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1.
Donor aKIR genes influence the risk of EBV and CMV reactivation after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation
Gao, F., Shi, Z., Shi, J., Luo, Y., Yu, J., Fu, H., Lai, X., Liu, L., Yuan, Z., Zheng, Z., et al
Hla. 2023
Abstract
Hematopoietic stem cell transplantation (HSCT) offers the highest curative potential for patients with hematological malignancies. Complications including infection, graft-versus-host disease (GVHD), and relapse reflect delayed or dysregulated immune reconstitution. After transplantation, NK cells rapidly reconstitute and are crucial for immune surveillance and immune tolerance. NK cell function is tightly regulated by killer immunoglobin-like receptors (KIRs). Previous studies have revealed that donor KIRs, especially some activated KIRs (aKIRs) are closely related to transplant outcomes. Here, we performed a retrospective study, including 323 patients who received haploidentical (haplo) HSCT in our center. In univariate analysis, donor KIR2DS1, KIR2DS3 and KIR3DS1 gene protected patients with lymphoid disease from Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation, while donor KIR2DS1, KIR2DS5 and KIR3DS1 gene conferred a higher risk of CMV reactivation for patients with myeloid disease. Multivariate analysis confirmed that donor telomeric (Tel) B/x and KIR2DS3 gene best protected patients with lymphoid disease from EBV (p = 0.017) and CMV reactivation (p = 0.004). In myeloid disease, grafts lacking Tel B/x and KIR2DS5 gene correlated with the lowest risk of CMV reactivation (p = 0.018). Besides, donor aKIR genes did not influence the rates of GVHD, relapse, non-relapse mortality (NRM) and overall survival (OS) in this study. The reactivation of EBV and CMV was associated with poor prognosis of haplo-HSCT. In conclusion, we found that donor aKIR genes might have a synergistic effect on CMV and EBV reactivation after haplo-HSCT. Whether the influence of donor aKIR genes varies with disease types remained to be studied.
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2.
Lower dose of ATG combined with basiliximab for haploidentical hematopoietic stem cell transplantation is associated with effective control of GVHD and less CMV viremia
Huang, Z., Yan, H., Teng, Y., Shi, W., Xia, L.
Frontiers in immunology. 2022;13:1017850
Abstract
Currently, the graft-versus-host disease (GVHD) prophylaxis consists of an immunosuppressive therapy mainly based on antithymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). GVHD remains a major complication and limitation to successful allogeneic haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We modified the ATG-based GVHD prophylaxis with the addition of basiliximab in the setting of haplo-HSCT and attempted to explore the appropriate dosages. We conducted a retrospective analysis of 239 patients with intermediate- or high-risk hematologic malignancies who received haplo-HSCT with unmanipulated peripheral blood stem cells combined or not with bone marrow. All patients received the same GVHD prophylaxis consisting of the combination of methotrexate, cyclosporine or tacrolimus, mycofenolate-mofetil, and basiliximab with different doses of ATG (5-9mg/kg). With a median time of 11 days (range, 7-40 days), the rate of neutrophil engraftment was 96.65%. The 100-day cumulative incidences (CIs) of grade II-IV and III-IV aGVHD were 15.8 ± 2.5% and 5.0 ± 1.5%, while the 2-year CIs of total cGVHD and extensive cGVHD were 9.8 ± 2.2% and 4.1 ± 1.5%, respectively. The 3-year CIs of treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) were 14.6 ± 2.6%, 28.1 ± 3.4%, 60.9 ± 3.4%, 57.3 ± 3.4%, respectively. Furthermore, the impact of the reduction of the ATG dose to 6 mg/kg or less in combination with basiliximab on GVHD prevention and transplant outcomes among patients was analyzed. Compared to higher dose of ATG(>6mg/kg), lower dose of ATG (≤6mg/kg) was associated with a significant reduced risk of CMV viremia (52.38% vs 79.35%, P<0.001), while the incidences of aGVHD and cGVHD were similar between the two dose levels. No significant effect was found with regard to the risk of relapse, TRM, and OS. ATG combined with basiliximab could prevent GVHD efficiently and safely. The optimal scheme of using this combined regimen of ATG and basiliximab is that administration of lower dose ATG (≤6mg/kg), which seems to be more appropriate for balancing infection control and GVHD prophylaxis.
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3.
Post-Transplant cyclophosphamide is associated with increase in Non-CMV Herpesvirus infections in Acute leukemia and MDS patients
Singh, A., Dandoy, C. E., Chen, M., Kim, S., Mulroney, C. M., Kharfan-Dabaja, M. A., Ganguly, S., Maziarz, R. T., Kanakry, C. G., Kanakry, J. A., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND There is increasing use of post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis for both haploidentical and fully matched transplants. Published studies have reported an increased incidence of CMV infection with the use of PTCy. Limited data exist regarding the incidence and outcomes of infection with non-CMV herpes viruses (NCHV) in this setting. OBJECTIVE The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplant-specific outcomes in patients receiving haploidentical transplant with PTCy(HaploCy), matched sibling donor transplant with PTCy (SibCy) or matched sibling donor transplant with calcineurin inhibitor based prophylaxis (SibCNI). We hypothesized that, like CMV infection, patients receiving haploidentical transplant with PTCy will have higher risk of NCHV infections. STUDY DESIGN Using the CIBMTR database, we analyzed patients (HaploCy, n=757; SibCNI, n=1605; SibCy, n=403) receiving first hematopoietic stem-cell transplant between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome. RESULTS The cumulative incidence of non-CMV herpes virus infection at six months post-transplant in the HaploCy, SibCy and SibCNI were 13.9% (99%CI=10.8-17.3%), 10.7% (99%CI=7.1-15%), and 5.7% (99%CI=4.3-7.3%), p<0.001 respectively. This was primarily due to a higher frequency of HHV-6 viremia reported in patients receiving PTCy. Incidence of Epstein-Barr viremia was low in all groups and no cases of post-transplant lymphoproliferative disorder were seen in PTCy groups. The incidence of non-CMV herpes virus organ disease was low in all three cohorts. Development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, and disease-free survival. Patients in PTCy cohorts who did not develop non-CMV herpes virus infection had lower rates of cGVHD. CONCLUSIONS This study demonstrates that the use of PTCy is associated with increased risk of NCHV infection. Development of NCHV infection is associated with increased non-relapse mortality, especially in HaploCY group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for better understanding of the clinical relevance of viral reactivation in different transplant settings.
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4.
Risk factors associated with early viral reactivation following haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide: a pilot study
Baskett, J., Culos, K. A., Satyanarayana, G., Patel, D., Engelhardt, B., Savani, B., Jagasia, M., Kassim, A. A., Gatwood, K. S.
Annals of hematology. 2020
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5.
Comparative study of mizoribine and mycophenolate mofetil combined with a calcineurin inhibitor-based immunosuppressive regimen in patients with alternative donor hematopoietic cell transplantation: Mizoribine vs mycophenolate mofetil for hematopoietic cell transplantation
Huang, Y., Han, M., Yang, D., Zhang, R., Ma, Q., Pang, A., Zhai, W., He, Y., Wei, J., Jiang, E., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
BACKGROUND AND OBJECTIVE Cytomegalovirus (CMV) infection and graft versus host disease (GvHD) remain the major causes of nonrelapse mortality (NRM) in patients following alternative donor HCT. Mizoribine (MZR) showed an anti-CMV effect in addition to its immunosuppressive effect in patients with renal transplantation. In this study, we aimed to evaluate the efficacy and safety of MZR combined with CNIs as a method of prophylactic immunosuppression in recipients following alternative donor HCT. METHODS Eighty patients were enrolled in the study and randomized to the MZR (n=40) and MMF (n=40) cohorts before transplant conditioning. Analyses involved a comparison of the outcomes between the two cohorts as well as risk analyses of early NRM and severe CMV infection. RESULTS In contrast to MMF, MZR resulted in a lower but statistically nonsignificant median CMV DNA peak load (p=0.075), significantly fewer episodes of persistent/refractory infection (OR=0.12), and a lower failure rate of CMV treatment (OR=0.82), but the occurrence of hyperuricemia was significantly increased (OR=2.75). The transplant efficacy was comparable between the two cohorts regarding engraftment, the development of secondary poor graft function (sPGF) and GvHD, and the estimated OS and PFS. The 1-y NRM of the MZR cohort was not different from that of the MMF cohort, while the rate of 1-y NRM caused by viral infections was reduced in the MZR cohort and was of borderline statistical significance (p=0.05). In the multivariate analysis, lower doses of CD34+ cells in grafts (HR=3.65) and persistent/refractory CMV infections (vs w/o CMV infection: HR=7.31; vs CMV infection that was not persistent/refractory: HR=4.46) were predictors of increased 1-y NRM. The use of MMF (vs MZR cohort: OR=11.54) and grade to acute GvHD (OR=15.32) were independent risk factors for developing persistent/refractory CMV infections. CONCLUSIONS When combined with CNIs, MZR functioned well in terms of both immunosuppression and the reduction of the severity of CMV infection; however, further studies are warranted to verify whether it could be used as a potential immunosuppressant for alternative donor HCT.
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6.
Low incidence of HHV-6 reactivation in haploidentical hematopoietic stem cell transplantation with corticosteroid as graft-versus-host disease prophylaxis compared with cord blood transplantation
Tamaki, H., Ikegame, K., Yoshihara, S., Kaida, K., Yoshihara, K., Inoue, T., Kato, R., Nakata, J., Fujioka, T., Soma, T., et al
Transplant infectious disease : an official journal of the Transplantation Society. 2019;:e13073
Abstract
BACKGROUND Human leukocyte antigen (HLA) mismatch and the administration of immunosuppressive agents are considered risks for human herpesvirus 6 (HHV-6) reactivation after stem cell transplantation (SCT). However, the incidence of HHV-6 reactivation in HLA-mismatched related SCT remains unknown. METHODS We monitored plasma HHV-6 DNA loads weekly using real-time quantitative polymerase chain reaction for 5 weeks after SCT and compared serum IL-6 levels in HLA-mismatched SCT groups. RESULTS Compared with detection in all 11 umbilical cord blood transplantation (CBT) patients (100%), plasma HHV-6 DNA was detected in only 3 of 42 haplo-SCT patients (7.1%) despite the use of methylprednisolone and antithymocyte globulin as graft-versus-host disease prophylaxis and a reduced-intensity conditioning regimen, respectively. Correspondingly, serum IL-6 levels in haplo-SCT patients were significantly lower than those in CBT patients. No HHV-6-associated encephalitis developed in either groups. CONCLUSIONS Neither HLA disparity nor the use of methylprednisolone and antithymocyte globulin were risk factors for HHV-6 reactivation in our haplo-SCT patients. Rather than increasing risk, the administration of immunosuppressive agents potentially prevented HHV-6 reactivation after haplo-SCT by suppressing IL-6 production. This article is protected by copyright. All rights reserved.
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7.
Delay expression of NKp30 on NK cells correlates with long-term mycophenolate mofetil treatment and higher EBV viremia post allogenic hematological stem cells transplantation
Yu, X., Cao, X., Yan, H., Luo, X. Y., Zhao, X., Sun, Y., Wang, Y., Xu, L., Zhang, X., Chang, Y., et al
Clinical immunology (Orlando, Fla.). 2019
Abstract
Mycophenolate mofetil (MMF) is an immunosuppressive agent that is widely used in graft-versus-host disease prophylaxis because of its inhibitory function on T cells and B cells. However, the effect of MMF on natural killer cell reconstitution after allogenic hematological transplantation is largely unknown. The present study examined the effects of different MMF administration durations after haploidentical allo-HSCT on NK cell reconstitution. Ninety patients were enrolled in this study and defined into two groups in term of MMF duration. We found that MMF patients in the long-term MMF group were associated with a poor reconstitution of NK cells and a significantly lower cytotoxicity from day 30 to day 180 post-transplantation. Especially, the long-term MMF group inhibits reconstitution of NKp30 NK subsets, which correlated with higher risk of EBV viremia. Multivariate analysis showed that a better reconstitution of NKp30 cells was associated with lower EBV viremia (HR0.957, p=.04). In vitro experiments demonstrated that the active metabolite of MMF, mycophenolic acid (MPA), inhibited the proliferation and cytotoxicity of NK cells from healthy donors or patients at day 30 post-transplantation. In summary, our findings demonstrated that long-term MMF administration delayed the quality and quantity of NK cells, especially NKp30 subpopulations, which was associated with decreased EBV viremia post allogeneic HSCT.