Recovery of Specific Subsets of Natural Killer and T Cells Highly Associated with Graft-Versus-Host Disease after Haploidentical Stem Cell Transplantation in Acute Leukemia

Background In the allogeneic hematopoietic stem cell transplantation, recent studies showed that T cell and natural killer (NK) cells recovery are implicated in the graft-versus-host disease (GVHD) and graft versus leukemia (GVL) effects. However, the significance of specific subsets of NK and T cell recovery in relation to transplantation outcomes remains to be elucidated in the haploidentical stem cell transplantation (haploSCT). Methods Clinical data of patients with acute myeloid leukemia (n = 21) and acute lymphoblastic leukemia (n = 24) who underwent their first haploSCT between September 2009 and December 2017 were analyzed. Peripheral blood mononuclear cells obtained from 27 patients were examined by multiparametric flow cytometric analysis. PD-1 and Tim-3 expression were examined in CD4+ and CD8+ T-cells and NK cell receptor (NKG2D, NKG2A, NKG2C, DNAM1 and NKp46) expression were analyzed in NK cells, respectively, at the 3 determined times (immediate prior to conditioning therapy, 28 and 90 days after haploSCT). Results Median age at haploSCT was 38 years (range, 21-62) and median follow-up duration was 31.6 months. Myeloablative conditioning was used for 32% and reduced intensity regimen for 68% of patients. GVHD prophylaxis was based on post-transplant cyclophosphamide for 8 (18%) or on anti-thymocyte-globulin for 36 (82%) plus standard prophylaxis. Incidence of grade II-IV acute GVHD was 50%, gastrointestinal tract (GIT) GVHD was 55.6%, non-GIT acute GVHD 35.7%, and chronic GVHD was 52.4%. Longitudinal analysis of immune reconstitution after haploSCT showed that the incidence of acute GVHD was associated with a delayed expansion of the NK cell population and incidence of chronic GVHD was associated with the extent of CD4+ T cell reconstitution. The incidence of acute GVHD was significantly higher in patients with lower counts of CD56bright CD16neg cell (100% for patients with less than 30 cells/uL at day 28 vs 50% for patients with higher counts, P = 0.026), particularly in NKG2A (P = 0.002) and DNAM1 (P = 0.027)-positive NK cell subsets. In univariate analysis, early CMV replication (P < 0.001), chronic GVHD (P = 0.001), donor age ≥ 28years (P = 0.018), CD4/CD8 ratio of product ≥ 2.4 (P = 0.033), and dose of infused T cells ≥ 3.91 x 108 /kg (P = 0.022) were significantly associated with lower 3-year cumulative incidence of relapse after haploSCT. Donor age ≥ 28years was significantly associated with high incidence of chronic GVHD (P = 0.002).