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Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV+, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4+ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.
Subject(s)
HIV Infections , Hematopoietic Stem Cell Transplantation , Simian Acquired Immunodeficiency Syndrome , Simian Immunodeficiency Virus , Animals , Macaca fascicularis , Viral LoadABSTRACT
Circular mRNA (cmRNA) is particular useful due to its high resistance to degradation by exonucleases, resulting in greater stability and protein expression compared to linear mRNA. T cell receptor (TCR)-engineered T cells (TCR-T) represent a promising means of treating viral infections and cancer. This study aimed to evaluate the feasibility and efficacy of cmRNA in antigen-specific-TCR discovery and TCR-T therapy. Using human cytomegalovirus (CMV) pp65 antigen as a model, we found that the expansion of pp65-responsive T cells was induced more effectively by monocyte-derived dendritic cells transfected with pp65-encoding cmRNA compared with linear mRNA. Subsequently, we developed cmRNA-transduced pp65-TCR-T (cm-pp65-TCR-T) that specifically targets the CMV-pp65 epitope. Our results showed that pp65-TCR could be expressed on primary T cells for more than 7 days. Moreover, both in vitro killing and in vivo CDX models demonstrated that cm-pp65-TCR-T cells specifically and persistently kill pp65-and HLA-expressing tumor cells, significantly prolonging the survival of mice. Collectively, our results demonstrated that cmRNA can be used as a more effective technical approach for antigen-specific TCR isolation and identification, and cm-pp65-TCR-T may provide a safe, non-viral, non-integrated therapeutic approach for controlling CMV infection, particularly in patients who have undergone allogeneic hematopoietic stem cell transplantation.
Subject(s)
Cytomegalovirus Infections , Hematopoietic Stem Cell Transplantation , Humans , Animals , Mice , Cytomegalovirus Infections/genetics , Cytomegalovirus Infections/therapy , Cytomegalovirus/genetics , T-Lymphocytes , Receptors, Antigen, T-Cell/genetics , Viral Matrix Proteins/geneticsABSTRACT
Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, and plasma cytokine levels and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase-deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective, and kidney impairment was not improved in either model.
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BACKGROUND: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterised by lymphoproliferation, dysgammaglobulinaemia, and multi-organ autoimmunity including cytopenias and colitis. OBJECTIVE: To examine the outcome of HSCT for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4-Ig therapy and pre-HSCT immune dysregulation on survival and immunological outcome. METHODS: Retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the Inborn Errors Working Party of EBMT. Primary endpoints were overall survival (OS) and disease- and chronic GvHD-free survival (DFS). Secondary endpoint was immunological outcome assessed by Immune Dysregulation Disease Activity (IDDA) score. RESULTS: Forty patients were included over a 25-year period. Pre-HSCT, 60% received CTLA-4-Ig and IDDA was 23.3 (3.9-84.0). Median age at HSCT was 14.2 (1.3-56.0) years. Patients received PBSC (58%) or marrow (43%) from MUD (75%), MMUD (12.5%) or MFD (12.5%). Median follow-up was 3 years (0.6-15 years) and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, 28/30 surviving patients are in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity pre-HSCT (IDDA<23, p=0.002 and p=0.006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant-related in 7/8 patients. CONCLUSION: This is the largest retrospective study of HSCT for CTLA-4 insufficiency to date. HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity.
ABSTRACT
Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is prevalent after immunotherapy with chimeric antigen receptor-T (CAR-T) and can be manifested with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Our literature review aims to investigate the genetic susceptibility in endothelial injury syndromes after HSCT and CAR-T cell therapy. Variations in complement pathway- and endothelial function-related genes have been associated with the development of HSCT-TMA. In these genes, CFHR5, CFHR1, CFHR3, CFI, ADAMTS13, CFB, C3, C4, C5, and MASP1 are included. Thus, patients with these variations might have a predisposition to complement activation, which is also exaggerated by other factors (such as acute graft-versus-host disease, infections, and calcineurin inhibitors). Few studies have examined the genetic susceptibility to SOS/VOD syndrome, and the implicated genes include CFH, methylenetetrahydrofolate reductase, and heparinase. Finally, specific mutations have been associated with the onset of CRS (PFKFB4, CX3CR1) and ICANS (PPM1D, DNMT3A, TE2, ASXL1). More research is essential in this field to achieve better outcomes for our patients.
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BACKGROUND: Although the prognosis of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) has improved with the introduction of tyrosine kinase inhibitors (TKIs) and stem cell transplantation, prevention of relapse after transplantation remains a concern. The aim of this study was to compare the impact of TKI prophylaxis with imatinib and dasatinib on long-term outcomes after transplantation. METHODS: Patients with Ph+ ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) and received TKI prophylaxis after allo-HSCT were included in this retrospective analysis. Two cohorts were established based on the choice of TKI prophylaxis: the imatinib (Ima) and dasatinib (Das) cohorts. The survival and safety outcomes of these cohorts were compared. RESULTS: Ninety-one patients in the Ima cohort and 50 in the Das cohort were included. After a median follow-up of 50.6 months, the 5-year cumulative incidence of relapse, nonrelapse mortality rate, and overall survival in the Ima and Das cohorts were 16.1% and 12.5%, 5.2% and 9.8%, and 86.5% and 77.6%, respectively, with no statistical differences. The cumulative incidence of mild chronic graft-versus-host disease was higher in the Das cohort. The most common adverse event was neutropenia (64.7% vs. 69.5%). The Das cohort had a higher incidence of gastrointestinal bleeding (25.5% vs. 2.3%) and gastrointestinal reaction (48.9% vs. 31.4%) than the Ima cohort. The proportion of patients treated on schedule was significantly lower in the Das cohort than in the Ima cohort, and drug intolerance was the main reason for protocol violation. CONCLUSIONS: For patients with Ph+ ALL undergoing allo-HSCT in CR1, imatinib prophylaxis achieved long-term outcomes similar to those of dasatinib.
Subject(s)
Dasatinib , Hematopoietic Stem Cell Transplantation , Imatinib Mesylate , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Protein Kinase Inhibitors , Transplantation, Homologous , Humans , Dasatinib/therapeutic use , Dasatinib/adverse effects , Retrospective Studies , Male , Female , Adult , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Hematopoietic Stem Cell Transplantation/adverse effects , Middle Aged , Imatinib Mesylate/therapeutic use , Young Adult , Adolescent , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Treatment Outcome , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Graft vs Host Disease/prevention & control , Graft vs Host Disease/etiologyABSTRACT
Newborn screening (NBS) for severe combined immunodeficiency (SCID) has been introduced in various countries with the aim of reducing morbidity and mortality. However, studies analyzing outcomes before and after the implementation of NBS programs remain limited. This study sought to compare the outcomes of SCID patients identified through Switzerland's national SCID NBS program, introduced in January 2019, with those of a historical cohort diagnosed between 2007 and 2019. The study included seven patients (32%) identified through NBS, and 15 (68%) born before NBS implementation and diagnosed based on clinical signs. Children in the NBS group were younger at diagnosis (median age 9 days vs 9 months, P = .002) and at hematopoietic stem cell transplantation (HSCT, median age 5 months vs 11 months, P = .003) compared to the clinical group. The NBS group had a lower incidence of infections before HSCT (29% vs 93%, P = .004). Although not statistically significant, the overall survival rate on last follow-up was higher in the NBS group (86% vs 67%, P = .62). Importantly, patients with active infections undergoing HSCT had a significantly lower overall survival probability compared to those without (P = .01). In conclusion, the introduction of NBS in Switzerland has led to earlier and often asymptomatic diagnosis of affected children, enabling timely intervention, infection prevention, and prompt treatment. These factors have contributed to higher survival rates in the NBS group. These findings underscore the critical importance of NBS for SCID, offering potential life-saving benefits through early detection and intervention.
Subject(s)
Hematopoietic Stem Cell Transplantation , Severe Combined Immunodeficiency , Child , Infant, Newborn , Humans , Infant , Switzerland/epidemiology , Neonatal Screening , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/epidemiology , Severe Combined Immunodeficiency/therapy , MorbidityABSTRACT
We studied the associations between inflammation-related proteins in circulation and complications after pediatric allogenic hematopoietic stem cell transplantation (HSCT), to reveal proteomic signatures or individual soluble proteins associated with specific complications after HSCT. We used a proteomics method called Proximity Extension Assay to repeatedly measure 180 different proteins together with clinical variables, cellular immune reconstitution and blood viral copy numbers in 27 children (1-18 years of age) during a 2-year follow-up after allogenic HSCT. Protein profile analysis was performed using unsupervised hierarchical clustering and a regression-based method, while the Bonferroni-corrected Mann-Whitney U-test was used for time point-specific comparison of individual proteins against outcome. At 6 months after allogenic HSCT, we could identify a protein profile pattern associated with occurrence of the complications such as chronic graft-versus-host disease, viral infections, relapse and death. When protein markers were analyzed separately, the plasma concentration of the inhibitory and cytotoxic T-cell surface protein FCRL6 (Fc receptor-like 6) was higher in patients with cytomegalovirus (CMV) viremia [log2-fold change 1.5 (P = 0.00099), 2.5 (P = 0.00035) and 2.2 (P = 0.045) at time points 6, 12 and 24 months]. Flow cytometry confirmed that FCRL6 expression was higher in innate-like γδ T cells, indicating that these cells are involved in controlling CMV reactivation in HSCT recipients. In conclusion, the potentially druggable FCRL6 receptor on cytotoxic T cells appears to have a role in controlling CMV viremia after HSCT. Furthermore, our results suggest that system-level analysis is a useful addition to the studying of single biomarkers in allogenic HSCT.
Subject(s)
Cytomegalovirus Infections , Cytomegalovirus , Hematopoietic Stem Cell Transplantation , Proteomics , Transplantation, Homologous , Virus Activation , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Child , Child, Preschool , Proteomics/methods , Cytomegalovirus/immunology , Cytomegalovirus/physiology , Infant , Adolescent , Female , Male , Cytomegalovirus Infections/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , Receptors, Fc/metabolism , BiomarkersABSTRACT
BACKGROUND: The immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is crucial for preventing infections and relapse and enhancing graft-versus-tumor effects. B cells play an important role in humoral immunity and immune regulation, but their reconstitution after allo-HSCT has not been well studied. METHODS: In this study, we analyzed the dynamics of B cells in 252 patients who underwent allo-HSCT for 2 years and assessed the impact of factors on B-cell reconstitution and their correlations with survival outcomes, as well as the development stages of B cells in the bone marrow and the subsets in the peripheral blood. RESULTS: We found that the B-cell reconstitution in the bone marrow was consistent with the peripheral blood (p = 0.232). B-cell reconstitution was delayed by the male gender, age >50, older donor age, the occurrence of chronic and acute graft-versus-host disease, and the infections of fungi and cytomegalovirus. The survival analysis revealed that patients with lower B cells had higher risks of death and relapse. More importantly, we used propensity score matching to obtain the conclusion that post-1-year B-cell reconstitution is better in females. Meanwhile, using mediation analysis, we proposed the age-B cells-survival axis and found that B-cell reconstitution at month 12 posttransplant mediated the effect of age on patient survival (p = 0.013). We also found that younger patients showed more immature B cells in the bone marrow after transplantation (p = 0.037). CONCLUSION: Our findings provide valuable insights for optimizing the management of B-cell reconstitution and improving the efficacy and safety of allo-HSCT.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Female , Humans , Male , Transplantation, Homologous , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Graft vs Host Disease/epidemiology , B-Lymphocytes , RecurrenceABSTRACT
OBJECTIVE: To document the results of outpatient hematopoietic stem cell transplantation (HSCT) from the peripheral blood (PB) of sibling donors without anti-thymocyte globulin (ATG) in the conditioning regimen. MATERIAL AND METHODS: Patients from a low-income population with severe AA who received a PB, unmanipulated sibling HLA-identical HSCT between 2000 and 2020 at a single institution were studied. Survival was the primary outcome. RESULTS: Forty-one transplants were performed. Time between diagnosis and transplant was five months (1-104). Median age was 37 (range, 4-61) years; 25 (61 %) recipients were males and 32 (78 %) had treatment failure, 9 (22 %) have not received treatment. ATG was administered in 5 (12.2 %) cases; the graft source was PB in 38 (92.7 %) transplants. Twenty-six (63.4 %) transplants were carried out in the outpatient setting. Infections developed in 14 (34.1 %) patients. Primary graft failure (GF) occurred in 3 (7.3 %) patients. The 15-year OS was 81 %, EFS was 77.4 %. Patients with high pre-HSCT transfusion burden had lower OS (p = 0.035) and EFS (p = 0.026). Previous treatment failure and age were not associated with lower OS (p = 0.115, p = 0.069) or EFS (p = 0.088, p = 0.5, respectively). CONCLUSIONS: HLA-identical T-cell replete outpatient HSCT from the PB of sibling donors for AA patients using ATG-free conditioning offers excellent long-term survival.
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BACKGROUND: Droplet digital PCR (ddPCR) is widely applied to monitor measurable residual disease (MRD). However, there are limited studies on the feasibility of ddPCR-MRD monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially targeting multiple molecular markers simultaneously. METHODS: Our study collected samples from patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) in complete remission after allo-HSCT between January 2018 and August 2021 to evaluate whether posttransplant ddPCR-MRD monitoring can identify patients at high risk of relapse. RESULTS: Of 152 patients, 58 (38.2%) were MRD positive by ddPCR within 4 months posttransplant, with a median variant allele frequency of 0.198%. The detectable DTA mutations (DNMT3A, TET2, and ASXL1 mutations) after allo-HSCT were not associated with an increased risk of relapse. After excluding DTA mutations, patients with ddPCR-MRD positivity had a significantly higher cumulative incidence of relapse (CIR, 38.7% vs. 9.7%, P < 0.001) and lower rates of relapse-free survival (RFS, 55.5% vs. 83.7%, P < 0.001) and overall survival (OS, 60.5% vs. 90.5%, P < 0.001). In multivariate analysis, ddPCR-MRD positivity of non-DTA genes was an independent adverse predictor for CIR (hazard ratio [HR], 4.02; P < 0.001), RFS (HR, 2.92; P = 0.002) and OS (HR, 3.12; P = 0.007). Moreover, the combination of ddPCR with multiparameter flow cytometry (MFC) can further accurately identify patients at high risk of relapse (F+/M+, HR, 22.44; P < 0.001, F+/M-, HR, 12.46; P < 0.001 and F-/M+, HR, 4.51; P = 0.003). CONCLUSION: ddPCR-MRD is a feasible approach to predict relapse after allo-HSCT in AML/MDS patients with non-DTA genes and is more accurate when combined with MFC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06000306. Registered 17 August 2023 -Retrospectively registered ( https://clinicaltrials.gov/study/NCT06000306?term=NCT06000306&rank=1 ).
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Neoplasm, Residual , Recurrence , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Male , Female , Middle Aged , Adult , Retrospective Studies , Myelodysplastic Syndromes/therapy , Myelodysplastic Syndromes/genetics , Polymerase Chain Reaction , Young Adult , Adolescent , Aged , Mutation/geneticsABSTRACT
AIMS: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for hematological malignancies. However, viral infections, particularly EBV infection, frequently occur following allo-HSCT and can result in multi-tissue and organ damage. Due to the lack of effective antiviral drugs, these infections can even progress to post-transplant lymphoproliferative disorders (PTLD), thereby impacting the prognosis. In light of this, our objective is to develop a prediction model for EBV infection following allo-HSCT. METHODS: A total of 466 patients who underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) between September 2019 and December 2020 were included in this study. The patients were divided into a development cohort and a validation cohort based on the timing of their transplantation. Our aim was to develop and validate a grading scale using these cohorts to predict the risk of EBV infection within the first year after haplo-HSCT. Additionally, single-cell RNA sequencing (sc-RNAseq) data from the bone marrow of healthy donors were utilized to assess the impact of age on immune cells and viral infection. RESULTS: In the multivariate logistic regression model, four predictors were retained: donor age, female-to-male transplant, graft MNC (mononuclear cell) dose, and CD8 dose. Based on these predictors, an EBV reactivation predicting score system was constructed. The scoring system demonstrated good calibration in both the derivation and validation cohorts, as confirmed by the Hosmer-Lemeshow test (p > 0.05). The scoring system also exhibited favorable discriminative ability, as indicated by the C statistics of 0.72 in the derivation cohort and 0.60 in the validation cohort. Furthermore, the clinical efficacy of the scoring system was evaluated using Kaplan-Meier curves based on risk ratings. The results showed significant differences in EBV reactivation rates between different risk groups, with p-values less than 0.001 in both the derivation and validation cohorts, indicating robust clinical utility. The analysis of sc-RNAseq data from the bone marrow of healthy donors revealed that older age had a profound impact on the quantity and quality of immune subsets. Functional enrichment analysis highlighted that older age was associated with a higher risk of infection. Specifically, CD8 + T cells from older individuals showed enrichment in the pathway of "viral carcinogenesis", while older CD14 + monocytes exhibited enrichment in the pathway of "regulation of viral entry into host cell." These findings suggest that older age may contribute to an increased susceptibility to viral infections, as evidenced by the altered immune profiles observed in the sc-RNAseq data. CONCLUSION: Overall, these results demonstrate the development and validation of an effective scoring system for predicting EBV reactivation after haplo-HSCT, and provide insights into the impact of age on immune subsets and viral infection susceptibility based on sc-RNAseq analysis of healthy donors' bone marrow.
Subject(s)
Epstein-Barr Virus Infections , Hematopoietic Stem Cell Transplantation , Humans , Female , Male , Hematopoietic Stem Cell Transplantation/adverse effects , Antiviral Agents , CD8-Positive T-Lymphocytes , CalibrationABSTRACT
Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74- NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.
Subject(s)
Bone Marrow Transplantation , Graft vs Host Disease , Killer Cells, Natural , Transplantation, Homologous , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Animals , Mice , Humans , Bone Marrow Transplantation/adverse effects , Chronic Disease , Male , Female , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Disease Models, Animal , Hematopoietic Stem Cell Transplantation/adverse effects , Mice, Inbred C57BL , Immune Reconstitution , Bronchiolitis Obliterans SyndromeABSTRACT
In this retrospective cohort study of adult stem cell transplanted patients (n = 8463), a significant increased risk of both MOF and hip fractures was seen compared with the Swedish population and occurred in mean more than 2 years after stem cell transplantation. PURPOSE: To explore the risk for osteoporotic fracture in patients who have undergone hematopoietic stem cell transplantation (HSCT) compared with the Swedish population. METHODS: The risk of osteoporotic fractures was determined in a retrospective population cohort study of adult (≥ 18 years) Swedish patients (n = 8463), who were transplanted with HSCT 1997-2016 and compared with all adults living in Sweden during the same period. RESULTS: In the total study group (n = 8463), 90 hip fractures (1.1% both in males and females) and 361 major osteoporotic fractures (MOF) (3.2% in men and 6.0% in women) were identified. In the total study population, the ratio of observed and expected number of hip fracture for women was 1.99 (95% CI 1.39-2.75) and for men 2.54 (95% CI 1.91-3.31). The corresponding ratio for MOF in women was 1.36 (CI 1.18-1.56) and for men 1.61 (CI 1.37-1.88). From 2005 onwards, when differentiation in the registry between allo- and auto-HSCT was possible, the observed number of hip fracture and MOF in allo-HSCT (n = 1865) were significantly increased (observed/expected hip fracture 5.24 (95% CI 3.28-7.93) and observed/expected MOF 2.08 (95% CI 1.63-2.62)). Fractures occurred in mean 2.7 (hip) and 2.5 (MOF) years after allo-HSCT. Graft-versus-host disease (GVHD) was not associated with an increased risk of fracture. CONCLUSION: Patients who underwent HSCT had an increased risk of both hip and major osteoporotic fracture compared with the Swedish population and occurred in 4.3% of patients. GVHD was not statistically significantly associated with fracture risk.
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BACKGROUND: Different prophylactic protocols are available for preventing graft-versus-host disease (GVHD) after matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to compare the effectiveness of post-transplantation cyclophosphamide plus cyclosporine A (PT-CY/CSA) versus methotrexate plus CSA (MTX/CSA) as GVHD prophylaxis protocols in adult acute myeloid leukemia (AML) patients who received peripheral blood stem cells (PBSC) from fully matched donors. METHODS: The 1-year outcomes of 89 patients treated with PT-CY/CSA and 90 patients treated with MTX/CSA who had MSD allo-HCT for AML using unmanipulated mobilized PBSC were examined and compared. RESULTS: The cumulative incidence of acute GVHD at 100 days was considerably lower in the PT-CY/CSA group (4% vs 19.3%, p = 0.002), however there were no statistically significant difference in the cumulative incidence of chronic GVHD at 1-year (19.6% vs 37.4%, p = 0.053). Significant delays in neutrophil and platelet engraftments were reported in the PT-CY/CSA group (17 vs 12 days) and (13 vs 12 days), respectively (p < 0.001). The cumulative incidences of relapse (19.1% vs 13.7%, p = 0.470), overall survival (79.1% vs 77.3%, p = 0.986), non-relapse mortality (16.5% vs 16.8%, p = 0.837), and the GVHD and relapse-free survival (GRFS) (53.7% vs 46.6%, p = 0.478) did not differ statistically at 1-year. CONCLUSION: PT-CY/CSA demonstrated a significant decrease in the rate of acute GVHD. However, it was associated with engraftment delay.
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BACKGROUND AIMS: Cyclosporin A (CsA) remains a major component of immunosuppressive regimens applied in allogeneic hematopoietic stem cell transplantation (HSCT). The impact of CsA trough levels during the first weeks after HSCT has not yet been investigated specifically in anti-T-lymphocyte globulin (ATLG)-based HSCT from matched related and unrelated donors. METHODS: To address this issue, we have retrospectively examined 307 consecutive matched related (n = 145) and unrelated (n = 162) HSCTs, using peripheral blood stem cells or bone marrow. HSCTs for active, uncontrolled malignancies were excluded. The initial three weeks' average mean CsA trough levels were analyzed in landmark and multi-state models, using a cut-off of 200 ng/mL. RESULTS: CsA levels >200 ng/mL were associated with a reduced risk of acute graft-versus-host disease (GVHD) grade 3-4 at the first-week landmark (subdistribution hazard ratio [SHR] 0.59, P = 0.03) and the second-week landmark (SHR 0.48, P = 0.004), whereas there was no impact at the third-week landmark (HR 0.87, P = 0.69). This was supported by a multi-state model, in which week 1 (hazard ratio [HR] 0.53, P = 0.006) and week 2 (HR 0.48, P = 0.003), but not week 3 (HR 0.80, P = 0.44) CsA levels >200 ng/mL were associated with a reduced acute GVHD 3-4 risk. Relapse incidence was not significantly affected by week 1 through 3 CsA levels. Despite ATLG's inherent GVHD-preventive properties, week 1 CsA trough levels >200 ng/mL following ATLG-based HSCT (n = 220) were associated with a significantly reduced risk of non-relapse mortality (SHR 0.52, P = 0.02) and improved overall survival (HR 0.61, P = 0.02). CONCLUSIONS: Our findings emphasize the continuing importance of ensuring CsA levels ≥200 ng/mL immediately post-transplant in the setting of ATLG-based HSCT.
Subject(s)
Cyclosporine , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Transplantation, Homologous , Humans , Cyclosporine/therapeutic use , Graft vs Host Disease/drug therapy , Hematopoietic Stem Cell Transplantation/methods , Male , Female , Middle Aged , Adult , Transplantation, Homologous/methods , Retrospective Studies , Lymphocyte Depletion/methods , T-Lymphocytes/immunology , Immunosuppressive Agents/therapeutic use , Adolescent , Aged , Acute Disease , Young AdultABSTRACT
We studied the incidence of relapse, transformation to myelodysplastic syndrome/acute myeloid leukemia, and survival in patients with aplastic anemia (AA) surviving more than 1 year after ATG/ALG-based immunosuppressive therapy (IST) between 1985 and 2020. Four-hundred seventy patients (413 adults and 57 children) were studied, and data were compared with 223 patients who underwent matched sibling donor transplant (MSD HSCT). Median follow-up is 50 months (12-359). Relapse occurred in 21.9% at a median time of 33.5 months (5-228) post IST. Twenty-six (5.5%) patients progressed to PNH, while 20 (4.3%) evolved to MDS/AML. Ten-year estimated overall survival (OS) is 80.9 ± 3% and was significantly better in patients without an event (85.1 ± 4%) compared to relapse (74.6% ± 6.2%) or clonal evolution (12.8% ± 11.8%) (p = 0.024). While the severity of AA (p = 0.011) and type of ATG (p = 0.028) used predicted relapse, only age at IST administration influenced clonal evolution (p = 0.018). Among HSCT recipients, relapse rates were 4.9% with no clonal evolution, and the 10-year OS was 94.5 ± 2%. In patients who survived 1 year following IST, outcomes were good except with clonal evolution to MDS/AML. These outcomes, however, were still inferior compared to matched sibling donor HSCT.
Subject(s)
Anemia, Aplastic , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Adult , Child , Humans , Graft vs Host Disease/etiology , Retrospective Studies , Hematopoietic Stem Cell Transplantation/adverse effects , Immunosuppression Therapy/adverse effects , Myelodysplastic Syndromes/therapy , Myelodysplastic Syndromes/complications , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/complications , RecurrenceABSTRACT
For patients with acute myeloid leukemia (AML) who are not candidates for allogeneic stem cell transplantation (SCT) or do not have a human leukocyte antigen (HLA)-matched donor, it is unclear whether autologous SCT (ASCT) has a better prognosis after the first complete response (CR1) compared to further chemotherapy treatment. A meta-analysis evaluating ASCT compared to further chemotherapy for AML patients in CR1 was performed. The Medline, Embase, Cochrane Controlled Trials Registry, Cochrane Library, Web of Science, and National Knowledge Infrastructure of China databases were searched for relevant literature as of May 26, 2023. Eligible studies included prospectively enrolled adults with AML and randomized first-time respondent patients who did not have a matched sibling donor. Fourteen randomized controlled trials were identified and included 4281 participants, of which 1499 patients received ASCT and 2782 underwent chemotherapy and continued follow-up. In patients with AML in CR1, a lower relapse rate was associated with ASCT compared to chemotherapy [odds ratio (OR) = 0.49, 95% confidence interval (CI) = 0.41-0.57]. Significant disease-free survival (DFS; OR = 1.37, 95% CI = 1.02-1.84) and relapse-free survival (RFS; OR = 2.78, 95% CI = 1.28-6.02) ASCT benefits were documented, and there was no difference in the overall survival (OS) when the studies were pooled (OR = 1.12, 95% CI = 0.85-1.48). The study results indicated that after the first remission, AML patients receiving autologous stem cell transplantation had higher DFS and RFS, similar OS, and lower relapse compared to patients undergoing chemotherapy treatment. This indicated that autologous stem cell transplantation may have a better prognosis.
ABSTRACT
Natural killer (NK) cells are equipped with anti-Epstein-Barr virus (EBV) function, however, whether EBV infection will affect NK cells reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. To identify the characteristics of NK cells, we prospectively enrolled 11 patients who occurred EBV reactivation post allo-HSCT and 11 patients without EBV infection as control. We found that that EBV infection induced the expansion of CD56bright and NKG2A+KIR- NK subsets,and decreased the cytotoxicity function of NK cells. The frequency of NKG2A+KIR- NK cells were higher in patients who progressed into post-transplant lymphoproliferative disorder (PTLD) than EBV viremia patients, which also correlated with decreased proliferation and cytotoxic function. By screening the activation receptors of NK cells, we found the DNAM-1+CD56bright NK cells is significantly increased after EBV stimulation, further we demonstrated that DNAM-1 is essential for EBV induced NK cells activation as the cytokine release against EBV-transformed lymphoblastoid cell lines(EBV-LCLs) of CD56bright NK cells were significantly decreased after DNAM-1 blockade. NK cells infusion suppressed the progression of EBV-related tumor mice model. A prospective cohort indicated that old donor age was an independent risk factor for EBV infection. Rapid CD56bri expansion and high expression of DNAM-1 on CD56bri NK cells in response to EBV reactivation correlated with rapid EBV clearance post allo-HSCT in patients with younger donors. In summary, our data showed that high expression of DNAM-1 receptors on NK cell may participate protective CD56bri NK cells response to EBV infection after allo-HSCT.
Subject(s)
CD56 Antigen , Epstein-Barr Virus Infections , Hematopoietic Stem Cell Transplantation , Herpesvirus 4, Human , Killer Cells, Natural , Virus Activation , Humans , Killer Cells, Natural/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , CD56 Antigen/metabolism , Epstein-Barr Virus Infections/immunology , Herpesvirus 4, Human/immunology , Female , Male , Adult , Middle Aged , Animals , Mice , Prospective Studies , Adolescent , Young Adult , Transplantation, Homologous/adverse effects , Allografts , Antigens, Differentiation, T-LymphocyteABSTRACT
T lymphoblastic leukemia /lymphoma (T-ALL/LBL) is a rare and highly aggressive neoplasm of lymphoblasts. We evaluated 195 T-ALL/LBL adolescent and adult patients who received ALL-type chemotherapy alone (chemo,n = 72) or in combination with autologous hematopoietic stem cell transplantation(auto-HSCT,n = 23) or allogeneic hematopoietic stem cell transplantation(allo-HSCT,n = 100) from January 2006 to September 2020 in three Chinese medical centers. 167 (85.6%) patients achieved overall response (ORR) with 138 complete response (CR) patients (70.8%) and 29 partial response (PR) patients (14.8%). Until October 1, 2023, no difference was found in 5-year overall survival (5-OS) and 5-year progression free survival(5-PFS) between allo-HSCT and auto-HSCT (5-OS 57.9% vs. 36.7%, P = 0.139, 5-year PFS 49.4% vs. 28.6%, P = 0.078) for patients who achieved CR, for patients who achieved PR, allo-HSCT recipients had higher 5-OS compared with chemo alone recipients (5-OS 23.8% vs. 0, P = 0.042). For patients undergoing allo-HSCT, minimal residual disease (MRD) negative population showed better 5-OS survival compared with MRD positive patients (67.8% vs. 19.6%, p = 0.000). There were no significant differences between early T-cell precursor (ETP), NON-ETP patients with or without expression of one or more myeloid-associated or stem cell-associated (M/S+) markers (NON-ETP with M/S+, NON-ETP without M/S+) groups in allo-HSCT population for 5-OS. (62.9% vs. 54.5% vs.48.4%, P > 0.05). Notch mutations were more common in patients with non-relapsed/refractory disease than relapsed/refractory disease (χ² =4.293, P = 0.038). In conclusion, Allo-HSCT could be an effective consolidation therapy not just for patients with CR, but also for those who achieved PR. The prognosis is significantly improved by obtaining MRD negative prior to allogeneic transplantation.