scholarly journals Cytomegalovirus Infection in Solid Organ and Hematopoietic Cell Transplantation: State of the Evidence

2020 ◽  
Vol 221 (Supplement_1) ◽  
pp. S23-S31 ◽  
Author(s):  
Ghady Haidar ◽  
Michael Boeckh ◽  
Nina Singh
Keyword(s):  
T Cell ◽  
Hematopoietic Cell Transplantation ◽  
Solid Organ Transplantation ◽  
Immune Monitoring ◽  
Hematopoietic Cell ◽  
Preemptive Therapy ◽  
Solid Organ ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Hematopoietic Cell Transplant

Abstract This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy. Prophylaxis effectively prevents CMV infection after solid organ transplantation (SOT) but is associated with high rates of neutropenia and delayed-onset postprophylaxis disease. In contrast, preemptive therapy has the advantage of leading to lower rates of CMV disease and robust humoral and T-cell responses. It is widely used in hematopoietic cell transplant recipients but is infrequently utilized after SOT due to logistical considerations, though these may be overcome by novel methods to monitor CMV viremia using self-testing platforms. We review recent developments in CMV immune monitoring, vaccination, and monoclonal antibodies, all of which have the potential to become part of integrated strategies that rely on viral load monitoring and immune responses. We discuss novel therapeutic options for drug-resistant or refractory CMV infection, including maribavir, letermovir, and adoptive T-cell transfer. We also explore the role of donor factors in transmitting CMV after SOT. Finally, we propose a framework with which to approach CMV prevention in the foreseeable future.

scholarly journals Prophylaxis vs preemptive therapy in prevention of CMV infection: new insight on prophylactic strategy after allogeneic hematopoietic cell transplantation

2020 ◽  
Vol 51 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Jan Styczyński
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Primary Prophylaxis ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Preemptive Therapy ◽  
Solid Organ ◽  
Cell Transplant ◽  
Cmv Infection ◽  
American Society

AbstractCytomegalovirus (CMV), the beta-human herpesvirus type 5 (HHV-5), is a major cause of morbidity in immunocompromised hosts, especially recipients of allogeneic hematopoietic cell transplantation (HCT) or solid organ transplantation. The standard-of-care approach to CMV prevention based on CMV surveillance-guided preemptive therapy is being challenged by the recent approval of letermovir (LMV) for primary prophylaxis. Real-word clinical data show dramatic improvement in the reduction of risk of CMV infection and any CMV viremia in all studies performed so far. LMV is the drug that is breaking the paradigm of preemptive therapy with shift to prophylaxis. A summary of reported data presented in 2019 annual meetings of American Society of Transplantation and Cellular Therapy (ASTCT), European Society for Blood and Marrow Transplantation (EBMT) and American Society of Hematology (ASH), as well as already published results, is presented in this review. A total number of 401 adult high-risk patients on primary prophylaxis after HCT were reported in 11 studies up to January 1, 2020. It was shown that fewer patients in the LMV arms had any CMV reactivation or need for CMV treatment compared with the any other prophylactic or preemptive approaches. In conclusion, LMV is much highly effective than CMV-guided preemptive therapy in preventing CMV infection and CMV disease. The use of LMV in prophylaxis results in an improvement in overall survival during the first 24 and 48 weeks. LMV has a favorable safety profile, as it does not cause myelotoxicity. Current guidelines of European Conference on Infections in Leukemia (ECIL7) recommend LMV for the use in prophylaxis of CMV infection in patients after allogeneic hematopoietic cell transplant.

scholarly journals Recipient-specific T-cell repertoire reconstitution in the gut following murine hematopoietic cell transplant

2020 ◽  
Vol 4 (17) ◽  
pp. 4232-4243
Author(s):  
Pingping Zheng ◽  
John Tamaresis ◽  
Govindarajan Thangavelu ◽  
Liwen Xu ◽  
Xiaoqing You ◽  
...  
Keyword(s):  
T Cell ◽  
Hematopoietic Cell Transplantation ◽  
Cell Receptor ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Gi Tract ◽  
Hematopoietic Cell Transplant ◽  
Cell Repertoire ◽  
T Cell Reconstitution ◽  
Tcr Repertoire

Abstract Graft-versus-host disease (GVHD) is a complication of hematopoietic cell transplantation (HCT) caused by alloreactive T cells. Murine models of HCT are used to understand GVHD and T-cell reconstitution in GVHD target organs, most notably the gastrointestinal (GI) tract where the disease contributes most to patient mortality. T-cell receptor (TCR) repertoire sequencing was used to measure T-cell reconstitution from the same donor graft (C57BL/6 H-2b) in the GI tract of different recipients across a spectrum of matching, from syngeneic (C57BL/6), to minor histocompatibility (MHC) antigen mismatch BALB.B (H-2b), to major MHC mismatched B10.BR (H-2k) and BALB/c (H-2d). Although the donor T-cell pools had highly similar TCR, the TCR repertoire after HCT was very specific to recipients in each experiment independent of geography. A single invariant natural killer T clone was identifiable in every recipient group and was enriched in syngeneic recipients according to clonal count and confirmatory flow cytometry. Using a novel cluster analysis of the TCR repertoire, we could classify recipient groups based only on their CDR3 size distribution or TCR repertoire relatedness. Using a method for evaluating the contribution of common TCR motifs to relatedness, we found that reproducible sets of clones were associated with specific recipient groups within each experiment and that relatedness did not necessarily depend on the most common clones in allogeneic recipients. This finding suggests that TCR reconstitution is highly stochastic and likely does not depend on the evaluation of the most expanded TCR clones in any individual recipient but instead depends on a complex polyclonal architecture.

scholarly journals Cytomegalovirus (CMV) Cell-Mediated Immunity and CMV Infection After Allogeneic Hematopoietic Cell Transplantation: The REACT Study

2020 ◽  
Author(s):  
Roy F Chemaly ◽  
Lynn El Haddad ◽  
Drew J Winston ◽  
Scott D Rowley ◽  
Kathleen M Mulane ◽  
...  
Keyword(s):  
At Risk ◽  
Hematopoietic Cell Transplantation ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Cell Mediated Immunity ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Patients At Risk

Abstract Background Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients. CMV cell-mediated immunity (CMV-CMI) as determined by a peptide-based enzyme-linked immunospot (ELISPOT) CMV assay may identify patients at risk for clinically significant CMV infection (CS-CMVi). Methods The CS-CMVi was defined as CMV viremia and/or disease necessitating antiviral therapy. CMV-CMI was characterized as high when the intermediate-early 1 (IE-1) antigen spot counts (SPCs) were >100 (cutoff 1) or when the IE-1 and phosphoprotein 65 antigen SPCs were both >100 SPCs per 250 000 cells (cutoff 2), and a low CMV-CMI when SPCs were below these thresholds. In this prospective multicenter study, we evaluated CMV-CMI every 2 weeks from the pretransplant period until 6 months posttransplantation in 241 allo-HCT recipients with positive CMV serostatus. The primary endpoint was CS-CMVi occurring within 2 weeks of the last measurement of CMV-CMI. Results CS-CMVi occurred in 70 allo-HCT recipients (29%). CMV-CMI was low in patients who experienced CS-CMVi (94%), whereas those who had a high CMV-CMI were less likely to have CS-CMVi (P < .0001). Patients with CS-CMVi had higher all-cause mortality (P = .007), especially those with low CMV-CMI (P = .035). On multivariable analysis, CMV-CMI, sex, race, antithymocyte globulin, and steroid use were independent predictors of CS-CMVi, and the time from transplant to engraftment was the only predictor of mortality. Conclusions Measurement of CMV-CMI using a novel ELISPOT assay would be useful clinically to monitor allo-HCT recipients and distinguish between those at risk of developing CS-CMVi and requiring antiviral prophylaxis or therapy and those who are protected.

Population Pharmacokinetics Study of Tacrolimus in Chinese Hematopoietic Cell Transplant Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4668-4668
Author(s):  
Ling Xue ◽  
Jian-Zhong Rui ◽  
Yan Zhang ◽  
Li-Yan Miao
Keyword(s):  
Population Pharmacokinetics ◽  
Solid Organ Transplantation ◽  
Hematopoietic Cell ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Solid Organ ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Mixed Effect ◽  
Transplant Patients

Abstract Abstract 4668 Background The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. The population pharmacokinetics (PPK) of tacrolimus have been reported in solid organ transplantation patients, but few investigation of tacrolimus PPK in hematopoietic cell transplant patients. Our study is to characterize the factors that influence tacrolimus population pharmacokinetics in Chinese hematopoietic cell transplant patients. Methods Sixty-eight patients undergoing hematopoietic cell transplant were enrolled. The database (671 data points) collected from the patients was analyzed by using the nonlinear mixed-effect model (NONMEM) program. Patients were administered oral or/and intravenous tacrolimus as part of immunosuppressive regimen that also included corticosteroids. And the robustness and accuracy of the model were assessed using bootstrap. A number of covariates including demographic characteristic, biochemical and hematological index, drug combination, IOV (inter-occasion variability) and other factors (e.g. Cause, POD, the type of transplantation and the sources of donor) were evaluated for their influence on the tacrolimus population pharmacokinetic parameters. Results The basic model was selected a one-compartment pharmacokinetic model with first-order absorption and elimination. The typical values of tacrolimus CL, V, F were 12.1 L·h-1, 686 L, 42.2%, respectively. And the inter-individual variations of CL, V, F were 23.5%, 96.4%, 43.8%, respectively. The absorption rate constant was fixed 4.3 h-1. The residual error between observed and model-predicted concentration was 3.03 ng·ml-1. The covariates that influenced the population pharmacokinetics parameters of tacrolimus included inhibitor (INHI), post operation days (POD), age and hemoglobulin (HGB) in the final regression model. The IOV of CL, V, F were 22.2%, 6.23%, 30.3%, respectively. Conclusion The covariates included INHI, POD, AGE, HGB and IOV would significantly influence tacrolimus population pharmacokinetics parameters in hematopoietic cell transplant patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals How we treat cytomegalovirus in hematopoietic cell transplant recipients

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5711-5719 ◽  
Author(s):  
Michael Boeckh ◽  
Per Ljungman
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Quantitative Polymerase Chain Reaction ◽  
Antiviral Treatment ◽  
Hematopoietic Cell ◽  
Preemptive Therapy ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Treatment And Prevention ◽  
Cmv Disease ◽  
Drug Resistant Strains

AbstractCytomegalovirus (CMV) continues to cause major complications after hematopoietic cell transplantation (HCT). Over the past decade, most centers have adopted preemptive antiviral treatment or prophylaxis strategies to prevent CMV disease. Both strategies are effective but also have shortcomings with presently available drugs. Here, we review aspects of CMV treatment and prevention in HCT recipients, including currently used drugs and diagnostics, ways to optimize preemptive therapy strategies with quantitative polymerase chain reaction assays, the use of prophylaxis, management of CMV disease caused by wild-type or drug-resistant strains, and future strategies.

scholarly journals Management of Herpesvirus Infections in Hematopoietic Cell Transplant Recipients

2021 ◽  
Vol 2 (1) ◽  
pp. 8-21
Author(s):  
Jan Styczynski
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cellular Therapy ◽  
Hematopoietic Cell ◽  
Host Cells ◽  
Preventive Strategy ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Screening Assay ◽  
Specific Level

Following primary infection, herpesviruses establish latency in infected individuals in the host cells and may reactivate upon external stimuli and during periods of immunosuppression. The objective of this paper was to the present current strategies on preventive and therapeutic management of infections with herpesviruses in recipients of hematopoietic cell transplantation. Strategies of antiviral management include prophylaxis, pre-emptive treatment and targeted treatment. Empirical therapy is not used in antiviral strategies. Prophylaxis can be done at universal (preventive strategy) and specific level. Universal prophylaxis includes non-pharmacologic methods of prevention of infection or reactivation. Risk-adapted specific prophylaxis includes use of specific antivirals or cellular therapy or other specific methods in order to prevent specific infection, in high-risk groups. Pre-emptive therapy means use of therapeutic approaches in asymptomatic infection, detected by a screening assay. Targeted therapy is used in established specific viral end-organ infections. The following sections of the paper refer to prophylaxis and treatment strategies, respectively, against CMV, EBV, HSV, VZV, HHV-6, HHV-7, and HHV-8 after allogeneic hematopoietic cell transplantation.

scholarly journals The Hematopoietic Cell Transplant Comorbidity Index predicts survival after allogeneic transplant for nonmalignant diseases

Blood ◽  
2019 ◽  
Vol 133 (7) ◽  
pp. 754-762 ◽  
Author(s):  
Monica S. Thakar ◽  
Larisa Broglie ◽  
Brent Logan ◽  
Andrew Artz ◽  
Nancy Bunin ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Cox Regression ◽  
Bone Marrow Failure ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Research Database ◽  
Hematopoietic Cell Transplant ◽  
Risk Of Death ◽  
Increased Risk ◽  
Comorbidity Index

Abstract Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases.

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