CMV Replication After Allogeneic Hematopoietic Cell Transplantation and Relapse Risk: Evidence for Early Protection Against Relapse in Acute Leukemia and Lymphoma

Recently an association between cytomegalovirus (CMV) replication after allogeneic hematopoietic cell transplantation (HCT) and decreased risk of relapse was described in a cohort of patients with acute myeloid leukemia (AML) [Blood. 2011;118(5):1402]. We evaluated this proposed protective effect of CMV replication in a larger cohort of consecutive patients with AML (n=761), as well as patients with acute lymphoblastic leukemia (ALL) (n=322), chronic myelogenous leukemia (CML) (n=646), and lymphoma (n=254) who received an allogeneic HCT at the FHCRC between 1995 and 2005. All patients underwent weekly surveillance for CMV replication with pp65-antigenemia through day 100 after HCT. Antiviral therapy with ganciclovir was initiated after any positive antigenemia. In multivariable models, CMV antigenemia at any level was associated with a decreased risk of morphologic relapse by day 100 among patients with AML (adjusted HR 0.56, 95%CI 0.34-0.91, P=0.02), ALL (adjusted HR 0.21, 95% CI 0.05-1.00, P=0.05) and lymphoma (adjusted HR 0.37, 95% CI 0.13-1.02, P=0.05) but not CML (adjusted HR 0.72, 95%CI 0.2-2.3, P=0.58). Higher levels of antigenemia (>10 positive cells, and >10 positive cells for two consecutive weeks) were not associated with incremental protection from relapse for any group.  The effect appeared to be independent of acute GvHD (grade 3-4) or ganciclovir-related neutropenia (ANC< 500).  The association between early CMV reactivation and relapse protection in patients with acute leukemia and lymphoma persisted at 1 year after HCT (adjusted HR 0.69, 95% CI 0.5-0.9, P=0.006) but was undetectable at 3 years.  However, there was no difference in overall survival at either 100 days or 1 year after HCT among patients with any level of CMV antigenemia compared to patients with no CMV reactivation. In conclusion, these data demonstrate an association between CMV reactivation and decreased risk of early relapse among AML, ALL and lymphoma, but not CML, patients after allogeneic HCT. Further laboratory investigations are warranted to define the mechanisms of this protection.