Cytomegalovirus Reactivation After Allogeneic Stem Cell Transplantation Is Associated With a Reduced Risk Of Relapse In Patients With Acute Myeloid Leukemia: The Japan Society For Hematopoietic Cell Transplantation (JSHCT) Transplantation-Related Complication Working Group

Cytomegalovirus (CMV) infection is still a major infectious complication following allogeneic hematopoietic cell transplantation (allo-HCT). Recently, it is reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study is to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSC in a large cohort of patients.

The Transplantation-related Complication Working Group of JSHCT retrospectively surveyed the database of the Transplant Registry Unified Management Program (TRUMP) at the JSHCT. Patients with AML (n=1836), acute lymphoblastic leukemia (ALL) (n=911), chronic myeloid leukemia (CML) (n=223) and myelodysplastic syndrome (MDS) (n=569) who underwent their first allo-HCT from HLA matched related or unrelated donors between 2000 and 2009, and who survived without disease relapse until day 100 after transplantation were analyzed. Patient who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment and the start of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, non-relapse and overall mortality. CMV reactivation and acute/chronic GVHD were evaluated as time-dependent covariates.

CMV reactivation was associated with a decreased cumulative incidence of relapse among patients with AML (20.3% versus 26.4%, p=0.027), but not in patients with ALL, CML or MDS by Gray’s test. Among 1836 AML patients, CMV reactivation occurred in 795 patients (43.3%) at median 42 days (-8 - 407 days), and 436 patients (23.7%) relapsed at median 221 days (101-2057 days) after allo-HCT. Grades II to IV acute GVHD developed in 630 patients (34.3%). On multivariate analysis taking competing risk factors into account, three factors significantly associated with a decreased risk of AML relapse: CMV reactivation (HR 0.765, 95%CI 0.59-0.99), unrelated donor compared to related donor (HR 0.593, 95%CI 0.42-0.84) and development of chronic GVHD (HR 0.773, 95% CI 0.60-0.99). However, no benefit in relapse-free survival associated with CMV reactivation was observed (HR 1.025, 95%CI 0.85-1.24). CMV reactivation was associated with increased non-relapse mortality (HR 1.160, 95%CI 1.02-1.32) and overall mortality (HR 1.370, 95%CI 1.11-1.69). Pre-transplant CMV serostatus was not extracted as a risk factor for relapse, non-relapse and overall mortality.

A beneficial effect of CMV reactivation on the subsequent relapse risk was observed in patients with AML but no other hematological malignancies in our large cohort study. However, this benefit was canceled out by the increased non-relapse mortality. The underlying mechanism is unclear, but the immunological activation against CMV reactivation plays an essential role in this association. Thus, the immune augmentation treatment options including vaccination and adoptive T-cell transfer might be useful to take advantage of the efficacy of CMV reactivation with minimal increase of non-relapse mortality.

Miyamura:Novartis: Speakers Bureau; JRC Nagoya 1st Hospital: Employment. Nakamae:Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other. Fukuda:the Japanese Ministry of Health, Labour, and Welfare: Research Funding.