of Science, Scopus, Trip and CENTRAL were searched up to June 2020. The inclusion criteria were English-language articles that studied the effects of luspatercept on improving anemia severity in patients with β-thalassemia in a clinical setting. The search strategy yielded 273 potentially relevant articles. After searching the databases, scanning of titles, abstracts and full texts for relevancy was performed to identify suitable articles. A total of 77 articles were confirmed for full text analysis. The estimated number of patients needed to treat (NNT) for luspatercept treatment, using data derived from conducted clinical trials, according to a reduction in transfusion need of ≥ 33% or ≥ 50 from baseline, during week 13–24/week 37–48/any 12- and 24-week intervals as outcomes, was 3–5 in patients with β-thalassemia. Based on the conducted studies, the effectiveness of luspatercept on transfusion burden and hemoglobin levels was outstanding in β-thalassemia patients. Further large and well-designed clinical studies are needed to identify any unforeseen complications subsequent to use of luspatercept, particularly when used with other treatments with potentially serious adverse effects such as anti-osteoporotic and iron chelator agents.

Background Each year nearly 10,000 children with thalassaemia major are born in India, but among them, very few are optimally managed mainly in urban regions even though the Government of India has incorporated their care and treatment in the 12th Five-Year Plan. Data on prescribing patterns and drug-related problems (DRPs) in paediatric thalassaemia patients in India are limited. Methods In this prospective interventional study, the medications prescribed were recorded after reviewing the treatment charts, thalassaemia register, thalassaemia card, nurses’ notes, as well as discharge summaries. When DRPs and/or medication errors were identified, the same was discussed with the concerned health care professionals and suitable suggestions were made at the earliest. Results Out of the enrolled 54 patients, only 94% (n = 51) of the patients received iron chelation therapy with deferasirox and/or deferiprone, Folic acid tablet was prescribed for 100% of the patients (n = 54). Five percent of patients (n = 3) had undergone splenectomy and was prescribed with amoxicillin prophylactically. There were a total of 16 DRPs and 15 medication errors were identified and suitable measurements were taken to solve these problems. Conclusions The prescribing patterns, DRPs and medication errors in transfusion-dependent paediatric thalassaemia patients were discussed in this study. Our study was effective in identifying and solving the DRPs and medication problems that occurred in thalassaemia patients.

The aim of the study was to determine serum ferritin level in transfusion dependent thalassaemia patients. A total of 64 transfusion dependent thalassaemia (TDT) patients was included in this cross sectional study from April, 2018 to September, 2019 according to selection criteria. Body iron load was estimated by serum ferritin level. The study sample consisted of 43 male and 21 female TDT patients, with a mean age of 25.5 years. Most of the patients (43.8%) patients had serum ferritin level in between 1000-2500 ng/ml. 12 patients (18.7%) had serum ferritin level >5000 ng/ml and 3 patients (4.7%) had serum ferritin in between 2501-5000 ng/ml. The mean serum ferritin was found 2462.6 ± 2792.7ng/ml with range from 207.0 -11891.2ng/m.

Background and Objective Transfusion-dependent β-thalassemia (TDT) is a rare genetic disease characterized by a deficiency of functional β-globin, ultimately leading to lifelong dependence on blood transfusions. There is little patient- and caregiver-reported data with which to understand the holistic and societal impact of TDT. The objective of this study was to evaluate the patient- and caregiver-reported disease-management, symptom, and quality-of-life burden of TDT. Methods We conducted a prospective, observational, real-world study of adults with TDT and caregivers of adolescents with TDT, in Italy, the UK, and the USA. Over 90 days, participants used a smartphone application to respond to surveys about their or their dependent’s TDT, including bespoke background and disease-management surveys, the Brief Fatigue Inventory (BFI), the Transfusion-dependent Quality of life questionnaire (TranQol), and the Brief Pain Inventory Short Form (BPI-SF). Results Eighty-five individuals participated. Mean BFI and TranQol scores on enrollment were 5.0 (0–10 scale; 10 = worst symptoms) and 51 (0–100 scale; 100 = best quality of life), respectively. Mean transfusion frequency was every 3.2 weeks. Mean time spent on TDT management was 592 min on transfusion days and 91 min on non-transfusion days (11 h per week). Mean BFI and BPI-SF “worst fatigue” and “worst pain” scores were higher in the 5 days pre-transfusion than in the 5 days post-transfusion (fatigue 5.05 vs 4.29; pain 4.33 vs 3.85; 0–10 scale; 10 = worst symptoms). Conclusions The patient- and caregiver-reported burden of TDT is high, influenced by disease-management time, fatigue, pain, and quality-of-life impairment. Electronic supplementary material The online version of this article (10.1007/s40271-020-00473-0) contains supplementary material, which is available to authorized users.

ObjectivesCardiac T2* MRI (T2*CMR), for accurate estimation of myocardial siderosis, was introduced as part of a QI collaborative to optimise chelation therapy in order to improve cardiac morbidity in transfusion dependent thalassaemia (TDT) patients. We report the impact of this QI initiative from two thalassaemia centres from this collaborative.Design and settingA key driver based quality initiative was implemented to improve chelation in TDT patients registered at these two centres in Karachi, Pakistan. Protocol optimisation and compliance to treatment through training, communication and feedback were used as the drivers for QI intervention. Preintervention variables (demographics, chelation history, T2*CMR, echocardiography and holters) were collected from January 2015 to December 2016) and compared with variables in the post implementation phase (January to December 2019). A standardised adverse event severity for chelators and its management was devised for safe drug therapy as well as ensuring compliance to the regimen. Preintervention and postintervention variables were compared using non-parametric test. P valueResults100 patients with TDT, median age 17 (9–34) years, were included. An increase or stabilisation of T2*CMR was documented in 82% patients in the postintervention phase especially in patients with severe myocardial iron overload (5.5 vs 5.3 ms, p ConclusionThis QI initiative improved the chelation therapy leading to improved cardiac status in TDT patients at the participating centres.

Background: Regular blood transfusion and iron chelation is the primary treatment of thalassemia patientsto maintain their life. Iron chelatormay alter serum total calcium and magnesium level in TDT patients. Objective: To evaluateany alteration of serum total calcium and magnesium level in transfusion dependent thalassemia patients treated with iron chelator. Method: The present cross sectional study was carried out in the department of Physiology, BSMMU, Dhaka between September 2017 to February 2019. Thirty cases of TDT, aged 5-40 year were included in the study group. Age and sex matched 30 healthy subjects were also studied as control. All the TDT patients were selected from the outpatient Department of Hematology and Transfusion Medicine, BSMMU, Dhaka. Serum total calcium, magnesium and ferritin levels were measured by colorimetric method. For statistical analysis independent sample t test and Chi-Square test and Pearson correlation coefficient test were used. Result: The mean serum total calcium and magnesium levels were significantly (p

Introduction Xmn1-Gγ polymorphism has been significantly associated with disease severity in HbE/β-thalassemia patients. The aim of this study is to determine the factors affecting health related quality of life (HRQoL) and its association with Xmn1-Gγ polymorphism among transfusion-dependent β-thalassemia and HbE/β-thalassemia adolescents. Materials and Methods A cross-sectional study was conducted from day care thalassemia centers and thalassemia clinics of tertiary centers in East Coast Malaysia. The Malay version of the Pediatric Quality of Life Inventory™ 4.0 Generic Core Scale was used to evaluate quality of life. Associated factors were analyzed using multivariate regression analysis. Results The lowest QoL mean score was school functioning at 59.69 (16.23). Xmn1-Gγ polymorphism was significantly associated with physical functioning (p = 0.018) and emotional functioning (p = 0.013). Frequency of blood transfusion per year was found to be significantly associated with social functioning (p = 0.005) while gender and age onset of anemia were significantly associated with school functioning (p = 0.009 and p = 0.009). Xmn1 heterozygous CT was significantly associated with a higher physical functioning score by 0.192 and a higher emotional functioning score by 0.202 compared to Xmn1 homozygous wild-type CC. It is reportedly significantly higher concentration of HbF in patients with a “T” nucleotide change at the -158 locus at the Gγ-globin promoter compared to those without the polymorphism. Conclusion The precise factors that influence HRQoL empowers a better understanding to the effectiveness of thalassemia disease management in the country.

Among the haemoglobinopathies non-transfusion dependent thalassaemia (NTDT) are more common than the major patients. Bangladesh is located within the thalassaemia belt, moreover, Hb-E is prevalent here. So, the burden of non-transfusion dependent haemoglobinopathies is pretty massive. Due to less severe presentation and unawareness of general people, most patients with NTDT present with complications. On the other hand, cardiac complications are the major causes of death in these patients, and, negligence in early treatment increases the death. This review discusses haemoglobinopathies in general, followed by pathogenesis, clinical features and management of cardiac complications.

Background Alloantibody production is one of the most challenging complications in transfusion-dependent thalassaemia patients. Haemolytic anaemia, an increase in blood consumption, difficulty in haematopoietic stem cell transplantation and reduced quality of life are consequences of alloimmunisation. The most predisposed antigens (Ags) for alloantibody development are Rh and Kell blood group Ags. Objective The aim of the present study is to evaluate any correlation between HLA-DRB1 alleles and Rh and Kell alloantibodies. Materials and methods Fifty-two non-responders (control) and 54 responders (case) were enrolled in this study. Alloantibody detection was performed using the tube method. Genotyping of HLA-DRB1*01 and HLA-DRB1*15 was conducted by single-specific primer-polymerase chain reaction. Results In the responder group, 77.8% were hyper-responders (more than one alloantibody), and only 22.2% were mono-responders. Most detected alloantibodies were Anti-K (94.4%), followed by Anti-E (64.8%), Anti-C (29.6%) and Anti-D (25.9%). There was a significant difference in HLA-DRB1*15 between responder and non-responder groups, 73.7% vs 26.3%, respectively. (P = .029, OR = 3.290; 95%CI). Our results showed that HLA-DRB1*15 was more frequent in hyper-responders than mono-responders (92.9% vs 7.1%) (P = .007). The greatest HLA-DRB1*15 was seen in Anti-K (P = .014, odds ratio [OR = 3.784]; 95% confidence interval [CI]) and Anti-E (P = .011, OR = 3.609; 95%CI) alloantibodies. There is no association between HLA-DRB1*01 and alloimmunisation. Conclusion Our findings showed that there is a significant correlation between HLA-DRB1*15 and Anti-K and Anti-E alloantibodies. These findings can be useful in detecting susceptible thalassaemic patients and improving transfusion management.

INTRODUCTION β-thalassemia is one of the most common inherited monogenic diseases. Many patients are dependent on a lifetime of red blood cell (RBC) transfusions and iron chelation therapy. Although treatments have a significant impact on quality of life (QoL), life expectancy, and long-term health outcomes have improved in recent decades through safer RBC transfusion practices and better iron chelation strategies. Advances in the understanding of the pathology of β-thalassemia have led to the development of new treatment options that have the potential to reduce the RBC transfusion burden in patients with transfusion-dependent (TD) β-thalassemia and improve QoL. AREAS COVERED This review provides an overview of currently available treatments for patients with TD β-thalassemia, highlighting QoL issues, and providing an update on current clinical experience plus important practical points for two new treatments available for TD β-thalassemia: betibeglogene autotemcel (beti-cel) gene therapy and the erythroid maturation agent luspatercept, an activin ligand trap. EXPERT OPINION Approved therapies, including curative gene therapies and supportive treatments such as luspatercept, have the potential to reduce RBC transfusion burden, and improve clinical outcomes and QoL in patients with TD β-thalassemia. Cost of treatment is, however, likely to be a significant barrier for payors and patients.

Hyperhemolysis is a life-threatening condition of exaggerated hemolysis of red blood cells which occurs in patients receiving chronic transfusion therapy. We present a 19-year-old male with the β-thalassemia major with an episode of hyperhemolysis. Hemolysis was initially unresponsive to immunosuppression but responded after the addition of eculizumab. Several weeks after stabilization, hemolysis returned; which was also managed with immunosuppression and eculizumab. Hyperhemolysis presents significant challenges in β-thalassemia due to the underlying dysfunctional erythropoiesis and transfusion dependence. Aggressive immunosuppression combined with eculizumab successfully slowed the hemolysis and allowed for the resumption of transfusions.

Transfusion-dependent beta thalassemia (TDT) is a severe form of beta thalassemia in which there is a minimal to no beta globin chain production in the body [1]. This situation eventually leads to ...

Beta thalassemias are autosomal recessive hemoglobin disorders related to a defect in the beta-globin chain production. Most of the major forms of beta-thalassemia are transfusion dependent leading to iron overload. Today, three iron chelators are available in France. We report the case of a patient suffering from β+ major transfusion-dependent thalassemia who presented with severe skin reactions to deferoxamine and deferasirox as well as with agranulocytosis after deferiprone administration. The patient benefited from successful tolerance induction to deferasirox. With the increasing number of children suffering from iron overload, we believe that our protocol can be useful to pediatric hematology teams confronted with multiple iron chelator reactions.

Introduction Betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia) gene therapy is being evaluated for the treatment of transfusion-dependent β-thalassemia (TDT). Initial positive results of beti-cel in the phase 3 studies, HGB-207 (NCT02906202; non-β0/β0 genotypes) and HGB-212 (NCT03207009; β0/β0, β0/β+ IVS-I-110 and β+ IVS-I-110/β+ IVS-I-110 genotypes), showed 10/12 adult patients achieved transfusion independence. The studies expanded enrollment to include adolescents and children. We present interim results from pediatric patients Methods After mobilization and apheresis, autologous CD34+ cells were transduced ex vivo with BB305 lentiviral vector, containing a modified human β-globin gene to produce beti-cel drug product (DP). Patients underwent busulfan myeloablation and infusion with beti-cel and were then followed longitudinally. Transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without transfusions for ≥12 mo) was the primary endpoint in HGB-207 and a secondary endpoint in HGB-212. Transfusion reduction (≥60% reduction in transfusion volume between Month 12 to 24 versus baseline) is the primary endpoint in HGB-212. Hb levels, TI characteristics, and quality of life were secondary endpoints. Assessments of ineffective erythropoiesis were exploratory. Data presented as median (min-max). Results Twenty-four pediatric patients were treated including 13 patients 3 mo follow-up achieved platelet engraftment and had platelets ≥100 x109/L by Month 12; one 17-yr old patient did not have platelets ≥100 x109/L until Month 15. In HGB-207, 6/7 (86%) patients 3 mo follow-up have stopped transfusions for ≥6 mo. TI was achieved in 3/4 (75%) evaluable patients In HGB-212, 3/5 (60%) patients 3mo follow-up have stopped transfusions for ≥6 mo. TI was achieved in 1/2 evaluable patients Post-infusion non-hematologic grade ≥3 adverse events (AEs) in ≥3 patients aged Summary Interim results in HGB-207 and HGB-212 show that after treatment with beti-cel, pediatric patients Disclosures Thompson: CRISPR/Vertex: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Baxalta: Research Funding; BMS: Consultancy, Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Kwiatkowski:Novartis: Research Funding; Agios: Consultancy; Sangamo: Research Funding; bluebird bio,Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Imara: Consultancy; BMS: Consultancy; Terumo Co: Research Funding; Celgene: Consultancy. Porter:Vifor Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; La Jolla Pharmaceuticals: Honoraria; Silence Therapeutics: Honoraria; Protagonist Therapeutics: Honoraria; BMS: Consultancy, Honoraria. Kulozik:Novartis: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thuret:Novartis pharma: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; Apopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials. Lal:Insight Magnetics: Research Funding; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Terumo Corporation: Research Funding; Agios Pharmaceuticals: Consultancy; Chiesi USA: Consultancy; La Jolla Pharmaceutical Company: Research Funding; bluebird bio, Inc.: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guo:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Liu:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Colvin:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Walters:Veevo Biomedicine: Consultancy; AllCells, Inc: Consultancy; Editas: Consultancy. Locatelli:Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction We investigated the impact of β-thalassemia genotypes and disease genetic modifiers including HBA and KLF1 genotype and sentinel single-nucleotide polymorphism (SNP) genotypes at 3 major HbF quantitative trait loci (QTL) on clinical outcomes of TDT patients treated with beti-cel gene therapy in two phase 3 studies, HGB-207 (NCT02906202) and HGB-212 (NCT03207009). Methods HBA deletions and triplications were determined by gap-polymerase chain reactions. HBG2 (including rs7482144, Xmn1 site) and HBG1 promoters, HBA2, HBA1, and KLF1 underwent individual nucleotide sequencing. Multiplex amplification refractory mutation system (ARMS) tests were used to identify HbF QTL SNPs (rs10128556 in HBBP1; rs766432, rs1427407, rs10189857 in BCL11A; rs9399137, rs66650371 in HMIP). Thalassemia severity score (TSS) was calculated as defined by Danjou et al, Haematologica, 2015, considering gender, HBB and HBA genotypes, and 4 SNPs in HbF QTL (HBG2, BCL11A, HMIP). Correlative analyses were performed to assess relationships between genotype, presence/absence of non-HBB mutations (HBA2, HBA1, KLF1), presence/absence of HbF QTL SNPs (HBG2, BCL11A, HMIP), and TSS with the achievement of transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without red blood cell [RBC] transfusions for ≥12 months). Correlation coefficients used percentage bend correlation. Statistical significance threshold was p ≤ 0.05. Results As of 3 March 2020, 38 patients were treated in HGB-207 and HGB-212 (β0/β0 genotype n=9; non-β0/β0 genotype n=29 [β+/β+ n=8; β0/β+ n=15; βE/β0 n=6]). All patients were heterozygous or homozygous for mutations or SNPs that may modulate disease severity; 20 patients were homozygous for ≥1 mutation or SNP. Patients had the following alleles associated with higher HbF synthesis: HBG2 rs7482144 C>T (Xmn1 site), C/T n=9, T/T n=1; BCL11A rs1427407 G>T, G/T n=8; BCL11A rs10189857 A>G, A/G n=16, G/G n=18; HMIP rs9399137 T>C, T/C n=9, C/C n=2. Three patients were heterozygous for single α-globin gene deletion (-α/αα) and 2 were heterozygous for α-globin gene triplication (αα/ααα). Median TSS was 3.65 (min - max 0.4 - 8.1). TI was achieved by 23/27 (85%) evaluable patients; 4 patients with ≥ 12 months follow-up have been transfusion free for > 10 months but were not yet evaluable for TI (Figure). β-thalassemia genotype did not strongly correlate with TI (two-sided Fisher's Exact Test, p-value = 0.78). Month 12 median (min - max) peripheral blood vector copy number (PB VCN) was 1.5 (0.2 - 5.0) c/dg in TI or transfusion-free patients (n=27) and 0.2 (0.2 - 0.4) c/dg in patients who did not achieve TI (n=4). The transfusion-free patient (β0/β0) with the lowest month 12 PB VCN was homozygous for T/T at rs7482144 (HBG2Xmn1 site) and G/G at rs10189857 (BCL11A), and heterozygous for single α-globin gene deletion. Endogenous Hb (5.9 g/dL HbF + 0.2 g/dL HbA2) and gene therapy-derived HbAT87Q (4.4 g/dL) at month 12 enabled this patient to stop transfusions. Tests of association of SNPs and mutations with TI were not significant; no p-value < 0.31 (chi-squared test). As only 4 patients did not achieve TI, the power to detect an association was limited. Larger sample sizes are needed to determine if individual SNPs and mutations may have an impact on TI. In TI or transfusion-free patients (n=27), TSS correlated strongly with month 12 endogenous unsupported Hb (HbA + HbA2 + HbF + HbE without RBC transfusions for 60 days) (correlation coeff. = -0.76, p < 0.0001), but not with HbAT87Q (correlation coeff. = 0.26, p = 0.19) or unsupported total Hb (correlation coeff. = 0.32, p = 0.10). Beti-cel-related adverse events (AE) in >1 patient were abdominal pain (n=2 non-β0/β0; n=1 β0/β0), thrombocytopenia (n=3 non-b0/b0). Serious AEs in ≥3 patients post-infusion were thrombocytopenia (n=2 non-β0/β0; n=1 β0/β0), pyrexia (n=1 non-b0/b0; n=2 β0/β0), veno-occlusive disease (n=3 non-β0/β0). Summary Genetic characterization of TDT patients treated with beti-cel revealed diverse HBB and non-HBB mutations and polymorphisms that may influence disease severity. Higher PB VCN and HbAT87Q levels were associated with increased likelihood of TI. In instances of lower HbAT87Q, higher endogenous HbF might be a determinant in whether TI is achieved. Despite genetic heterogeneity, beti-cel enabled patients to achieve TI regardless of β-thalassemia genotype, TSS, disease genetic modifiers including HBA, and HbF QTL SNP genotypes. Disclosures Walters: Veevo Biomedicine: Consultancy; AllCells, Inc: Consultancy; Editas: Consultancy. Chui:bluebird bio, Inc.: Other: Payment for lab use for the sequencing analyses done for the studies. Lal:bluebird bio, Inc.: Research Funding; Agios Pharmaceuticals: Consultancy; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding; Novartis: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Terumo Corporation: Research Funding; Chiesi USA: Consultancy; Insight Magnetics: Research Funding. Locatelli:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Apopharma: Research Funding; Bristol Myers Squibb: Consultancy; Imara: Consultancy; Celgene: Consultancy; Sangamo: Research Funding; Terumo Corp: Research Funding; Novartis: Research Funding. Porter:bluebird bio, Inc.: Consultancy, Honoraria; Vifor Pharmaceuticals: Honoraria; La Jolla Pharmaceuticals: Honoraria; Protagonist Therapeutics: Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Silence Therapeutics: Honoraria. Thuret:Apopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis pharma: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials. Kulozik:Novartis: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Thrasher:4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership. Yannaki:bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; SANDOZ: Speakers Bureau; Gilead: Speakers Bureau. Yang:bluebird bio,Inc.: Current Employment, Current equity holder in publicly-traded company. Whitney:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Petrusich:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Colvin:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Thompson:BMS: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; CRISPR/Vertex: Research Funding; Biomarin: Research Funding; Baxalta: Research Funding.

The aim of the study was to determine the frequency of hypothyroidism in transfusion dependent thalassaemia patients. A total of 64 transfusion dependent thalassaemia (TDT) patients were included in this cross-sectional study from April, 2018 to September, 2019 according to selection criteria. Thyroid hormone status was assessed by estimation of serum FT4 and serum TSH. Body iron load was estimated by serum ferritin level. The study sample consisted of 43 male and 21 female TDT patients, with a mean age of 25.5 years. Total 28% patients were found hypothyroid, 11% were overt hypothyroid and 17% were subclinical hypothyroid. Mean serum ferritin level was 2462.6 ng/ml. Significant correlation was not found between serum TSH and Serum ferritin level (p = 0.055). Total unit of transfusion (p=0.001) and duration of transfusion therapy (p=0.003) were significantly associated with development of hypothyroidism.

Background Beti-cel ex vivo gene therapy integrates a modified HBB gene into hematopoietic stem cells of patients with TDT, aiming to enable lifelong, stable production of functional adult hemoglobin (Hb). The efficacy and safety of the treatment have been demonstrated in a total of 63 patients treated across 4 clinical trials (HGB-204,-HGB-205, HGB-207, and HGB-212). Here, we present the first patient who received beti-cel outside of the clinical trial setting, a 14-year-old male with a β 0/β + (IVS-1-6) genotype. Methods Following hematopoietic stem cell collection via granulocyte-colony stimulating factor plus plerixafor mobilization and apheresis, CD34+ cells were transduced with the BB305 lentiviral vector encoding HbA T87Q. The patient received hypertransfusion before mobilization and conditioning, maintaining a pre-transfusion Hb level of >11 g/dL. Six days prior to beti-cel infusion, single-agent busulfan myeloablation was initiated (16 single doses at 0.8 mg/kg body weight; 3.2 mg/kg/24 h) with concomitant clonazepam (see Table for treatment timeline). Ursodeoxycholic acid therapy was continued as hepatic veno-occlusive disease (VOD) prophylaxis through inpatient treatment. Results The patient was diagnosed with TDT at the age of 2 years in his home country and has been treated in Germany since the age of 9. Regular transfusion therapy was initiated soon after diagnosis (Table). Aged 9, the patient was started on desferasirox for iron elimination therapy. His annualized red blood cell (RBC) transfusion volume was 174 ml/kg in 2018 and 185 ml/kg in 2019, maintaining his pre-transfusion Hb at or above 9 g/dl. No HLA-related donor was available for allogeneic transplant. At informed consent, the patient was 13 years old and met the eligibility criteria for beti-cel treatment as outlined in the summary of product characteristics (SmPC). The patient was physically fit, with a 90% Lansky score and regular participation in school sports, but reported physical limitations when running extensively. The patient underwent a thorough assessment before admission (Table), which did not reveal any remarkable abnormalities except TDT-related splenomegaly and signs of slight iron overload (liver iron content, 2.0 mg/g dry weight [normal range, 0.17-1.8]). On 11/Feb/2021, the patient was infused with 5.1 × 10 6 CD34+ cells/kg. The patient received 4 RBC and 8 platelet transfusions following infusion until Day 13 and 27, respectively (Table). Neutrophil and platelet engraftment occurred on day 27 post beti-cel infusion. The patient was discharged from inpatient treatment the same day, in excellent general condition, with 90% Lansky score, Hb of 8.2 g/dl, a reticulocyte count of 9.3%, a total white cell count of 1.55/nl, a neutrophil count of 0.75/nl, and a platelet count of 24/nl. At last follow-up (+100 days), the patient felt well and exhibited normal exercise tolerance. He has received neither red blood cell nor platelet transfusions or chelation therapy since discharge. Total Hb was 11.8 g/dl (Table). Granulocytes and lymphocytes had recovered to normal levels. The patient showed continued, albeit slowly improving, thrombocytopenia (platelet count, 31/nl [29/nl at +60 days]), consistent with previous observations after beti-cel therapy. Myeloablation and beti-cel infusion were tolerated well. Adverse events post infusion were febrile neutropenia, elevated C-reactive protein levels, pruritus, gingivitis, mild mucositis, and vertigo, consistent with the SmPC. At +23 and +26 days, the patient experienced transient subjective hearing loss (quickly resolved). No VOD events occurred. Conclusions This is the first real-world patient with TDT treated with beti-cel therapy. The treatment regimen had a tolerability profile consistent with that of mobilization, apheresis, and busulfan myeloablation, matching clinical trial observations. Following treatment, this 14-year-old patient reached a total Hb of 11.8 g/dL at +100 days without requirement of red cell transfusions and continues to exhibit prolonged but slowly improving and asymptomatic thrombocytopenia. Figure 1 Figure 1. Disclosures Schmitt: TolerogenixX Ltd: Current Employment; Therakos/Mallinckrodt: Research Funding; Hexal: Other: Travel grant; Jazz Pharmaceuticals: Other: Travel grant. Schmitt: Bluebird Bio: Other: Travel grants; Novartis: Other: Travel grants, Research Funding; TolerogenixX: Current holder of individual stocks in a privately-held company; Apogenix: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Hexal: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants. Kulozik: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria; BioMedX: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: Nonlinear measure of heart rate variability (HRV) is an emerging tool to detect changes in cardiac autonomic nerve function (CANF) in transfusion dependent thalassemic (TDT) patients. Slow breathing exercise (SBE) can significantly improve HRV in health and various diseases. Objective: To observe the effect of slow breathing exercise (SBE) on non linear measures of HRV in TDT patients. Methods: This prospective interventional study was done in the Department of Physiology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka in 2018 on 60 male TDT patients aged 15-30 years. Thirty patients received conventional treatment and 30 patients performed slow breathing exercise along with the conventional treatment for 3 months. Age and sex matched 30 healthy control were enrolled. All subjects were followed up at baseline and after 3 months. Non linear (Poincare) HRV parameters were recorded by Power Lab 8/35 AD Instrument, Australia. For statistical analysis paired sample ‘ t’ test and independent sample ‘t’ test were used. Result: SD1, SD2 and SD1/SD2 were found significantly lower in TDT patients compared to healthy control at baseline. After 3 months of slow breathing exercise, significant increment of these parameters occurred with trend of improvement in cardiac autonomic nerve function in this group of patients. Conclusion: Slow breathing exercise may improve cardiac autonomic nerve function and sympathovagal balance in transfusion dependent thalassemic patients. J Bangladesh Soc Physiol. 2019, June; 14(1): 26-32

INTRODUCTION: Endocrine dysfunction due to iron overload secondary to frequent blood transfusions is a common complication in children with transfusion-dependent thalassaemia (TDT). We ascertained the prevalence of endocrine dysfunction in children with TDT seen in a hospital setting in Malaysia. METHODS: We reviewed all patients with TDT who had ≥ 8 blood transfusions per year. Patients who had a history of stem cell transplantation, concurrent autoimmune diseases or were newly diagnosed to have TDT were excluded. Standard diagnostic criteria were used in the diagnosis of various endocrine dysfunctions. RESULTS: Of the 82 patients with TDT, 65% had at least one endocrine dysfunction. Short stature was the commonest (40.2%), followed by pubertal disorders (14.6%), hypoparathyroidism (12.3%), vitamin D deficiency (10.1%), hypocortisolism (7.3%), diabetes mellitus (5.2%) and overt hypothyroidism (4.9%). Subclinical hypothyroidism and pre-diabetes mellitus were seen in 13.4% and 8.6% of the patients, respectively. For children aged < 10 years, the prevalence of both thyroid dysfunction and hypoparathyroidism was 9.1%. CONCLUSION: Two-thirds of children with TDT experienced at least one endocrine dysfunction. Thyroid dysfunction and hypoparathyroidism may be missed if endocrine screening is only performed in children with TDT > 10 years of age. Close monitoring for endocrine dysfunction and hormonal therapy is essential to prevent long-term adverse outcomes.