Higher Dose of CD34+ cells Promotes Early Reconstitution of Natural Killer Cells and Is Associated with Better Outcomes After Unmanipulated Hematopoietic Stem Cell Transplantation for Myeloid Malignancies

Abstract

Natural killer (NK) cells are the first lymphocyte population to recover after allogenic hematopoietic stem cell transplantation (allo-HSCT) and mediate potent graft versus leukemia effect, particularly in the settings of T-cell depletion. However, the significance of NK cells after unmanipulated transplantation is less clear, and factors affecting early NK reconstitution remain elusive. We retrospectively analyze 180 patients with acute myeloid leukemia or myelodysplastic syndrome who received unmanipulated allografts. We focus on the early NK reconstitution and its association with disease relapse, overall survival, and cytomegalovirus (CMV) reactivation. We also analyze factors that affect NK recovery, such as dose of CD34⁺ cells in the graft and T-cell recovery after transplantation. Penalized splines and receiver operator characteristic curves demonstrate a strong association between blood NK counts at 30 days after allo-HSCT (NK30) and all-cause mortality, with the cutoff value being close to the median value that divides patients dichotomously. Subsequent analysis shows that rapid NK recovery (higher NK30 or higher NK60) is associated with reduced disease relapse and better survival. Robust NK recovery (NK30 and NK60) also correlates with lower incidence of CMV reactivation. We find that NK30 is associated with the numbers of CD34⁺ cells (r = 0.739, P < .001) but not mature NK cells contained in the graft. In a small subset (N = 12) of the cohort, patients in continuous complete remission (N = 6) demonstrate higher frequencies of CD34⁺CD7⁺ progenitor cells and CD56^bright NK cells in the day 30 bone marrow as compared to patients with disease relapse within 1 year (N = 6). Furthermore, neither T-cell recovery after transplantation nor application of anti-thymocyte globulins (ATG) in the conditioning regimen demonstrate suppressive effect on NK recovery. Rapid NK cell recovery is associated with improved prognosis of unmanipulated transplantation for myeloid malignancies. Manipulation of NK cell recovery represents a feasible approach to improve transplant outcomes for example by optimizing CD34⁺ cells in the graft.

Keywords: Allogeneic hematopoietic stem cell transplantation; CD34; Immune reconstitution; Natural killer; Relapse.