Although the widespread use of preemptive therapy has descreased the incidence of CMV end organ disease after HCT, the association of CMV reactivation (CMV-R) with proposed indirect effects, such as graft-versus-host-disease (GVHD) and infection, remains poorly defined. These additional effects of CMV could be part of a composite endpoint in clinical trials of novel CMV therapeutics or vaccines. We examined the association of CMV reactivation with acute and chronic GVHD and infectious outcomes after allogeneic HCT.
This cohort study included patients who had a first allogeneic HCT from 1995 through 2013. Cord blood recipients were excluded. Demographic and clinical data, including routine evaluations for acute (aGVHD) and chronic GVHD (cGVHD, NIH criteria) were retrieved from a prospectively collected database. CMV-R was monitored weekly after HCT by pp65 antigenemia (AG) or PCR testing until day 100. Multivariable Cox models were constructed to estimate the association between CMV viremia and acute/chronic GVHD, bacteremia, and invasive fungal infections (IFI). Cumulative incidences of GVHD and CMV-R were estimated, treating death as a competing risk.
The cohort included 4394 HCT recipients. In multivariable models, adjusted hazard ratios (aHR) estimating the association between CMV-R and aGVHD that progresses to grade 2-4 or 3-4 were 1.09 (95% CI 0.97-1.22) and 0.91 (95%CI 0.68-1.21) respectively (p=NS). In our cohort aGVHD developed before CMV-R (Fig.1). CMV-R was also not associated with subsequent development of cGVHD (aHR 0.94, 95% CI 0.8-1.1, p=NS). CMV-R was associated with an increased risk of IFI (aHR 1.52, 95% CI 1.2-2.0, p=0.002).
In this large cohort of HCT recipients in the era of preemptive therapy, CMV reactivation was not associated with subsequent development of either acute (either grade 2-4 or grade 3-4) or chronic GVHD. However,other hypothesized indirect effects of CMV infection (IFI), were significantly more common in patients with CMV viremia even after controlling for other risk factors for infection such as neutropenia. These could be considered as part of composite endpoint for CMV interventional trials.
M. L. Green,
Merck: Research Contractor , Research support
T. Gooley, Astellas: Investigator , Research support
P. J. Martin, Astellas: Investigator , Research support
M. Boeckh, Chimerix Inc.: Consultant and Investigator , Consulting fee and Research support
Astellas: Consultant and Investigator , Consulting fee and Research support
Shire: Consultant and Investigator , Consulting fee and Research support
Gilead: Consultant and Investigator , Consulting fee and Research support
Merck: Consultant and Investigator , Consulting fee and Research support
Roche/Genentech: Consultant and Investigator , Consulting fee and Research support
Clinigen: Consultant , Consulting fee