Genetic Variants Associated with Cytomegalovirus Infection after Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2021 ◽  
Author(s):  
Amanda Casto ◽  
Sachiko Seo ◽  
David Levine ◽  
Barry E Storer ◽  
Xinyuan Dong ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Genetic Variants ◽  
Hematopoietic Cell Transplantation ◽  
Genome Wide Association Study ◽  
Antiviral Treatment ◽  
Clinical Importance ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
A Genome ◽  
Cmv Reactivation

Human cytomegalovirus (CMV) reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Despite routine screening for CMV reactivation and early antiviral treatment, the rates of CMV-related complications after HCT remain high. Genetic variants in both the donor and recipient have been associated with the risk of CMV reactivation and disease after HCT, but these associations have not been validated and their clinical importance remains unclear. In this study, we assessed 117 candidate variants previously associated with CMV-related phenotypes for association with CMV reactivation and disease in a cohort of 2169 CMV-seropositive HCT recipients. We also carried out a genome-wide association study (GWAS) for CMV reactivation and disease in the same cohort. Both analyses used a pre-specified discovery and replication approach to control the risk of false-positive results. Among the 117 candidate variants, our analysis implicates only the donor ABCB1 rs1045642 genotype as a risk factor for CMV reactivation. This synonymous variant in P-glycoprotein may influence the risk of CMV reactivation by altering the efflux of cyclosporine and tacrolimus from donor lymphocytes. In the GWAS analysis, the donor CDC42EP3 rs11686168 genotype approached the significance threshold for association with CMV reactivation, although we could not identify a mechanism to explain this association. The results of this study suggest that most genomic variants previously associated with CMV phenotypes do not significantly alter the risk for CMV reactivation or disease after HCT.

scholarly journals Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation

2020 ◽  
Vol 4 (14) ◽  
pp. 3224-3233
Author(s):  
Paul J. Martin ◽  
David M. Levine ◽  
Barry E. Storer ◽  
Sarah C. Nelson ◽  
Xinyuan Dong ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Genetic Variants ◽  
Hematopoietic Cell Transplantation ◽  
Genome Wide Association Study ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
European Ancestry ◽  
A Genome ◽  
Grade 3 ◽  
Highly Correlated

Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

scholarly journals Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data

2020 ◽  
Author(s):  
Patrick Derigs ◽  
Aleksandar Radujkovic ◽  
Maria-Luisa Schubert ◽  
Paul Schnitzler ◽  
Tilman Schöning ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Real World ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Control Group ◽  
Real World Data ◽  
Cytomegalovirus Reactivation ◽  
Clinically Significant ◽  
Cmv Reactivation

AbstractMorbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). We evaluated 80 seropositive patients transplanted consecutively between March 2018 and March 2019 who received letermovir (LET) prophylaxis from engraftment until day +100 and retrospectively compared them with 80 patients without LET allografted between January 2017 and March 2018. The primary endpoint of this study was the cumulative incidence (CI) of clinically significant CMV infection (CS-CMVi) defined as CMV reactivation demanding preemptive treatment or CMV disease. With 14% CI of CS-CMVi at day +100 (11 events) was significantly lower in the LET cohort when compared to the control group (33 events, 41%; HR 0.29; p < 0.001). Whereas therapy with foscarnet could be completely avoided in the LET group, 7 out of 80 patients in the control cohort received foscarnet, resulting in 151 extra in-patient days for foscarnet administration (p = 0.002). One-year overall survival was 72% in the control arm vs 84% in the LET arm (HR 0.75 [95%CI 0.43–1.30]; p < 0.306). This study confirms efficacy and safety of LET for prophylaxis of CS-CMVi after alloHCT in a real-world setting, resulting in a significant patient benefit by reducing hospitalization needs and exposure to potentially toxic antiviral drugs for treatment of CMV reactivation.

scholarly journals Time-dependent prediction of mortality and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation using machine learning

2021 ◽  
Author(s):  
Lisa Eisenberg ◽  
Christian Brossette ◽  
Jochen Rauch ◽  
Andrea Grandjean ◽  
Hellmut Ottinger ◽  
...  
Keyword(s):  
Machine Learning ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Time Dependent ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Individual Risk ◽  
Multiple Time ◽  
Prediction Of Mortality ◽  
Cmv Reactivation

Allogeneic hematopoietic cell transplantation (HCT) treats high-risk hematologic diseases effectively but can entail HCT-specific complications, which may be minimized by appropriate patient management and accurate, individual risk estimation. Existing clinical scores typically provide a single risk assessment before HCT and do not incorporate additional data as it becomes available. We developed machine learning models which integrate both baseline patient data and time-dependent laboratory measurements to individually predict mortality and cytomegalovirus (CMV) reactivation after HCT at multiple time points per patient. These models provide well-calibrated time-dependent risk predictions and achieved areas under the receiver-operating characteristic of 0.92 and 0.83 and areas under the precision-recall curve of 0.58 and 0.62 for prediction of mortality and CMV reactivation, respectively, in a 21-day time window. Both were successfully validated in a non-interventional, prospective study and performed on par with expert hematologists in a pilot comparison.

scholarly journals Epstein–Barr virus and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation in patients with non–Hodgkin lymphoma: the prevalence and impacts on outcomes

2021 ◽  
Author(s):  
Yiyang Ding ◽  
Yuhua Ru ◽  
Tiemei Song ◽  
Lingchuan Guo ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Transplantation ◽  
Epstein Barr Virus ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Barr Virus ◽  
Non Hodgkin Lymphoma ◽  
Epstein Barr ◽  
Cmv Reactivation

AbstractEpstein–Barr virus (EBV) and cytomegalovirus (CMV) reactivations are common complications after allogeneic hematopoietic cell transplantation (allo-HCT), but data focusing on non–Hodgkin lymphoma (NHL) are limited. We retrospectively analyzed the prevalence of EBV and CMV reactivation post-allo-HCT and the impacts on transplant outcomes in 160 NHL patients. The 1-year incidences of EBV and CMV reactivation were 22.58% and 25.55%, respectively. Independent impactors for EBV reactivation were more than 6 lines of chemotherapy (P = 0.030), use of rituximab (P = 0.004), and neutrophil recovery within 30 days post-HCT (P = 0.022). For T-cell lymphoblastic lymphoma patients, the International Prognostic Index (IPI) (P = 0.015) and chronic GVHD (P = 0.001) increased the risk of CMV reactivation. CMV reactivation was independently related to a lower risk of relapse (P = 0.027) but higher transplant-related mortality (TRM) (P = 0.038). Although viral reactivation had no significant impact on overall survival (OS) in the whole cohort, it led to an inferior 2-year OS (67.6% versus 92.5%, P = 0.005) and TRM (20.1% versus 4.7%, P = 0.020) in recipients surviving for more than 180 days. We concluded that EBV and CMV reactivation post-allotransplant still deserved concern particularly in NHL patients with high-risk factors, since it is generally related to a deteriorated prognosis. Large-scale studies are warranted to validate our findings.

scholarly journals Vancomycin use and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation

2020 ◽  
Vol 4 (12) ◽  
pp. 2640-2643 ◽  
Author(s):  
Shijia Zhang ◽  
Ryan Shanley ◽  
Daniel J. Weisdorf ◽  
Armin Rashidi
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Allogeneic Hct ◽  
Gram Positive Bacteria ◽  
Cytomegalovirus Reactivation ◽  
Increased Risk ◽  
Key Points ◽  
Cmv Reactivation

Key Points Vancomycin exposure in the pre-engraftment period was associated with an increased risk for CMV reactivation after allogeneic HCT. Some gram-positive bacteria may protect against CMV reactivation.

scholarly journals Combined Analysis of Early CD4+ T Cell Counts and CMV Serostatus May Improve CMV Risk Assessment after Allogeneic Hematopoietic Cell Transplantation

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3318
Author(s):  
Saskia Leserer ◽  
Esteban Arrieta-Bolaños ◽  
Ulrike Buttkereit ◽  
Dietrich Beelen ◽  
Amin Turki
Keyword(s):  
Risk Assessment ◽  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Risk Groups ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Cell Counts ◽  
Early Risk ◽  
Cmv Reactivation

The incidence and severity of viral complications after cellular therapy are highly variable. Recent publications describe relevant interactions between the human Cytomegalovirus (CMV) and host immunity in recipients of allogeneic hematopoietic cell transplantation (HCT). Although immune monitoring is routinely performed in HCT patients, validated cut-off levels correlating with transplant outcomes such as survival or CMV reactivation are mostly limited to day +100, which is later than the median time for CMV reactivation in the absence of medical prophylaxis. To address this gap in early risk assessment, we applied an unsupervised machine learning technique based on clustering of day +30 CD4+ helper T cell count data, and identified relevant cut-off levels within the diverse spectrum of early CD4+ reconstitution. These clusters were stratified for CMV recipient serostatus to identify early risk groups that predict clinical HCT outcome. Indeed, the new risk groups predicted subsequent clinical events such as NRM, OS, and high CMV peak titers better than the most established predictor, i.e., the positive CMV recipient serostatus (R+). More specifically, patients from the R+/low CD4+ subgroup strongly associated with high CMV peak titers and increased 3-year NRM (subdistribution hazard ratio (SHR) 10.1, 95% CI 1.38–73.8, p = 0.023), while patients from the R-/very high CD4+ subgroup showed comparable NRM risks (SHR 9.57, 95% CI 1.12–81.9, p = 0.039) without such an association. In short, our study established novel cut-off levels for early CD4+ T cells via unsupervised learning and supports the integration of host cellular immunity into clinical risk-assessment after HCT in the context of CMV reactivation.

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