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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.

BACKGROUND: Ineffective hematopoiesis in patients with myelodysplastic syndromes (MDS) often results in transfusion dependence. The burden of frequent transfusions in the real-world MDS population is largely unknown.STUDY DESIGN AND METHODS: An observational, retrospective, population-based study, using the HemoBase registry, was performed including all patients diagnosed with MDS between 2005 and 2017 in Friesland, a province in the Netherlands with approximately 650,000 inhabitants. Detailed clinical information was collected from the electronic health records. Transfusion burden was classified according to the International Working Group 2018 criteria: not transfusion dependent, low (LTB), or high transfusion burden (HTB). Univariate and multivariable regression analyses were performed.RESULTS: Of 292 patients, 136 (46.6%) had a HTB of ≥8 units/16 weeks and 17 (5.8%) had a LTB of 3-7 units/16 weeks. This was present in all types of MDS patients, but patients aged 75-84 years (odds ratio [OR] 4.02, 95% confidence interval [CI]: 1.84-8.82), high-risk MDS patients (OR 2.88, 95% CI: 1.08-7.68) and MDS-EB-2 patients (OR 7.07, 95% CI: 2.17-22.90) were particularly at risk for a HTB.DISCUSSION: This study provides a reliable estimate of the transfusion burden in real-world MDS patients, with almost half of the patients having a HTB. A HTB was observed in all MDS subtypes and both low- and high-risk MDS. Therefore, we conclude that the entire MDS population might benefit from novel agents that reduce the transfusion need and that might have beneficial effects on patient outcomes and healthcare utilization outcomes.

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.

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.

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.

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 ...

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.

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.

Tissue iron overload is a life-threatening scenario in children with transfusion-dependent β-thalassemia major, miRNAs that are involved in iron hemostasis could serve as therapeutic targets for control of iron overload. We aimed to find out the association between three iron-related miRNAs “miR-let-7d, miR-122, and miR-200b” and excess iron in tissues, in transfusion-dependent β-thalassemia major patients. Circulating miRNA expressions are measured in peripheral blood (PB) samples using qPCR of transfusion-dependent (TDT) β-thalassemia patients (n = 140) and normalized to non-transfusion-dependent (NTDT) β-thalassemia (n = 45). Results revealed that plasma expression levels of miR-let-7d and miR-200b were significantly downregulated in TDT patients; however, miR-122 was upregulated. In terms of tissue iron load, aberrant expression of miRNAs was significantly associated with increased—iron accumulation in hepatic and cardiac tissues. We concluded that circulating miRNAs are strong candidates that associate iron hemostasis in transfusion-dependent β-thalassemia major patients. And by extension, targeting miR-let-7d, miR-122, and miR-200 might serve as novel sensitive, specific and non-invasive predictor biomarkers for cellular damage under condition of tissue iron excess.

Pure red cell aplasia (PRCA) is an uncommon condition, which is rarely associated with Systemic Lupus Erythematosus (SLE). Prompt identification and management of the underlying SLE results in correction of anemia. We report the case of a young female who presented due to severe anemia since the last two years. The cause of her anemia on initial investigations was not elicited in these two years, during which response to hematinics was poor and she remained transfusion dependent. Bone marrow biopsy showed PRCA after which autoimmune workup revealed SLE. Subsequently, treatment of SLE with steroids led to normalization of hemoglobin levels within a follow-up period of three months.

Background: One of the main obstacles of providing home-based palliative care to transfusion-dependent hematology patients is the lack of home transfusions services. While healthcare professionals are concerned with safety and cost of home transfusions, the attitude of the patients toward home transfusions are mostly unknown. Aim: To obtain quantitative data regarding the willingness and concerns of transfusion-dependent patients with hematological diseases toward the option of home transfusions. Design: A cross sectional survey including a self-administered questionnaire in one of the three main spoken languages in Israel was administered to patients in 17 hospital hematology outpatient clinics between May 2019 and March 2020. Results: About 52% of 385 patients that participated in the survey preferred home transfusions to hospital transfusions. Gender, age, education, or type of disease were not associated with preference for home transfusions, nor were hospital location or its size. The likelihood to prefer home transfusions was significantly higher among the Hebrew-speakers and those who had not experienced adverse effects previously. The most significant factor associated with preference of home transfusions was a perceived negative effect of hospital-based transfusion on quality of life. The main reason to reject home transfusions was fear of possible adverse effects and concerns over losing contact with the medical staff at the treating hospital. Conclusion: These data suggest that a significant portion of transfusion-dependent patients in Israel view home transfusions as a preferred treatment option and that its successful implementation requires maintaining ongoing contact with the treating hospital.

Since February 2020 the SARS-CoV-2 virus pandemic caused the reduction of spaces and medical and nurse staff dedicated to outpatients because of the urgent needs in the intensive, sub-intensive, and ward units in Lombardia region in Italy. In our Centre we regularly follow patients with hereditary anemias (ThSA), and hemochromatosis (HH). We aimed to evaluate these patients’ emotional responses during the pandemic through online survey. 44 ThSA (55%) and 54 HH (54%) answered the questionnaire. Both ThSA and HH reported high level of anxiety, worries and concern regarding SARS-Cov-2 pandemic that was the sum of several components: i. general fear for a new and potentially lethal disorder; ii. additional disease-related risk; iii. decreased standard care. About 40% of ThSA and more than half HH asked for more attention, information and protection regarding SARS-Cov-2 infection. These findings indicate: i. the need to guarantee adequate management of patients with rare diseases even in the case of an emergency as SARS-Cov-2 was and could be in the next future; ii. the need for exhaustive information to develop “healthy concern” in patients in order to contain both their anxiety and defensive attitude, thus preventing them from denial with ensuing greater exposure to risk.

Objective: Increased life span with regular transfusion and iron chelator treatments enhances the importance of nutrition in beta thalassemia. Controlling Nutritional Status (CONUT) score is a nutritional index calculated on serum albumin, total cholesterol and lymphocyte count. We aim to evaluate need for transfusion and the clinical conditions which cause morbidity with CONUT score in patients with adult transfusion dependent beta thalassemia (BTD). Method: We conducted a retrospective study at the Denizli Thalassemia Center. We used Mann Whitney Utest for comparing. We applied logistic regression analysis and ROC analysis to evaluate CONUT score and clinical effects. Results: A total of 102 patients with BTD were included. 89 were beta thalassemia major and 13 were transfusion dependent thalassemia intermedia (44 male,58 female). The median age was 26. The mean follow up period was 26 months. The median of CONUT score was 3.0 (min: 0-max: 6). CONUT score of 54 patients (52.9%) was high (>3). We found significant difference with CONUT score >3 (median:32 units) and CONUT score of 3) (p = 0.001). CONUT score is a distinguishing parameter for hypogonadism (p = 0.001; AUC = 0.922) and low bone mass (p = 0.001; AUC = 0.867). Conclusion: CONUT score can be used as a predictor to evaluate need for transfusion and morbidity of patients with BTD. If nutritional status is closely followed with CONUT score and nutritional deficiency is corrected, cost and complications will be decreased and expanctancy of life can be increased.

We describe two unrelated patients, both heterozygous for an unstable hemoglobin (Hb) variant named Hb Calgary (HBB: c.194G>T) that causes severe hemolytic anemia and dyserythorpoietic, resulting in transfusion dependence and iron overload. The molecular pathogenesis is a missense variation on the β-globin gene, presumed to lead to an unstable Hb. The phenotype of Hb Calgary is particularly severe presenting as transfusion-dependent anemia in early infancy, precluding phenotypic diagnosis and highlighting the importance of early genetic testing in order to make an accurate diagnosis.

Bitopertin is a small molecule selective inhibitor of glycine transporter 1 (GlyT1), initially developed to increase brain extracellular levels of glycine in the vicinity of neuronal N-methyl-D-aspartate receptors for the treatment of schizophrenia. GlyT1, the pharmacological target of bitopertin, is also present as a transmembrane transporter in erythroid cells1 and accounts for 50–55% of glycine uptake in human red blood cells (RBCs).2, 3 Erythroid GlyT1 inhibition by bitopertin leads to reduced intracellular glycine availability, interfering with the first step of haem synthesis, in which 5-aminolevulinate synthase catalyses the condensation reaction between glycine and succinyl-coenzyme A, forming 5-aminolevulinic acid.1

OBJECTIVE: To compare the blood transfusion pattern between children with transfusion dependent Eβ-thalassemia and β-thalassemia major. METHODS: 168 children (age 3 months to 12 years) with transfusion dependent Eβ thalassemia and β thalassemia major were admitted to the hospital. 120 children who met our inclusion criteria, were selected and detailed history including various parameters indicating the blood transfusion pattern were recorded. RESULTS: In this study 72 children (60%) of the patients were transfusion dependent Eβ thalassemia. They started receiving blood transfusion (BT) at a later age(p

Patients with β-thalassemia major (β-TM) show ineffective erythropoiesis and iron overload, which is the leading cause of mortality and organ injury. The present study aimed to investigate the relationships between two iron regulatory hormones, hepcidin and erythroferrone (ERFE) levels, and iron status parameters in Iraqi patients with β-TM. Iron status parameters and hormones were measured in 60 patients and compared with 30 healthy controls. The results indicated significant changes in different iron status parameters, while ferritin with the ∼11-fold increase showed the most change. Significant reduction in hepcidin and an increase in ERFE levels were detected in patients when compared to the control group, while no direct correlation was identified with the other measured iron status parameters. The receiver operating characteristic (ROC) analysis showed that the z-score of the composite of ERFE + ferritin has a full diagnostic ability for β-TM. In conclusion, our findings indicated the correlation between different iron status parameters and ferritin as the leading predictor of iron overload and two main iron regulatory hormones.

Few data are available on the treatment with DFX in patients with transfusion dependent Ph- Myeloproliferative Neoplasms in fibrotic phase. Here we report 48MPNpatients and iron overload treated with DFX. Starting DFX dose was 20 mg/Kg in 23 patients, 15 mg/Kg in 20 patientsand 10 mg/Kg in 5 patients. After a median treatment of 27.6 months, 5 patients achieved ferritin500 ng/ml, 11 1000 ng/ml and 3 a reduction50% of basal ferritin with a global response rate of 41%. As to hematological improvement, 9/47 patients (19.1%) showed a persistent rise of Hb1.5 g/dl, with disappearance of transfusion requirement in 6 cases. The median OS from DFX initiation in patients with chelation response was 61.0 months compared to 15.8 months in patients without chelation efficacy. Treatment with DFX is feasible and effective in MPN with iron overload and a hematological improvement can occur in a sizeable rate of patients.

The response to hydroxyurea (HU) therapy of 44 Yemeni transfusion-dependent β-thalassemia (β-thal) patients in Sana'a City, Yemen, was assessed. All patients were treated with a dose of 15 mg/kg/day HU for 4-10 months. Thirty-six patients responded partially to HU with clinical improvement of anemia and extramedullary hematopoiesis features, whereas the rest remained almost at the same baseline levels of transfusion dependency. Hydroxyurea was shown to have a variable favorable effect on β-thal in Yemeni patients. Further study is required to identify the various response factors to HU therapy, as well as to investigate its long-term efficacy and safety.

OBJECTIVE Pegylated IFN-α2a has been reported in two case reports as being efficacious in treating CDA-I patients. This study aims to assess its efficacy on a series of CDA-I patients. METHODS Study sample consisted of seven CDA type 1 transfusion-dependent patients. They received pegylated interferon alpha-2a at an initial dose of 90-180 µg once a week, tapered according to clinical response and side effects. Good response was defined as Hb ≥ 10 g/dL for ≥3 months, partial response was defined as 7 ≤ Hb

Thalassemia is one of the most prevalent monogenic diseases most frequently caused by quantitative defects in the production of β-globin leading to severe anemia. Technological advances in genome sequencing, stem cell selection, viral vector development, transduction and gene-editing strategies now allow for efficient ex-vivo genetic manipulation of human stem cells that can lead to correction leading to a meaningful clinical benefit in thalassemia patients. In this review, the status of the gene-therapy approaches available for transfusion dependent thalassemia are discussed, along with the critical criteria that affect efficacy and lessons that have been learned from the early phase trials. Salient steps necessary for the clinical development, manufacturing, and regulatory approvals of gene therapies for thalassemia are also highlighted, so that the potential of these therapies can be realized. It is highly anticipated that gene therapies will soon become a treatment option for patients lacking compatible donors for hematopoietic stem cell transplant and will offer an alternative for definitive treatment of β- thalassemia. This article is protected by copyright. All rights reserved.

Thalassaemia are the most common inherited autosomal recessive single gene disorders characterized by chronic hereditary haemolytic anaemia due to the absence or reduced synthesis of one or more of the globin chains. Haemoglobin E-β thalassaemia is the genotype responsible for approximately one half of all severe beta-thalassaemia worldwide. This study proposes to evaluate the effect of various molecular parameters on the response of hydroxyurea. Hydroxyurea was started at an initial dose of 10 mg/kg of body weight/day on 110 transfusion-dependent HbE-β thalassaemia patients. HbF level was measured by HPLC analysis. β-Thalassaemia mutations, XmnI and five other SNPs, and α-globin gene deletions and triplications were detected by ARMS-PCR, RFLP-PCR and Gap-PCR, respectively. Based on the factors for evaluating hydroxyurea-response, 42 patients were responders as they showed an increment of Hb from a mean baseline value of 6.45 g/dl (± 0.70) to 7.78 g/dl (± 0.72) post-therapy. Based on increase in HbF above the median value (14.72%) post-therapy, 78 patients were found to be responders. All the 78 responders showed mean decrease in transfusion of 74.26% (± 8.32) with a maximum decrease of 98.43%. There was a significant correlation between decrease in transfusion and increase in HbF level for all 78 responders. XmnI polymorphism showed the strongest association (p

Chemotherapies approved for defined subgroups promise personalized oncologic care, but their off-label impact is unclear. Lenalidomide is approved for lower-risk, transfusion-dependent (TD) myelodysplastic syndromes (MDS) with del(5q), but frequently used in MDS outside this indication. We characterized lenalidomide use and outcomes among non-TD patients with MDS. Patients 65 or older diagnosed with MDS between 2007 and 2013 were identified using SEER; linked Medicare claims were evaluated for transfusions, lenalidomide use, and incident toxicities. TD was ≥2 transfusion episodes within an 8-week period; responses were transfusion independence (TI) and ≥50% transfusion reduction (minor response). We compared overall survival for non-TD patients receiving lenalidomide versus those not receiving lenalidomide, matched on disease and patient characteristics. We identified 676 patients who had received lenalidomide, including 275 (40.7%) TD and 401 (59.3%) non-TD; 18.5% (125/676) had zero claims for RBC transfusion prior to receiving lenalidomide. Incident toxicities among patients prescribed lenalidomide were similar in TD and non-TD groups, except incident thromboembolic events were higher among non-TD patients (10.8% vs. 6.0%, P = .04). Comparing 191 non-TD patients receiving lenalidomide within 6 months of MDS diagnosis to risk-matched MDS controls, lenalidomide was not associated with improved OS (P = .78). Among TD patients (n = 275), 31% achieved TI, and 30% achieved minor hematologic response, with a median time to TI of 4.1 weeks. In conclusion, we confirmed the benefit of lenalidomide among TD patients with MDS; however, many non-TD patients also received lenalidomide. These patients experienced accompanying toxicity without evidence of benefit in terms of transfusion needs or overall survival.

Hospice provides high-quality end-of-life care, but patients with leukemias use hospice services less frequently than those with solid tumors. Transfusion dependence (TD) may hinder or delay enrollment, because hospice organizations typically disallow transfusions. We examined the association between TD and end-of-life outcomes among Medicare beneficiaries with leukemia. From the Surveillance, Epidemiology, and End Results-Medicare database, we selected beneficiaries with acute and chronic leukemias who died in 2001-2011. We defined TD as ≥2 transfusions within 30 days before death or hospice enrollment. End points included hospice enrollment and length of stay, reporting relative risk (RR) adjusted for key covariates. Among 21 033 patients with a median age of 79 years, 20% were transfusion dependent before death/hospice enrollment. Use of hospice increased from 35% in 2001 to 49% in 2011. Median time on hospice was 9 days and was shorter for transfusion-dependent patients (6 vs 11 days; P < .001). Adjusting for baseline characteristics, TD was associated with a higher use of hospice services (RR, 1.08; 95% confidence interval [CI], 1.04-1.12) but also with 51% shorter hospice length of stay (RR, 0.49; 95% CI, 0.44-0.54). Hospice enrollees had a lower likelihood of inpatient death and chemotherapy use and lower median Medicare spending at end-of-life, regardless of TD status. In conclusion, relatively increased hospice use combined with a markedly shorter length of stay among transfusion-dependent patients suggests that they have a high and incompletely met need for hospice services and that they experience a barrier to timely referral. Policy solutions supporting palliative transfusions may maximize the benefits of hospice for leukemia patients.

Posterior reversible encephalopathy syndrome (PRES) has diverse etiologies and is closely linked to hematopoietic stem cell transplant (HSCT). Headache and seizures are the most common clinical presentations. Although near total recovery is seen in the majority of patients with appropriate management, the implications of its occurrence in the setting of an HSCT is much more than the residual neurological deficits. Graft rejection and occurrence of graft versus host disease has been reported. We analyzed retrospectively our data of 35 pediatric HSCT recipients over the last 2 years at our center. In total, 17% (n=6) patients developed PRES. Headache and seizures were the most common clinical presentations. All patients were on calcineurin inhibitors at the onset of symptoms. The median time after HSCT to the onset of PRES was 21 days. In total, 34% (n=2) patients developed residual neurological deficit. One patient died of acute graft versus host disease at a later date, and 50% (n=3) patients had graft rejection and return to transfusion dependence. The implications of PRES on HSCT outcomes are grave, and better immunosuppression transition protocols need to be developed.

Effective iron chelation therapy is an important part of treatment in patients with transfusion-dependent thalassaemia and lower-risk myelodysplastic syndromes (MDS). Key strategies for optimising iron chelation therapy include ensuring good adherence and preventing and managing adverse events (AEs). Good adherence to iron chelation therapy with deferoxamine and deferasirox has been linked to improved survival and/or reductions in complications related to iron overload; however, maintaining good adherence to iron chelators can be challenging. Patients with transfusion-dependent thalassaemia or lower-risk MDS showed better adherence to the deferasirox film-coated tablet (FCT) formulation than to the deferasirox dispersible tablet formulation in the ECLIPSE trial, reflecting in part the improved palatability and convenience of deferasirox FCT. As well as affecting adherence, AEs may lead to dose reduction, interruption or discontinuation, resulting in suboptimal iron chelation therapy. Preventing and successfully managing AEs may help limit their impact on adherence, and following dosage and administration recommendations for iron chelators such as deferasirox may help minimise AEs and optimise treatment in patients with transfusion-dependent thalassaemia and lower-risk MDS.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Currently, hematopoietic stem cell transplantation (HSCT) is the most reliable curative treatment with excellent results for patients with HLA-matched family or unrelated donors. However, even after fully myeloablative preparative regimens, mixed donor chimerism is a potential concern. We performed a retrospective chart review of 12 children who underwent allogeneic HSCT for WAS to report our experience. The median age at transplant was 10.5 months (range, 3 to 39). The median nucleated cell dose from the marrow was 4.55 × 109/kg (range, .3 to 7.9). The median times to neutrophil and platelet engraftment were 19 days (range, 13 to 27) and 18.5 days (range, 12 to 31), respectively. The rate of overall survival was 92% with median follow-up of 67 months (range, 3 to 146). Two patients developed grade IV acute graft-versus-host disease, and 1 died on day +99. Five of 12 patient's (42%) had mixed donor chimerism (range, 12% to 85%) at day +180. None of the pretransplant patient parameters was predictive of mixed chimerism. Nonetheless, of these 5 patients, 2 had normalization of the platelet count despite the mixed chimerism, 2 had full donor chimerism after receiving a second transplant with the same donor, and 1 remains transfusion dependent awaiting a second transplant. Hence, even with a significant rate of mixed chimerism, HSCT provides substantial benefit to WAS patients, with excellent overall survival.

BACKGROUND β-Thalassemia is a common hemoglobinopathy in the Arabian Peninsula. Red blood cell (RBC) transfusion is a cornerstone for its management, but can create significant challenges including RBC alloimmunization. Herein, we examine alloimmunization risk factors in Omani patients with transfusion-dependent β-thalassemia. Existing literature is summarized. STUDY DESIGN AND METHODS A retrospective review of all patients attending our center over 25 years was performed. Clinical and transfusion records were examined. Chi-square test was used to assess the association between the categorical variables. Nonparametric Mann-Whitney test was used to assess the association between transfusion and risk of alloimmunization. RESULTS A total of 268 patients were identified (168 adults and 100 pediatrics), of whom 226 are alive (84.3%). Males accounted for 53.4%. The cohort had a median age of 22 years (range, 2-43 years). The most common blood group was O+ (39%). The prevalence of alloimmunization was 9.3% with anti-E (24%) and anti-K (24%) being the commonest antibodies identified. There was a significant association between age and alloimmunization, with 68% of alloimmunized patients in the age group of 19 to 30 years (p

The thalassemias are genetically complex and usually autosomal recessive. We describe 5 unrelated individuals with non-transfusion-dependent β-thalassemia (NTDT), some with apparently dominant transmission, because of a single β-thalassemia mutation coinherited with a triplicated α-globin locus. Each had an initial, incorrect diagnosis of β-thalassemia trait. The correct diagnosis of NTDT was made at a mean of 7 years of age. Despite reports of this compound genotype causing NTDT, it remains unfamiliar to many clinicians. To increase awareness, we highlight its varied and sometimes subtle clinical and laboratory features and the need for comprehensive genetic testing for timely and correct diagnosis.

We present the case of a novel β-globin gene variant associated with early-onset transfusion-dependent anemia compatible with a β-thalassemia major (β-TM) phenotype in a patient of British descent....

Background Clinical development of new therapies in transfusion-dependent beta-thalassemia has several challenges. Patient enrollment in rare diseases requires multi-center multi-country studies, and the lack of reliable surrogate endpoint for dose selection requires powering for clinical endpoints usually used in Phase 3 trials. An acceptable endpoint from a regulatory perspective which is based on responders analysis, such as proportion of patients experiencing ≥50% reduction in Red Blood Cell (RBC) transfusion burden and a reduction of ≥2 units, requires 12 weeks screening period to establish baseline transfusion burden for reliable comparison. Importantly, higher randomization ratio of treatment:placebo can improve patients' motivation to enroll into a trial, but it is less statistically efficient and requires higher sample size. We designed a Phase-2b, double-blind, randomized, placebo controlled, multi-center study with Vamifeport (NCT04938635) to assess the efficacy and safety of multiple doses of a new therapy in adults with transfusion-dependent beta-thalassemia. The proposed design follows the Bayesian framework with borrowing from published historical control data. The historical control data is used to construct an informative prior for the control arm to reduce the burden of patients randomized to a control arm and improve the trial's efficiency in performing dose selection. Study Design and Methods Adults (18 to 65 y.o.) with documented diagnosis of β-thalassemia or hemoglobin E / β-thalassemia will be randomized to three doses of the investigational drug or placebo plus best supportive care. RBC transfusion dependence is defined as at least 6 RBC Units in the 24 weeks prior to randomization and no transfusion-free period for ≥35 days during that period. The primary endpoint is the proportion of patients experiencing ≥33% reduction of RBC units from baseline and a reduction of ≥2 units assessed from week 13 to week 24. The key secondary endpoints include proportion of patients experiencing ≥33% reduction from week 37 to week 48; proportion of patients experiencing ≥50% reduction over any consecutive 12-week interval from week 1 to week 48 and the mean change from baseline in RBC transfusions (units) from week 13 to week 24. The primary and key-secondary analysis will be conducted in a hierarchical fashion to account for multiplicity. We proposed a Bayesian design with the use of noninformative, or weakly informative, priors for the active dose arms while using a robustified informative prior for the control arm. Historical control data will be "borrowed" in an informative prior for the control arm rate from the Phase 3 trial - BELIEVE. The robustification is required in order to control the level of borrowing depending on the level of prior-data conflict. Prior-data conflict can arise from multiple sources like population heterogeneity between the historical and current study. Therefore, the selection of historical data (BELIEVE trial) addresses similarity in inclusion / exclusion criteria, standard of care etc. The robustification of the informative prior does not take into account prior-data conflict in terms of population or study characteristics but directly focuses on the informative prior of the parameter of interest and the corresponding likelihood of the current data. For example, in the BELIEVE study, out of 112 patients randomized to the control arm, 5 patients (4.5%) had a ≥33% reduction in transfusion burden over 24 weeks. A prior-data conflict may arise if the Phase-2b trial of interest here, suggests that the proportion is substantially different that 4.5% and this can inflate the frequentist Type-I or Type-II error rates examined via simulations. We evaluated Type-I error rates of the proposed design with 5000 Monte-Carlo runs for each scenario of the response rates. Using informative prior with no prior-data conflict the type-I error with no robustification is ≈ 2.4%. As the prior-data conflict increases, without robustification, the type-I error cannot be controlled. However, with a robustification weight of 0.5 the type-I errors can be controlled in line with regulatory requirements. Discussion A proposed Bayesian design with robustified informative prior for the control arm helps reduce patients' burden of randomization to control arm and reduce overall sample size for a rare disease trial when recruitment and trial duration are challenging. Disclosures Muehlemann: Vifor Pharma AG: Consultancy. Mukherjee: Vifor Pharma AG: Consultancy. Taher: Bristol Myers Squibb: Consultancy, Research Funding; Vifor Pharma: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Gudmundsdottir: Vifor Pharma AG: Current Employment. Morin: Vifor Pharma AG: Current Employment. Richard: Vifor Pharma AG: Current Employment.

Haemopoietic stem cell transplantation (HSCT) is a well-established treatment modality for the cure of transfusion dependent thalassaemia (TDT) and sickle cell disease (SCD). Clonal evolution has recently been identified as a concerning event in the setting of mixed chimerism and/or ineffective haemopoiesis following conventional bone marrow transplantation and gene therapy for haemoglobinopathies. This has so far been restricted to SCD only, with the presumption that despite both conditions sharing an ineffective erythropoietic marrow compartment, there may be inflammatory and hypoxic differences enabling clonal evolution, in addition to the different exposure to hydroxycarbamide as a therapeutic agent. However, there is a need to investigate whether this may also be an occurrence in TDT. From 2011 to 2021, over a ten-year period, sixty-five consecutive paediatric patients received a sibling HSCT (n=55) or a haploidentical HSCT (n=10) for TDT in our institution. Conditioning intensity was minimised at the start of this cohort in order to limit toxicity and late effects, abandoning the use of Bu/Cy, which resulted in approximately 50% of the patients having stable mixed chimerism long-term. Sibling HSCT was conditioned with fludarabine 160 mg/m 2, treosulfan 42 g/m 2, thiotepa 10 mg/kg and ATG (Thymoglobulin) or alemtuzumab, and received GvHD prophylaxis with ciclosporin and MMF. Haploidentical HSCT was conditioned with fludarabine 150 mg/m 2, cyclophosphamide 30 mg/kg, TBI 2 or 4 Gy, and ATG 4.5 mg/kg (thiotepa 10 mg/kg added if TBI 2 Gy only) with GvHD prophylaxis provided by two doses of post-transplantation cyclophosphamide 50 mg/kg, sirolimus and MMF. All patients had pre-transplantation endogenous haemopoiesis was suppressed pre-transplantation with hypertransfusions for a minimum of 8 weeks, and/or the use of hydroxycarbamide and azathioprine. GvHD prophylaxis was provided with ciclosporin and MMF. All patients were Pesaro class I or II at the time of transplantation. The median age was 5 years (2 - 19). The median survival was 26.8 months (2.6-101.8). The OS was 93.8% and DFS was 89.2%. Three patients in this cohort developed clonal evolution in the context of myeloid mixed chimerism identified due to the development of cytopenias and transfusion dependence. All patients had a complex karyotype and it involved deletion of chromosome 7: Patient 1 had a sibling BMT at 3 years and 2 months. Day +28 chimerism was >95% in whole blood and 95% in T cells. The myeloid fraction had a progressive reduction from day +60 onwards. At 15 months post-transplantation clonal evolution was identified [18% ring sideroblasts, 46;XY, del (7) (q22 q34) [5]/46;XY [5], chimerism 13% donor in whole marrow and 41% marrow T cells. Two months later he became red cell transfusion dependence. A second BMT with busulfan based conditioning resulted in long-term cure. Patient 2 had a sibling BMT at 3 years and 8 months of age. Day +28 chimerism was 99% donor in whole blood and 99% donor in T cells. Day +161 post-transplantation he started requiring erythropoietin support to maintain him transfusion independent and on day +217 we first identified in the bone marrow the appearance of myeloid mixed chimerism (75% donor in whole marrow and 91% marrow T cells) and complex clonal evolution involving -7 and FISH identified deletion of one copy of KMT2E (7q22) and MET (7q31) detected [16/200]. The patient is under monitoring at present with a progressive reduction of the size of the abnormal clones. Patient 3 had a haplo BMT at 5 years and 8 months. Day +28 chimerism was 97% donor in whole blood and 99% donor in T cells. She developed mixed myeloid chimerism following cessation of immunosuppression on day +206: 86% donor whole blood and 99% donor in T cells. At 22 months post-BMT she started to require transfusion and a complex clonal evolution involving deletion 7 in her bone marrow when the chimerism was 42% donor whole blood and 81% donor marrow T cells. FISH identified deletion of one copy of KMT2E(7q22) and MET(7q31) detected[22/100]. She is being prepared for a second bone marrow transplant. In conclusion, complex clonal evolution also occurs post HSCT in TDT, at least in the context of reduction of conditioning intensity and development of mixed myeloid chimerism. This finding warrants further investigation and may have significant implications for the design of both conventional HSCT and gene therapy strategies. Disclosures No relevant conflicts of interest to declare.

Introduction : In Greece, official data confirm that blood supply is consistently declining, primarily because of decreased voluntary blood donations. At this rate, it is unclear whether there will be sufficient red blood cell (RBC) units to meet future demand for patients with β-thalassemia. We modeled future blood demand in patients with transfusion-dependent β-thalassemia (TDT) over the next 15 years to assess whether such a demand can be met. Methods: A discrete time, stochastic, individual-based model, was developed to assess future blood needs of patients with TDT in Greece. The model adopted a cohort approach and patients enter the model shortly after birth and exit at death. The model was seeded with data from the National Registry for Hemoglobinopathies in Greece (NRHG; patient population) and data from the National Blood Centre (RBC units) (Table). To quantify the decrease in TDT incidence, a linear regression model was fitted to the incident cases as described by Voskaridou (Voskaridou E, et al. Ann Hematol 2019;98:55-66). The calculated annual reduction rate was then applied to the observed thalassemia major (TM) and thalassemia intermedia (TI) incident cases for 2012 (Voskaridou E, et al. Ann Hematol 2012;91:1451-1458). The model assumes the reduction would continue through to 2020, from which time the incidence curve would be constant. Results: The model estimates a decrease in both target population, primarily due to the implementation of the national prenatal screening program and TM related mortality, (9.2%, 18.6%, and 26.0% in 2025, 2030, and 2034, respectively) and in demand for RBC units (100,665, 89,428 and 80,565, respectively) over the next 15 years. After accounting for any blood donated, based on latest (2017) data as projected to 2020, Greece is expected to be short of 56,716 RBC units to meet needs of patients with TDT in 2020. By 2025, 2030, and 2034, cumulative required RBC units for patients with TDT are estimated to be 307,150, 501,698, and 617,074, respectively. Assuming RBC units are divided among patients ≥ 18 years and those < 18 years in line with the population mix in the NRHG, cumulative RBC units required for adult patients with TDT are estimated to be 292,837, 464,337, and 554,083 by 2025, 2030, and 2034, respectively. Conclusions: Though blood demand for patients with TDT is expected to decrease in line with a decrease in the patient population, it will remain a challenge for the healthcare system in Greece to meet the demand, primarily due to a continuing shortage of available RBC units from voluntary donations. This annual deficit is estimated to accumulate to over 600,000 units over the next 15 years. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Myelodysplastic syndrome (MDS) is a group of disorders involving hematopoietic dysfunction, with a leukemic transformation characteristic. The risk based therapeutic strategy was well applied in clinical. And for patients with IPSS low or intermediate risk-1, NCCN guideline recommended hematopoietic stimulation therapy, immune suppression therapy (IST), as well as demethylation therapy, along with best supportive care. Eltrombopag (EPAG) was firstly approved as the second line option for immune thrombocytopenia (ITP), and recently it was also investigated for treatment of aplastic anemia and MDS. In MDS, based on available reports, the EPAG was mostly used along with hypomethylating-agent, or as salvage treatment after treatment failure. However, there was study showed that the combination of EPAG to azacitidine (AZA) may worsen platelet recovery, with lower response rate and increased trend of leukemic transformation. The successful EPAG monotherapy for MDS case was report, with complete hematologic remission and blasts elimination. To date, limited study was focus on investigating the benefit of EPAG as initial monotherapy for transfusion dependent (TD) patients with low to intermediate risk-1 MDS, as well as its safety. Herein, we reviewed cases of elderly TD-MDS patients who received EPAG as front-line single treatment in our center, and 7 patients was enrolled from July, 2019 to September, 2020. Patients received EPAG 25mg to a maximum 75mg. The side effects, numbers of transfusion, improvement of peripheral blood and bone-marrow blast were recorded. The 12weeks overall response rate was 85.7%, with 2 robust response (RR), and 4 hematologic response. In patients got response, 66.7% (4/6) became platelet transfusion independent, with an answering period from 19 days to 55 days. No drug adverse events were observed within 12 week-treatment, and no obvious increased blasts as well as myelofibrosis were observed. 2 patients repeated the next-generation sequencing, and no new mutations were found. After the 12-week treatment, the 2 RR patients were still taking EPAG and got continued complete remission with a median follow up of two years. Two patient (No.3 and No.4) relapsed after EPAG withdrawn and became transfusion depend again. Patient No.1 and No.6 died of infection and cerebral hemorrhage during the follow up. In summary, EPAG may improve the hematopoiesis of TD-patient with low to intermediate risk-1 MDS, and was well tolerant with a dose of 25mg to 75mg for Asian population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Iron overload is a potentially preventable complication of blood transfusion dependency. The effectiveness and safety of early start of iron chelation therapy in young children with transfusion-dependent Beta-thalassemia (TDB-T) prior to development of iron overload have been recently demonstrated. The aim of this study was to evaluate the long term effectiveness and safety of continued iron chelation in these children. Methodology: This is a multi-center, investigator initiated, one year prospective randomized study of children with TDB-T who completed the randomized START study (NCT03591575), which had evaluated the safety and efficacy of the oral iron chelator (DFP) in children who did not yet meet the criteria for starting chelation therapy as per standard practice. Enrolment is shown in follow-up chart below; 48 children with TDBT from 3 centers were eligible to be enrolled and were randomized in 1:1 ratio to receive either DFP (n=23) or deferasirox (DFX) (n=25). Half of patients in this study were naïve to chelation (on placebo in START study); had received DFP at a dose; 75 mg/kg/ day or DFX in a dose; 20-25mg/kg/d in 2:1 ratio respectively, while those on DFP in START had continued on either DFP or DFX in 1:2 ratio with same doses. Patients were kept on regular transfusion to keep pre-transfusion Hb >8gm/dl. The primary endpoint was safety and secondary endpoints were changes in serum ferritin (SF) and growth enhancement (height, weight) both were assessed quarterly. An informed consent was signed by parents of all patients before start of the study. Statistical significance between DFP and DFX treated groups was calculated via t-test for continuous variables and Fisher's exact test for discrete variables. Results: In the current study; 66% of the children were males, at enrolment; their age ranged from 20-68 (median 38) months; those who were on DFP or placebo in START had received comparable transfusion units (median 11 and 9 respectively) and SF (880 and 1150 ng/ml respectively). At 12 month of continuation on iron chelation 22% and 60% of children on DFP vs 12% and 48% of those on DFX had SF5cm (p value 33% from baseline on 2 successive visits were observed in 0% in DFP vs. 12% in DFX. No unexpected, serious, or severe AEs were reported in both groups. Conclusion: Children with TDB-T whether on DFP or DFX showed uncommon mild AEs, with no serious or severe AEs. Patients on DFP after an early start of DFP showed adequate growth velocity and better control of iron-overload on serial measurement of SF; compared with those who were on placebo. Figure 1 Figure 1. Disclosures Hamdy: ApoPharma: Honoraria; Amgen: Honoraria; Bayer: Honoraria; Novartis: Honoraria; NovoNordisk: Honoraria; Roche: Honoraria; Takeda: Honoraria.

63rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) -- DEC 11-14, 2021 -- Atlanta, GA, [No Abstract Available], Amer Soc Hematol