Cytomegalovirus Reduces the Relapse Risk for Acute Leukemia After Transplant: There Is a Virus-Versus-Leukemia Effect.

Abstract 2261

Poster Board II-238

Cytomegalovirus reactivation (HCMV) occurs frequently after hematopoetic stem cell transplantation and is associated with an increased treatment-related mortality. We aimed first to evaluate the cytotoxic effects of CMV on AML in vitro, and further, the clinical outcome of patients with AML with a documented CMV reactivation after transplant.

First, we show that HCMV infects acute leukemia cell line Kasumi-1 (AML) and SD-1 (ALL), inhibits their proliferation and induces apoptosis almost in all cells after 14 days. HCMV further inhibits the proliferation of bone marrow progenitor cells derived from healthy volunteers as demonstrated here by the reduction of the number and size of colony forming units in methylcellulose assays. The induction of apoptosis is unusual because HCMV possesses various strategies to prevent apoptosis in infected cells in order to delay their cell death and maintain its own virus replication. Apoptosis via a caspase-dependent pathway occurred although HCMV induced a significant up-regulation of the anti-apoptotic gene cFLIP and anti-stress gene Gadd45a and simultaneously down-regulation of pro-apoptotic genes p53, Bcl-2, Gadd45γ in Kasumi-1 and SD-1 cells, showing that the anti-apoptotic mechanisms of HCMV to prevent cell death failed. Concordantly, the coapplication of the caspase-specific inhibitor zVAD.fmk to HCMV- infected Kasumi-1 cells inhibited the induction of apoptosis to a great extent.

In the second part of our study we evaluated the clinical outcome of patients with AML after transplant in whom a HCMV reactivation occurred. We evaluated a homogenous group of 140 patients with AML after myeloablative conditioning, non-T cell depleted allogeneic HSCT from a HLA-identical sibling donor, and compared the clinical results to 60 patients with CML after transplant. CMV reactivation was documented by CMV-related matrix protein pp65 antigenemia test and routinely accompanied by a CMV preemptive therapy with ganciclovir.

CMV reactivation in AML patients was associated with reduced risk for relapse (11.6% v 50.5%; p&lt;0.0001) and improved overall survival estimates (73.6% v 42.5%, p=0.039), but increased risk for acute graft-versus-host-disease (GVHD) grade 2-4 (75.1% v 37.5%, p=0.004) and TRM in our analyses, whereas CML-patients had no advantageous effects. Multivariate analyses for risk of relapse confirmed CMV reactivation as an independent factor (RR 0.15, 0.03-0.67;[95% CI], p<0.013) besides chronic GVHD, disease stage, and cytogenetics.

We show here for the first time a strong anti-leukemic effect of HCMV in AML, which improves the outcome of patients after transplant, and might be defined as “virus versus leukemia effect”.