Incidence Of II-IV Acute Graft-versus-host Disease Research Articles

Association between Haploidentical Hematopoietic Stem Cell Transplantation Combined with an Umbilical Cord Blood Unit and Graft-Versus-Host Disease in Pediatric Patients with Acquired Severe Aplastic Anemia

Introduction: Haploidentical hematopoietic stem cell transplantation (haplo HSCT) based on granulocyte colony-stimulating factor plus anti-thymocyte regimens ("Beijing Protocol") provides a salvage treatment for patients of acquired severe aplastic anemia (SAA) in China. However, graft-versus-host disease (GVHD) is a major impediment of haplo HSCT due to HLA disparity. Human umbilical cord blood (UCB) is characterized by lower numbers of mature or primed T-cells. Additionally, UCB has been reported to be a rich and rapidly accessible source of regulatory T cells (Tregs) and mesenchymal stromal cells (MSCs). These characteristics of UCB make it a potential prophylactic method for GVHD. Recently, haplo HSCT combined with umbilical cord blood (UCB) (haplo-cord HSCT) is performed in clinical trials to potentially reduce the risk of severe GVHD. Nevertheless, studies comparing GVHD in pediatric patients receiving haplo and haplo-cord HSCT for SAA are limited. Herein, we aim to investigate the impact of UCB co-infusion on GVHD in pediatric patients receiving haplo HSCT for SAA. Methods: Data from 91 consecutive children with SAA treated with "Beijing Protocol"-based haploidentical transplantation with or without co-infusion of UCB between April 2015 and July 2021 in the Children's Hospital of Soochow University were retrospectively analyzed. The cohort included 35 patients in the haplo group and 56 patients in the haplo-cord group. All patients received uniform non-myeloablative conditioning, GVHD prophylaxis. We compared baseline characteristics and transplant outcomes between the haplo and haplo-cord recipients. Log-rank test and Cox proportional regression model were used for univariate and multivariate analysis, respectively. A significance level of 0.05 was used for all analyses. Results: No significant differences in the baseline information were observed between haplo and haplo-cord groups. All 91 patients achieved hematopoietic recovery from haploidentical donors, with a higher 30-day cumulative incidence of platelet engraftment observed with haplo group as compared to haplo-cord group (98.2% versus 97.1%, p = 0.028). Cox regression analysis revealed that the haplo or haplo-cord transplant type was not associated with the time to platelet engraftment, while a low CD34+ cell dose in haploidentical grafts was correlated with delayed platelet recovery (hazard ratio (HR), 2.495; 95% confidence interval (CI), 1.570-3.964; p < 0.001). The haplo-cord group showed a higher incidence of peri-engraftment syndrome compared to the haplo group (75.0% versus 48.6%, p = 0.029), and Cox regression analysis identified haplo-cord HSCT as the only significant factor associated with a higher incidence of peri-ES (HR, 1.767; 95% CI, 1.002-3.115; p = 0.049). Of note, the haplo-cord group showed a lower incidence of II-IV acute GVHD (aGVHD) than the haplo group (16.1% versus 42.9%, p = 0.002). Observed incidences of chronic GVHD (cGVHD) and moderate to severe cGVHD in the haplo-cord group were also lower than that in the haplo group (25.6% versus 51.3%, p = 0.019; 16.2% versus 41.3%, p = 0.016, respectively). Haplo-cord HSCT was identified as the only factor associated with a lower incidence of II-IV aGVHD (HR, 0.335; 95% CI, 0.143-0.784; p = 0.012) and cGVHD (HR, 0.429; 95% CI, 0.203-0.907; p = 0.027) in Cox regression analysis. No differences were observed between the two groups in CMV, EBV infection, overall survival, failure-free survival and GVHD, failure-free survival. Conclusions: Our study provided compelling results of descriptive analysis suggesting that co-infusion of a third-party UCB unit with haplo HSCT might be associated with a lower risk of II-IV aGVHD and cGVHD. Although this co-infusion protocol may come with a higher risk of peri-ES, the survival outcomes may not be negatively affected. Despite the limited sample size, this study is the first real-world comparative study to investigate the impact of haplo-cord HSCT on GVHD in SAA children, which may stimulate further research of haplo-cord HSCT in pediatric patients with SAA and hematologic malignancies, as well as the potential association with GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A study of human leukocyte antigen-haploidentical hematopoietic stem cells transplantation combined with allogenic mesenchymal stem cell infusion for treatment of severe aplastic anemia in pediatric and adolescent patients.

The clinical applications of human leukocyte antigen (HLA) haploidentical hematopoietic stem cells transplantation (haplo‐HSCT) have offered most of the young severe aplastic anemia (SAA) patients an opportunity to accept curative therapy at the early stage of bone marrow lesions. However, the outcome of juvenile SAA patients received haplo‐HSCT remain to be improved due to high incidence of graft failure and graft vs host disease (GVHD). Mesenchymal stem cells (MSCs) have been characterized by their hematopoiesis‐supporting and immunomodulatory properties. In the current study, we designed a combination of haplo‐HSCT with allogenic MSC for treatment of SAA in pediatric and adolescent patients and evaluated its effects. Juvenile patients (<18 years) with SAA (n = 103) were given HLA‐haploidentical HSC combined with allogenic MSC after a conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin and an intensive GVHD prophylaxis, including cyclosporine, short‐term methotrexate, mycophenolate mofetil, and basiliximab. Neutrophil engraftment was achieved in 102 of 103 patients in a median time of 14.3 days (range 9‐25 days). The median time of platelet engraftment was 25.42 days (range 8‐93 days). The cumulative incidence of II‐IV acute GVHD at day +100 was 26.32% ± 0.19% and III‐IV acute GVHD was 6.79% ± 0.06% at day +100, respectively. The cumulative incidence of chronic GVHD was 25.56% ± 0.26%. The overall survival was 87.15% ± 3.3% at a median follow‐up of 40 (1.3‐98) months. Our data suggest that cotransplantation of HLA‐haploidentical HSC and allogenic mesenchymal stem cell may provide an effective and safe treatment for children and adolescents with SAA who lack matched donors.

Patients Lacking a KIR-Ligand of HLA Group C1 or C2 Have a Lower Incidence of Grades II-IV Acute Graft-Vs-Host Disease after Umbilical Cord Blood Transplantation

Introduction: Natural killer (NK) cells are important part of the innate immunity defense system and play an antiviral, anti-tumor and immunomodulatory role in the body's immune response. NK cells are the first lymphocytes recovered after umbilical cord blood transplantation (UCBT). By attacking on the host cell, leukemia cells and antigen-presenting cells, the allogeneic reactive NK cells help realize successful implantation, mediate Graft-versus-leukemia (GVL) to reduce the recurrence, and lower the incidence of graft versus host disease (GVHD) respectively, thereby improving overall survival (OS) ultimately. The effect is based on the interaction of killer-cell immunoglobulin-like receptors (KIR) of donor NK cells with ligands of the major histocompatibility complex found on the surface of the target cells. HLA-C1 subtypes provide the ligand for KIR2DL2 and KIR2DL3, and the HLA-C2 subtypes for KIR2DL1. Therefore, we want to study the impact of the killer cell immunoglobulin like receptor/human leukocyte antigen(KIR/HLA) receptor ligand model in UCBT Method: Between July 2012 and June 2018, 270 patients with malignant hematologic disease receiving single-unit UCBT were divided into two groups based on the absence or the presence of one of the C-ligands for inhibitory KIR. Group 1 (n=174) patients lacked a C-ligand for inhibitory KIR present on UCB NK cells, (patients homozygous C1/C1 or C2/C2). Group 2 (n=96) patients had heterozygous C1/C2 in which KIR-mediated GVL effect was not expected (presence of both C ligands for inhibitory KIR in the receptor). Group 1 (mean age 13y, r 1-62; male 90) and group 2 (mean age 14.5y, r 1-59; male 56) had no significant differences in age, gender, weight, underline diseases, state of disease, and HLA match (low-resolution). All patients' conditioning regimen was myeloablative and did not contain anti-thymocyte globulin (ATG). Cyclosporine combined with mycophenolate mofetil was applied as GVHD prophylaxis. Results: The median follow-up time since the transplant for the surviving patients was 25 months (11-84 months). We compared some indicators related to UCBT between the two groups. The median time to neutrophil engraftment for group 1 and 2 was 16 days vs. 17 days (P = 0.705), and median time to platelet engraftment was 35 days vs.38.5 days (P = 0.317). The cumulative incidence of II-IV acute GVHD in 100 days was 42.5% (38.7% for group 1 vs. 50.0% for group 2, P = 0.0751), but multi-variate analysis showed that HLA-C ligand absence was an independent risk factor for II-IV acute GVHD after transplantation (HR=1.5280, P=0.0356). Patients with absence of a C-ligand for inhibitory KIRs (Group 1) showed a lower relapse rate than patients with both C-ligands (group 2):17.7% VS 22.7% at 3 years (P=0.288). The 3-year OS was 69.3% for group 1 and 60.5% for group 2 (P=0.0792). Non-relapse mortality for group 1 was 16.8% and for group 2 was 20.8% (P=0.328). There was no statistically significant difference between the two groups in 3-year disease-free survival (64.9% vs 55.4%, P=0.0819). Conclusion: Our results suggest that patients lacking a KIR-ligand of HLA group C1 or C2 had a lower incidence of grades II-IV acute GVHD after UCBT. The absence of HLA-C ligands in recipients had no statistically significant effect on other transplant survival prognosis, which may be related to the conditioning regimen without removing T cells. A beneficial impact mediated by NK alloreactivity between UCB and recipient may be observed during longer follow-up. Therefore, the absence of a C-ligand could be considered as one of the critical factors for the selection of UCBT. No conflict of interest to declare. Disclosures No relevant conflicts of interest to declare.