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1.
In vivo measurement of RBC survival in patients with sickle cell disease before or after hematopoietic stem cell transplantation
Leonard, A., Furstenau, D., Inam, Z., Luckett, C., Chu, R., Demirci, S., Essawi, K., Gudmundsdottir, B., Hinds, M., DiNicola, J., et al
Blood advances. 2024
Abstract
Stable, mixed donor-recipient chimerism after allogeneic hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD) is sufficient for phenotypic disease reversal and results from differences in donor/recipient red blood cell (RBC) survival. Understanding variability and predictors of RBC survival among patients with SCD before and after HSCT is critical for gene therapy research which seeks to generate sufficient corrected hemoglobin to reduce polymerization thereby overcoming the red cell pathology of SCD. This study utilized biotin-labeling of RBCs to determine the lifespan of RBCs in patients with SCD compared to patients who have successfully undergone curative HSCT, participants with sickle cell trait (HbAS), and healthy (HbAA) donors (NCT04476277). Twenty participants were included in the analysis (N=6 SCD pre-HSCT, N=5 SCD post-HSCT, N=6 HbAS, N=3 HbAA). The average RBC lifespan was significantly shorter for participants with SCD pre-HSCT (64.1 days, range 35-91) compared to those with SCD post-HSCT (113.4 days, range 105-119), HbAS (126.0 days, range 119-147), and HbAA (123.7 days, range 91-147) (p<0.001). RBC lifespan correlated with various hematologic parameters, and strongly correlated with the average final fraction of sickled RBCs after deoxygenation (p<0.001). No adverse events were attributable to the use of biotin and related procedures. Biotin labeling of RBCs is a safe and feasible methodology to evaluate RBC survival in patients with SCD before and after HSCT. Understanding differences in RBC survival may ultimately guide gene therapy protocols to determine hemoglobin composition required to reverse the SCD phenotype as it relates directly to RBC survival.
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2.
Speckle tracking echocardiography-derived left ventricular global longitudinal strain in ex-thalassaemics
Paul, A., Kulkarni, U., Yadav, B., Aboobacker, F. N., Devasia, A. J., Korula, A., Abraham, A., George, B., George, P. V., Srivastava, A.
PloS one. 2023;18(11):e0293452
Abstract
AIMS: Long term survivors of haematopoietic stem cell transplantation (HSCT) for β-thalassemia major are designated "ex-thalassaemics". Whether ex-thalassaemics continue to harbour residual myocardial dysfunction and thereby stand the risk of heart failure-related morbidity and mortality is unknown. The aim of this study was to assess the prevalence and predictors of subclinical left ventricular (LV) dysfunction in an apparently normal ex-thalassaemic population. METHODS We conducted a single centre cross-sectional study among 62 ex-thalassaemic patients, who had undergone HSCT for β-thalassaemia major at our centre. The primary outcome variable was LV systolic dysfunction, as assessed by 1) LV global longitudinal strain (GLS) derived by 2D speckle tracking echocardiography and 2) LV ejection fraction (EF) derived by 2D Simpsons Biplane method. RESULTS Among the 62 patients included in the study, 7 [11.3%] were found to have LV systolic dysfunction, all of which were subclinical. Of these, 4 [6.5%] had abnormal GLS and LVEF, 2 [3.2%] had abnormal GLS with normal LVEF, and 1 [1.6%] had abnormal LVEF with low normal mean GLS. There were no statistically significant predictors of LV dysfunction in this cohort. CONCLUSION There was a high prevalence of subclinical myocardial dysfunction in the ex-thalassaemic population reiterating the need for close follow up of these patients. 2D Speckle tracking echocardiography-derived LV global longitudinal strain is an effective tool in detecting subclinical myocardial dysfunction in this cohort.
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3.
Lung function after matched-related donor allogeneic hematopoietic stem cell transplantation in children with sickle cell disease
Gros, M., Pondarre, C., Arnaud, C., Kamdem, A., Bernaudin, F., Maitre, B., Epaud, R., Delestrain, C.
American journal of hematology. 2023
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4.
Posterior Reversible Encephalopathy Syndrome in Pediatric Hematopoietic Stem Cell Transplantation with Beta Major Thalassemia: The Association between the PRES Occurrence and Class of Beta Major Thalassemia
Jafari, L., Behfar, M., Tabatabaie, S., Karamlou, Y., Kashani, H., Radmard, A. R., Mohseni, R., Naji, P., Ghanbari, F., Ashkevari, P., et al
Clinical transplantation. 2023;:e15164
Abstract
INTRODUCTION Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive curative option for β-major thalassemia patients (β-MT). Posterior reversible encephalopathy syndrome (PRES) is a pervasive neurological complication which typically occurs following HSCT. β-MT patients are prone to a higher PRES incidence due to long-term immunosuppression; thus, it is imperative that these patients are closely monitored for PRES after HSCT. PATIENTS AND METHODS We included 148 pediatric patients with β-MT who underwent HSCT between March 2015 and August 2022 in Children's Medical Center. Patients in this study were divided into two groups. The association between PRES and class of β-MT and other risk factors were assessed and the overall survival rate was determined. RESULTS Fourteen out of 112 patients (12%) with class I and II β-MT developed PRES. However, PRES occurred in 11 out of 36 patients (30.5%) with β-MT-III. Our results indicated that there was a significant association between class III β-MT and the occurrence of (P = .004). Additionally, acute graft-versus-host disease (aGVHD) occurred in 80% and 44.7% of patients in the PRES and non-PRES groups, respectively (P = .001). The results of the Kaplan-Meier analysis revealed that the 5-year overall survival (OS) was 75.6% in the PRES group versus 95% in the non-PRES group, which was statistically significant (P = .001). CONCLUSION Based on our results, pediatric β-MT III patients are at a higher risk of developing PRES. Additionally, pediatric β-MT patients with a history of aGVHD, regardless of disease class, are more likely to develop PRES. Considering these results, PRES has a higher chance of being the etiology of symptoms and should be considered more often in these patients.
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5.
Effect of serum panel reactive antibodies on allogeneic hematopoietic stem cell transplantation in pediatric thalassemia patients: A single-center experience
Malbora, B., Sarbay, H., Dogusan, Z., Atay, A. A.
Pediatric transplantation. 2023;:e14648
Abstract
BACKGROUND The aim of this study was to assess the impact of serum panel reactive antibodies (PRA) on the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric thalassemia patients. METHODS A total of 73 pediatric patients with thalassemia were included in this single-center study. Pre-transplant PRA levels were evaluated, and the patients were divided into two groups: PRA-negative (group 1; n = 44) and PRA-positive (group 2; n = 29). Patient characteristics, including age, gender, donor type, stem cell source, and HLA compatibility, were analyzed. Transplant outcomes, including engraftment, transfusion requirements, and transplant-related complications, were compared between the two groups. Further subgroup analysis was performed based on MFI values. RESULTS At the time of transplantation, patients in group 1 were younger than those in group 2 (p = .008). The number of fully matched donors within the family (MSD and MFD) was significantly higher in group 1 (p = .049). Additionally, Rh blood group incompatibility was higher in group 2 (p = .03). There was no statistically significant difference in the engraftment days of neutrophils, platelets, and erythrocytes between the two groups. The frequency of poor graft function and graft failure was higher in the group 2, but there was no statistically significant difference. Post-transplant transfusion requirements for platelets and red blood cells were significantly higher in the group 2 (p < .001). Transplant-related complications such as VOD, PRES, and aGvHD were more common in the group 2, but no statistical significance was detected. CONCLUSIONS Serum PRA in pediatric thalassemia patients may impact the outcomes of HSCT. PRA-positive patients had higher rates of blood product transfusion requirements. Although poor graft function, graft failure, and post-transplant complications were more common in the group 2, statistical significance was not observed. Identifying patients with high PRA levels can assist in optimizing transplant strategies and post-transplant care, leading to improved outcomes for the patients.
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6.
Cerebral hemodynamics and oxygenation in adult patients with sickle cell disease after stem cell transplantation
Afzali-Hashemi, L., Dovern, E., Baas, K. P. A., Schrantee, A., Wood, J. C., Nederveen, A. J., Nur, E., Biemond, B. J.
American journal of hematology. 2023
Abstract
Sickle cell disease (SCD) is characterized by chronic hemolytic anemia associated with impaired cerebral hemodynamics and oxygen metabolism. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for patients with SCD. Whereas normalization of hemoglobin levels and hemolysis markers has been reported after HSCT, its effects on cerebral perfusion and oxygenation in adult SCD patients remain largely unexplored. This study investigated the effects of HSCT on cerebral blood flow (CBF), oxygen delivery, cerebrovascular reserve (CVR), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO(2) ) in 17 adult SCD patients (mean age: 25.0 ± 8.0, 6 females) before and after HSCT and 10 healthy ethnicity-matched controls (mean age: 28.0 ± 8.8, 6 females) using MRI. For the CVR assessment, perfusion scans were performed before and after acetazolamide as a vasodilatory stimulus. Following HSCT, gray and white matter (GM and WM) CBF decreased (p < .01), while GM and WM CVR increased (p < .01) compared with the baseline measures. OEF and CMRO(2) also increased towards levels in healthy controls (p < .01). The normalization of cerebral perfusion and oxygen metabolism corresponded with a significant increase in hemoglobin levels and decreases in reticulocytes, total bilirubin, and LDH as markers of hemolysis (p < .01). This study shows that HSCT results in the normalization of cerebral perfusion and oxygen metabolism, even in adult patients with SCD. Future follow-up MRI scans will determine whether the observed normalization of cerebral hemodynamics and oxygen metabolism prevents new silent cerebral infarcts.
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7.
Bone Marrow Quality Index: A predictor of acute GVHD in hematopoietic stem cell transplantation for thalassemia
Agarwal, R. K., Dhanya, R., Sedai, A., Ankita, K., Parmar, L., Ramprakash, Ds Md, Sandeep,, Trivedi, Dd Md, Shah, Dv Md, Bhat, Dn Md, et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Bone marrow continues to be the preferred source of stem cells in allogenic transplantations for non-malignant disorders. Granulocyte-colony stimulating factor (G-CSF)-primed bone marrow (BM) is associated with low rates of acute GVHD and allows reduced collection volumes while ensuring speedy engraftment. However, variability in bone marrow harvest quality is a concern. OBJECTIVE(S): This report analyses the utility of a novel indicator - Bone Marrow Quality Index (BMQI), which is a ratio of marrow cell count to peripheral blood cell counts, to predict acute GVHD. STUDY DESIGN We analysed 184 consecutive first matched related donor bone marrow transplants for thalassemia using G-CSF-primed bone marrow over 6 years from March-2017 to April-2023 across 2 centres in India. Bone Marrow Quality Index (BMQI) was defined as the ratio of WBC count of G-CSF primed bone marrow to Peripheral WBC count within 24 hours of harvest. EBMT criteria were used for grading GVHD. Log-rank test was used to assess the impact of BMQI on GVHD. Chi-squared test was used to compare categorical data and Wilcoxon test was used to compare the numeric data. Cox proportional-hazards model was used to investigate the association of BMQI vis-à-vis other factors on acute GVHD. RESULTS Of the 184 patients, 19 had a BMQI <0.9 and 18 between 0.9 and 1. The remaining 147 had BMQI >1. The proportion of patients with acute GVHD grade II-IV was 37%, 22% and 12% respectively for patients who received BMQI <0.9, 0.9-1 and >1 (p= 0.018). Patients who received BMQI <0.9 had a 3.1 times higher chance (95% CI being 0.9 to 10.6) of developing aGVHD II-IV and in those with BMQI 0.9-1 this was 2 times (95% CI being 0.5 to 6.6) higher. BMQI was the significant predictor associated with GVHD hazard (p=0.014). CONCLUSION BMQI seems to be the most relevant and controllable predictor of acute GVHD. BMQI is a novel, informative, and very simple indicator which could influence GVHD prophylaxis decision-making. Our indicator is accurately measurable, inexpensive, precise, and timely; further it does not involve any sophisticated equipment, thus may be widely applicable. Prior knowledge of poor marrow quality may help intensify prophylaxis and monitoring for acute GVHD besides triggering review of collection procedures.
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8.
Gut microbiota trajectory in β-thalassemia major children who underwent allogeneic hematopoietic stem cell transplantation
Luo, H., Liu, T., Qu, Y., Kuang, C., Xiao, M., Sun, J., Chen, H., Wu, J., Liu, X., Jiang, H.
Transplant infectious disease : an official journal of the Transplantation Society. 2023;:e14111
Abstract
BACKGROUND The gut microbiota of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) changes, leading to complications such as acute graft-versus-host disease (GVHD). This study aimed to evaluate the human microbiota composition before and after HSCT in β-thalassemia major (β-TM) children. METHOD Twenty-two β-TM children who received allo-HSCT between December 2018 and March 2020 were enrolled. They were followed up for more than 100 days after HSCT, and their gut microbiota information and disease data were recorded at five-time points. RESULTS The dominant bacteria were Bacteroidetes and Firmicutes at the phylum level and Lachnospiraceae at the family level before and after HSCT. In the differential analysis, Ruminococcaceae constantly decreased after HSCT. Besides, Rothia mucilaginosa was the most abundant 2 months after HSCT compared to before it. Additionally, GVHD patients presented decreased levels of Bacteroidetes compared to those without GVHD. Moreover, Blautia levels significantly decreased in critically ill GVHD patients. CONCLUSION The gut microbiota of the 22 β-TM children showed a clear trend of destruction and reconstruction within 100 days after HSCT. The extra-oral infections and inflammations of Rothia mucilaginosa, a Gram-positive bacterium of the normal oropharyngeal tract microbiota, might play an important role in the recovery process of HSCT. Finally, decreased Bacteroidetes levels were associated with GVHD onset.
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9.
Magnetic resonance imaging assessment of the changes of cardiac and hepatic iron load in thalassemia patients before and after hematopoietic stem cell transplantation
Xu, F., Li, D., Tang, C., Liang, B., Guan, K., Liu, R., Peng, P.
Scientific reports. 2023;13(1):19652
Abstract
To investigate the value of T(2)(*) technique on 3.0 T magnetic resonance imaging (MRI) in evaluating the changes of cardiac and hepatic iron load before and after hematopoietic stem cell transplantation (HSCT) in patients with thalassemia (TM), the 141 TM patients were divided into 6 group for subgroup analysis: 6, 12, 18, 24 and > 24 months group, according to the postoperative interval. The T(2)(*) values of heart and liver (H-T(2)(*), L-T(2)(*)) were quantified in TM patients before and after HSCT using 3.0 T MRI T(2)(*) technology, and the corresponding serum ferritin (SF) was collected at the same time, and the changes of the three before and after HSCT were compared. The overall H-T(2)(*) (P = 0.001) and L-T(2)(*) (P = 0.041) of patients after HSCT were higher than those before HSCT (mean relative changes = 19.63%, 7.19%). The H-T(2)(*) (P < 0.001) and L-T(2)(*) (P < 0.001) > 24 months after HSCT were significantly higher than those before HSCT (mean relative changes = 69.19%, 93.73%). The SF of 6 months (P < 0.001), 12 months (P = 0.008), 18 months (P = 0.002) and > 24 months (P = 0.001) were significantly higher than those before HSCT (mean relative changes = 57.93%, 73.84%, 128.51%, 85.47%). There was no significant improvement in cardiac and liver iron content in TM patients within 24 months after HSCT, while the reduction of cardiac and liver iron content in patients is obvious when > 24 months after HSCT.
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10.
Immunosuppression Boost With Mycophenolate Mofetil for Mixed Chimerism in Thalassemia Transplants
Mehta, P., Singh, A., Halder, R., Verma, M., Agrawal, N., Ahmed, R., Bhurani, D.
Transplantation and cellular therapy. 2023;29(2):122.e1-122.e6
Abstract
Declining mixed chimerism (MC) portending impending graft failure is an undesirable outcome. However, for hemoglobinopathies in a stable state of MC, residual host cells persist without rejection in 30% to 40% of patients after hematopoietic stem cell transplantation (HSCT). Early detection and level of MC have been attributed to be significant in predicting the outcome of MC. Common clinical approach on MC is removal of immunosuppression. We retrospectively evaluated MC in transfusion dependent thalassemia patients who underwent HSCT in our institution between September 2013 and January 2022 to determine the outcome of MC on the basis of our approach of immunosuppression boost in comparison to conventional approach of immunosuppression tapering. Among 90 patients, 22 (24.4 %) had MC at some time point after transplantation with a median follow-up of 496 (67-1492) days. Immunosuppression withdrawal was done in 12 (54.5%) patients, whereas immunosuppression boost was given in 8 (36.3%) patients. In the immunosuppression withdrawal group, 2 (16.6%) patients evolved to complete chimerism, 5(41.6%) patients had persistent MC (PMC), whereas 5 (41.6%) patients had secondary rejection. All these rejections were at median of 186 (89-251) days after transplantation. In the immunosuppression boost group, all patients (n = 8) had PMC with no secondary rejection until median follow-up of 255(97-812) days after transplantation. We acknowledge that we need more experience with our unconventional approach of immunosuppression boost to obtain statistical significance in comparison to the conventional approach of tapering of immunosuppression.