Clinical Outcome Associated with Cytomegalovirus (CMV) Infection/Disease in CMV-Seropositive Adult Patients after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Peffault De Latour Regis , Chevallier Patrice , Blaise Didier , Clement Aurore , Allavoine Thierry , Tadmouri Abir , Blomkvist Josefin , Duhamel Alain , Yakoub-Agha Ibrahim 
Published: October 2019

Abstract
Recipients of allogeneic hematopoietic stem cell transplant (HSCT) who have positive cytomegalovirus (CMV) serology are at increased risk for morbidity and mortality after HSCT. However, the exact correlation between early CMV infection and post-HSCT outcomes, notably relapse, is still a source of conflicting data, especially in the era of viral surveillance through polymerase chain reaction (PCR) and preemptive antiviral therapy. We thus decided to retrospectively investigate the clinical impact of early, post-HSCT CMV infection/disease, in a large multi-center cohort of French patients.
All consecutive CMV-seropositive adults (≥ 18 years old) who received a first HSCT in 3 French centers between January 1st 2010 and December 31th 2014 were eligible. Cord blood transplantation or a second HSCT were not considered here, as these procedures are associated with a significantly higher risk of morbidity and mortality. Study data were primarily derived from existing electronic health records. The study was conducted in accordance with the Declaration of Helsinki. CMV infection/disease was defined by the initiation of a preemptive and/or a curative anti-CMV treatment in the presence of a CMV viremia detected by a quantitative PCR.
The primary objective of this study was to assess the association between CMV infection/disease and overall mortality within the first-year post-transplantation. Secondary clinical endpoints addressed the association between CMV infection/disease and the following outcomes within the first-year of HSCT: graft failure, relapse of the underlying disease, non-relapse mortality (NRM), incidence of acute and chronic graft-versus-host disease (GvHD), and the occurrence of infections other than CMV. Relapse was considered as a competing risk for non-relapse mortality, and death for other events of interest (relapse, incidence of acute and chronic GvHD, and occurrence of infections).
Models were adjusted for disease type, disease status at HSCT, age at HSCT, sex, donor type, stem cell source, and conditioning regimen (MAC versus RIC, use of total body irradiation or anti-thymocyte globulin).
Five hundred seventy-two patients (54.5% male, 71.2% with Karnofsky >90, and median age 54 years) met the inclusion criteria. Underlying diseases were acute leukemia (33.9%), lymphoid neoplasms (25.9%), and myelodysplastic/ myeloproliferative neoplasms (22.6%). The disease was generally in complete remission at the time of HSCT (56.5%) or stable at the time of HSCT (16.4%). The majority of patients had received a reduced intensity conditioning regimen HSCT (72.5%), and peripheral blood stem cells (71.3%). Donor type was as follows: HLA-matched unrelated donor, 34.1%; HLA-matched relative donor, 46.5%; mismatched unrelated donor, 16.3% and mismatched related donor, 3.10%. CMV infection/disease was observed in 227 patients (39.7%) at a median time of 39.5 days (range, 3-295 days) post-transplant. Overall survival rate as per Kaplan-Meier analysis was 70.9% at 1-year post-HSCT. After adjusting for significant risk factors and considering CMV infection/disease as a time-dependent variable in a Cox model, overall mortality at 1-year was significantly increased in patients developing CMV infection/disease (HR 1.86, [95%CI 1.16 - 3.00], p=0.011). The Fine and Gray competing risk model showed that CMV infection/disease during the first-year post-transplant was significantly associated with higher risk of infections other than CMV (HR 2.34, 95%CI [1.63 - 3.37], p<0.0001) and, consequently, an increased risk for NRM (HR 2.62, 95%CI [1.59 - 4.30], p=0.0001). We did not find any significant association between CMV infection/disease and acute or chronic GvHD, as well as with relapse.
In this large cohort of 572 consecutive CMV-seropositive adults undergoing allo-HSCT, and who were monitored with a PCR-based strategy according to routine clinical practice, we identified that CMV infection/disease were significantly associated with an increased risk of 1-year overall and non-relapse mortality, related to higher rates of infections other than CMV. Therefore, post-HSCT CMV infection/disease seemed to be a major concern in the recent healthcare setting, affecting mortality and morbidity.

Disclosures
Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Clement:MSD: Employment. Allavoine:MSD: Employment. Tadmouri:ClinSearch: Employment. Blomkvist:ClinSearch: Employment.