Cyclosporine area under the curve after allogeneic hematopoietic stem cell transplantation is an indicator of Epstein–Barr virus DNAemia

Christopeit, Maximilian; Janssen, Nils; Weber, Thomas; Bacher, Ulrike; Lautenschläger, Christine; Oehme, A.; Kekulé, Alexander S.; Schmoll, Hans‐Joachim

doi:10.3109/10428194.2012.705001

Cited by 7 publications

(12 citation statements)

References 21 publications

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“…In the immune-compromised milieu created by SCT, pathogen control is lost with viral reactivation and viremia as possible results. 3 Several risk factors have been associated with PTLD after SCT. 1,4 It is particularly common with EBV-related complications when different in vivo Tcell depletion strategies have been used for the prevention of graft-versus-host disease (GVHD) and/or following reduced intensity conditioning (RIC).…”

Section: Introductionmentioning

confidence: 99%

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o norder to decrease the lag time for CTL transfer. Among other things, interferon-gamma capture of virus-specific CTL and allogeneic CTL banks containing CTL against the most common HLA haplotypes have been used with some success. 16,22,23 Our group has tried separation of peptide-specific T cells with the help of magnetic beads and MHC multimers. 17,18 Even though this has shown promising results, none of these strategies is yet part of standard clinical practice.In this retrospective analysis we analyzed possible risk factors associated with the development of PTLD after SCT at our center. The earlier part of the cohort of patients was previously included in the studies by Sundin et al. and Omar et al. 1,24 We found several factors that were independently associated with an increased risk of PTLD. Some of the factors seem to act synergistically, which adds additional risk of PTLD in the patients. Moreover, in spite of improved prophylaxis and rituximab use, the long-term survival of affected patients is poor. Methods PatientsIn total 1021 patients who underwent SCT at Karolinska University Hospital in Huddinge, Stockholm, between 1996 and 2011 were included in this retrospective analysis of risk factors for and clinical outcome of PTLD. This study was approved by the regional ethical committee in Stockholm (n. 425/97). A review of patients' charts and the clinical database identified 40 cases of verified PTLD. The characteristics of patients with and without PTLD are displayed in Table 1. Diagnosis and treatment of Epstein-Barr virus-associated post-transplant lymphoproliferative diseaseThe diagnosis of PTLD was made according to the histological criteria reported for B-cell lymphoproliferative states following transplantation. 25 After July 2005 (total of 446 individuals) all patients considered to be at high risk of developing PTLD were screened weekly or biweekly for EBV during the first 3 months post-SCT. In patients at low risk, quantitative polymerase chain reaction (PCR) analysis was performed if EBV reactivation was suspected. From July 2005 all patients were treated with rituximab if the EBV load was >10 000 copies/mL. Thirty-five of the patients were treated with rituximab. More details are available in the Online Supplementary Methods section.Conditioning regimen, graft-versus-host disease prophylaxis and stem-cell source RIC was used in 402 patients, while myeloablative conditioning was given to 619 patients. Antithymocyte globulin (ATG) was given to 705 patients as part of the conditioning with the last dose on day -1. ATG was used in all patients with an unrelated or mismatched donor and in all patients with a non-malignant disease, independently of the type of donor. A few patients with a sibling donor treated with RIC (n=44) were also given ATG. The graft source was bone marrow in 361 cases, peripheral blood in 608 and umbilical cord blood in 52. For more details regarding conditioning regimens, GVHD prophylaxis and stem-cell source see th...

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Section: Introductionmentioning

confidence: 99%

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

et al. 2013

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“…In some cases, thresholds were not readily comparable because there was no direct conversion between the units of measurement used. In two studies [45,91], active EBV infection was defined as a reactivation event because all patients showed positive EBV serology when the follow-up period started. In other studies, no distinction was made between primary infection and reactivation: both were considered active EBV infection.…”

Section: Resultsmentioning

confidence: 99%

“…The sensitivity analyses highlighted a variation of the pooled estimate from 2.07 to 4.00 and of I 2 from 28% to 58%. The studies by Christopeit et al [45] and Cohen et al [46] had the greatest influence on the pooled estimate and heterogeneity. The pooled estimate was no longer significant if a single study was removed from the analysis, except for the study by Christopeit et al [45], which was carried out with the smallest sample.…”

Section: Graft-versus-host Disease Prophylaxis/treatmentmentioning

confidence: 96%

“…ATG use appears to be an important risk factor for the development of active posttransplant EBV infection or PTLD. Among 15 multivariate studies [4,41,45,46,51,53,56,66,68,69,74,79,85,86,96] that examined the association between ATG and active post-transplant EBV infection, 10 found a statistically significant association: Cesaro et al [41] (HR = 13.0 (95% CI: 2-96)), Fan et al [53] (OR = 7.69 (95% CI: 1.17-50.49)), Juvonen et al [66] (HR = 5.78 (95% CI: 2.47-13.5)), Liu et al [74] (HR = 14.081 (95% CI: 6.02-32.92)), Peric et al [85] (SHR = 4.9 (95% CI: 1.1-21.0)), Van Esser et al [96] (HR = 3.4 (95% CI: 1.6-1)), Gao et al [56] (HR = 6.3 (95% CI: 1.6-24.0)), Düver et al [51] (OR = 10.68 (95% CI: 1.15-98.86)), Ru et al [86] (HR = 4.29 (95% CI: 2.64-6.97)) and Kullberg-Lindh et al [68] (slope = 1.34; p = 0.004). All studies compared patients who received ATG versus those who did not, but one: Van Esser et al [96] reported the risk of EBV infection in patients receiving T-cell depleted (TCD) grafts with ATG versus patients receiving non-TCD grafts.…”

Section: Graft-versus-host Disease Prophylaxis/treatmentmentioning

confidence: 99%

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Factors Associated with Post-Transplant Active Epstein-Barr Virus Infection and Lymphoproliferative Disease in Hematopoietic Stem Cell Transplant Recipients: A Systematic Review and Meta-Analysis

et al. 2021

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This systematic review was undertaken to identify risk factors associated with post-transplant Epstein–Barr virus (EBV) active infection and post-transplant lymphoproliferative disease (PTLD) in pediatric and adult recipients of hematopoietic stem cell transplants (HSCT). A literature search was conducted in PubMed and EMBASE to identify studies published until 30 June 2020. Descriptive information was extracted for each individual study, and data were compiled for individual risk factors, including, when possible, relative risks with 95% confidence intervals and/or p-values. Meta-analyses were planned when possible. The methodological quality and potential for bias of included studies were also evaluated. Of the 3362 titles retrieved, 77 were included (62 for EBV infection and 22 for PTLD). The overall quality of the studies was strong. Several risk factors were explored in these studies, but few statistically significant associations were identified. The use of anti-thymocyte globulin (ATG) was identified as the most important risk factor positively associated with post-transplant active EBV infection and with PTLD. The pooled relative risks obtained using the random-effect model were 5.26 (95% CI: 2.92–9.45) and 4.17 (95% CI: 2.61–6.68) for the association between ATG and post-transplant EBV infection and PTLD, respectively. Other risk factors for EBV and PTLD were found in the included studies, such as graft-versus-host disease, type of conditioning regimen or type of donor, but results are conflicting. In conclusion, the results of this systematic review indicate that ATG increases the risk of EBV infection and PTLD, but the link with all other factors is either nonexistent or much less convincing.

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“…11 Christopeit et al reported an association between a high serum cyclosporine A (CsA) level and EBV DNAemia after allogeneic HCT. 12 Nevertheless, ATG and CsA are generally postulated to act by targeting T cells, but the specific T-cell subset involved in immunosuppression-related EBV reactivation has not been clarified. Mycophenolate mofetil (MMF) is another common immunosuppressant used in the setting of transplantation.…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2⁺T cells activities after hematopoietic transplantation for blood malignancies

Liu

Gao

et al. 2020

J Immunother Cancer

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background Following the extensive use of immunosuppressive drugs in the clinic, immunosuppression-associated side effects have received increasing attention. Epstein-Barr virus (EBV) reactivation and related lymphoproliferative diseases (LPD) are the lethal complications observed after allogeneic hematopoietic cell transplantation (alloHCT). While studies generally suggest an association between immunosuppressants and EBV reactivation, the effects of specific immunosuppressive drugs and which T-cell subsets mediate these correlations are unclear. Vδ2 + T cells are correlated with EBV reactivation after alloHCT. Researchers have not determined whether Vδ2 + T-cell activities are affected by immunosuppressants and thereby facilitate EBV reactivation and related LPD. Methods A clinical cohort study of 170 patients with hematopoietic malignancies who received haploidentical hematopoietic cell transplantation (haploHCT) was performed to investigate whether the early cessation of mycophenolate mofetil (MMF) decreases EBV reactivation and related LPD and to determine whether this change is associated with the recovery of Vδ2 + T cells after transplantation. The effects of MMF on the expansion and anti-EBV capacity of Vδ2 + T cells were detected in vitro and in an immunodeficient mouse model. results A reduction in the course of MMF significantly improved the recovery of Vδ2 + T cells from 30 to 90 days after haploHCT (p=0.002, p=0.042 and p=0.035, respectively), accompanied by a significant decrease in EBV reactivation (from 26% to 13%, p=0.033) and EBV-LPD (from 10.6% to 2.4%, p=0.029). The day-30 Vδ2 + T level remained an independent factor for EBV reactivation in patients with different MMF durations (p=0.007). In the in-vitro experiments, MMF inhibited Vδ2 + T-cell expansion and its cytotoxicity on EBV-transformed malignant cells. Furthermore, the therapeutic and prophylactic effects of adoptively transferred human Vδ2 + T cells were attenuated by the MMF treatment in immunodeficient mice with EBV-LPD.

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Cyclosporine area under the curve after allogeneic hematopoietic stem cell transplantation is an indicator of Epstein–Barr virus DNAemia

Cited by 7 publications

References 21 publications

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

Factors Associated with Post-Transplant Active Epstein-Barr Virus Infection and Lymphoproliferative Disease in Hematopoietic Stem Cell Transplant Recipients: A Systematic Review and Meta-Analysis

Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2⁺T cells activities after hematopoietic transplantation for blood malignancies

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Cyclosporine area under the curve after allogeneic hematopoietic stem cell transplantation is an indicator of Epstein–Barr virus DNAemia

Cited by 7 publications

References 21 publications

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

Factors Associated with Post-Transplant Active Epstein-Barr Virus Infection and Lymphoproliferative Disease in Hematopoietic Stem Cell Transplant Recipients: A Systematic Review and Meta-Analysis

Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2+T cells activities after hematopoietic transplantation for blood malignancies

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Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2⁺T cells activities after hematopoietic transplantation for blood malignancies