The relationship between circulating natural killer cells after reduced intensity conditioning hematopoietic stem cell transplantation and relapse-free survival and graft-versus-host disease

Abstract

Natural killer cells are known to have anti-tumor activity in haploidentical hematopoietic stem cell transplantation. We hypothesized that reconstituted circulating natural killer cells may be associated with improved relapse-free survival after HLA-matched hematopoietic stem cell transplantation. Serial peripheral blood absolute natural killer cell counts were prospectively measured by flow cytometry of lymphocytes expressing CD56 and CD16 in 167 patients. Cluster analysis was used at engraftment and 60 days post-transplant to distinguish patients with high and low absolute natural killer cell counts. At engraftment 80 patients had high counts (> 22.2/mm3) and 43 had low counts. At 60 days post-transplant 84 patients had high counts (> 18.2/mm3) and 38 had low counts. The primary study end-points were death, relapse and acute graft-versus-host disease. The median follow-up was 373 days (range, 67-1767). Among patients given reduced intensity conditioning, a low absolute natural killer cell count at 60 days post-transplant was independently associated with relapse [adjusted hazard ratio (AHR) = 28.4, 95% confidence interval (CI) 4.3-186.4] and death (AHR = 17.5, 95% CI 4.3-71.3). Furthermore, patients given reduced intensity conditioning who had a high absolute natural killer cell count at 60 days had a significantly better 1-year survival than those with a low count by Kaplan-Meier analysis (83% vs. 11%, p<0.001). Multivariate analysis confirmed that low 60-day absolute natural killer count in patients given reduced intensity conditioning was independently associated with an increase in relapse or death (AHR = 20.22, 95% CI 4.76-85.40). In contrast, there was no significant association between 60-day absolute natural killer cell counts and clinical outcomes in patients receiving myeloablative conditioning. There was no significant association between absolute natural killer cell count and graft-versus-host disease. High natural killer cell reconstitution is associated with reduced relapse and death without an increased incidence of graft-versus-host-disease after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Measuring reconstituted natural killer cells expressing CD56(+)/CD16(+) post-transplant may have novel prognostic and therapeutic implications.