Transfusion-dependent Thalassemia Research Articles

PB2233: SYSTEMATIC LITERATURE REVIEW OF HEALTH-RELATED QUALITY OF LIFE BURDEN IN PATIENTS ACROSS THE SPECTRUM OF THALASSEMIA

Background: Recent systematic literature reviews (SLRs) have highlighted the health-related quality of life (HRQoL) burden in transfusion-dependent thalassemia (TDT), particularly β-thalassemia (β-thal). However, less is known about HRQoL in non–transfusion-dependent thalassemia (NTDT) and alpha-thalassemia (α-thal). Aims: To conduct an SLR on the real-world HRQoL burden across the entire spectrum of thalassemia and report evidence gaps. Methods: Searches (2010 to September 2021) were conducted in MEDLINE, Embase, Cochrane Database of Systematic Reviews, Health Technology Assessment Database, NHS Economic Evaluation Database, and EconLit for real-world studies reporting on HRQoL, utilities, and patient-reported outcomes in adult and pediatric patients with thalassemia. Conference abstracts from 2017 to September 2021 were also searched. References were screened at title/abstract and then full text by two independent reviewers. Data extraction was undertaken by one reviewer and validated by a second independent reviewer. Results were grouped by genotype (β-thal/α-thal) and transfusion phenotype (TDT/NTDT) to support comparisons. Results: A total of 2,541 records were screened at title/abstract, 441 at full-text and 7 references were identified through other sources. A total of 126 publications reporting on 116 study populations were included. Most evidence was published since 2015 (n=95) and sample sizes ranged from 22 to 1240. The number of publications by transfusion phenotype (TDT/NTDT) and thalassemia genotype (β-thal/α-thal) is shown in Table 1. Overall, most TDT/NTDT studies were conducted in β-thal or did not report genotype. Four studies included patients with α-thal but did not report HRQoL results separately for this subgroup. Across 52 studies reporting on TD β-thal, most showed that both adult and pediatric patients have reduced HRQoL. One study found EQ-VAS utility values to be poorer in adults than in children with TDT (mean [SD]: 75.04 [17.86] for >18 years vs. 84.97 [15.16] for ≤18 years; P<0.001). Four studies in pediatric patients noted the negative impact of TDT on caregivers’ HRQoL. Very few studies assessed HRQoL for NTDT patients vs healthy controls, and none were in adult population. One pediatric study found NTDT patients had worse total and domain PedsQOL scores (all P<=0.05) than healthy controls. Several studies compared NTDT and TDT patients. Using the SF-36, one study found significantly poorer HRQoL in NTDT than in TDT adults (mean total score [SD]: 66.5 [16.1] vs. 75.8 [18.8]; P=0.021). A prospective, non-interventional study found significantly lower SF-36 mental component scores at baseline in NTDT compared to TDT adults (mean [SD]: 47.4 [8.4] vs. 51.6 [7.2]; P <0.01), and NTDT patients had worse HRQoL change from baseline at 24 weeks than TDT patients. In pediatric patients, one study found poorer HRQoL in TDT compared to NTDT (mean PedsQL total score [SD]: 42.25 [20.61] vs. 67.76 [18.31]; P=0.0001). However, both NTDT and TDT patients had poorer HRQoL than healthy controls (83.45 [15.6]); P<0.0001). Image:Summary/Conclusion: This SLR highlights the negative impact of thalassemia on HRQoL. Adding to previously published SLRs, it shows limited evidence is available for NTDT patients; however, studies suggest that HRQoL burden may be worse in NTDT than TDT patients, particularly in adults. Characterizing the HRQoL burden of α-thal is a clear evidence gap. High-quality, real-world studies in NTDT and α-thal are needed to better understand the HRQoL burden and the potential impact of new treatments on HRQoL.

P1507: CLINICAL PROFILE OF COVID-19 INFECTION AND IMMUNE RESPONSE AFTER 3AND6 MONTH VACCINATION AGAINST SARS-COV-2 IN ADULT PATIENTS WITH TRANSFUSION-DEPENDENT THALASSAEMIA-THE EXPERIENCE OF A GREEK CENTER

Background: Patients with transfusion-dependent-thalassaemia (TDT) are considered as increased risk population for severe and/or morbid COVID-19 infection. Timely vaccination is the main preventive method for severe COVID-19. Aims: To provide an overview of the clinical profile and outcome of COVID-19 infection in patients with TDT as well as to study the immune response after 3 and 6 months after vaccination against COVID-19 in adult patients with transfusion-dependent thalassaemia. Methods: This analysis focused on the evaluation in TDT patients on the long-term immune response post vaccination and on the course of COVID-19 infection and its correlation with immunization status. Serum was collected at 4 pre-defined time points, namely, just before 1st dose (TP1), 7 weeks after the 1st dose (TP2), 3 months (TP3) and 6 months (TP4) after 2nd dose. Neutralizing antibodies (NAbs) against SARS-CoV-2 were measured using FDA-approved methods. According to manufacturer, the scale of NAbs titer is 0-100%, with ≥30% considered as positive and ≥50% as clinically relevant viral inhibition. Age-matched healthy volunteers (median age: 46 years, range: 24-64 years, 24 males / 53 females) who received mRNA vaccines served as the control group for NAbs evaluation. Results: 340 (170female/170male) TDT patients older than 18 years (mean 43.6±11.5 years) followed in a single unit were included in the analysis. 270 patients (79%) were vaccinated with 2 or 3 doses. Immune response to vaccination was evaluated in 90 patients (median age: 46 years, range: 19-63 years, 40 males / 50 females). NAbs were at the level of non-immunity in all the patients at baseline (TP1) (mean 16.57% ±11.85) and showed a significant increase after the second dose (TP2) mean 86.96%±12.95 (p<0.0001). At TP3 and TP4 Nabs showed a significant decrease but remained in protective levels for the majority of the patients (mean 88.75% ±9.7 and 74.64% ±17.2 respectively(p<0.0001). The kinetics of NAbs were similar to controls except for levels at TP4 (p=0.02) (Figure 1). Up to 10/FEB/2022, 43 TDT patients (median age 43.52 range 18.6-57.9 years) were diagnosed with COVID-19, with 1 of them being infected twice. Of them, 17 were unvaccinated, 18 had received 2 doses of vaccine, while 8 had received 3 doses of the vaccine. Τhe incidence rate was 9.6% and 24.3% for vaccinated and unvaccinated patients, respectively. The severity of the COVID-19 for vaccinated and unvaccinated patients were as follows, respectively,; Grade 1 (asymptomatic): 0 and 1, Grade 2 (mild symptoms, symptomatic therapy, no COVID19 specific therapy): 23 and 9, Grade 3 (mild symptoms, symptomatic therapy, with COVID19 specific therapy): 1 and 3, Grade 4 (moderate: pneumonia, thrombophlebitis, hospitalization): 2 and 3, Grade 5 (hospitalization requiring ICU, death): 0 and 1. Thrombotic event was documented in 1 patient. All patients except one from unvaccinated group are alive. Image:Summary/Conclusion: Immune response to vaccination may wean faster in TDT patients. in Unvaccinated TDT patients were more likely to be infected and to develop more serious COVID-19 infection compared to vaccinated patients.

P1558: EARLY-START DEFERIPRONE IN INFANTS/YOUNG CHILDREN WITH TRANSFUSION-DEPENDENT BETA THALASSEMIA: EVIDENCE FOR IRON SHUTTLING TO TRANSFERRIN—RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (START)

Background: Children with transfusion-dependent beta thalassemia will develop iron overload unless treated with an iron chelator such as deferiprone (DFP), deferasirox (DFX), or deferoxamine (DFO). Current practice delays chelation therapy until patients reach the iron overload criteria of serum ferritin (SF) levels ≥1000 µg/L or >10 transfusions. This “late-start” strategy was thought to minimize toxicity risks of iron depletion from biological stores or iron-bound proteins, such as transferrin, observed during “early-start” studies with DFO. This delay may increase the risk of iron overload toxicities later in life due to labile iron accumulation in organs difficult to reach with chelation. DFP is a membrane-permeable iron chelator with a lower iron affinity (pFe3+=19.3) than DFO (pFe3+=26.6), DFX (pFe3+=23.5), or transferrin (pFe3+=22.3). These pharmacological properties suggest “early-start” DFP could reduce the risks/toxicities associated with early iron overload and iron depletion by shuttling labile iron to transferrin. Previously, we reported that “early-start” DFP can be safely initiated in infants and young children with beta-thalassemia (START study NCT03591575) and maintain subthreshold SF levels in significantly more patients than placebo for up to 12 months. Aims: To evaluate the ability of “early-start” DFP to shuttle iron to transferrin in infants and young children with transfusion-dependent beta thalassemia using transferrin-saturation (TSAT) measurements from the START study. Methods: Infants or children with beta thalassemia who received ≥2 blood transfusions and had SF levels between 200–600 μg/L were randomly assigned 1:1 to DFP or placebo. Double-blinding continued until study end. Treatment continued until SF levels were ≥1000 μg/L at 2 consecutive visits (SF threshold) or 12 months. Patients started at 25 mg/kg/d DFP, escalated to 50 mg/kg/d DFP, with some to 75 mg/kg/d DFP, depending on iron load. The efficacy endpoint included imputation of % patients not reaching the SF threshold each month. DFP’s ability to shuttle iron to transferrin was evaluated at each month by comparing: 1) proportion of patients with ≥60% TSAT and 2) mean TSAT levels for DFP vs placebo groups. All iron measured in serum is total bound iron, which is the basis for calculating TSAT. The patient’s parent or legal guardian provided written informed consent before any study intervention. Results: Mean (SD) age was 3.0 (2.4) and 2.6 (1.7) years in the DFP (n=32; 63% male) and placebo (n=32; 66% male) groups, respectively. At month 12, 66% of patients receiving DFP remained below the SF threshold versus 39% of patients receiving placebo (p=0.045). Significantly more patients had TSAT ≥60% early with DFP than placebo at months 3–6 (each p<0.05); range: DFP 56%–66%, placebo 16%–34%. Similarly, mean TSAT levels with DFP were significantly higher than with placebo at months 3, 4, 6, 9, and 11 (each p<0.05); range: DFP 60%–69%, placebo 41%–55%. At 12 months, no DFP-treated patients were iron-depleted or reported iron depletion-associated adverse events (AEs). There were no significant differences between DFP and placebo in number of AEs (p=1.00), serious AEs (p=0.43), or AEs possibly related to DFP (p=1.00). Summary/Conclusion: Early-start DFP chelation therapy initiated before reaching current iron-load criteria was safe and efficacious in preventing iron overload in most transfusion-dependent children with beta thalassemia. START provides the first clinical evidence supporting preclinical studies that DFP can shuttle iron from labile pools to transferrin.

PB2232: TRIAL IN PROGRESS: A PHASE 2, OPEN-LABEL STUDY EVALUATING THE SAFETY AND EFFICACY OF THE ERYTHROCYTE PYRUVATE KINASE ACTIVATOR ETAVOPIVAT IN PATIENTS WITH THALASSEMIA OR SICKLE CELL DISEASE

Background: In sickle cell disease (SCD), a single β-globin gene mutation results in sickle hemoglobin (HbS) that polymerizes upon deoxygenation, causing red blood cells (RBCs) to sickle leading to various complications. In thalassemia, RBCs have an imbalance in the ratio of α/β globin chains and aggregated, unpaired globin chains increase metabolic demands. These stresses result in ineffective erythropoiesis and shorten RBC lifespan, leading to chronic anemia. The resultant anemias, exacerbated by impaired RBC health, are associated with lower ATP levels than in healthy RBCs. Supportive care and agents like hydroxyurea are used most in treating SCD, with some patients (pts) on regular transfusions. Regular or episodic transfusions, with their own set of complications, are the mainstay of treatment for thalassemia. Etavopivat, an investigational, once-daily, selective, erythrocyte pyruvate kinase (PKR) activator increases ATP and decreases 2,3-DPG.1,2 In a Phase 1 study, etavopivat 300-600 mg once daily in pts with SCD not regularly transfused was well tolerated, improved hematologic markers, decreased hemolysis and improved markers of RBC health.1,2 Etavopivat 200 and 400 mg once daily (doses predicted to provide desired pharmacodynamic response profiles) are being evaluated in a Phase 2/3 study of pts with SCD not on chronic transfusions (The Hibiscus Study, NCT04624659). Aims: Describe the design of a Phase 2, open-label, multicenter study (NCT04987489) evaluating efficacy and safety of etavopivat in pts with SCD on chronic transfusions (Cohort A), transfusion-dependent thalassemia (Cohort B) and non-transfusion-dependent thalassemia (Cohort C). Methods: Key eligibility criteria and study design are outlined in the Figure. Pts will receive etavopivat 400 mg once daily for 48 wks. Pts will provide written informed consent. Baseline assessments will include medical, disease, transfusion and medication histories. Transfusions received during the study (every ~3-5 wks) will be recorded and include Hb values before and ≥15 min after transfusion, transfusion dates, number of RBC units, volume of packed RBCs and hematocrit of the transfused unit (if available). If a pt has an increase ≥1.0 g/dL in pre-transfusion Hb vs baseline, the investigator may delay transfusion 1 wk or reduce the number of RBC units transfused. RBC-exchange transfusions may also be performed in pts with SCD. The primary endpoints are outlined in the Figure. Secondary and exploratory endpoints include the proportion of pts with a reduction in transfusions ≥33% and ≥50%, respectively, over 12 wks; reduction in transfusions over 12, 24 and 48 wks (Cohorts A/B); Hb response at Wks 24 and 48; and change from baseline in Hb over 12, 24 and 48 wks (Cohort C). Additional endpoints will be assessed in all cohorts: change from baseline in quality of life (using SF-36 and PROMIS); change from baseline in serum ferritin level at 12, 24 and 48 wks; liver iron at 48 wks; 2,3-DPG and ATP; pharmacokinetics; and safety. Primary endpoints will be analyzed using a 1-sided test at α=0.025. Results: Results are not yet available for this trial in progress. Planned enrollment includes ≤20 pts (aged 12-65 y) in each of the 3 cohorts (Figure). Image:Summary/Conclusion: Etavopivat is a novel, investigational, once-daily, selective PKR activator with potential to improve RBC health and lifespan. This Phase 2 study will assess the safety of etavopivat and its impact on Hb levels and transfusion burden in pts (12-65 y) with SCD or thalassemia. 1Brown et al, Blood 2021. 2Kalfa et al, Blood 2021.

P1737: QUALITY OF LIFE IN CHILDREN WITH BETA-THALASSEMIA MAJOR: A CROSS-SECTIONAL STUDY IN CHINA

Background: Thalassemia is a hereditary hemolytic anemia disease. Most Chinese thalassemia patients can be diagnosed in initial episode, due to the fact that the prevention and treatment of thalassemia has achieved remarkable effects in recent two decades. The research of new therapies have also made considerable progress. Patients with transfusion-dependent thalassemia, especially those with β-Thalassemia Major(β-TM), require regular blood transfusions and iron chelation therapy. This places a large burden on patients and their families. The burden is not only physical pain, but also includes psychological and social dimensions. The unmet needs of the patient population are also worth studying. However, the overall QoL of Chinese thalassemia patients and its affecting factors remain unclear. Aims: The aim of this study was to investigate the level of QoL and ascertain its influencing factors in children with β-TM in China. Methods: The study data came from a nationwide and cross-sectional survey of patients with thalassemia in China (NCSTC, Ethical ID: IIT2021045-EC-1). Participants were recruited from 9 provinces and 1 municipality. Recruitment was based on the Beijing AngelMom Charity Foundation. Multistage stratified cluster sampling method was used for the sampling. The study used a web-based questionnaire to collect the QoL of children and the burden level of caregivers. The QoL was assessed using the Pediatric Quality of Life Inventory (PedsQL4.0), which contained 23 items in 4 dimensions (physical, emotional, social, and school functioning). The caregiver’s burden level was assessed by Zarit Burden Interview-22 (ZBI-22). The multiple linear regressions were used to analyze. Results: A total of 519 children (aged 2-17 years) with β-TM were obtained from NCSTC. The mean of PedsQL total score was 65.7 (standard deviation, 18.1). In the multi-adjusted linear regression model, participants with younger age (2-4 years= 72.1; 5-7 years= 67.8; 8-12 years = 64.3; 13-17 years= 60.5), without complications (with complications vs. no complications: 61.6 vs. 75.4), shorter course of disease (< 8 years vs. s 8 years: 67.6 vs. 63.8), without iron chemotherapy (with iron chemotherapy vs. without chemotherapy: 64.9 vs. 68.8), with lower caregiver burden level (0-20: 79.3, 21-40: 68.5, 41-60: 57.7, 61-80: 46.1), and receive transplantation treatment (with HLA transplantation vs. without HLA transplantation: 71.9 vs. 64.0) have higher PedsQL total score. The younger age, without complications, with shorter course of disease, with lower caregiver burden level, and receive transplantation treatment were all related to higher performance of physical, emotional, social, and school functioning (Figure 1). Image:Summary/Conclusion: The health-related QoL assessed by PedsQL scores in Chinese children with β-TM were lower than that in previous studies. Multiple factors were associated with the QoL of Chinese children with β-TM, and should be comprehensively paying attention to physical, emotional, social, and school functioning in β-TM patients.

P1522: LONG-TERM EFFICACY AND SAFETY OF THE ORAL PYRUVATE KINASE ACTIVATOR MITAPIVAT IN ADULTS WITH NON–TRANSFUSION-DEPENDENT ALPHA- OR BETA-THALASSEMIA

Background: Thalassemia is characterized by ineffective erythropoiesis and hemolysis that occur due to imbalanced production and precipitation of globin chains. Thalassemic red blood cells (RBCs) have insufficient levels of adenosine triphosphate (ATP) to meet increased energy demands associated with globin chain imbalance, protein degradation, and cellular oxidative stress responses. Mitapivat is a first-in-class, small molecule, oral activator of RBC pyruvate kinase (PKR), a key glycolytic enzyme regulating ATP production. In a phase 2, open-label trial of mitapivat in adults with α- or β-non–transfusion-dependent (NTD) thalassemia (NCT03692052), 80% (16/20) of patients (pts) met the primary endpoint of a hemoglobin (Hb) response (≥1.0 g/dL increase from baseline [BL] at ≥1 assessments between Weeks (Wks) 4–12, inclusive). Improvements in markers of hemolysis and ineffective erythropoiesis were also observed and mitapivat was generally well tolerated. Aims: To report data from the ongoing long-term extension (LTE) period (≤Wk 72; data cutoff 27Mar2021). Methods: Pts aged ≥18 years (yrs) with a known medical history of α- or β-thalassemia, Hb concentration ≤10.0 g/dL, and ≤5 RBC units transfused in prior 24 wks and none in 8 wks prior to study drug were eligible. All pts started mitapivat 50 mg twice daily (BID), escalating to 100 mg BID based on individual safety and Hb assessments. After completion of the 24-wk core period, pts with a Hb response or a delayed Hb response (after Wk 12), with no ongoing study drug-related grade ≥3 treatment-emergent adverse events (AE), continued on mitapivat in the LTE at the same dose as the Wk 24 visit. Study visits occur every 12 wks for ≤10 yrs. Results: Of 19 pts who completed the core period, 17 entered the LTE (mitapivat 100 mg BID, n=16; 50 mg BID, n=1). As of the data cutoff, 1 pt discontinued (pt decision). Median duration of treatment for pts in the LTE was 70.9 wks (range 54.7, 105.6); 8 pts received ≥72 wks of treatment as of data cutoff. Median pt age in the LTE was 44 yrs (range 29, 67). Mean (standard deviation [SD]) BL Hb, total bilirubin and lactate dehydrogenase (LDH) were 8.1 (1.2) g/dL, 40.1 (26.2) μmol/L, and 272.4 (121.7) U/L, respectively. Median BL erythropoietin (EPO) was 70.5 (range 15, 11191) IU/L. Hb improvements achieved in the core period were sustained in the LTE (Figure). Mean (SD) Hb increase from BL to Wk 60 (α-thalassemia, n=4; β-thalassemia, n=9) and Wk 72 (β-thalassemia, n=8) were 1.5 (0.4) and 1.7 (0.5) g/dL, respectively. Improvements in markers of hemolysis and ineffective erythropoiesis observed in the core period were maintained in the LTE up to Wk 72 (mean [SD] bilirubin and LDH, –15.8 [16.6] μmol/L and –63.6 [216.0] U/L, respectively; median [range] EPO, –33.0 [–72.0, –16.0] IU/L). The safety profile was consistent with that observed in the core period. AEs in ≥15% of pts were headache (5/17) and back pain (3/17), none were grade ≥3. No trends for decreases in bone mineral density were observed. No treatment-related serious AEs occurred. Image:Summary/Conclusion: In pts with either α- or β-thalassemia, a favorable efficacy-safety profile was observed with long-term treatment with mitapivat. Data show sustained improvements in Hb, hemolysis, and ineffective erythropoiesis despite globin genotypic heterogeneity, and no new safety findings. Mitapivat, through its unique mechanism of action, may represent a novel therapeutic approach for this condition. Two phase 3 trials of mitapivat in α- and β-thalassemia for both NTD (ENERGIZE, 2021-000211-23) and transfusion-dependent (ENERGIZE-T, 2021-000212-34) pts are enrolling.

Genetic bases and modifiers of β-thalassemia in Argentina

Introductionβ-syndromes are still a challenge for health professionals and many efforts are performed to achieve adequate diagnosis and develop novel treatments. The molecular bases of these syndromes are sequence variants in the HBB gene, which prevent the expression of β-globin chains. There are also modifiers that can alter the α:β-globin chain unbalance responsible for the pathophysiology of these syndromes, and modify the clinical course of these syndromes, preventing a correlation between the genotype of the patients and the exhibited phenotypes. MethodsIn this work, the β-globin sequence variants and secondary modifiers (KLF1, rs7482144, rs11886868, rs4895441, rs2071348, rs4296276, rs3191333 and rs77685897) were individually analyzed by several techniques in a cohort of 63 Argentinean patients with severe β-thalassemia. ResultsIn 41 samples a genotype-exhibited phenotype correlation was corroborated. KLF1 analysis in this cohort revealed only one functional variant: rs79334031. SNVs associated with modifier loci (HBG2, HBBP1, HBS1L-MYB, BCL11A, KLF10 and AHSP) were analyzed in patients with transfusion-dependent and non-transfusion dependent thalassemia. Only for rs11886868 in BCL11A, the protective allele showed a statistically different distribution in the groups. A variant that maps in a potential target for hsa-miR-144-3p, rs77685897, in the 3’ UTR region of NFE2L2 was detected in heterozygous state in three patients. ConclusionThe evaluation of the α and β-globin clusters by itself could not explain the genotype-phenotype correlation in 22 patients. The analysis of previously validated modifiers in our population highlighted the role of rs11886868 and revealed the need to further characterize genetic loci that could alter the clinical course of these syndromes.

Assessment of iron overload in a cohort of Sri Lankan patients with transfusion dependent beta thalassaemia and its correlation with pathogenic variants in HBB, HFE, SLC40A1, and TFR2 genes

BackgroundIron overload (IO) is a complication in transfusion dependent beta thalassaemia (TDT). Pathogenic variants in genes involving iron metabolism may confer increased risk of IO. The objective of this study was to determine the magnitude of the cardiac and hepatic IO and determine whether pathogenic variants in HFE, SLC40A1 and TFR2 genes increase the risk of IO in a cohort of TDT patients in Sri Lanka.Materials and MethodsFifty-seven (57) patients with TDT were recruited for this study. Serum ferritin was done once in 3 months for a period of one year in all. Those who were ≥ 8 years of age (40 patients) underwent T2* MRI of the liver and heart. Fifty-two (52) patients underwent next generation sequencing (NGS) to identify pathogenic variants in HBB, HFE, SLC40A1 and TFR2 genes.ResultsThe median age of the patients of this cohort was 10 years. It comprised of 30 (52.6%) boys and 27 (47.4%) girls. The median level of serum ferritin was 2452 ng/dl. Hepatic IO was seen in 37 (92.5%) patients and cardiac IO was seen in 17 (42.5%) patients. There was no statistically significant correlation between serum ferritin and hepatic or cardiac IO.Thirty-two (61.5%), 18 (34.6%), 2 (3.8%) of patients were homozygotes, compound heterozygotes and heterozygotes for pathogenic variants in the HBB gene. Eight (15.4%) and 1 (1.9%) patients were heterozygotes for pathogenic and likely pathogenic variants of HFE genes respectively. There were no pathogenic variants for the TfR2 and SLC40A1 genes. The heterozygotes of the pathogenic variants of the HFE were not at increased risk of IO.ConclusionsCardiac T2* MRI helps to detect cardiac IO in asymptomatic patients. It is important to perform hepatic and cardiac T2* MRI to detect IO in patients with TDT. There was no statistically significant correlation between pathogenic variants of HBB and HFE genes with hepatic and cardiac IO in this cohort of patients.

Preparing next-gen cellular immunotherapies for commercialization

David McCall, Editor,&#160;Cell &amp; Gene Therapy Insights,&#160;talks to Peter Olagunju, Chief Technology Officer, TCR&#178; TherapeuticsPeter Olagunju is a Cell &amp; Gene Therapy Executive, who has successfully worked to drive four C&gt; products through clinical development to commercialization: PROVENGE&#174;, ZYNTEGLO&#174;, ABECMA&#174;, and SKYSONA&#174;. Mr Olagunju joined TCR&#178; in 2021 as Chief Technology Officer. He brings over 20 years of experience in cell and gene therapy, clinical development, program management, manufacturing and technical operations. Prior to joining the company, he was Senior Vice President of Technical Operations at FerGene Inc., where he led the technical operations function for the commercialization of a gene therapy for bladder cancer. Before that, Mr Olagunju was Vice President of Global Patient Operations at bluebird bio, Inc., where he held several roles of increasing responsibility and was the program lead and functional head of manufacturing supporting the European approval for ZYNTEGLO&#174;, a transformational gene therapy for Transfusion dependent Thalassemia. Earlier in his career, he held senior positions in Commercial Technical Operations and served as the Head of Quality at Dendreon Corp. and ZymoGenetics, Inc. Mr Olagunju holds an MBA from the University of Washington and a BS in Biology from the University of Illinois at Urbana–Champaign.

The Effect of COVID-19 on Hemoglobinopathy Patients’ Daily Lives While Quarantined: Four Greek Hospitals’ Experiences

During a pandemic, people are fearful of becoming infected with the virus, which causes anxiety, loss of purpose, and depression. This study aimed to evaluate the social and psychological impact, as well as the impact on homecare, of patients with hemoglobinopathies during the pandemic. Material and Methods: In total, 130 patients from four Thalassemia and Sickle Cell Disease Units of the National Health System of Greece Hospitals were examined via an anonymous questionnaire developed and distributed through stratified sampling. Results: Transfusion-dependent thalassemia, transfused sickle cell disease, and other hemoglobinopathies were represented by 130 patients. During the pandemic, the main concern of patients was the affordability of blood for transfusion. During the lockdown, patients’ moods varied, and their daily lives were disrupted by a lack of access to basic goods and communication with friends and family. Their eating habits, access to exercise, and, to a lesser extent, their financial situation have all been affected in their daily lives. It is crucial to highlight that while access to health services did not suffer in terms of medication and regular visits for their actual disease, it did suffer in terms of the systematic monitoring of complications.

Pulmonary Function in Children With Transfusion-Dependent Thalassemia and Its Correlation With Iron Overload

To assess the pulmonary function of children with transfusion-dependent thalassemia, and to correlate its pattern with serum iron status. Cross-sectional study done in the pediatrics department of a tertiary care hospital from June, 2018 to May, 2019. 66 children aged 5-18 years with b-thalassemia and HbE/b-thalassemia, admitted for blood transfusion, and with a history of minimum 20 transfusions, were enrolled. Estimation of forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio by spirometer, estimation of serum ferritin and CRP, and chest X-rays were done in all the participants. 53 (80.3%) children had HbE/b-thalassemia, and 47 (71.2%) showed restrictive pulmonary dysfunction. The mean serum ferritin with impaired pulmonary function was 5616 (70.34) ng/mL and serum ferritin level had significant correlation with pulmonary function (P<0.001). Restrictive pattern of pulmonary dysfunction was common in children with thalassemia, and body iron status had a significant association with pulmonary impairment.

Promoting Adherence to Iron Chelation Treatment in Beta-Thalassemia Patients.

Thalassaemia is one of the commonest inherited genetic disorders world-wide with around 25,000 births of the most severely affected transfusion dependent children annually. Patients with transfusion dependent thalassaemia require regular blood transfusions to maintain life but because of this will develop iron overload. To remove the excess iron, patients are required to take iron chelation therapy (ICT). ICT requires lifelong adherence to treatment to prevent end organ damage from developing. Many of these preventable complications make adherence to therapy more complex for patients. In this review, we focus on two commonly encountered patient scenarios and discuss how different psychological models and a relational theory can be used to understand and support adherence to treatment.

Supply Chain of Iron Chelators for Thalassaemia in Malaysia: An Overview for Process Optimisation

Iron chelating therapy (ICT) drugs are prescribed to transfusion dependent thalassaemia (TDT) patients to prevent iron overload complications. The high number of TDT patients in Malaysia strained the public healthcare resources. This paper aims to provide an insight on existing supply chain management of ICT medicines in Malaysia and to explore ways for a more efficient system. A rapid review of literatures was conducted in electronic databases (PubMed, Emerald, Scopus and ScienceDirect) and other relevant Malaysian government documents. Supply of ICT to thalassaemia patients is publicly funded but much availability of oral ICT is restricted due to financial consideration. ICT in Malaysia is supplied through central procurement but purchasing and inventory management are decentralised to each hospital. Vendor-managed inventory system is an ideal option to the inventory management practice in Malaysian public healthcare facilities as it could provide better efficiency and reduces inventory management costs.

Prevalence and characteristics of inflammatory rheumatic diseases in patients with thalassemia.

Reports of inflammatory rheumatic diseases (IRD) in thalassemia are limited. This study aimed to determine the prevalence and clinical characteristics of IRD in patients with thalassemia disease. Consecutive adult patients with thalassemia disease, confirmed by hemoglobin typing, attending the Hematology Clinic between June 2019 and May 2021 were invited to join this study. All of them had their history taken and a physical examination for IRD. Those with IRD had their medical records reviewed. Sixty-three patients (transfusion-dependent in 50) were included in this study. There was α-, β-, and co-inheritance of α- and β-thalassemia in 22.22%, 73.02%, and 4.76% of the patients, respectively, with β-thalassemia/Hb E disease in 53.97%. Twenty-three patients had IRD (rheumatoid arthritis in 9, gout in 6, systemic lupus erythematosus in 3, spondyloarthropathy in 2, and one patient each with dermatomyositis, overlap syndrome, and unclassified polyarthralgia). Clinical manifestations and laboratory findings were similar to IRD patients in general. In 40 patients without IRD, direct and indirect Coombs tests and antinuclear antibody (ANA) were positive in 51.72%, 27.59%, and 10.26%, respectively. When comparing among these 40 patients, between those with non-transfusion-dependent thalassemia (n = 10) and those with transfusion-dependent thalassemia (n = 30), the latter had non-significantly more positive direct Coombs (60.87% vs. 16.67%), indirect Coombs (30.43% vs. 16.67%), and ANA tests (13.33% vs. 0%). The prevalence of IRD in patients with thalassemia disease was rather high. Positive direct Coombs test and ANA were common in transfusion-dependent patients.

A Comparison of Arc of Motion, Radiological Parameters of the Wrist and Patient Rated Wrist Evaluation between Adult Transfusion Dependent Thalassemics and Normal Subjects.

Background: Bony deformities and arthropathies have been noticed in thalassemia patients. The aim of this study is to compare the arc of motion and radiological parameters of the wrist and patient rated wrist evaluation (PRWE) between adult transfusion-dependent thalassemics and normal subjects. Methods: An observational cross-sectional study was done in the department of orthopaedics over a period of 2 years where a total of 30 skeletally mature thalassemia major patients (group A) were assessed. The data was then compared with the data of demographically matched 30 healthy adults (group B). Arc of motion of the dominant wrist that included flexion, extension, radial and ulnar deviation, pronation and supination was measured using a handheld goniometer for both groups. Radiographs of the dominant wrist were obtained in both groups and used to determine the radial height, radial articular angle and carpal slip. PRWE was used to assess the function of the wrist. A p-value of <0.05 was considered statistically significant. Results: Clinical abnormalities at the wrist joint were found in 80% of thalassaemia patients. There was a statistically significant increase in ulnar deviation, wrist extension and decrease in wrist flexion in group A compared to group B. Radiological abnormalities were found in 100% of thalassaemia patients. All the radiological parameters were significantly increased in group A compared to group B. There were no differences in PRWE scores between both groups. Conclusion: Clinical and radiological changes of wrist joint occur in skeletally mature thalassaemia major patients due to shortened ulna compared to healthy adults. This may be due to disease itself, bone marrow expansion, osteopenia, drug (chelating agent) or iron toxicity. Understanding the changes at the wrist in patients with thalassemia major is important to increasing the life expectancy of these patients. Level of Evidence: Level IV (Diagnostic).

Response of Thalidomide in Spleen Size Reduction of Transfusion Dependent Thalassemia

Background: Thalassemia is the most common single gene hereditary disease worldwide. Hb E-β Thalassemia is the commonest severe form of thalassemia in south-east Asia including Bangladesh. The clinical benefit of increased Hb-F in thalassemia treatment is well established which act by decreasing the imbalance between β&amp; non- β chains and the consequent reduction of haemolysis. Recent study showed outstanding results on haemoglobin level and transfusion requirement in thalassemia patients treated with thalidomide. Objectives: Aims of our study is to evaluation of thalidomide in spleen size reduction of transfusion dependent thalassemia. Methods and Materials: In this quasi-experimental study 50 patients &gt;12 years old attended in Thalassemia clinic, Department of Haematology, Dhaka Medical College &amp; Hospital, Dhaka were recorded as study cases. All relevant collected prospectively from patients and recorded in prescribed form (Data collection sheet).After full explanation, informed written consent were taken from the selected patients informing the details of the purpose of the study. Data processed and analyzed with the help of computer programme SPSS (Statistical package for social sciences) win version 25&amp; presented in the form of tables, graphs &amp; chart. Results: In study cases it was found that there were significant increment of Hb, Hematocrit, HbF% and improvement of performance status 6months after thalidomide therapy (mean 6.36 ±0.78 vs 7.49±0.59, 19.89±2.57 vs 25.88±2.47, 23.03±14.61% vs 39.42±13.31% and 2.24±0.43 vs 1.50±0.54; respectively; all p &lt;0.001). It also reveledthat after 6 months of thalidomide therapy there were significant reduction of transfusion requirement, spleen size, nRBC count, Serum LDH, Serum Bilirubin (total) and Serum ferritin (100.06±27.2 vs 54.48±18.34 ml/kg/year, 12.3±6.73 vs 9.28±5.26 cm, 42.28±61.02 vs 16.96±30.14nRBC/100 WBC, 502.60±124.54 vs 413.28±152.43 U/L, 3.00±1.36 vs 2.12±0.78 mg/dl, 2235.3±2225.6 vs 1574.9±1540.7; .......

Response of Thalidomide in Hemoglobin Increment of Transfusion Dependent Thalassemia

Background: Thalassemia is the most common single gene hereditary disease worldwide. Hb E-β Thalassemia is the commonest severe form of thalassemia in south-east Asia including Bangladesh. The clinical benefit of increased Hb-F in thalassemia treatment is well established which act by decreasing the imbalance between α &amp; non α chains and the consequent reduction of haemolysis. Recent study showed outstanding results on haemoglobin level and transfusion requirement in thalassemia patients treated with thalidomide. Objective: Aims of our study is evaluate the response of thalidomide in hemoglobin increment of transfusion dependent thalassemia. Method: In this quasi-experimental study 50 patients &gt;12 years old attended in Thalassemia clinic, Department of Haematology, Dhaka Medical College &amp; Hospital, Dhaka were recorded as study cases. All relevant collected prospectively from patients and recorded in prescribed form (Data collection sheet). After full explanation, informed written consent was taken from the selected patients informing the details of the purpose of the study. Data processed and analyzed with the help of computer programme SPSS (Statistical package for social sciences) win version 25 &amp; presented in the form of tables, graphs &amp; chart. Result: In study cases it was found that there was significant increment of Hb, Hematocrit, HbF% and improvement of performance status 6months after thalidomide therapy (mean 6.36 ±0.78 vs 7.49±0.59, 19.89±2.57 vs 25.88±2.47, 23.03±14.61% vs 39.42±13.31% and 2.24±0.43 vs 1.50±0.54; respectively; all p &lt;0.001). It also reveled that after 6 months of thalidomide therapy there were significant reduction of transfusion requirement, spleen size, nRBC count, Serum LDH, Serum Bilirubin (total) and Serum ferritin (100.06±27.2 vs 54.48±18.34 ml/kg/year, 12.3±6.73 vs 9.28±5.26 cm, 42.28±61.02 vs 16.96±30.14 nRBC/100 WBC, 502.60±124.54 vs 413.28±152.43 U/L, 3.00±1.36 vs 2.12±0.78 mg/dl, 2235.3±2225.6 vs 1574.9±1540.7; ...............

Prevalence and risk factors of fractures in transfusion dependent thalassemia - A Hong Kong Chinese population cohort.

ObjectiveTo delineate the prevalence and associated risk factors of low BMD, osteoporosis/bone fragility and fracture in transfusion‐dependent thalassemia (TDT) in the Chinese population in Hong Kong.Design, Patients and MeasurementsA retrospective cohort study design was employed. Patients of TDT who had serial Hologic dual‐energy X‐ray absorptiometry (DXA) from 2010 to 2016 and received regular transfusion for at least 5 years were recruited. Clinical and biochemical data, from 5 years before the first DXA scan, were retrieved from the electronic record system of the Hospital Authority, till 30 June 2020. Low bone mineral density and osteoporosis/bone fragility are defined by the ISCD 2019 position guidelines.ResultsSeventy‐seven patients were included in the analysis. The fracture prevalence of TDT among the Chinese population in Hong Kong was 15.58%. Up to 55.84% of patients had low bone mineral density, and 5.19% patients had osteoporosis/bone fragility state. The median age at first fracture was 31.73 years (range 24.06–44.18 years). In the regression analysis, a higher log(10) transformation of average ferritin levels over 5 years before the first DXA scan was significantly associated with fracture occurrence regardless of bisphosphonate treatment (OR 310.73, 95% CI 3.99–24183.89, p = .010). Mean average ferritin level over 5 years was 6695.5 ± 2365.7 pmol/L (fracture group) versus 4350.7 ± 3103.2 pmol/L (non‐fracture group), p = .016. Hip and spine BMD Z‐score did not have statistically significant association with fracture occurrence.ConclusionIron overloading plays an important role in adverse bone health in TDT. Dual X‐ray densitometry is insufficient in predicting fracture risk.

Post-COVID-19 Lymphocytopenia and Opportunistic Pathogens Infection in a Thalassemia Major Patient

Transfusion-dependent thalassemia patients undergo transfusion immunomodulating effects, which result in a general immune response depression and, consequently, an increase in the frequency of infectious episodes and neoplastic events due to a reduction in phagocytic function. Altered natural killer functions and IL-2-mediated lymphocytic response, defects in antigen presentation due to monocyte–macrophage cells, and decreases in bone marrow precursors and HLA II+ cells all play key roles in immunodepression in thalassemia major. SARS-CoV-2 infection presents marked lymphopenia, occurring in 96.1% of severe cases. COVID-19-related lymphopenia is due to various mechanisms, which lead to an increase in lymphocytic apoptosis. Post-COVID-19 lymphocytic quantitative and functional disorders may compromise immune response and promote the onset of infections via opportunistic pathogens. Herein, we report a case of a thalassemia major patient who developed severe post-COVID-19 lymphocytopenia, which may have facilitated the onset of a severe Klebsiella Pneumoniae infection.

Pulmonary Dysfunction in Transfusion-Dependent Thalassemia and Response to Intensive Chelation Therapy

To evaluate pulmonary functions in children with transfusion-dependent thalassemia, and its reversal (lung dysfunction) using intensive intravenous chelation with desferrioxamine (DFO) (4 weeks). This descriptive study enrolled 77 children with transfusion-dependent thalassemia. Pulmonary function test (PFT) and iron load (serum ferritin (SF) andT2* MRI of heart and liver) were done. PFT included spirometry, total lung capacity (TLC) by helium dilution test and diffusion capacity by carbon monoxide (DLCO). Follow-up PFT was available for 13 children with moderate to severe lung dysfunction given intravenous DFO. 50 (68.8%) patients had lung dysfunction, most commonly diffusional impairment (48; 96%), and reduced TLC (11; 22%); and none had obstructive pattern. 9 (81.8%) patients with restrictive defect had moderate to severely deranged DLCO. PFT and T2* MRI values were inversely correlated with serum ferritin. Among 13 patients receiving intensive chelation for 4 weeks, significant improvement was noticed in forced expiratory volume in one minute/ forced vital capacity ratio (DFEV1/FVC) (P=0.009), DDLCO (P=0.006) and DSF (P=0.01). Pulmonary dysfunction is common in children with multi-transfused thalassemia, and routine screening by PFT needs to be part of the management guidelines.