Early CMV Reactivation Still Remains a Cause of Increased Transplant Related Mortality in the Current Era: A CIBMTR Analysis
Authors: Ramanathan Muthalagu , Teira Pierre , Battiwalla Minoo , Barrett A. John , Lindemans Caroline A , Auletta Jeffery , Ahn Kwang Woo , Chen Min , Riches Marcie L , Boeckh Michael 
Published: October 2019

Abstract
Introduction: Since the early days of allogeneic hematopoietic cell transplantation (HCT), positive serology for cytomegalovirus (CMV) in either the recipient or the donor, and CMV reactivation have been associated with poorer outcomes. In the 90’s, development of effective monitoring and potent antiviral drugs minimized and occasionally abrogated this negative impact. Recently, some studies have reported an unexpected association between early CMV reactivation and decreased incidence of relapse in AML. The Center for International Blood and Marrow Research (CIBMTR) sought to conduct a retrospective large scale study to reassess the impact of CMV serology and CMV reactivation in the current era.
Methods: The analysis includes comprehensive data of 11,153 patients undergoing first allogeneic HCT between 2003 and 2010 reported to the CIBMTR. Separate analyses were conducted for each of the 6 patient categories: AML transplanted with bone marrow (BM) or peripheral blood stem cell (PBSC) (n=5310), AML transplanted with cord blood (CB) (n= 925), ALL with BM/PBSC (n=1883), ALL with CB (n= 759), CML with BM/PBSC (n=1079) and MDS with BM/PBSC (n=1197). CMV serology from the donor (D) or recipient (R), and reactivation of CMV (as a time-dependent co-variate) within the first year after HCT were analyzed as risk factors for outcomes. The median duration of follow up was 56 months (1 – 127 months).
Results: The median time to CMV reactivation was 40 days (1 – 362 days) after HCT and 98% of reactivations occurred before day 100 (D+/R+ 32%, D+/R- 11%, D-/R+ 34%, D-/R- 4%). In multivariable analysis, throughout the 6 groups, a positive serology (D+/R+, D+/R-, D-/R+) vs a negative serology (D-/R-),had no effect on the risk of GVHD (acute or chronic) or the risk of relapse, except for an increased risk of chronic GVHD for BM/PBSC recipients with ALL. CMV positive serology was associated with a higher transplant related mortality (TRM) and a poorer overall survival (OS). For a R+ patient, a D- compared to a D+, had no negative impact except for ALL with BM/PBSC where a D- was associated with a poorer OS.
After PBSC/BM transplantation, CMV reactivation was associated with a higher TRM for MDS (RR=1.61, p=0.0002), CML (RR=1.86, p=0.0004), AML (RR=1.68; p<0.0001) and ALL (RR=1.95; p<0.0001), translating into lower OS (range of RR from 1.27 to 1.49; p value from 0.003 to <0.0001). Only among AML patients following CB transplantation, CMV reactivation did not worsen OS. Moreover, CMV reactivation had no effect on the incidence of relapse irrespective of the diagnosis or the source of stem cells. Finally, we conducted a subset analysis focusing on the group of AML, transplanted with PBSC after a myeloablative conditioning regimen and with a GVH prophylaxis relying on Ciclosporine and Methotrexate only. In multivariable analysis, there was no difference in the risk of relapse based on CMV reactivation as a time-dependent co-variate [RR 0.96 (0.65 – 1.4), p=0.8385].
Conclusion: Positive D/R CMV serology still results in increased TRM and decreased OS after HSCT in the current era. Early CMV reactivation did not prevent relapse in patients with AML, MDS, CML or ALL after HCT.

Disclosures
Boeckh: Chimerix: Consultancy, Research Funding; Viropharma: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.