Early Cytomegalovirus Reactivation and Expansion of CD56brightCD16dim/-DNAM1+ Natural Killer Cells Are Associated with Antileukemia Effect after Haploidentical Stem Cell Transplantation in Acute Leukemia

Abstract

Cytomegalovirus (CMV) infection is a major complication after allogeneic hematopoietic stem cell transplantation but is suggested to exert a strong antileukemia effect in part due to alterations in the composition of natural killer (NK) cells. We evaluated the impact of early CMV reactivation and changes in NK cell subset recovery on relapse rate and survival after haploidentical stem cell transplantation (haploSCT) for acute leukemia. Fifty patients with acute leukemia who received haploSCT were analyzed. Expression of T cells and specific receptors (NKG2A, NKG2D, DNAM1, and CD57) on circulating NK cells (CD56^brightCD16^dim/- or CD56^dimCD16⁺ cells) was serially measured using multiparametric flow cytometry. CMV reactivation during the first 100 days was observed in 41 patients (82%) at a median of 23 days after haploSCT. The incidence of acute graft-versus-host disease (GVHD) and chronic GVHD tended to be higher in patients with CMV reactivation, although this difference was not statistically significant. Multivariate analysis showed that CMV reactivation (P = .011) and a dose of infused T cells > 3.2 × 10⁸/kg (P = .027) were independent predictors of a reduced relapse risk and only CMV reactivation (P = .029) was an independent predictor of improved leukemia-free survival. CD56^brightCD16^dim/-DNAM1⁺NK cell counts increased from day 30 to 90 in patients with CMV reactivation but decreased after day 30 in patients without CMV reactivation. An increase in CD56^brightCD16^dim/-DNAM1⁺ NK cells was not associated with the occurrence of chronic GVHD but was associated with a reduced cumulative relapse rate (16.4% versus 58.0%, P = .019). Multivariate analysis indicates that an increase in the CD56^brightCD16^dim/-DNAM1⁺NK cell count was an independent predictor of reduced relapse risk. Our study demonstrates a significant correlation between low relapse rates and CMV reactivation as well as the recovery of CD56^brightCD16^dim/-DNAM1⁺ NK cells, providing valuable information for understanding the plausible immunologic mechanism of the graft-versus-leukemia effect.

Keywords: Acute leukemia; Cytomegalovirus; DNAM1; Haploidentical stem cell transplantation; Natural killer cells; Relapse.