Transfusion-dependent Thalassemia Patients Research Articles

Obesity, liver steatosis and metabolic syndrome: The hidden enemies in transfusion-dependent thalassaemia.

In their paper, the authors quantified liver iron concentration (LIC) and hepatic steatosis (HS) using MRI-T2* technology in transfusion-dependent thalassaemia (TDT) patients and healthy controls and found that the prevalence of HS among patients with TDT was 36.4%. In comparison with healthy controls, the hepatic fat fraction (FF) was significantly higher in the TDT population (p = 0.013). Active hepatitis C virus infection, body mass index (BMI) and LIC were independent predictors of HS. An inverse correlation between hepatic FF and high-density lipoprotein cholesterol (p = 0.042) and a significant association of high glycaemia level (p = 0.037) with higher hepatic FF and a significant relationship (p = 0.026) between HS and higher BMI (though in a 'lean' group of patients) in TDT patients indicated that 'metabolic syndrome' was present in this subset with TDT. The impact of metabolic syndrome on TDT, including cardiac disease unrelated to iron overload, needs further study. Commentary on: Ricchi etal. Liver steatosis in patients with transfusion-dependent thalassaemia. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19496.

Liver steatosis in patients with transfusion-dependent thalassaemia.

We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism.

Serum Zinc and Copper Levels in Children with Thalassemia Major

Background: Thalassemia is a frequent hereditary genetic with different clinical manifestations from mild to severe based on its genetic. Beta thalassemia major is the worse form of this disease caused by decreased or absent beta globin chains of hemoglobin. Regular blood transfusion is the main aim leads to iron overload and deposition of iron in different organs.Objectives: To determine different serum distribution levels and correlation of copper and zinc in transfusion dependent thalassemia patients Material and Methods: This was a descriptive cross-sectional study in which a non-probability convenient sampling technique was used for sample collection. This study was conducted in KPK in a total of 137 patients, who were diagnosed cases of thalassemia major by hemoglobin electrophoresis, enzyme linked immunosorbent assay (ELISA) method and receiving iron and folate therapy. SPSS version 22 was used and Pearson's correlation coefficient was applied. P-value 0.05 was considered significant.Results: In this study mean age was 6.7±3.49 years. 77 (56%) percent children were male while 64 (44%) children were female. Mean hemoglobin (Hb) level was 7.43±1.3 gm/dl. Mean SGPT score was 26.28 ± 7.51. Mean blood urea was 21.10 ± 8.49 mmol/l while mean serum creatinine level was 0.56 ± 0.26 mg/dl. Mean serum zinc level was 13.36 ± 11.12mg/dl while mean serum copper level was 1.21± 0.60 mg/dl and mean serum ferritin level was 6682 ± 533 Ug/l.Conclusion: This study showed hypozincemia in thalassemia major patients, but copper deficit was not present. There was no substantial variance between serum ferritin level and mean serum concentration of zinc and copper in this study. Ancillary assessments in this respect is recommended. Keywords: Copper, Thalassemia, Zinc

Analysis of Hepcidin and Interleukin-6 Levels among Transfusion-Dependent Thalassemia Patients With and Without Alloimmunization/Autoimmunization

Analysis of Hepcidin and Interleukin-6 Levels among Transfusion-Dependent Thalassemia Patients With and Without Alloimmunization/Autoimmunization

A Cross-Sectional, Multicentric, Disease-Specific, Health-Related Quality of Life Study in Greek Transfusion Dependent Thalassemia Patients.

The assessment of health-related quality of life (HRQoL) in thalassemia offers a holistic approach to the disease and facilitates better communication between physicians and patients. This study aimed to evaluate the HRQoL of transfusion-dependent thalassemia (TDT) patients in Greece. This was a multicentric, cross-sectional study conducted in 2017 involving 283 adult TDT patients. All participants completed a set of two QoL questionnaires, the generic SF-36v2 and the disease-specific TranQol. Demographic and clinical characteristics were used to predefine patient subgroups. Significant factors identified in the univariate analysis were entered into a multivariate analysis to assess their effect on HRQoL. The SF-36 scores of TDT patients were consistently lower compared to the general population in Greece. The mean summary score of TranQol was relatively high (71 ± 14%), exceeding levels observed in national surveys in other countries. Employment emerged as the most significant independent factor associated with better HRQoL, whereas age had the most significant negative effect. This study represents the first comprehensive QoL assessment of a representative sample of the TDT population in Greece. The implementation of TranQol allowed for the quantification of HRQoL in Greece, establishing a baseline for future follow-up, and identifying more vulnerable patient subgroups.

Pancreatic iron in pediatric transfusion-dependent beta-thalassemia patients: A longitudinal MRI study.

In pediatric transfusion-dependent thalassemia (TDT) patients, we evaluated the prevalence, pattern, and clinical associations of pancreatic siderosis and the changes in pancreatic iron levels and their association with baseline and changes in total body iron balance. We considered 86 pediatric TDT patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Iron overload (IO) was quantified by R2* magnetic resonance imaging (MRI). Sixty-three (73%) patients had pancreatic IO (R2*>38Hz). Global pancreas R2* values were significantly correlated with mean serum ferritin levels, MRI liver iron concentration (LIC) values, and global heart R2* values. Global pancreas R2* values were significantly higher in patients with altered versus normal glucose metabolism. Thirty-one patients also performed the follow-up MRI at 18±3months. Higher pancreatic R2* values were detected at the follow-up, but the difference versus the baseline MRI was not significant. The 20% of patients with baseline pancreatic IO showed no pancreatic IO at the follow-up. The 46% of patients without baseline pancreatic IO developed pancreatic siderosis. The changes in global pancreas R2* between the two MRIs were not correlated with baseline serum ferritin levels, baseline, final, and changes in MRI LIC values, or baseline pancreatic iron levels. In children with TDT, pancreatic siderosis is a frequent finding associated with hepatic siderosis and represents a risk factor for myocardial siderosis and alterations of glucose metabolism. Iron removal from the pancreas is exceptionally challenging and independent from hepatic iron status.

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.

Assessment of Serum Ferritin Levels in Transfusion Dependent Thalassaemic Patients at Rajasthan Southern Region

Assessment of Serum Ferritin Levels in Transfusion Dependent Thalassaemic Patients at Rajasthan Southern Region

Longitudinal prospective comparison of pancreatic iron by magnetic resonance in thalassemia patients transfusion-dependent since early childhood treated with combination deferiprone-desferrioxamine vs deferiprone or deferasirox monotherapy.

In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on pancreatic iron of a combined deferiprone (DFP) + desferrioxamine (DFO) regimen versus either oral iron chelator as monotherapy over a follow-up of 18 months. We selected patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network who received a combined regimen of DFO+DFP (No.=28) or DFP (No.=61) or deferasirox (DFX) (No.=159) monotherapy between the two magnetic resonance imaging scans. Pancreatic iron overload was quantified by the T2* technique. At baseline no patient in the combined treatment group had a normal global pancreas T2* (≥26 ms). At follow-up the percentage of patients who maintained a normal pancreas T2* was comparable between the DFP and DFX groups (57.1 vs 70%; p=0.517).Among the patients with pancreatic iron overload at baseline, global pancreatic T2* values were significantly lower in the combined DFO+DFP group than in the DFP or DFX groups. Since changes in global pancreas T2* values were negatively correlated with baseline pancreas T2* values, the percent changes in global pancreas T2* values, normalized for the baseline values, were considered. The percent changes in global pancreas T2* values were significantly higher in the combined DFO+DFP group than in either the DFP (p=0.036) or DFX (p=0.030) groups. In transfusion-dependent patients who started regular transfusions in early childhood, combined DFP+DFO was significantly more effective in reducing pancreatic iron than was either DFP or DFX.

Study of thyroid functions in transfusion dependent thalassemia patients of pediatric age group with reference to serum ferritin level in a tertiary care centre

Hypothyroidism is one of the most common endocrine complication in transfusion dependent thalassemia patients. Its prevalence and severity is variable and the natural history is poorly described. The frequency of hypothyroidism in Beta Thalassemia Major (BTM) children ranges from 6 to 30%. To determine the levels of serum TSH and FT4 in patients with transfusion-dependent thalassemia (TDT), as well as their relationship to the degree of iron excess indicated by serum ferritin levels. This observational descriptive study was undertaken on 200 patients (5 to15 yrs of age) in the department of Pediatrics in SCB Medical College, Cuttack, Odisha, India from to after obtaining clearance from institutional ethical committee. Out of total 200 TDT children, 141(70.50%) were euthyroid and 59(29.50%) were hypothyroid. Among hypothyroid children, 9(4.5%) had overt hypothyroidism and 50(25%) children had subclinical hypothyroidism. In children <10 years of age group there was a positive correlation between serum ferritin and rise in serum TSH (p < 0.05, r= .553). The rise in serum ferritin was statistically not significant with fall in serum FT4 (p < 0.05, r= .122). In children >10 years of age group, there was positive correlation between serum TSH and serum ferritin (p < 0.05,r=.845). There was an inverse relation between rise in serum ferritin and fall in serum FT4 (p < 0.05, r= -.406). Hypothyroidism was associated in significant number of transfusion dependent thalassemia patients. Adequate iron chelation therapy to keep serum ferritin level within normal limit and early detection of hypothyroidism preferably below 10 years of age will prevent hypothyroidism and its complications in transfusion dependent thalassemia.

Transfusion‐dependent thalassemia patients develop cognitive impairment with gut dysbiosis

AbstractBackgroundThalassemia is an auto‐recessive hemoglobinopathy affecting populations worldwide. Although life expectancy of thalassemia patients has been increasing due to therapeutic advancements, neurocognitive complications have been continuously reported among transfusion‐dependent thalassemia (TDT). Interestingly, the relationships among cognitive decline, systemic iron burden, and gut microbial alterations in TDT patients remain to be determined.MethodTwenty‐eight participants, including 14 TDT patients and 14 heathy controls, were recruited to evaluate a cognitive function using the Mental State Examination T10 (MSET10) test. Serum ferritin was employed to reflect a severity of systemic iron burden. Stool was collected to determine a gut microbial profile using a next‐generation sequencing of bacterial 16s rRNA V3‐V4 regions.ResultTDT patients had the cognitive impairment, higher systemic iron burden, and gut dysbiosis when compared with the controls. TDT patients also had lower MSET10 scores than the controls (Figure 1A). In addition, an increase in serum ferritin was observed in the TDT, indicating that there was the iron burden in the TDT (Figure 1B). Moreover, gut dysbiosis in TDT patients as indicated by higher bacterial diversity and different microbial compositions in comparison with the controls were observed (Figure 1C and 1D). The MSET10 scores were negatively correlated with the levels of serum ferritin and gut microbial diversity (Figure 1E and 1F). Interestingly, the levels of serum ferritin were positively correlated with the gut microbial diversity (Figure 1G).ConclusionThese findings suggest that a systemic iron burden may involve in an alteration of gut microbiota, and the systemic iron burden together with the gut dysbiosis may concurrently deteriorate a cognitive function in TDT patients. Therefore, an iron reduction with a gut microbial manipulation, such as a combined usage of an iron chelator with a probiotic supplement, should provide benefits to prevent neurodegeneration as well as gut microbial disturbance in TDT patients.

Increased Proportion of Black Transfusion Dependent Thalassemia Patients in a Single Southeast U.S. Center

Thalassemia is a common disorder worldwide but remains relatively rare in the United States (U.S). Over the past decade, there has been a significant demographic shift as more patients are entering care as either international adoptees or refugees from under-resourced countries. We analyzed our own center's demographic evolution from 2014 to 2023. Only transfusion dependent thalassemia (TDT) patients fully managed within our pediatric center are represented in Table 1. We did not include non-transfusion dependent thalassemia (NTDT) patients nor TDT patients who have graduated to adult care, relocated, or those who travel to our center only for comprehensive visits from out of state. When compared to the national data collected by the Cooley's Anemia Foundation (CAF), we saw a similar increase in patients from China and Southeast Asia (SEA), reflecting the increased number of adoptees in the period from 2014-2019 (Tables 1 & 2). Since that time, we have seen an increase in patients from South Asia (SA) and the Middle East (ME). These patients are mostly refugees from regional conflicts (Syria, Afghanistan, Myanmar, etc.). This trend is similar to other centers, according to the CAF (unpublished communication). Interestingly, however, our center has a significantly larger proportion of Black TDT patients compared to the national data (Table 2 ). As can be seen in the tables below, we have nearly 20x more Black patients (20-22.9% vs. 0.9-1.2%) when compared to the national data. This may be in part due to our center's location in Atlanta, Georgia. However, according to the latest U.S. Census data, Georgia's population is 33.1% Black, compared to 13.6% in the U.S population as a whole. Based on this, we would expect a 2.4x increase, as opposed to a 20x increase. Vichinsky et al published a study in Pediatr Blood Cancer in 2017 using data collected from 4 Comprehensive Thalassemia Treatment Centers (CTTC) in the Northeast, Midwest and West coast of the U.S. looking at the racial distribution and changes of NTDT patients. They also found a higher-than-expected proportion of Black patients, about 17%. Of our 65 NTDT patients, 26% are Black and an additional 5% are mixed race, Black and Asian. The majority (60%) have Hemoglobin H disease. We looked to see if our TDT patients were relatives of sickle cell disease (SCD) patients, since our center has the largest pediatric SCD population in the U.S. However, only 20% (2/10) report family members with any form of SCD. The majority (8/10) of the patients identify as African American, whereas the remaining 2 are 1st generation Somalian and Ghanaian. Genotype data is available for 9/10 patients, with three ß0/ß0 and six ß+/ß0. The most common mutations seen were IVS II-849 A>G (ß0), -29nt A>G (ß+), Promoter -88nt G>T (ß+) and Codon 5 (-CT) frameshift (ß0). All are mutations predominantly found in Blacks. Clinically, as a group, they had a high rate of splenomegaly (8/10) and skull changes (6/10) before transfusions began. Transfusions began ages 6mos-9 yrs. with 50% occurring after age 3 yrs. Black TDT patients may face unique challenges in the U.S. where there are >50 SCD patients for every thalassemia patient. Indications for transfusion and overall clinical management are vastly different for these two diseases, but providers with little experience in the treatment of Thalassemia may inappropriately treat them like SCD patients.

Alterations of Gut Microbiota Related with Status of Iron-Overload in Thalassemia Patients: A Cross-Sectional Pilot Study

Background: Gut dysbiosis can cause an impaired gut-barrier function and may contribute to the pathogenesis of various diseases. Iron overload is a common complication in thalassemia patients and can result in numerous complications, including those affecting the cardiovascular, endocrine, and immune systems. However, it is unclear how iron overload affects the gut microbiota of patients with thalassemia. Objective: To characterize the profiles of the gut microbiome in thalassemia patients compared with healthy participants, as well as to determine the association of these profiles with iron status. Method: Transfusion-dependent thalassemia (TDT) patients and healthy controls aged ≥ 18 years old were enrolled in the study. Stool samples were collected prior to receiving regular blood transfusions in the thalassemia group. Paired-end sequencing of 16s rRNA bacterial DNA extracted from each stool sample was performed. Serum ferritin levels were assessed in each participant to reflect iron status. Results: A total of 14 adult TDT patients and 14 healthy controls were enrolled, with a similar proportion of age and sex. The TDT patients had a significantly higher iron overload status than the controls (median serum ferritin level = 1424 in the TDT group and 197 in the control group; p < 0.001). The Shannon diversity index demonstrated a significant increase in gut microbial diversity in TDT patients as compared to healthy controls (7.06 vs. 6.48; p = 0.001). The TDT group showed a higher abundance of several gram-negative bacterial phyla, such as Bacteroidota, but a reduction in the abundance of Actinobacteriota as compared to the control group. Serum ferritin levels showed a positive correlation with higher gut diversity index. Conclusions: Our study suggests that TDT patients develop gut dysbiotic characteristics compared to the healthy population, with gut diversity associated with serum ferritin levels. This association suggests that iron overload induces gut dysbiosis.

RBC Exchange Transfusion As an Adjunct Therapy to Control Iron Overload in Patients with Transfusion-Dependent Thalassemia

Background Patients with transfusion-dependent thalassemia (TDT) require red blood cell (RBC) transfusions as frequently as every 2-4 weeks to maintain a pre-transfusion hemoglobin of 9.0-10.5 g/dL for patients without cardiac complications. Chronic RBC transfusions increase body iron stores leading to iron deposition in liver, pancreatic, and cardiac tissues. Deferoxamine, deferiprone, and deferasirox are the iron chelators currently licensed for clinical use to manage iron overload in TDT patients with side effects ranging from nausea to nephrotoxicity and hearing loss. RBC exchange transfusion (RBCX), particularly in conjunction with isovolumic hemodilution, has been utilized for patients with sickle cell disease as a means of stabilizing iron overload. The 2015 ASFA Red Blood Cell Exchange consensus supports RBCX to reduce or prevent iron overload in sickle cell disease. Review of literature shows that RBCX can be beneficial as an acute intervention for patients with TDT and pulmonary hypertension however there is a paucity of literature documenting chronic RBCX use in TDT patients with iron overload. Case series This series presents five patients with TDT who were transitioned from chronic simple RBC transfusions to chronic RBCX after developing treatment-refractory iron overload as evidenced by serum ferritin elevation. Patients were treated on a transfusion schedule with a pre-transfusion goal hemoglobin of 9.5g/dL or higher and interval 4-6 weeks. Patient A is a 14 year-old male who developed significant iron overload (peak ferritin of 7077) on deferasirox 20 mg/kg/day and MRI T2 imaging suggestive of iron deposition. After transition to RBCX, ferritin decreased significantly with a post-RBCX mean of 1382. Blood utilization was 4200 ml three months pre-RBCX and 5625 ml three months post-RBCX. Patient B is a 23 year-old male with a peak ferritin of 1310 prior to RBCX on 23 mg/kg/day of deferasirox complicated by mild hearing loss. Serum ferritin has shown stabilization, with a mean post-RBCX ferritin of 880. Blood utilization was 2400 ml three months pre-RBCX and 8100 ml three months post-RBCX. Patient C is a 17 year-old male with a peak ferritin of 1400 with deferasirox management complicated by acute renal injury. Mean serum ferritin of 633 post-RBCX. Blood utilization was 1200 ml three months pre-RBCX and 5200 ml three months post-RBCX. Patient D is a 17 year-old male managed on 23 mg/kg/day of deferasirox with a peak ferritin of 3060 on pre-RBCX. The patient transitioned to chronic RBCX with mean serum ferritin of 1073. Blood utilization was 1800 ml three months pre-RBCX and 7700 ml three months post-RBCX. Patient E is a 17 year-old male with peak ferritin of 3404 despite 20 mg/kg/day of deferasirox prior to chronic RBCX. Mean serum ferritin after transition to RBCX was found to be 1282. Blood utilization was 1500 ml three months pre-RBCX and 4900 ml three months post-RBCX. All 5 patients have tolerated RBC exchange procedures without complications. Serum ferritin levels pre- and post-RBC exchange were trended pre- and post- RBCX (Figure 1). Serum ferritins were averaged together for each patient to obtain an equal number of time points considered prior to and after starting RBCX therapy. Descriptive statistics (Table 1) were used to summarize average ferritin levels for the patient group. A Wilcoxon signed-rank test was performed to assess the median difference in ferritin level from pre-RBCX to post-RBCX. All analyses were conducted in SAS version 9.4. P <0.05 is considered statistically significant. Median pre-RBCX ferritin level for the study group is 2489.3 (Inter-quartile range (IQR): 1190.0, 2659.0). The median post-RBCX ferritin level for the series is 1329.3 (IQR: 941.0, 1711.0). After subtracting the post-RBCX ferritin level from the pre-RBCX ferritin level, the median change for the group is 457 (IQR: 249.0, 1160.0) (p=0.06). Conclusion This case series documents the successful clinical application of chronic RBCX in TDT patients as a means of stabilizing serum ferritin levels over time. Mean ferritin levels were significantly lower, clinically, after transitioning from chronic simple RBC transfusion to RBCX (Table 1), though analysis is limited due to cohort size. Blood utilization increased after transitioning to RBCX. Next steps in evaluating our practice for the patient group will be to evaluate iron deposition status with MRI T2* imaging.

Treosulfan Based Haploidentical Αß T Cell Depleted HSCT Represents a Curative Alternative in Pediatric and Adult Patients with Transfusion Dependent Thalassaemia

Background: Quality of life remains severely compromised in patients suffering from Transfusion Dependent Thalassemia (TDT) despite optimal supportive care. HSCT with a MSD, the current curative option, achieving a 92.1% 2y-OS in children and 84.4% in adults (EBMT registry). Unfortunately, availability of MDs is limited, so that haploidentical HSCT is increasingly explored. Methods: 13 TDT patients (median age: 11 years; range: 2-23) received either a CD3 +/CD19 + (n=4; all class II/III) or αß/CD19 + (n=10; 7 class II, II/III) T-haplo-HSCT and were compared with 8 TDT-patients (7 class II, II/III, III) receiving a BM graft from a MSD (median age: 11 years; range: 4-22). Indication for T-haplo HSCT patients was severe iron overload/ transfusion-associated complications. All patients received an identical conditioning regimen consisting of treosulfan, thiotepa, fludarabine (FTT) and ATG-Grafalon, with the only difference in the timing of ATG (upfront in T-haplo-HSCT, prior to d0 in MSD-HSCT). Immunosuppression (IST) was maintained for a minimum of 180 days consisting of calcineurin inhibitors (mainly tacrolimus) and MMF. Results: The OS and DFS for MSD and T-haplo-HSCT was 100%/100% and 100%/92%, respectively (Table 1). The median follow-up was 30 months for MSD (range 4-72) and 38 months for T-haplo-HSCT (range 4-86). Neutrophil engraftment was achieved after a median of 31 days for MSD patients and 17 days for T-haplo-HSCT with a median of 5 x 10 8 TNC/kg (range: 3.28-7.88) and 15 x 10 6 CD3 +/CD19 + or αβ/CD19 + depleted CD34 + cells/kg (range: 9.2-24.2), respectively. One patient received two T-haplo HSCT, due to primary graft failure partly due to a major AB0 incompatibility. A mixed chimerism was observed in 3/7 MSD-HSCT (median 92%; range 27.5-100%) and in T-haplo-HSCT in 2/13 patients (median 99%; range: 45.3 -100%). Transfusion independence was achieved in all MSD and in all but one T-haplo patient. In MSD and in T-haplo-HSCT, IST was terminated after a median of 173 days and 226 days (range: 112-347), respectively. MSD patients reached CD4 counts >50/µl on day +43 (median; range: 25-125) and T-haplo-HSCT patients on day +114 (median; range: 33-173). The treosulfan-based conditioning regimen was well tolerated with no VOD/SOS observed in this high-risk population. No case of acute or chronic Graft-versus-Host disease (GvHD) was observed in the MSD population. In T-haplo-HSCT, 3 patients experienced grade I acute GvHD (skin) which resolved with prednisolone and in 2 cases with additional extracorporeal photopheresis. Only the oldest patient experienced mild chronic skin GvHD, which resolved by day +580. No severe infectious complications occurred despite a prolonged chimerism-triggered weaning of the IST. Conclusions: Independent of donor availability, graft rejection and iron-overload related organ damage (VOD/SOS) are major pitfalls in transplanting advanced stage TDT patients. Treosulfan demonstrated to be an excellent alternative to busulfan in this setting reflected in the safety and efficacy data of this pilot series. Overall, outcomes of T-haplo-HSCT in TDT are very encouraging with a competitive OS, so that a transplant indication in pediatric and AYA TDT patients lacking a MD is feasible.

Evolving Changes in the Characteristics of Death in Transfusion Dependent Thalassemia in Greece

Introduction: During the last decades, improvements in the treatment of transfusion-dependent thalassemia (TDT) with safer transfusion schemas, improved management of iron overload and of comorbidities, have resulted in significantly increased life expectancy. With increased survival, the pattern of characteristics of death is changing. Aim: The aim of our study was to analyze the causes and other characteristics of death in transfusion-dependent thalassemia patients in Greece during the last 45 years. Patients and Methods: A retrospective cohort study was conducted in our Unit, which is the largest one in country, where around 15-20% of Greek patients (pts) are followed. The study included all deaths in TDT pts occuring between 1979 and 2023. The observation period was analyzed in 5 years' segments. For each patient, data on the age of death, cause of death, age of splenectomy, age at first chelation treatment and mean ferritin values for the last two years before death, were captured. Patients were classified into two groups: (1) mild (ferritin < 2500 μg/L) and (2) moderate-severe (ferritin: <2.500g/L). Statistical analysis performed with RStudio v.3.6.2. Results: A total of 172 deaths (male/female: 107/65) were recorded during this observation period. Pts' characteristics are summarized in table1. The overall incidences of the main causes of death are heart disease (57%), malignancy (12%), infections (included HIV and sepsis) (12%), liver failure (4.6%) and accidental events (4.6%). Distribution of causes of death during the different intervals are shown in figure 1. Malignancies (20 pts) are the most prevalent cause of death for the last observation period 2019-2023 and include liver cancer (11pts), renal cancer (2 pts), colorectal cancer (2 pts), lymphoma (2 pts), lung cancer (1 pt), pancreatic cancer (1 pt) and cholangiocarcinoma (1 pt). Malignancy has gradually replaced cardiac disease as the leading cause of death over the last years. Infections increased as a cause of death in the last 5 years and reached similar levels to the initial observation time segment. A gradual increase in the age of pts at the time of death was noted, starting from a mean (±SD) of 15.7±.3.6 years at the period of 1979-1983 to 46.6±.6.0 years for 2019-2023. The percentage of splenectomized pts varies significantly throughout the observation period. There is a positive correlation between ferritin levels and causes of death due to cardiovascular disease. The percentage of deceased pts on chelation therapy gradually increased while the age of starting chelation therapy gradually decreased during the observation period. Conclusions: The present study shows that there is a shift in the main cause of death in transfusion-dependent thalassemia patients the last 45 years, from cardiovascular to malignancies, while there is variability in the distribution of all causes of death during the different 5-year intervals. This reflects the overall changes in the treatment of TDT, which has transformed TDT from a pediatric disease of guarded prognosis to a chronic disease of adulthood.

Allogeneic Stem Cell Transplant for High-Risk Transfusion Dependent Thalassemia [Tdt] - a Comparative Analysis of Flu/Bu/Cy/ATG Versus Flu/Thio/Treo Regimen

Background & Significance: Allogeneic stem cell transplantation (allo-SCT) is the curative treatment for transfusion dependent thalassemia (TDT), until the gene therapy is readily accessible, which could revolutionize the treatment approach. 1 Later, Mathews et al. identified additional factors affecting outcomes, leading to the recognition of a specific very high-risk subgroup within Class III, referred to as Vellore high risk (HR) or Class IIIB. 2, 3 Following the identification of Class IIIB, treosulfan (Treo) was introduced as a treatment option due to its favorable low hepatic toxicity profile. 4, 5 Several studies have reported the use of Treo-based conditioning in the high-risk subset, showing treatment-related mortality (TRM) rates ranging from 7 to 21%. 6 - 8 Here, we present our (allo-SCT) experience for transfusion-dependent thalassemia (TDT) using the Flu/Bu/Cy/rabbit ATG or Flu/Thio/Treo as a conditioning regimen in a high risk cohort. Study design & Methods: We did a retrospective analysis of all transfusion dependent thalassemia [TDT] patients who underwent allogeneic stem cell transplant [allo-SCT] with Flu/Bu/Cy/ATG or Flu/Thio/Treo as a conditioning regimen. TDT patients who have received conditioning other than this were excluded from the study. The objective of the study is the assess the rate of thalassemia free survival [TFS], thalassemia GVHD free survival [TGFS], overall survival [OS], graft rejection and non-relapse mortality [NRM]. Results: We included a total of 64 patients in our study. Forty-one patients in Flu/Bu/Cy/ATG group and 23 patients were in Flu/Thio/Treo group. The median age of the patients was 9 years (range: 8 -14) and 10 years (8 - 15) in Flu/Bu/Cy/ATG and Flu/Thio/Treo group respectively. Upon presentation, the distribution of patients among Class I, II, and III were 2(4.9%) v/s 1(4.4%), 27(65.8%) v/s 11(47.8%), and 12(29.3%) v/s 11(47.8%) respectively. The graft source was bone marrow in 38 (92.7%) patients all in Flu/Bu/Cy group, whereas 3 (7.3%) v/s 23(100%) in peripheral blood stem cells. The mean CD34 stem cell dose administered was 3.4 × 10^6/kg (range: 0.7 - 9.8) v/s 5 × 10^6/kg (1.65 - 6.1). Neutrophil and platelet engraftment occurred at a median of 17 days (range: 11 - 26) v/s 15.5 days (range: 12 - 20) and 18 days (11 - 47) v/s 15 (9 - 41) respectively. Table:1 Primary rejection was in 3 (7.3%) whereas 2 (4.8%) were secondary rejection in Flu/Bu/Cy group only. Mixed chimerism was observed in a higher percentage of patients in the Flu/Bu/Cy/ATG group 17 (41.5%) compared to the Flu/Thio/Treo group 4 (17.4%). Veno-occlusive disease was reported in 14 (34.1%) v/s 4 (17.4%) patients, with [6 (14.6%) v/s 0] cases being mild, [6 (14.6%) v/s 3 (13%)] cases moderate, and [2 (4.8%) v/s 1 (4.3%)] case severe. Acute and Chronic graft-versus-host disease occurred in patients [7 (17.1%) v/s 10 (43.5%)] and [1 (2.4%) v/s 7 (30.4)] patients respectively. Fortunately, there were no cases of treatment-related mortality in Flu/Bu/Cy/ATG whereas 3 (13.3%) TRM was observed in Flu/Thio/Treo group. The overall survival at a median follow-up of 25 months were 100% v/s 87% [CI: 64.8 - 95.6] was statistically significant (p=0.02). Thalassemia GVHD free survival at a median follow-up was highly significant with a p value of 0.024 {83.7% [CI: 66.9 - 92.5] v/s 55% [CI: 31.3 - 73.5] (p = 0.024)} in Flu/Bu/Cy and Flu/Thio/Treo group respectively. Fig:1 Conclusion: In conclusion, the study suggests that the Flu/Bu/Cy/ATG conditioning regimen resulted in better overall survival [OS] and thalassemia GVHD free survival [TGFS] compared to Flu/Thio/Treo regimen in a high-risk transfusion dependent thalassemia [TDT] patients undergoing allo-SCT. However, it is essential to consider the limitations of the study, such as its retrospective nature and the relatively small sample size, before making any definitive conclusion. Further research with large sample sizes and prospective study designs may be needed to confirm these finding.

Atrial Fibrillation Prevalence and Its Management in Transfusion-Dependent Thalassemias: The Fathal Study

Atrial fibrillation (AF) represents an emerging issue in the thalassemia population related to increased life expectancy. However, data on AF in these patients are limited, and the current management is based on the guidelines for the general population. Nevertheless, AF in these patients has distinctive features that could require specific management. We conducted a multicentric retrospective study supported by the Italian Society of Thalassemia and Hemoglobinopathies (SITE) to elucidate the prevalence of AF in transfusion-dependent thalassemia (TDT) adults in Italy and to study its management, particularly the use of transcatheter ablation and anticoagulation management. Patients followed between June 1, 2003 and May 31, 2023 with a diagnosis of alpha- or beta-transfusion-dependent thalassemia with at least one episode of AF were included in the study. Clinical data of patients have been retrospectively collected with dedicated digital case report form (CRF). So far, 3 centers (Cagliari, Ferrara, Milano) have participated in the study. Eight-hundred-sixty-one adult TDT patients are regularly followed in the participating centers. Data from 130 adult TDT with AF were included. At enrollment, 119 patients were alive (71 males, 60%), the mean age at enrollment was 51.9 years, and 71% were splenectomized. Almost all (98%) had beta-thalassemia, of which 20% had thalassemia intermedia and became transfusion dependent during their life. The mean age at the first AF episode was 39.7 yr. Overall, AF prevalence in TDT was 13.8%, with a significant rise above the age of 50 (age 51-65: prevalence 26.4%, age>65 33.3%), differently from the general population in which the prevalence is 2-4%, and patients are older. As in the general population, prevalence was higher in males (18.2% vs 10.2%). Among the known risk factors for AF, the most frequent were diabetes (16%, n=111) and previous heart failure (22%, n=111). Regarding disease-specific factors contributing to the pathophysiology of AF, cardiac iron overload, defined as at least one between T2*<20 ms and serum ferritin>2500 ng/ml, was present in half of the patients (48.7%, n=76) at any time before AF and in approximately one-third (29%, n=93) at the time of the first event. Thirty-eight patients did not show cardiac iron overload before or at the time of the first AF episode. Most subjects had left atrial dilatation (58.1%), which can result from chronically increased cardiac output due to anemia. In most patients (87%), a rhythm control strategy was chosen at any time. Amiodarone was the most widely used drug. Transcatheter ablation was performed in 29 patients (22%), with a total of 39 procedures, and 20 (77%) patients reported improvement in symptoms after the last ablation. CHA 2DS 2-VASc score at the first AF episode detected a low risk of thromboembolism in 66 (50.8%) patients and a high risk in 19 (14.6%). However, 72 patients, including 40 low-risk subjects, initiated anticoagulation after the first episode. Four patients had a hemorrhagic event (3.1%), but only one had major bleeding during anticoagulant therapy without significant sequelae. Interestingly, management was heterogenous between different centers for both transcatheter ablation use and anticoagulation strategy. The prevalence of stroke in TDT AF patients was 5%, rising to 7.6% when also considering transient ischemic attacks. Compared to the literature, this prevalence is at least 10-fold higher than the general TDT population. Of note, splenectomy, a well-known risk factor for thrombosis, was present in all patients with stroke at the time of the event. In conclusion, AF represents significant morbidity in adult TDT, and its management is heterogeneous. It generally occurs at a younger age than the general population, and iron overload and atrial dilatation play a central role in its genesis. For symptomatic patients, we propose a rhythm control strategy to improve their quality of life, among which ablation could be the best option. Moreover, because stroke represents a major and frequent complication in TDT patients with AF, early detection of AF and prompt initiation of anticoagulant therapy, irrespective of CHA 2DS 2-VASc, which does not capture potential disease-specific risk factors, including splenectomy, should be considered. Further studies to support our approach are needed.

Pharmacokinetics (PK) of Deferasirox in Transfusion Dependent Thalassemia

Iron overload is a major cause of organ dysfunction and death in transfusion-dependent thalassemia (TDT) and advances in iron chelation are urgently needed. The iron chelator, deferasirox, is widely used in TDT, however, many patients accumulate iron despite taking maximum recommended doses and many experience dose-limiting toxicity, including renal and liver failure. There is high inter-individual variability in the plasma concentrations of patients taking comparable deferasirox doses and low exposure correlates with inadequate chelation response. The cause of variable drug levels remains unknown, in part because prior deferasirox PK studies primarily include limited sample sizes and/or homogenous patients. There is an urgent unmet need to determine (1) what patient characteristics contribute to the observed variability in deferasirox-plasma concentrations, and (2) how dosing strategies can be tailored to achieve optimal therapeutic plasma-drug concentrations in all patients. We initiated a 2 year, single center observational pharmacokinetic (PK) pilot study to describe the PK of deferasirox in a diverse group of TDT patients from 2 years old through adulthood with a goal accrual of 50 patients. Our aim is to develop a population PK (popPK) model of deferasirox that will be evaluated in a future prospective study to individualize dosing and optimize exposure. The eligibility criteria are broad to capture a diverse population. Patients are eligible if they: 1) have a diagnosis of TDT, 2) are taking deferasirox, and 3) are able to provide informed consent (or have a guardian provide informed consent). For quantification of plasma deferasirox concentrations, 0.5 ml of whole blood are collected prior to transfusions at 4 regularly scheduled transfusion visits. Samples are then analyzed by a validated high performance liquid chromatography assay. Baseline labs, liver iron concentration and information on concomitant chelators are collected at the start of the study and labs, fed/fasted state, time and dose of last deferasirox, deferasirox regimen, and concomitant chelators are collected at each study visit. The planned analysis is to use nonlinear mixed effect modeling to calculate drug exposure and develop the popPK model. We have enrolled 39 patients with TDT, including 27 patients with beta thalassemia major, 10 patients with hemoglobin E beta thalassemia, 12 patients with hemoglobin H constant spring and one patient with beta thalassemia intermedia. Median age is 28 years old, with a range from 6 - 63 years old. Pre-study iron status also varied considerably, with median liver iron concentration 4.5 mg/g (range 1.5 -30 mg/g) and median ferritin 1500 ug/L (range 460 - 5600 ug/L). Thirty one patients have completed the study and 141 samples have been collected. Initial analysis of the first 15 patients who completed the study show a wide range of steady state plasma-deferasirox concentrations, consistent with prior reports. The means for the 4 samples collected per patient were calculated and found to have a median of 36.3 ug/ml with a range of 13.4 - 56.0 ug/ml. For the individual sample collections, the range of plasma deferasirox concentrations was even greater (0.18 - 99.9 ug/ml). These results need to be analyzed further to account for the dosing regimen, iron burden and other individual patient characteristics. In this study, we also collected genomic DNA from the buffy coat to evaluate the impact of single nucleotide polymorphisms in enzymes involved in drug metabolism and distribution. Once all data is collected, we will evaluate whether patient age, weight, laboratory values, fed/fasted state, concomitant chelators or pharmacogenomics impact deferasirox serum concentrations and can inform individualized deferasirox dosing. This study is unique, unlike prior deferasirox PK studies which collected intensive PK, we are using sparse sampling to collect real world data on deferasirox at steady state in TDT patients. Our hope is that this study will enable safer more effective dosing of deferasirox in patients with TDT.

A plenary survey on the Incidence of cardiac complications amongst transfusion-dependent thalassemia patients

A plenary survey on the Incidence of cardiac complications amongst transfusion-dependent thalassemia patients