Pre-engraftment Cytomegalovirus DNAemia in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Incidence, Risk Factors and Clinical Outcomes
Conditions: CMV DNAemia Pre-engraftment
Sponsor: Fundación para la Investigación del Hospital Clínico de Valencia

NCT number 
NAV-CMV-2019 
Date 
May, 2018 
Study Title: 
Pre-engraftment Cytomegalovirus DNAemia in allogeneic 
hematopoietic stem cell transplant recipients: incidence, risk 
factors and clinical outcomes  
Request Date: 
  
Principal Investigator 
Contact Information 
David Navarro  
Name:  
David Navarro  
Title: 
MD, PhD  
Address 1 
Av. Blasco Ibáñez 17  
Address 2 
  
City, ST, Zip 
Valencia, 4600646006 
Phone/Fax: 
0034-961973683/0034961973686  
David.navarro@uv.es  
 
Institution Contact 
Information 
INCLIVA, Institución de Investigación Sanitaria, Hospital Clínico de Valencia  
Name:  
INCLIVA, Institución de Investigación Sanitaria, Hospital Clínico de Valencia  
Address 1 
Avenida de Menéndez y Pelayo, 4, 46010 Valencia   
Address 2 
  
City, ST, Zip 
Valencia, 46010 
Phone/Fax: 
961 97 35 17/18 961 97 35 17/18  
website 
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Number of Subjects: 878 
 

Background and Rationale  
 Cytomegalovirus DNAemia occurs frequently in allogeneic hematopoietic stem cell 
transplant (allo-HSCT) recipients [1] Both high-level and persistent virus DNAemia are 
known risk factors for CMV end-organ disease and perhaps non-relapse mortality [2]. 
CMV DNAemia is usually documented after engraftment, but it may occur before. The 
virological features and clinical consequences of these latter early-onset episodes 
remain largely unexplored. The U.S. Food and Drug Administration (FDA) has recently 
approved letermovir for prophylaxis of CMV infection and disease in adult CMV-
seropositive allo-HSCT recipients (PREVYMIS™, Merck & Co., New Jersey, USA). In 
accordance with the design of the phase III, double-blind trial [3] the drug may be 
administered as early as the day of transplant and no later than 28 days post-transplant. 
Nevertheless, the timing of drug inception should be contingent on the clinical impact of 
very early episodes of CMV DNAemia.  In a recent work from our group (single-center 
study) [4] we  found that a total 38 out of the 197 patients in our series developed CMV 
DNAemia before engraftment (cumulative incidence, 19%; 95% CI, 10-30.3%). Nine 
episodes of CMV DNAemia were detected prior to the time of donor progenitor cell 
infusion. A greater number of post-engraftment episodes required preemptive antiviral 
therapy compared with pre-engraftment episodes (62.5% vs 44.7%; P=0.05). The cellular 
content of the donor progenitor cell infusion and transplant characteristics of patients 
did not differ between patients with pre- or post-engraftment CMV DNAemia. The 
cumulative incidence of overall mortality by days 100 and 365, aGvHD by day 100 and 
relapse by day 365 were not significantly different between patients with pre-
engraftment or post-engraftment CMV DNAemia. Our study was limited by the 
retrospective and single-center design and the scarce number of pre-engraftment CMV 
DNAemia episodes included; therefore, the results may not be extrapolated to other 
transplantation centers or patient cohorts. Further retrospective and prospective 
studies are thus required to validate the data presented herein. 
References: 
 
1. Pérez Romero P, et al. An update on the management and prevention of cytomegalovirus infection 
following allogeneic hematopoietic stem cell transplantation. Future Virol 2015; 10:113–134. 
2.2.Green ML, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell 
 
transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 
2016;3:e119-27. 
3.3.Solano C, et al. Impact of cytomegalovirus DNAemia on overall and non-relapse mortality in allogeneic 
stem cell transplant recipients. Transpl Infect Dis 2017 Aug;19(4). E12717.. 
 
4. Solano et al., Pre-engraftment Cytomegalovirus DNAemia in allogeneic hematopoietic stem cell 
transplant recipients: incidence, risk factors and clinical outcomes (Bone Marrow Transplantation, 2018, 
in press). 
 
 
 
 
 
 
 
 
Objectives 

 
1. Assess the incidence of pre-engraftment CMV DNAemia using highly sensitive real-
time PCR assays in allo-HSCT 
 
 
2. Evaluate its impact of pre-engraftment CMV DNAemia on the time to engraftment, 
overall mortality, and non-relapse mortality.  
 
 
Hypothesis  
 
Very early episodes of CMV DNAemia have no impact on the occurrence of engraftment, 
overall mortality and non-relapse mortality.  
 
 
 
Study Design/Clinical Plan 
This is a multicenter, retrospective, observational and single arm study which will include 
all consecutive allo-HSCT recipients at risk of CMV infection allografted from 1st January 
2010 until 31th December 2019 in Spanish transplant centers belonging to the “Grupo 
Español de trasplante hematopoyetico y terapia cellular” (GETH group). No less than 10 
centers performing bot related and unrelated allo-HSCT in Spain will participate in the 
study.  
 
Inclusion criteria include: 
- 
Recipients >18 years old 
- 
CMV seropositive recipients and/or donors 
- 
DNA load monitoring by real-time PCR starting from day -7 and conducted on a 
weekly CMV basis (0, +7, +14,…) at least until day +100  
- 
First allo-HSCT 
T-cell replete allograft 
Essential variables which include patients, donor and transplant’s characteristics as well 
as post-transplant outcome will be retrieved from MED-A of PROMISE EBMT database. 
 
Specific CMV data (including one-year longitudinal PCR results, date of onset and type of 
pre-emptive antiviral therapy as well as CMV disease data) will be retrospectively reported 
by each participating center.  
 
Analysis of the clinical impact of CMV DNAemia will be performed by evaluation of: 
- 
Time to engraftment  
- 
Overall mortality 
 
The analysis will be performed comparing the clinical impact of CMV DNAemia as 
described before, in relation to time of CMV DNAemia initiation in the following groups: 
- 
Patients with DNAemia before engraftment vs after engrafmet 
- 
Patients with DNAemia before engraftment and before HSC infusion vs patients 
with DNAmia before engraftment after HCS infusion 
- 
Comparison of time of initiation of CMV DNAemia from day -7 to HCS infusion on a 
weekly basis until engraftment. 
 

Statistical Plans 
 
 
Non-parametric and semi-parametric analyses. The probabilities of CMV DNAemia, CMV 
DNAemia requiring pre-emptive therapy, CMV-D, NRM and relapse will be estimated by 
the cumulative incidence method (marginal probability).  
 
Competing events will be defined as follows; in the case of relapse, the competing event 
was NRM without the occurrence of the disease. For CMV DNAemia, CMV DNAemia 
requiring pre-emptive therapy, CMV-D and GVHD the competing event will be relapse or 
death without the event. For NRM the competing event will be relapse.  
 
The assumption of proportional hazards over time will be tested for all explanatory 
covariates using a time-dependent covariate. CMV DNAemia, CMV DNAemia requiring 
pre-emptive therapy and CMV-D will be treated as time-dependent co-variates.  
 
If time-dependent covariates are to be included in the final model multivariate analyses of 
mortality the analysis will be performed by Cox proportional hazards regression model, 
with inclusion of those variables with a P value less than 0.1 in the prior univariate testing.  
 
If either, early or late CMV DNAemia (included individually as time-dependent covariates) 
are found to have an impact on OS in the univariate analysis, semi-landmark plot will be 
constructed to illustrate visually the effect. 
 
Statistical analysis of the clinical impact of CMV DNAemia at different periods of time 
before engraftment will be performed as described previously for early or late CMV 
DNAemia  
 
All statistical analyses will be performed using SPSS version 20 (SPSS, Chicago, IL) and 
R version 2.12.2 (The CRAN project) with the packages survival v2.36-10, Design 2.3-0, 
prodlim v1.2.1 and cmprsk v2.2-221.