Transfusion-dependent Beta-thalassemia Research Articles

Assessment of Serum Autophagy Related Protein Beclin1 in Egyptian Adult Beta Thalathemic Patients

Abstract Background Beta-thalassemia is a chronic hemolytic anemia that is inherited in an autosomal recessive manner. It is characterized by reduced hemoglobin levels and red blood cell production. Aim of the Work Assessment of serum autophagy related protein beclin1 in Egyptian adult beta thalathemic patients and Its relation to ineffective erythropoiesis, transfusion requirements, iron overload. Subjects and Methods This is a case control study which was carried out at Ain Shams university hospitals. Internal medicine department, Clinical hematology and stem cell transplantation unit, outpatient clinic and inpatient department, during the period between January 2022 and August 2022. Results Our study revealed significant decreased fertility between patients group and control group (P = 0.011). Transfusion-dependent beta-thalassemia males have a high proportion of fertility impairment and iron overload might contribute to disturbed sperm quality and testicular tissue injury. Such findings might explain the high prevalence of impaired fertility in transfusion-dependent beta- thalassemia patients which agrees with our results. Also our study revealed significant differences between non-transfusion dependent group and transfusion-dependent group regarding spleen size (cm) below costal margin which was increased in (TD group), transfusion per year (ml/yr)(which was increased in (TD group), virology (HIV, HCV,HBV) revealed that percentage of HCV+ve higher in (TD group) with (P < 0.001): Our study revealed significant difference between non-transfusion- dependent group and Transfusion-dependent group regarding percentage of patients of with positive HCV which was increased in Transfusion-dependent group (P = 0.021): In our study Iron chelation therapy was found to be given in a higher percentage of TD patients compared to non TD patients (P < 0.001). Also our study revealed significant difference regarding cardic function(EF%) between patients group and control group (EF found to be lower in patients group than controls) (P < 0.001): Also our study showed that Beclin-1 level is significantly higher in patients group compared to control group (P < 0.001). We couldn’t find previous studies of Beclin-1 level in thalassemia patients. We postulate that Beclin 1 could be used as a marker of worsening cardiac functions in thalassemia patients, but further studies should measure serial levels of Beclin 1 and correlate it with cardiac parameters over longer periods of follow up. Conclusion Beclin 1 level increased in Adult Beta Thalasemia patients and it can be used as a prognostic marker for Adult Beta Thalasemia patients.

Characteristics of markers of ovarian reserve in women with transfusion-dependent beta thalassaemia major with a successful pregnancy outcome

Objective: Spontaneous fertility and successful pregnancies have been reported in well-chelated and transfused women with beta thalassaemia major (BTM) however majority of women are sub fertile due to hypogonadotropic hypogonadism (HH) and lack of ovulation. Little is known about the effect of iron overload on ovarian follicles and whether ovarian reserve is affected by the condition or treatment. The predictive value of markers of ovarian reserve in relation to live birth in this group of women remains unclear. The aim of this study was to characterize the markers of ovarian reserve in women with transfusion-dependent beta thalassaemia major who had at least one successful live birth. Study design: This is a retrospective study in which we collected data from 12 women with transfusion-dependent BTM and at least one successful live birth from our thalassaemia clinic between July 2007 to June 2022. Patient demographics, medical history, menstrual history, hormonal parameters (serum levels of FSH, oestradiol, TSH and AMH) and antral follicle count were recorded. Serum levels of ferritin, cardiac T2*, liver iron concentration and thyroid function results were recorded from clinic visit prior to either natural conception or assisted conception treatments. Results: There was a wide variation in serum levels of AMH and antral follicle counts amongst women with BTM who had a successful live birth. Low serum AMH levels were noted in 4 women with HH with a background of BTM (33.3%) as compared to the established normal ranges for women of similar age. Also, low AFC counts were noted in 7 women (out of which 6 had HH) with BTM (58.3%) as compared to the established normal ranges for women of similar age. Conclusion: Levels of serum AMH and antral follicle counts appeared lower in up to half the women with BTM and hypogonadotropic hypogonadism with a successful live birth as compared to established normal ranges for women of similar age suggesting that these markers may not accurately reflect the ovarian reserve for all in this group of women. There are limited data about the predictive value of contemporary markers ovarian reserve such as serum AMH and AFC levels in predicting successful fertility or pregnancy outcomes in women with transfusion dependent BTM and larger studies are needed.

Characteristics of markers of ovarian reserve in women with transfusion-dependent beta thalassaemia major with a successful pregnancy outcome

Objective: Spontaneous fertility and successful pregnancies have been reported in well-chelated and transfused women with beta thalassaemia major (BTM) however majority of women are sub fertile due to hypogonadotropic hypogonadism (HH) and lack of ovulation. Little is known about the effect of iron overload on ovarian follicles and whether ovarian reserve is affected by the condition or treatment. The predictive value of markers of ovarian reserve in relation to live birth in this group of women remains unclear. The aim of this study was to characterize the markers of ovarian reserve in women with transfusion-dependent beta thalassaemia major who had at least one successful live birth. Study design: This is a retrospective study in which we collected data from 12 women with transfusion-dependent BTM and at least one successful live birth from our thalassaemia clinic between July 2007 to June 2022. Patient demographics, medical history, menstrual history, hormonal parameters (serum levels of FSH, oestradiol, TSH and AMH) and antral follicle count were recorded. Serum levels of ferritin, cardiac T2*, liver iron concentration and thyroid function results were recorded from clinic visit prior to either natural conception or assisted conception treatments. Results: There was a wide variation in serum levels of AMH and antral follicle counts amongst women with BTM who had a successful live birth. Low serum AMH levels were noted in 4 women with HH with a background of BTM (33.3%) as compared to the established normal ranges for women of similar age. Also, low AFC counts were noted in 7 women (out of which 6 had HH) with BTM (58.3%) as compared to the established normal ranges for women of similar age. Conclusion: Levels of serum AMH and antral follicle counts appeared lower in up to half the women with BTM and hypogonadotropic hypogonadism with a successful live birth as compared to established normal ranges for women of similar age suggesting that these markers may not accurately reflect the ovarian reserve for all in this group of women. There are limited data about the predictive value of contemporary markers ovarian reserve such as serum AMH and AFC levels in predicting successful fertility or pregnancy outcomes in women with transfusion dependent BTM and larger studies are needed.

HHV6-Associated Hydrocephalus in a Pediatric Hematopoietic Stem Cell Transplant Recipient: An Unusual Presentation.

Human herpesvirus 6 (HHV-6) is a widely spread DNA virus that is ubiquitous and persistent with primary infection occurring in early childhood, with reactivation of the infection a common phenomenon in severely immunocompromised hosts, including hematopoietic stem cell transplant (HSCT) patients, influencing morbidity and mortality. A wide spectrum of clinical presentations is reported in the literature with HHV-6 reactivation including post-transplant limbic encephalitis (PALE). We report the unusual case of a 6-year-old female 107 days postallogenic HSCT due to transfusion dependent beta thalassemia major who developed acute cerebellitis with secondary supratentorial hydrocephalus that required invasive surgical intervention. In addition to accompanying imaging findings, the patient tested positive for HHV-6 by PCR from both serum and CSF samples and demonstrated dramatic improvement with the institution of steroid therapy in addition to ganciclovir treatment. The availability of rapid diagnostic measures in addition to a multidisciplinary approach is crucial to manage HHV-6 encephalitis and associated complications in HSCT patients.

Bone Mineral Density and Endocrinopathies in Adults with Transfusion-Dependent Beta-Thalassemia Major Patients from Oman

Bone Mineral Density and Endocrinopathies in Adults with Transfusion-Dependent Beta-Thalassemia Major Patients from Oman

In brief: Casgevy for beta thalassemia.

Exagamglogene autotemcel (Casgevy – Vertex), a cell-based gene therapy recently approved for treatment of sickle cell disease1, has now been approved by the FDA for treatment of patients ≥12 years old with transfusion-dependent beta thalassemia.

Impact of COVID-19 on Patients with Beta-Thalassemia Major: An Observational Study

Introduction: The prevalence of COVID-19 is slightly lower, and its mortality is higher in beta-thalassemia patients than in the general population. We evaluated the impact of COVID-19 in terms of incidence, clinical course, management, and specific antibody response to vaccination, in a cohort of patients with beta-thalassemia major. Methods: We retrospectively enrolled all transfusion-dependent beta-thalassemia major patients attending the Thalassemia Day Care Center of the University Hospital of Sassari, Italy, from March 1, 2020, to May 31, 2021. For each patient, demographic, clinical, laboratory, instrumental, and therapy data were collected. Patients aged ≥16 years received two doses of mRNA COVID-19 vaccine. Anti-SARS-CoV-2 serum antibodies were tested before and after the first vaccine dose. Results: A total of 68 patients (median age: 36.5 years; IQR: 13–42 years) were included. Nasopharyngeal swab (NPS) for SARS-CoV-2 detection by RT-PCR was positive in 5 (7.35%) of 68 patients (4 symptomatic). No COVID-19-related complications, hospitalizations, or deaths were observed. The transfusion regimen and iron chelation therapy were not significantly changed. Prior to COVID-19 vaccination, anti-SARS-CoV-2 antibodies were tested in 61 patients, 51 negative and 10 positive; five of the latter were also positive for SARS-CoV-2 on NPS. The 46 vaccinated subjects had an antibody response, with higher levels in subjects previously infected with SARS-CoV-2. Conclusion: Our findings suggest that patients with beta-thalassemia major are not at a higher risk of contracting SARS-CoV-2 infection and developing a severe form of COVID-19 despite being considered more vulnerable than the general population.

Haemoglobin lepore and beta thalassaemia traits – Prenatal testing by both sequence analysis and MLPA for HBB gene: A case report

Hb Lepore is a fusion globin protein made of fused chains of delta and beta globin. It is a deletion haemoglobinopathy. In homozygote form, it is similar to transfusion dependent beta thalassaemia major, and in the heterozygous form, it causes mild microcytic hypochromic anaemia. In this case report, the couple has heterozygous Hb Lepore and heterozygous beta thalassaemia, with a pregnancy of 15weeks gestation. Prenatal testing by amniocentesis and HBB gene analysis for the fetus was done by sequencing and MLPA to detect the different types of mutations present in the parents. This case report reveals the importance of MLPA to be done along with sanger sequencing, to detect all types of mutations in the HBB gene.

Awareness and practices regarding thalassemia among parents of transfusion dependent beta thalassemia patients registered with Hamza Foundation Peshawar, Pakistan

Thalassemia, a pervasive and chronic condition that impacts an estimated 200 million people worldwide, is predominantly caused by the beta-thalassemia gene, which is found in approximately 3% of the global population. The purpose of this research, which was carried out from June to December 2022 at the Haemophilia Hospital of the Hamza Foundation Welfare Thalassemia, was to evaluate the knowledge and behaviours of guardians of transfusion-dependent beta-thalassemia patients who were registered with the foundation. The findings of the research, which utilised non-probability convenience sampling to select 150 parents, indicated that 38.7% of the parents surveyed were cognisant of thalassemia, whereas permanent treatment was conspicuously unknown to them. Furthermore, it is noteworthy that a substantial proportion (94%) of parents readily shared food, underscoring the criticality of implementing educational and awareness campaigns targeting not only parents but the broader populace in order to rectify the lack of understanding regarding thalassemia. The fact that genetic counselling was availed of by a minuscule proportion (13.3%) of parents underscores a possible avenue for enhancement in comprehensive care approaches.

AsCas12a Gene Editing of HBG1/2 Promoters with Edit-301 Results in Early and Sustained Normalization of Hemoglobin and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

AsCas12a Gene Editing of HBG1/2 Promoters with Edit-301 Results in Early and Sustained Normalization of Hemoglobin and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

Beyond the promise: evaluating and mitigating off-target effects in CRISPR gene editing for safer therapeutics.

Over the last decade, CRISPR has revolutionized drug development due to its potential to cure genetic diseases that currently do not have any treatment. CRISPR was adapted from bacteria for gene editing in human cells in 2012 and, remarkably, only 11years later has seen it's very first approval as a medicine for the treatment of sickle cell disease and transfusion-dependent beta-thalassemia. However, the application of CRISPR systems is associated with unintended off-target and on-target alterations (including small indels, and structural variations such as translocations, inversions and large deletions), which are a source of risk for patients and a vital concern for the development of safe therapies. In recent years, a wide range of methods has been developed to detect unwanted effects of CRISPR-Cas nuclease activity. In this review, we summarize the different methods for off-target assessment, discuss their strengths and limitations, and highlight strategies to improve the safety of CRISPR systems. Finally, we discuss their relevance and application for the pre-clinical risk assessment of CRISPR therapeutics within the current regulatory context.

Audiologic and vestibular assessment in children and adolescents with transfusion dependent beta thalassemia major: The era of deferasirox film coated tablet

BackgroundHearing impairment has frequently been described in β-thalassemia patients with a significant impact on the patients’ quality of life. Most studies provided evidence of deferoxamine (DFO) dose-related ototoxicity, however, the data is scarce regarding deferasirox (DFX) as a sole iron chelator. AimWe aimed to assess the prevalence and risk factors of sensorineural hearing loss (SNHL) and vestibular dysfunction in regularly transfused β-thalassemia patients who had been treated with DFX film coated tablets. MethodsWe conducted a case control study on 57 transfusion dependent β-thalassemia patients with a mean age of 15.3 years who received DFX FCT as monotherapy for at least one consecutive year, and 57 healthy age and sex-matching controls. Comprehensive audiological evaluations using pure tone audiometry (PTA) and transient evoked otoacoustic emission (TEOAE) as well as vestibular evaluation using Video-nystagmography (VNG) were done. ResultsSNHL was identified in 12 patients (21.1 %) using PTA and a statistically significant difference was detected between controls and patients at 6 KHz and 12 KHz frequencies. A higher incidence of SNHL was detected using TEOAE, 22 patients (43.1 %) failed to pass TEOAE, with a statistically significant decrease in the signal at frequencies 1, 4 KHz bilaterally and at frequencies 1.5, 2 KHz in the right ear compared to controls. Canal paresis was detected in 21 (36.8 %) of thalassemic children using bithermal caloric test with significantly more unilateral weakness than control children (P = 0.008). We found no significant correlation between audio-vestibular dysfunction and age, sex, serum ferritin, frequency of blood transfusion and dose of DFX FCT in thalassemic children. ConclusionWe conclude that the incidence of SNHL and vestibular dysfunction was high among transfusion dependent β-thalassemia patients. Therefore, we recommend performing pre-treatment baseline audio-vestibular assessment and yearly audio-vestibular monitoring to early detect high risk patients and initiate timely management to prevent permanent damage.

Unraveling Impact of Hemoglobin F and A2 Levels: Correlation With Disease Severity and Treatment Response in Transfusion-Dependent Beta-Thalassemia.

Fetal hemoglobin (HbF) has been reported to be associated with disease severity and treatment response to HbF-inducing therapies like Hydroxyurea and thalidomide in patients suffering from transfusion-dependent beta-thalassemia (TDT). However, the role of hemoglobin A2 (HbA2) remains less clear in TDT, therefore this study aims to determine the impact of both HbF and HbA2 levels on disease severity and treatment response. A prospective observational study was conducted at the Peshawar Institute of Medical Sciences and Fatimid Foundation Peshawar from May 2023 to October 2023. A total of 232 TDT-diagnosed patients were enrolled using a convenient sampling technique, whereas coinheritance of beta-thalassemia with other hemoglobinopathies was excluded. This study reveals a significant impact of HbF on disease severity (p<0.05) but finds no substantial correlation (p>0.05) between HbA2 levels and disease severity. Additionally, HbF and HbA2 levels exhibit no association with treatment response categories in patients receiving HbF induction therapy, and various mutations do not significantly alter HbF and HbA2 levels or disease severity parameters in TDT patients. The study established a significant association between HbF and disease severity. However, regarding treatment response, neither HbF nor HbA2 levels impact response categories. Combinatorial treatment with hydroxyurea and thalidomide showed superior efficacy compared to monotherapy. A larger sample size and extended follow-up are recommended to further explore the impact of HbF, HbA2, and various mutations on disease severity and treatment response.

Hematopoietic stem cell transplantation for B-thalassemia major with alemtuzumab

While matched related donor (MRD) allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for transfusion-dependent beta-thalassemia (TDT), the use of alternative sources has increased, resulting in the exploration of novel transplant-conditioning regimens to reduce the contribution of graft-versus-host disease (GVHD) and graft failure (GF) to transplant-related morbidity and mortality. Alemtuzumab is a CD52 monoclonal antibody that has been successfully incorporated into myeloablative conditioning regimens for other hematologic conditions, yet there have been limited studies regarding the use of alemtuzumab in HSCT for TDT. The purpose of this study was to evaluate engraftment, incidence of GVHD, and transplant related morbidity and mortality in patients with TDT who received alemtuzumab in addition to standard busulfan-based conditioning. The primary endpoint was severe GVHD-free, event-free survival (GEFS). Our cohort included 24 patients with a median age of 6.8 years (range 1.5-14.9). Eleven patients received a 10/10 MRD HSCT, eleven 10/10 unrelated donor (UD), and two mismatched UD. All patients achieved primary engraftment. For all patients, 5-year GEFS was 77.4% and 5-year overall survival (OS) was 91%. The 5-year cumulative incidence of GF (attributed to poor graft function) without loss of donor chimerism was 13.8% (95% CI: 4.5, 35.3). We report low rates of significant acute GVHD grade II–IV (12.5%) and chronic GVHD (4.4%). Younger age and MRD were associated with significantly improved GEFS, OS and EFS. Our results show that the use of alemtuzumab promotes stable engraftment, may reduce rates of severe GVHD, and results in acceptable GEFS, OS, and EFS.

EE109 Healthcare Resource Utilization Among Patients with Transfusion-Dependent Beta-Thalassemia in France

EE109 Healthcare Resource Utilization Among Patients with Transfusion-Dependent Beta-Thalassemia in France

EE279 Model-Projected Long-Term Clinical Outcomes of Exagamglogene Autotemcel (exa-cel) Gene-Edited Therapy in Patients with Transfusion-Dependent Beta-Thalassemia in the United Kingdom

EE279 Model-Projected Long-Term Clinical Outcomes of Exagamglogene Autotemcel (exa-cel) Gene-Edited Therapy in Patients with Transfusion-Dependent Beta-Thalassemia in the United Kingdom

CO34 Mortality and Clinical Complications Among Patients with Transfusion-Dependent Beta-Thalassemia in France

CO34 Mortality and Clinical Complications Among Patients with Transfusion-Dependent Beta-Thalassemia in France

EE263 Economic and Healthcare Burden of Blood Transfusions in Transfusion-Dependent Beta-Thalassemia in Thailand and Brazil

EE263 Economic and Healthcare Burden of Blood Transfusions in Transfusion-Dependent Beta-Thalassemia in Thailand and Brazil

Oxidative Stress in Beta-thalassemia Patients: Role of Enzymatic and Non-enzymatic Modulators.

Oxidative stress is a pathophysiological state that arises due to an imbalance created between ROS generation and the antioxidant potential of the host cell. Transfusion- dependent beta-thalassemia major patients are at high risk of cellular and molecular damages induced by ROS mainly due to iron overload caused by repetitive blood transfusion. To analyze oxidative stress status levels in β-thalassemia patients. To analyze the expression profile of enzymatic (NOS2, OGG1, HuR, SOD2) and non-enzymatic (VDR) redox regulators in β-thalassemia patients. To assess polymorphism in VDR (rs2228570) and NOS2 (rs944725) in β-thalassemia patients. To analyze serum vitamin D levels of β-TM patients compared to healthy individuals. The present case-control study aimed to identify Vitamin D levels in the serum of β-thalassemia patients and compared it with healthy subjects. The study further analyzed VDR FOKI (rs2228570) polymorphism through ARMS-PCR. Expression profiling of VDR, anti-oxidant enzyme (SOD2 and GPx), and their respective regulator (HuR and NrF2) transcripts was done by the 2-ΔΔCt method. The study reports that there is no a significant difference between the Vitamin D levels among healthy and patients. VDR polymorphism analysis (rs2228570) demonstrates that although the C allele is prevalent in the study cohort, the frequency of the T allele is comparatively higher in β-thalassemia patients as compared to healthy subjects. Furthermore, patients express lower levels of anti-oxidant enzymes despite having increased oxidative stress. The study reports that β-thalassemia patients are at higher risk of cellular and molecular damages induced by oxidative stress and their associated pathologies inefficient enzymatic and non-enzymatic anti-oxidant defense systems.

Case Series of Paraspinal Extramedullary Hematopoiesis in Transfusion-Dependent Thalassemia Treated with Luspatercept

Introduction: Extramedullary hematopoietic (EMH) pseudo-tumors are commonly seen in patients with non-transfusion dependent thalassemia but rare in transfusion-dependent beta thalassemia (TDT). Paraspinal EMH is more prevalent in older patients with severe ineffective erythropoiesis and low fetal hemoglobin levels. Luspatercept, an inhibitor of the TGF-beta pathway, has been shown to reduce transfusion requirements and improving iron overload in TDT. Emerging data report risk of EMH in patients receiving luspatercept, resulting in updated safety labeling, yet there is scarce data on the optimal management of EMH. In this case series, we present four cases of paraspinal EMH in TDT patients in their twenties treated with Luspatercept, and report management approaches and treatment response. Methods: We conducted a retrospective analysis of adult patients with TDT receiving luspatercept in the Northern Alberta hemoglobinopathy program and identified those who developed EMH. Clinical, laboratory and imaging data were collected, including transfusion requirements, clinical presentation, management strategies, and response to treatment. Results: From June 2021-June 2023, 9 patients with TDT received luspatercept therapy. Three discontinued therapy early, median 2 months (range 1-4), due to side effects (2 severe headache, 1 erratic Hb). Six patients (2F, 4M) continued for long term use. One had baseline MR spine, and 1 had small thoracic EMH noted on cardiac MR; 5/6 underwent MR spine post luspatercept therapy, 1 for neurologic symptoms, 4 for EMH screening. We identified 4 cases of EMH. Luspatercept treatment median 17 months (range 14-20). All 4 patients were males, median age 24 years (range 20-29). All 4 patients had documented history of massive splenomegaly, 2 requiring splenectomy, 1 requiring partial splenic embolization. All 4 cases had significant elevations in reticulocyte count, nRBC, and 2/4 had thrombocytosis (Table 1). Case 1 presented with progressive leg weakness with resultant hemiplegia. Cases 2 and 3 were asymptomatic and found on screening MRI. Case 4 had pre-existing, asymptomatic paraspinal EMH first noted 4 years prior, had enlarged prior to luspatercept, and then enlarged further on CT chest 16 months post luspatercept. Treatment varied according to severity of EMH. Case 1 was hospitalized for 2 months, treated with 18 Gy radiation, dexamethasone for 2 months, hydroxyurea 2000 mg (24 mg/kg), hypertransfusion (goal Hb &amp;gt; 110 g/L) and luspatercept discontinuation. He regained mobility after therapy. Case 3 had impending spinal cord compression. Luspatercept was stopped, and he received radiation therapy 18 Gy, followed by hydroxyurea 1000 mg (16 mg/kg). Case 2, asymptomatic, continued luspatercept, hydroxyurea was added, with planned increased surveillance MR and physical examination. Case 4, initially asymptomatic, continued luspatercept, with increased transfusion threshold. Later he developed symptoms, luspatercept discontinued, and hydroxyurea initiated. Discussion: Paraspinal EMH is uncommon in TDT. However, our case series highlights the occurrence of paraspinal EMH in younger TDT patients treated with luspatercept. All four patients were male, with risk factors for EMH including massive splenomegaly and brisk reticulocytosis. Management options for paraspinal EMH include increased transfusions, hydroxyurea, radiotherapy, surgical decompression, or a combination thereof. Low-dose radiation has shown promising results although access in resource-limited settings and recurrence remain a concern. Limitations of this review include the retrospective nature and small number of patients; a causal relationship cannot be established. Further, given the lack of prior surveillance MRI spine, it is not clear the exact timing of EMH development. Further studies are needed to establish the long-term efficacy and safety of luspatercept in patients with TDT. Conclusion: Paraspinal EMH is a rare complication in TDT patients, but its occurrence should be considered, especially with the increasing use of luspatercept. Screening guidelines for EMH should be established to detect and manage this potentially debilitating condition promptly. In the absence of guidelines, based on the high rate of EMH noted in our cohort, we propose screening MRI spine as a baseline prior to luspatercept, with consideration of regular surveillance MRI post therapy.