Umbilical cord blood (UCB) and matched unrelated donors (MUD) are common alternative donor options in children with high-risk acute myeloid leukemia (AML). Emerging evidence suggests an augmented graft-versus-leukemia (GVL) effect of UCB, but uncertainties persist due to the heterogeneity of the hematopoietic cell transplantation (HCT) characteristics in the previous studies. We reviewed 1148 patients aged ≤18 years with AML, who underwent the first HCT between 2008 to 2017, using a publicly available dataset from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry data. Multivariable analyses evaluated predictors of DFS and other clinical outcomes, factoring in graft source, conditioning regimen, patient age, cytogenetic risk, and HCT year (significance at P < .01). Residual disease status was assessed both as a covariate and as a stratifying factor. Additionally, the differential effects of conditioning regimens were analyzed specifically within the UCB cohort. UCB was used most frequently (33.8%) followed by MUD (29.1%), both of which had comparable DFS and overall survival. In patients with minimal residual disease or not in remission prior to HCT, human-leukocyte antigen (HLA) ≤5/8 matched UCB was associated with lower relapse rates than MUD (hazard risk [HR]: 0.25 and 0.29, P = .005 and .006, respectively) but with increased nonrelapse mortality (HR: 32.8 and 7.5, P = .001 and .012, respectively). Conditioning regimens varies by graft type; total body irradiation (TBI)-based regimens, primarily combined with cyclophosphamide and fludarabine, were more common in the UCB cohort (45% in UCB versus 19% in the other grafts, P < .001). Within the 388 patients received UCB, multivariable analysis demonstrated comparable DFS and OS across variable busulfan- and TBI-based regimens, with no trend of superiority for either approach. In conclusion, highly HLA-mismatched UCB reduced relapse in pediatric AML with higher disease burden but increased nonrelapse mortality, resulting in similar DFS to MUD. Improved supportive care and toxicity mitigation may improve the outcomes of UCB transplant. Overall, UCB should be considered a viable alternative graft source with equally favorable outcomes to MUD. Further research is warranted to refine conditioning regimen, including TBI- and busulfan-based strategies, mitigate toxicity, and improve supportive care to optimize UCB HCT outcomes.
{"title":"Umbilical Cord Blood Reduced Relapse but Increased Nonrelapse Mortality Compared to Matched Unrelated Donor Transplantation in Pediatric Acute Myeloid Leukemia With Active Disease: A CIBMTR 2008 to 2017 Analysis of Donor Source and Residual Disease.","authors":"Takuto Takahashi, Franziska Wachter, Francesca Alvarez Calderon, Malika Kapadia, Muna Qayed, Amy K Keating","doi":"10.1016/j.jtct.2025.01.889","DOIUrl":"10.1016/j.jtct.2025.01.889","url":null,"abstract":"<p><p>Umbilical cord blood (UCB) and matched unrelated donors (MUD) are common alternative donor options in children with high-risk acute myeloid leukemia (AML). Emerging evidence suggests an augmented graft-versus-leukemia (GVL) effect of UCB, but uncertainties persist due to the heterogeneity of the hematopoietic cell transplantation (HCT) characteristics in the previous studies. We reviewed 1148 patients aged ≤18 years with AML, who underwent the first HCT between 2008 to 2017, using a publicly available dataset from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry data. Multivariable analyses evaluated predictors of DFS and other clinical outcomes, factoring in graft source, conditioning regimen, patient age, cytogenetic risk, and HCT year (significance at P < .01). Residual disease status was assessed both as a covariate and as a stratifying factor. Additionally, the differential effects of conditioning regimens were analyzed specifically within the UCB cohort. UCB was used most frequently (33.8%) followed by MUD (29.1%), both of which had comparable DFS and overall survival. In patients with minimal residual disease or not in remission prior to HCT, human-leukocyte antigen (HLA) ≤5/8 matched UCB was associated with lower relapse rates than MUD (hazard risk [HR]: 0.25 and 0.29, P = .005 and .006, respectively) but with increased nonrelapse mortality (HR: 32.8 and 7.5, P = .001 and .012, respectively). Conditioning regimens varies by graft type; total body irradiation (TBI)-based regimens, primarily combined with cyclophosphamide and fludarabine, were more common in the UCB cohort (45% in UCB versus 19% in the other grafts, P < .001). Within the 388 patients received UCB, multivariable analysis demonstrated comparable DFS and OS across variable busulfan- and TBI-based regimens, with no trend of superiority for either approach. In conclusion, highly HLA-mismatched UCB reduced relapse in pediatric AML with higher disease burden but increased nonrelapse mortality, resulting in similar DFS to MUD. Improved supportive care and toxicity mitigation may improve the outcomes of UCB transplant. Overall, UCB should be considered a viable alternative graft source with equally favorable outcomes to MUD. Further research is warranted to refine conditioning regimen, including TBI- and busulfan-based strategies, mitigate toxicity, and improve supportive care to optimize UCB HCT outcomes.</p>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143410258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10DOI: 10.1016/j.jtct.2025.02.002
Christopher C Dvorak, William C Temple, Gabriel Salinas Cisneros, Julia Chu, Lena E Winestone, Christine S Higham, Kristin A Shimano, Sandhya Kharbanda, Serine Avagyan, Philip Pauerstein, James N Huang, Geoffrey Cheng, Ella Waters, Beth Apsel Winger, Morton J Cowan, Janel R Long-Boyle
<p><p>Successful allogeneic hematopoietic cell transplantation (HCT) for genetic nonmalignant diseases (NMD) is dependent upon elimination of host hematopoietic stem cells (HSCs) and replacement with donor HSCs in stable numbers sufficient to correct the underlying disease. Donor myeloid chimerism (DMC) in peripheral blood (PB) is a surrogate marker for bone marrow HSC engraftment due to the rapid turnover of PB myeloid cells. Busulfan is commonly used during conditioning for patients with NMD, though its optimal exposure to avoid inadequate DMC is not fully known. Younger patients with NMD have more mixed chimerism compared to older patients when receiving melphalan-based conditioning, possibly due to increased marrow reserve; we hypothesized that a similar phenomenon would occur with busulfan-based conditioning. We performed a retrospective analysis of 105 consecutive patients with NMDs (median age of 3.9 years) undergoing first allogeneic HCT with myeloablative (cAUC ≥55 mg*hr/L) busulfan-based conditioning from 2007 to 2023 and evaluated risk factors for the development of mixed (<95%) and minimal (≤20%) DMC. Receiver operating curve analysis demonstrated that age <2.9 years was the cut-off associated with mixed DMC. The cohort was therefore divided into two age groups: <3 years (43.8% of patients) and ≥3 years; there was no difference in busulfan exposure between the groups. The 3-year cumulative incidence of developing mixed DMC was 20.3% (95% CI, 12.1% to 28.5%). Age was associated with mixed DMC by 3 years post-HCT: 45.2% (95% CI, 29.7% to 60.7%) in those <3 years versus 1.9% (95% CI, 0.1% to 5.4%) in those ≥3 years (P < .001). Busulfan exposure was also associated with mixed DMC: 24.8% (95% CI, 14.8% to 34.8%) in those with cAUC 55 to 74.9 mg*hr/L versus 5% (95% CI, 0.1% to 8.3%) in those with cAUC ≥75 mg*hr/L (P = .03). In patients ≥3 years of age, there was no impact of busulfan exposure on development of mixed DMC. The 3-year cumulative incidence of developing minimal DMC was 5.5% (95% CI, 0.8% to 10.2%). Only young age was significantly associated with minimal DMC by 3 years post-HCT: 12.8% (95% CI, 2.2% to 23.4%) in those <3 years versus 0% (95% CI, 0% to 6.1%) in those ≥3 years (P = .008). There was no impact of age or busulfan exposure on immunologic graft rejection, acute or chronic graft-versus-host-disease, or transplant-related mortality. There was no difference in sinusoidal obstruction syndrome (SOS) incidence based on busulfan exposure: 13.7% (95% CI, 6.3% to 21.1%) for a cAUC of 55 to 74.9 mg*hr/L compared to 20.8% (95% CI, 4.5% to 37.1%) for a cAUC of ≥75 mg*hr/L (P = .33). However, the incidence of SOS was impacted by patient age: 32.9% (95% CI, 19.2% to 46.6%) in patients <3 years compared to 1.7% (95% CI, 0.1% to 5%) in patients ≥3 years (P < .001). Age <3 years at time of HCT is the major risk factor for mixed and minimal DMC in patients with NMD who receive busulfan-based conditioning. Patients ≥3 years of age may no
{"title":"Younger children with nonmalignant disease have increased incidence of mixed myeloid chimerism after allogeneic hematopoietic cell transplantation with busulfan-based conditioning.","authors":"Christopher C Dvorak, William C Temple, Gabriel Salinas Cisneros, Julia Chu, Lena E Winestone, Christine S Higham, Kristin A Shimano, Sandhya Kharbanda, Serine Avagyan, Philip Pauerstein, James N Huang, Geoffrey Cheng, Ella Waters, Beth Apsel Winger, Morton J Cowan, Janel R Long-Boyle","doi":"10.1016/j.jtct.2025.02.002","DOIUrl":"10.1016/j.jtct.2025.02.002","url":null,"abstract":"<p><p>Successful allogeneic hematopoietic cell transplantation (HCT) for genetic nonmalignant diseases (NMD) is dependent upon elimination of host hematopoietic stem cells (HSCs) and replacement with donor HSCs in stable numbers sufficient to correct the underlying disease. Donor myeloid chimerism (DMC) in peripheral blood (PB) is a surrogate marker for bone marrow HSC engraftment due to the rapid turnover of PB myeloid cells. Busulfan is commonly used during conditioning for patients with NMD, though its optimal exposure to avoid inadequate DMC is not fully known. Younger patients with NMD have more mixed chimerism compared to older patients when receiving melphalan-based conditioning, possibly due to increased marrow reserve; we hypothesized that a similar phenomenon would occur with busulfan-based conditioning. We performed a retrospective analysis of 105 consecutive patients with NMDs (median age of 3.9 years) undergoing first allogeneic HCT with myeloablative (cAUC ≥55 mg*hr/L) busulfan-based conditioning from 2007 to 2023 and evaluated risk factors for the development of mixed (<95%) and minimal (≤20%) DMC. Receiver operating curve analysis demonstrated that age <2.9 years was the cut-off associated with mixed DMC. The cohort was therefore divided into two age groups: <3 years (43.8% of patients) and ≥3 years; there was no difference in busulfan exposure between the groups. The 3-year cumulative incidence of developing mixed DMC was 20.3% (95% CI, 12.1% to 28.5%). Age was associated with mixed DMC by 3 years post-HCT: 45.2% (95% CI, 29.7% to 60.7%) in those <3 years versus 1.9% (95% CI, 0.1% to 5.4%) in those ≥3 years (P < .001). Busulfan exposure was also associated with mixed DMC: 24.8% (95% CI, 14.8% to 34.8%) in those with cAUC 55 to 74.9 mg*hr/L versus 5% (95% CI, 0.1% to 8.3%) in those with cAUC ≥75 mg*hr/L (P = .03). In patients ≥3 years of age, there was no impact of busulfan exposure on development of mixed DMC. The 3-year cumulative incidence of developing minimal DMC was 5.5% (95% CI, 0.8% to 10.2%). Only young age was significantly associated with minimal DMC by 3 years post-HCT: 12.8% (95% CI, 2.2% to 23.4%) in those <3 years versus 0% (95% CI, 0% to 6.1%) in those ≥3 years (P = .008). There was no impact of age or busulfan exposure on immunologic graft rejection, acute or chronic graft-versus-host-disease, or transplant-related mortality. There was no difference in sinusoidal obstruction syndrome (SOS) incidence based on busulfan exposure: 13.7% (95% CI, 6.3% to 21.1%) for a cAUC of 55 to 74.9 mg*hr/L compared to 20.8% (95% CI, 4.5% to 37.1%) for a cAUC of ≥75 mg*hr/L (P = .33). However, the incidence of SOS was impacted by patient age: 32.9% (95% CI, 19.2% to 46.6%) in patients <3 years compared to 1.7% (95% CI, 0.1% to 5%) in patients ≥3 years (P < .001). Age <3 years at time of HCT is the major risk factor for mixed and minimal DMC in patients with NMD who receive busulfan-based conditioning. Patients ≥3 years of age may no","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143410457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10DOI: 10.1016/j.jtct.2025.02.005
Nancy Maltez, Mianbo Wang, Georges A Wells, Peter Tugwell, Murray Baron, Zora Marjanovic, Pauline Lansiaux, Dominique Farge, Marie Hudson
Systemic sclerosis (SSc) is a severe, progressive disease with limited treatment options. Autologous hematopoietic stem cell transplantation (AHSCT) has been shown to be an effective treatment for rapidly progressive SSc. The objective of this study was to evaluate the effectiveness of AHSCT for SSc compared to real-world clinical care. SSc patients from France who underwent AHSCT were compared to patients from Canada who met criteria for AHSCT (as defined in the ASTIS trial) but received conventional care. The primary outcome was overall survival. Secondary outcomes included modified Rodnan skin score (mRSS) and forced vital capacity (FVC). Overall survival was estimated by Kaplan-Meier survival curves. Measures of mRSS and FVC were compared using linear regression models. Analyses were adjusted for baseline scores and incorporated stabilized inverse probability of treatment weights to account for confounding by indication. Propensity scores were estimated using logistic regression. Forty-one AHSCT patients and 85 conventional care patients were compared. AHSCT was associated with a suggestive, though not statistically significant trend toward improvement in overall survival (log-rank P = .115). In follow-up, the mRSS was lower with AHSCT compared to conventional care: between group difference of 8.81; P ≤ .0001 at 12 months and 11.28; P = .011 at 60 months. There was no significant difference in FVC between groups at 12 months but at 24 months, AHSCT was associated with a higher FVC (between group difference of 10.53 (P = .05)). This study demonstrates with real-world long-term data that compared with conventional care, treatment with AHSCT may offer superior outcomes for SSc patients.
{"title":"Improvement in Skin Fibrosis and Lung Function with Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis.","authors":"Nancy Maltez, Mianbo Wang, Georges A Wells, Peter Tugwell, Murray Baron, Zora Marjanovic, Pauline Lansiaux, Dominique Farge, Marie Hudson","doi":"10.1016/j.jtct.2025.02.005","DOIUrl":"10.1016/j.jtct.2025.02.005","url":null,"abstract":"<p><p>Systemic sclerosis (SSc) is a severe, progressive disease with limited treatment options. Autologous hematopoietic stem cell transplantation (AHSCT) has been shown to be an effective treatment for rapidly progressive SSc. The objective of this study was to evaluate the effectiveness of AHSCT for SSc compared to real-world clinical care. SSc patients from France who underwent AHSCT were compared to patients from Canada who met criteria for AHSCT (as defined in the ASTIS trial) but received conventional care. The primary outcome was overall survival. Secondary outcomes included modified Rodnan skin score (mRSS) and forced vital capacity (FVC). Overall survival was estimated by Kaplan-Meier survival curves. Measures of mRSS and FVC were compared using linear regression models. Analyses were adjusted for baseline scores and incorporated stabilized inverse probability of treatment weights to account for confounding by indication. Propensity scores were estimated using logistic regression. Forty-one AHSCT patients and 85 conventional care patients were compared. AHSCT was associated with a suggestive, though not statistically significant trend toward improvement in overall survival (log-rank P = .115). In follow-up, the mRSS was lower with AHSCT compared to conventional care: between group difference of 8.81; P ≤ .0001 at 12 months and 11.28; P = .011 at 60 months. There was no significant difference in FVC between groups at 12 months but at 24 months, AHSCT was associated with a higher FVC (between group difference of 10.53 (P = .05)). This study demonstrates with real-world long-term data that compared with conventional care, treatment with AHSCT may offer superior outcomes for SSc patients.</p>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-07DOI: 10.1016/j.jtct.2025.02.004
Najla El Jurdi, Betty K Hamilton, Joseph A Pidala, Lynn Onstad, Christine Mun, Sandeep Jain, Stephanie J Lee
Background: Ocular graft-versus-host disease (oGVHD) is one of the most common initial manifestations of chronic GVHD (cGVHD) leading to significant morbidity and reduced quality of life. Early detection of oGVHD using susceptibility/risk biomarkers is urgently needed to enable preemptive therapy.
Objectives: In this subset analysis of patients enrolled on the CATCH Study (NCT04188912), we tested whether changes in tear film cytokines or ocular symptoms, as assessed by the Lee symptom scale (LSS) eye subscale, can predict oGVHD onset.
Study design: LSS eye subscores, Inflammadry (MMP9) and conjunctival washing samples were collected before hematopoietic cell transplantation (HCT) and every 2 months (mos) until 12 mos. A custom-designed 13-plex human cytokine magnetic bead panel was used to measure: IL-10, IL-17A, IL-1Ra, IL-1α, ELA2, IL-1β, LIGHT/TNFSF14, NGAL, OSM, IL-8, IP-10, TNF-α, and VEGF-A. Cytokine levels at the pre-HCT visit were compared across the groups using the Kruskal-Wallis test. Fold change (FC) of the cytokines, defined as post-HCT value divided by pre-HCT value, was calculated and FC ≥ 2 was used in further analyses. oGVHD diagnosis was based on the NIH diagnostic criteria and having an eye score ≥1. Cox regression models were used to examine the longitudinal relationships between potential predictors and oGVHD development.
Results: Of the 44 patients included, 18 developed oGVHD, 11 had cGVHD without oGVHD, and 15 did not have any cGVHD. Median age was 64.5 years, median time from HCT to cGVHD was 6.4 mos and to oGVHD was 8.3 mos. There were no significant differences in baseline cytokine levels among groups. None of the tear cytokines or the InflammaDry MMP9 test predicted oGVHD onset. Clinically meaningful change in LSS eye score was associated with subsequent oGVHD development when compared to cGVHD without eye involvement (HR 2.5, 95% CI 1.2-5.1, P = .01); and when compared to controls (HR 3.0, 95% CI 1.4-6.0, P = .004) but the PPV of LSS change ≥15 points was low (27.6%), with a higher NPV (89.4%).
Conclusions: This is the first prospective longitudinal study of tear cytokines and symptoms in a cohort of patients observed closely through HCT for development of cGVHD. We were not able to identify any biological susceptibility/risk markers for oGVHD. Patient-reported symptoms as measured by the LSS are associated with oGVHD development but the low PPV and overlap with diagnostic criteria limit its usefulness as a biomarker to guide preemptive treatment studies.
{"title":"Longitudinal Tear Cytokine Biomarkers: An Analysis from the Close Assessment and Testing for Chronic Graft-Versus-Host Disease (CATCH) Protocol.","authors":"Najla El Jurdi, Betty K Hamilton, Joseph A Pidala, Lynn Onstad, Christine Mun, Sandeep Jain, Stephanie J Lee","doi":"10.1016/j.jtct.2025.02.004","DOIUrl":"10.1016/j.jtct.2025.02.004","url":null,"abstract":"<p><strong>Background: </strong>Ocular graft-versus-host disease (oGVHD) is one of the most common initial manifestations of chronic GVHD (cGVHD) leading to significant morbidity and reduced quality of life. Early detection of oGVHD using susceptibility/risk biomarkers is urgently needed to enable preemptive therapy.</p><p><strong>Objectives: </strong>In this subset analysis of patients enrolled on the CATCH Study (NCT04188912), we tested whether changes in tear film cytokines or ocular symptoms, as assessed by the Lee symptom scale (LSS) eye subscale, can predict oGVHD onset.</p><p><strong>Study design: </strong>LSS eye subscores, Inflammadry (MMP9) and conjunctival washing samples were collected before hematopoietic cell transplantation (HCT) and every 2 months (mos) until 12 mos. A custom-designed 13-plex human cytokine magnetic bead panel was used to measure: IL-10, IL-17A, IL-1Ra, IL-1α, ELA2, IL-1β, LIGHT/TNFSF14, NGAL, OSM, IL-8, IP-10, TNF-α, and VEGF-A. Cytokine levels at the pre-HCT visit were compared across the groups using the Kruskal-Wallis test. Fold change (FC) of the cytokines, defined as post-HCT value divided by pre-HCT value, was calculated and FC ≥ 2 was used in further analyses. oGVHD diagnosis was based on the NIH diagnostic criteria and having an eye score ≥1. Cox regression models were used to examine the longitudinal relationships between potential predictors and oGVHD development.</p><p><strong>Results: </strong>Of the 44 patients included, 18 developed oGVHD, 11 had cGVHD without oGVHD, and 15 did not have any cGVHD. Median age was 64.5 years, median time from HCT to cGVHD was 6.4 mos and to oGVHD was 8.3 mos. There were no significant differences in baseline cytokine levels among groups. None of the tear cytokines or the InflammaDry MMP9 test predicted oGVHD onset. Clinically meaningful change in LSS eye score was associated with subsequent oGVHD development when compared to cGVHD without eye involvement (HR 2.5, 95% CI 1.2-5.1, P = .01); and when compared to controls (HR 3.0, 95% CI 1.4-6.0, P = .004) but the PPV of LSS change ≥15 points was low (27.6%), with a higher NPV (89.4%).</p><p><strong>Conclusions: </strong>This is the first prospective longitudinal study of tear cytokines and symptoms in a cohort of patients observed closely through HCT for development of cGVHD. We were not able to identify any biological susceptibility/risk markers for oGVHD. Patient-reported symptoms as measured by the LSS are associated with oGVHD development but the low PPV and overlap with diagnostic criteria limit its usefulness as a biomarker to guide preemptive treatment studies.</p>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-07DOI: 10.1016/j.jtct.2025.02.003
Daniel Drozdov, Xianghua Luo, Rebecca A Marsh, Roshini S Abraham, Christen L Ebens
Background: Allogeneic hematopoietic cell transplantation (HCT) can be curative for many inborn errors of immunity (IEI). Timely neothymopoiesis is paramount to favorable clinical outcomes after HCT. Neothymopoiesis can be quantified by flow cytometric measurement of circulating recent thymic emigrants (RTE; CD31+CD4+CD45RA+ T cells).
Objectives: We hypothesized that decreased RTE would be associated with baseline HCT characteristics of older age at time of HCT and exposure to greater HCT conditioning intensity, as well as with HCT outcomes including mixed (<95%) lymphoid donor chimerism and presence of acute graft-versus-host disease (GvHD).
Study design: In this retrospective analysis two cohorts of pediatric IEI HCT recipients were identified at two centers that collected RTE data following allogeneic HCT. For both cohorts, patient and HCT information was recorded including but not limited to patient age, lymphoid donor chimerism, and occurrence of acute GvHD. Mixed effects models were fitted for the repeated measures of RTE with these covariates and time.
Results: Between 2012 and 2021, a total of 162 pediatric IEI HCT recipients transplanted across both cohorts were eligible for inclusion. Cohort A (n = 34) included 23 males (68%). Median age at HCT was 2.2 years (interquartile range (IQR) 0.8 to 10.8). Eight (23.5%) underwent reduced intensity (RIC), 23 (67.7%) reduced toxicity myeloablative (RTC), and 3 (8.8%) myeloablative (MAC) conditioning. All received alemtuzumab serotherapy. Cohort B (n = 128) included 87 males (68%). Median age at HCT was 1.4 years (IQR 0.7 to 5.3). Seventy-six (59.4%) underwent RIC, 38 (29.7%) RTC, and 14 (10.9%) MAC. RIC and RTC patients received alemtuzumab serotherapy, MAC antithymocyte globulin. In the linear mixed effect model for RTE at 1 year after HCT for Cohort A, significant negative associations included increasing age (P < .0001) and RTC compared to RIC (P < .01). In the linear mixed effects model for RTE at 1 year after HCT for Cohort B, significant negative associations included increasing age (P < .0001), grade 2 to 4 acute GvHD (compared to grade 0 to 1; P < .01), MAC compared to RIC (P < .0001), MAC compared to RTC (P < .01), and RTC compared to RIC (P = .03).
Conclusions: Serial measurement of RTE is a useful assessment of thymic function after HCT. In pediatric patients with IEI, older age at transplantation, greater intensity of conditioning, and occurrence of grade 2 to 4 acute GvHD were strongly associated with slower thymic-derived immune reconstitution. Mixed lymphoid donor chimerism was not associated with RTE in the linear mixed effects model. In addition to augmenting current anticipatory guidance on HCT outcomes, these findings may guide personalization of regimens to optimize clinical outcomes in IEI HCT.
{"title":"Relevance of Recent Thymic Emigrants Following Allogeneic Hematopoietic Cell Transplantation for Pediatric Patients with Inborn Errors of Immunity.","authors":"Daniel Drozdov, Xianghua Luo, Rebecca A Marsh, Roshini S Abraham, Christen L Ebens","doi":"10.1016/j.jtct.2025.02.003","DOIUrl":"10.1016/j.jtct.2025.02.003","url":null,"abstract":"<p><strong>Background: </strong>Allogeneic hematopoietic cell transplantation (HCT) can be curative for many inborn errors of immunity (IEI). Timely neothymopoiesis is paramount to favorable clinical outcomes after HCT. Neothymopoiesis can be quantified by flow cytometric measurement of circulating recent thymic emigrants (RTE; CD31+CD4+CD45RA+ T cells).</p><p><strong>Objectives: </strong>We hypothesized that decreased RTE would be associated with baseline HCT characteristics of older age at time of HCT and exposure to greater HCT conditioning intensity, as well as with HCT outcomes including mixed (<95%) lymphoid donor chimerism and presence of acute graft-versus-host disease (GvHD).</p><p><strong>Study design: </strong>In this retrospective analysis two cohorts of pediatric IEI HCT recipients were identified at two centers that collected RTE data following allogeneic HCT. For both cohorts, patient and HCT information was recorded including but not limited to patient age, lymphoid donor chimerism, and occurrence of acute GvHD. Mixed effects models were fitted for the repeated measures of RTE with these covariates and time.</p><p><strong>Results: </strong>Between 2012 and 2021, a total of 162 pediatric IEI HCT recipients transplanted across both cohorts were eligible for inclusion. Cohort A (n = 34) included 23 males (68%). Median age at HCT was 2.2 years (interquartile range (IQR) 0.8 to 10.8). Eight (23.5%) underwent reduced intensity (RIC), 23 (67.7%) reduced toxicity myeloablative (RTC), and 3 (8.8%) myeloablative (MAC) conditioning. All received alemtuzumab serotherapy. Cohort B (n = 128) included 87 males (68%). Median age at HCT was 1.4 years (IQR 0.7 to 5.3). Seventy-six (59.4%) underwent RIC, 38 (29.7%) RTC, and 14 (10.9%) MAC. RIC and RTC patients received alemtuzumab serotherapy, MAC antithymocyte globulin. In the linear mixed effect model for RTE at 1 year after HCT for Cohort A, significant negative associations included increasing age (P < .0001) and RTC compared to RIC (P < .01). In the linear mixed effects model for RTE at 1 year after HCT for Cohort B, significant negative associations included increasing age (P < .0001), grade 2 to 4 acute GvHD (compared to grade 0 to 1; P < .01), MAC compared to RIC (P < .0001), MAC compared to RTC (P < .01), and RTC compared to RIC (P = .03).</p><p><strong>Conclusions: </strong>Serial measurement of RTE is a useful assessment of thymic function after HCT. In pediatric patients with IEI, older age at transplantation, greater intensity of conditioning, and occurrence of grade 2 to 4 acute GvHD were strongly associated with slower thymic-derived immune reconstitution. Mixed lymphoid donor chimerism was not associated with RTE in the linear mixed effects model. In addition to augmenting current anticipatory guidance on HCT outcomes, these findings may guide personalization of regimens to optimize clinical outcomes in IEI HCT.</p>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-07DOI: 10.1016/j.jtct.2025.01.892
Abby P Douglas, Frederic Lamoth, Teny M John, Andreas H Groll, Terri Lynn Shigle, Genovefa A Papanicolaou, Roy F Chemaly, Paul A Carpenter, Sanjeet S Dadwal, Thomas J Walsh, Dimitrios P Kontoyiannis
The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to create a guideline focusing on non-Aspergillus invasive molds, which are uncommon yet lethal invasive fungal diseases in the peri-hematopoietic cell transplant (HCT) period. We used a compendium-style approach by dissecting this broad, heterogeneous, and highly complex topic into a series of standalone frequently asked questions (FAQs) and tables. Adult and pediatric infectious diseases and HCT content experts developed, then answered FAQs, and finalized topics with harmonized recommendations. All the evidence for non-Aspergillus invasive mold infection is non-RCT and mostly level III, therefore there are no recommendation grades, and instead key references are provided. Through this format, this "8th" topic in the series focuses on the relevant risk factors, diagnostic considerations, prophylaxis, and treatment approaches relevant to rare mold infections in the pre- and post-transplant periods.
{"title":"American Society of Transplantation and Cellular Therapy Series: #8-Management and Prevention of Non-Aspergillus Molds in Hematopoietic Cell Transplantation Recipients.","authors":"Abby P Douglas, Frederic Lamoth, Teny M John, Andreas H Groll, Terri Lynn Shigle, Genovefa A Papanicolaou, Roy F Chemaly, Paul A Carpenter, Sanjeet S Dadwal, Thomas J Walsh, Dimitrios P Kontoyiannis","doi":"10.1016/j.jtct.2025.01.892","DOIUrl":"10.1016/j.jtct.2025.01.892","url":null,"abstract":"<p><p>The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to create a guideline focusing on non-Aspergillus invasive molds, which are uncommon yet lethal invasive fungal diseases in the peri-hematopoietic cell transplant (HCT) period. We used a compendium-style approach by dissecting this broad, heterogeneous, and highly complex topic into a series of standalone frequently asked questions (FAQs) and tables. Adult and pediatric infectious diseases and HCT content experts developed, then answered FAQs, and finalized topics with harmonized recommendations. All the evidence for non-Aspergillus invasive mold infection is non-RCT and mostly level III, therefore there are no recommendation grades, and instead key references are provided. Through this format, this \"8th\" topic in the series focuses on the relevant risk factors, diagnostic considerations, prophylaxis, and treatment approaches relevant to rare mold infections in the pre- and post-transplant periods.</p>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1016/j.jtct.2025.02.001
Mansour Alkhunaizi, Felipe Soto-Lanza, Cheuk Hong Leung, Neel Bhan, Lara Bashoura, Burton F Dickey, Husham Sharifi, Guang-Shing Cheng, Gregory A Yanik, Gabriela Rondon, Rima Saliba, George Chen, Gheath Al-Atrash, Chitra Hosing, Partow Kebriaei, Uday R Popat, Elizabeth J Shpall, Richard E Champlin, Liang Li, Amin M Alousi, Ajay Sheshadri
Introduction: Hematopoietic cell transplantation (HCT) can potentially cure hematologic malignancies, but despite advancements in HCT regimens and graft-versus-host disease (GVHD) management, post-HCT complications, remain a major challenge. The epidemiology of post-HCT pulmonary impairment causing restrictive ventilatory defect (RVD) has not been examined. This study investigates the incidence, etiology, and impact of new-onset RVD following HCT on overall survival (OS) and non-relapse mortality (NRM).
Methods: We conducted a retrospective review of adult patients who underwent their first allogeneic HCT for primary hematologic malignancies at The University of Texas MD Anderson Cancer Center between February 1999 and March 2018. RVD was defined by a total lung capacity (TLC) <5th percentile of the lower limit of normal. Patient data were analyzed using the Kaplan-Meier method, log-rank tests, and Cox regression models.
Results: Among 3030 patients, 50 had pre-HCT RVD and 1275 developed new pulmonary impairment post-HCT, of which, we found 270 cases of new-onset RVD. The most common causes of post-HCT RVD were respiratory tract infections (23%), interstitial lung disease (15%) and truncal sclerosis (11%). Multivariate analysis indicated increased age (HR 1.03 per year, 95% CI 1.03-1.04, P < .001), matched unrelated donor transplant (HR 1.29, 95% CI 1.04-1.60, P = .02), mismatched related transplant (HR 2.04, 95% CI 1.33-3.14, P = .001), cord blood stem cell source (HR 3.02, 95% CI 2.26-4.05, P < .001), RVD (HR 2.27, 95% CI 1.77-2.90, P < .001) and cGVHD (HR 1.72, 95% CI 1.44-2.05, P < .001) were associated with higher mortality. More severe restriction (HR 4.04, 95% CI 2.83-5.77, P < .001), progressive RVD (5.04, 95% CI 1.88-13.52, P = .001), and RVD onset within 1 year of HCT (HR 2.61, 95% CI 1.72-3.98, P < .001) were associated with higher mortality.
Conclusion: New-onset RVD post-HCT is associated with increased mortality. These findings emphasize the importance of identifying RVD through proactive pulmonary function monitoring to improve post-HCT outcomes.
{"title":"Restrictive Ventilatory Defects Following Hematopoietic Stem Cell Transplant Are Associated With Increased Mortality.","authors":"Mansour Alkhunaizi, Felipe Soto-Lanza, Cheuk Hong Leung, Neel Bhan, Lara Bashoura, Burton F Dickey, Husham Sharifi, Guang-Shing Cheng, Gregory A Yanik, Gabriela Rondon, Rima Saliba, George Chen, Gheath Al-Atrash, Chitra Hosing, Partow Kebriaei, Uday R Popat, Elizabeth J Shpall, Richard E Champlin, Liang Li, Amin M Alousi, Ajay Sheshadri","doi":"10.1016/j.jtct.2025.02.001","DOIUrl":"10.1016/j.jtct.2025.02.001","url":null,"abstract":"<p><strong>Introduction: </strong>Hematopoietic cell transplantation (HCT) can potentially cure hematologic malignancies, but despite advancements in HCT regimens and graft-versus-host disease (GVHD) management, post-HCT complications, remain a major challenge. The epidemiology of post-HCT pulmonary impairment causing restrictive ventilatory defect (RVD) has not been examined. This study investigates the incidence, etiology, and impact of new-onset RVD following HCT on overall survival (OS) and non-relapse mortality (NRM).</p><p><strong>Methods: </strong>We conducted a retrospective review of adult patients who underwent their first allogeneic HCT for primary hematologic malignancies at The University of Texas MD Anderson Cancer Center between February 1999 and March 2018. RVD was defined by a total lung capacity (TLC) <5th percentile of the lower limit of normal. Patient data were analyzed using the Kaplan-Meier method, log-rank tests, and Cox regression models.</p><p><strong>Results: </strong>Among 3030 patients, 50 had pre-HCT RVD and 1275 developed new pulmonary impairment post-HCT, of which, we found 270 cases of new-onset RVD. The most common causes of post-HCT RVD were respiratory tract infections (23%), interstitial lung disease (15%) and truncal sclerosis (11%). Multivariate analysis indicated increased age (HR 1.03 per year, 95% CI 1.03-1.04, P < .001), matched unrelated donor transplant (HR 1.29, 95% CI 1.04-1.60, P = .02), mismatched related transplant (HR 2.04, 95% CI 1.33-3.14, P = .001), cord blood stem cell source (HR 3.02, 95% CI 2.26-4.05, P < .001), RVD (HR 2.27, 95% CI 1.77-2.90, P < .001) and cGVHD (HR 1.72, 95% CI 1.44-2.05, P < .001) were associated with higher mortality. More severe restriction (HR 4.04, 95% CI 2.83-5.77, P < .001), progressive RVD (5.04, 95% CI 1.88-13.52, P = .001), and RVD onset within 1 year of HCT (HR 2.61, 95% CI 1.72-3.98, P < .001) were associated with higher mortality.</p><p><strong>Conclusion: </strong>New-onset RVD post-HCT is associated with increased mortality. These findings emphasize the importance of identifying RVD through proactive pulmonary function monitoring to improve post-HCT outcomes.</p>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1016/j.jtct.2025.01.894
Hannah Walker, Lorna McLeman, Deborah Meyran, Li-Yin Goh, Peter Summers, Julian Stopler, Diane Hanna, David Hughes, Stacie Wang, Claudia Toro, Elizabeth Williams, Roxanne Dyas, Lori Chait Rubinek, Kaitlyn Taylor, Chris J Selman, Anneke Grobler, Katherine J Lee, Tom Snelling, Theresa Cole, Amanda Gwee, Rachel Conyers
An adaptive platform trial (APT) offers the ability to incorporate several research questions in the same target population across multiple domains (interventions), with the ability to add new questions in a perpetual manner. An APT is particularly appealing for pediatric hematopoietic stem cell transplant (HCT); an area of high heterogeneity, limited trial availability, and high mortality. Ideally, all domains in an APT would have the same primary endpoint. Therefore, an ordinal endpoint with multiple categories that combines various clinical outcomes into a single outcome measure is particularly appealing for APTs. Unfortunately, there is no accepted ordinal endpoint for pediatric HCT trials. This article aims to describe the methodology used to co-design a novel primary ordinal endpoint for the pediatric HCT APT - BANDICOOT. BANDICOOT is a study that aims to build an adaptive novel platform design - improving the complications, cost-effectiveness, outcomes, and overall survival from hematopoietic stem cell transplantation.The results of this process identified two potential ordinal endpoints that could be used, one focusing on organ support and the other on a combination of organ support, viral reactivation, and immune reconstitution. We explored the data extraction required for these endpoints from electronic medical records that we will utilize to validate the endpoints and determine which will be used in the APT BANDICOOT. In an era in which APTs are becoming increasingly utilized to answer important questions in clinical care, this article describes a reproducible strategy for the design of high-quality and meaningful ordinal endpoints.
{"title":"Co-designing a Novel Ordinal Endpoint for an Adaptive Platform Trial, BANDICOOT, in Pediatric Hematopoietic Stem Cell Transplant.","authors":"Hannah Walker, Lorna McLeman, Deborah Meyran, Li-Yin Goh, Peter Summers, Julian Stopler, Diane Hanna, David Hughes, Stacie Wang, Claudia Toro, Elizabeth Williams, Roxanne Dyas, Lori Chait Rubinek, Kaitlyn Taylor, Chris J Selman, Anneke Grobler, Katherine J Lee, Tom Snelling, Theresa Cole, Amanda Gwee, Rachel Conyers","doi":"10.1016/j.jtct.2025.01.894","DOIUrl":"10.1016/j.jtct.2025.01.894","url":null,"abstract":"<p><p>An adaptive platform trial (APT) offers the ability to incorporate several research questions in the same target population across multiple domains (interventions), with the ability to add new questions in a perpetual manner. An APT is particularly appealing for pediatric hematopoietic stem cell transplant (HCT); an area of high heterogeneity, limited trial availability, and high mortality. Ideally, all domains in an APT would have the same primary endpoint. Therefore, an ordinal endpoint with multiple categories that combines various clinical outcomes into a single outcome measure is particularly appealing for APTs. Unfortunately, there is no accepted ordinal endpoint for pediatric HCT trials. This article aims to describe the methodology used to co-design a novel primary ordinal endpoint for the pediatric HCT APT - BANDICOOT. BANDICOOT is a study that aims to build an adaptive novel platform design - improving the complications, cost-effectiveness, outcomes, and overall survival from hematopoietic stem cell transplantation.The results of this process identified two potential ordinal endpoints that could be used, one focusing on organ support and the other on a combination of organ support, viral reactivation, and immune reconstitution. We explored the data extraction required for these endpoints from electronic medical records that we will utilize to validate the endpoints and determine which will be used in the APT BANDICOOT. In an era in which APTs are becoming increasingly utilized to answer important questions in clinical care, this article describes a reproducible strategy for the design of high-quality and meaningful ordinal endpoints.</p>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-04DOI: 10.1016/j.jtct.2025.01.893
Daniel Drozdov, Jessica Kandil, Susie E Long, Connor Demorest, Qing Cao, Troy C Lund, Ashish O Gupta, Jaap Jan Boelens, Paul J Orchard
Background: Rabbit anti-thymocyte globulin (rATG) decreases the risk of graft failure and graft-versus-host disease (GVHD) in a setting of allogenic hematopoietic cell transplantation (HCT) but has highly variable pharmacokinetics. Recently, it was shown that a dosing nomogram based on recipient bodyweight and absolute lymphocyte count reduced rATG overexposure, which led to faster immune reconstitution. The aim of this study is to evaluate the feasibility and benefits of using an rATG dosing nomogram to achieve early CD4+ immune reconstitution in pediatric patients with inborn errors of metabolism (IEM) undergoing umbilical cord blood transplantation.
Methods: The rATG dosing nomogram in pediatric patients with IEM receiving an umbilical cord blood transplant with busulfan-based myeloablative conditioning at the University of Minnesota Masonic Children's Hospital was used prospectively since 2017. The primary endpoint was CD4+ immune reconstitution (>50 CD4+ T-cells/mL) within 100 days after HCT. Secondary endpoints included overall survival, graft failure, acute and chronic GVHD, and viral reactivations.
Results: A total of 27 patients were included in the study. Median follow-up time was 31 months (interquartile range [IQR], 22-38) and median age was 1.5 years (IQR, 0.7-3.9). The underlying disease was Hurler syndrome in 17 (63%), Hunter syndrome in 4 (15%), and cerebral adrenoleukodystrophy in 4 (15%) patients; 2 patients were transplanted for other IEM. The CD4+ recovery (>50 CD4+ T cells/mL) at 100 days post-HCT was reached in 22 (85%) of 26 patients. Overall survival was 83% (95% confidence interval [CI], 67%-100%). No graft failure was observed. Two (7%) patients developed acute GVHD grade II to IV and no patients had chronic GVHD. Six patients (22%) had cytomegalovirus (CMV) viremia. One patient had Epstein-Barr virus reactivation requiring treatment.
Conclusion: In patients with IEM, individualized dosing of rATG was associated with a robust and early CD4+ immune reconstitution, with no graft failures and low GVHD incidence.
{"title":"Bodyweight and Absolute Lymphocyte Count-Based Dosing of Rabbit Anti-thymocyte Globulin Results in Early CD4<sup>+</sup> Immune Reconstitution in Patients with Inborn Errors of Metabolism Undergoing Umbilical Cord Blood Transplantation.","authors":"Daniel Drozdov, Jessica Kandil, Susie E Long, Connor Demorest, Qing Cao, Troy C Lund, Ashish O Gupta, Jaap Jan Boelens, Paul J Orchard","doi":"10.1016/j.jtct.2025.01.893","DOIUrl":"10.1016/j.jtct.2025.01.893","url":null,"abstract":"<p><strong>Background: </strong>Rabbit anti-thymocyte globulin (rATG) decreases the risk of graft failure and graft-versus-host disease (GVHD) in a setting of allogenic hematopoietic cell transplantation (HCT) but has highly variable pharmacokinetics. Recently, it was shown that a dosing nomogram based on recipient bodyweight and absolute lymphocyte count reduced rATG overexposure, which led to faster immune reconstitution. The aim of this study is to evaluate the feasibility and benefits of using an rATG dosing nomogram to achieve early CD4<sup>+</sup> immune reconstitution in pediatric patients with inborn errors of metabolism (IEM) undergoing umbilical cord blood transplantation.</p><p><strong>Methods: </strong>The rATG dosing nomogram in pediatric patients with IEM receiving an umbilical cord blood transplant with busulfan-based myeloablative conditioning at the University of Minnesota Masonic Children's Hospital was used prospectively since 2017. The primary endpoint was CD4<sup>+</sup> immune reconstitution (>50 CD4<sup>+</sup> T-cells/mL) within 100 days after HCT. Secondary endpoints included overall survival, graft failure, acute and chronic GVHD, and viral reactivations.</p><p><strong>Results: </strong>A total of 27 patients were included in the study. Median follow-up time was 31 months (interquartile range [IQR], 22-38) and median age was 1.5 years (IQR, 0.7-3.9). The underlying disease was Hurler syndrome in 17 (63%), Hunter syndrome in 4 (15%), and cerebral adrenoleukodystrophy in 4 (15%) patients; 2 patients were transplanted for other IEM. The CD4<sup>+</sup> recovery (>50 CD4<sup>+</sup> T cells/mL) at 100 days post-HCT was reached in 22 (85%) of 26 patients. Overall survival was 83% (95% confidence interval [CI], 67%-100%). No graft failure was observed. Two (7%) patients developed acute GVHD grade II to IV and no patients had chronic GVHD. Six patients (22%) had cytomegalovirus (CMV) viremia. One patient had Epstein-Barr virus reactivation requiring treatment.</p><p><strong>Conclusion: </strong>In patients with IEM, individualized dosing of rATG was associated with a robust and early CD4<sup>+</sup> immune reconstitution, with no graft failures and low GVHD incidence.</p>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.jtct.2024.12.001
Hongwen Xiao , Qiulin Huang , Yongrong Lai , Rongrong Liu
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) presents a promising therapeutic option for pediatric transfusion-dependent thalassemia, particularly in the scarcity of matched donors. Despite its potential, the comprehensive evaluation of this method through large-scale prospective studies remains lacking. This study aims to systematically summarize the efficacy and safety of haplo-HSCT in thalassemia, thereby providing further evidence-based insights for clinical practice. A comprehensive literature search was conducted across PubMed, Embase, and Web of Science databases through June 2024 to ensure a robust analysis of the available evidence. Data extraction was independently performed by 2 reviewers. The analysis utilized the inverse variance method with a 95% confidence interval (95% CI) to calculate the pooled proportion. To assess the heterogeneity among the studies, Cochran's Q test and Higgins' I-squared statistical methods were utilized. A random-effects model was employed to accommodate the variability between study results. Furthermore, subgroup analyses were explored differences in outcomes based on conditioning regimens and graft versus host disease (GVHD) prophylaxis. Conditioning regimens were categorized into reduced-intensity conditioning and myeloablative conditioning regimens. GVHD prophylaxis was classified into post-transplantation cyclophosphamide and non-post-transplantation cyclophosphamide. In this meta-analysis, we reviewed data from 10 studies encompassing 356 patients with thalassemia who underwent haplo-HSCT. Out of these, 328 patients survived until the follow-up date, resulting in a pooled overall survival rate of 92.4% (95% CI, 86.9-96.7; I² = 54.32%). The thalassemia-free survival was 84.5% (95% CI, 75.3-91.9; I² = 77.64%), and the graft failure rate was 8.1% (95% CI, 2.5-16.4; I² = 81.78%). The transplantation-related mortality stood at 7.4% (95% CI, 3.6-12.5; I² = 55.74%), with infections noted as the primary cause of death. The pooled proportion of acute graft versus host disease (aGVHD), grade 2-4 aGVHD, and grade 3-4 aGVHD were 29.6% (95% CI, 16.7-42.5, I² = 92.48%), 22.3% (95% CI, 10.1-42.1, I² = 80.06%), and 9.1% (95% CI, 2.8-17.7, I² = 67.92%), respectively. Subgroup analyses revealed no significant differences in these outcomes when comparing myeloablative conditioning to reduced-intensity conditioning, or post-transplantation cyclophosphamide to non-post-transplantation cyclophosphamide prophylaxis. However, variations in sample size, patient's age and geographic region among the studies suggest these factors as potential sources of heterogeneity.
Haploidentical hematopoietic stem cell transplantation utilizes donors who are partially HLA-matched, typically family members, making it a viable option for transfusion-dependent thalassemia when fully matched donors are not available.
{"title":"Haploidentical Hematopoietic Stem Cell Transplantation in Pediatric Transfusion-Dependent Thalassemia: A Systematic Review and Meta-Analysis","authors":"Hongwen Xiao , Qiulin Huang , Yongrong Lai , Rongrong Liu","doi":"10.1016/j.jtct.2024.12.001","DOIUrl":"10.1016/j.jtct.2024.12.001","url":null,"abstract":"<div><div>Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) presents a promising therapeutic option for pediatric transfusion-dependent thalassemia, particularly in the scarcity of matched donors. Despite its potential, the comprehensive evaluation of this method through large-scale prospective studies remains lacking. This study aims to systematically summarize the efficacy and safety of haplo-HSCT in thalassemia, thereby providing further evidence-based insights for clinical practice. A comprehensive literature search was conducted across PubMed, Embase, and Web of Science databases through June 2024 to ensure a robust analysis of the available evidence. Data extraction was independently performed by 2 reviewers. The analysis utilized the inverse variance method with a 95% confidence interval (95% CI) to calculate the pooled proportion. To assess the heterogeneity among the studies, Cochran's Q test and Higgins' I-squared statistical methods were utilized. A random-effects model was employed to accommodate the variability between study results. Furthermore, subgroup analyses were explored differences in outcomes based on conditioning regimens and graft versus host disease (GVHD) prophylaxis. Conditioning regimens were categorized into reduced-intensity conditioning and myeloablative conditioning regimens. GVHD prophylaxis was classified into post-transplantation cyclophosphamide and non-post-transplantation cyclophosphamide. In this meta-analysis, we reviewed data from 10 studies encompassing 356 patients with thalassemia who underwent haplo-HSCT. Out of these, 328 patients survived until the follow-up date, resulting in a pooled overall survival rate of 92.4% (95% CI, 86.9-96.7; I² = 54.32%). The thalassemia-free survival was 84.5% (95% CI, 75.3-91.9; I² = 77.64%), and the graft failure rate was 8.1% (95% CI, 2.5-16.4; I² = 81.78%). The transplantation-related mortality stood at 7.4% (95% CI, 3.6-12.5; I² = 55.74%), with infections noted as the primary cause of death. The pooled proportion of acute graft versus host disease (aGVHD), grade 2-4 aGVHD, and grade 3-4 aGVHD were 29.6% (95% CI, 16.7-42.5, <em>I²</em> = 92.48%), 22.3% (95% CI, 10.1-42.1, <em>I²</em> = 80.06%), and 9.1% (95% CI, 2.8-17.7, <em>I²</em> = 67.92%), respectively. Subgroup analyses revealed no significant differences in these outcomes when comparing myeloablative conditioning to reduced-intensity conditioning, or post-transplantation cyclophosphamide to non-post-transplantation cyclophosphamide prophylaxis. However, variations in sample size, patient's age and geographic region among the studies suggest these factors as potential sources of heterogeneity.</div><div>Haploidentical hematopoietic stem cell transplantation utilizes donors who are partially HLA-matched, typically family members, making it a viable option for transfusion-dependent thalassemia when fully matched donors are not available.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Pages 101.e1-101.e12"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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