56+ Cell Reconstitution Kinetics in HLA Matched Unrelated Donor Allografts: What Doesn't Kill You Makes You Stronger

Abstract

Introduction Patients who receive HLA matched allogeneic hematopoietic cell transplant (HCT) from donors with killer immunoglobulin-like receptor (KIR) haplotype B have improved survival, decreased acute GVHD, and less CMV reactivation when compared with those transplanted with KIR haplotype A donors. However, the effect of NK cell (CD56+) reconstitution kinetics on clinical outcomes in patients with different KIR haplotypes is not well studied. Objectives Compare CD 56+ cell reconstitution kinetics in HCT patients with donor KIR Haplotypes A and B and its effect on clinical outcomes. Methods We assessed absolute NK and T cell counts at days +30, +60 and +100 in 10/10 allele level HLA matched unrelated HCT recipients with known donor KIR typing. KIR haplotype B was assigned when KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5 or KIR3DS1 were present in the donor, and haplotype A in their absence. We also evaluated potential impact of NK cell and T cell count recovery on key post transplant outcomes in these patients. Results The study population consisted of 60 adult HCT patients with a median age of 52 years; 55% had lymphoid and 45% had myeloid disease; 57% received a reduced intensity conditioning regimen; 82% underwent T cell depletion with ATG; 88% received GCSF mobilized PBSCT. Recipients of donor haplotype A had a median absolute CD56+ cell count of 210mL−1 (±156) on day (d) +30; 189 (±225) on d+60, and 160 (±120) on d+100; recipients of haplotype B had median absolute CD56 cell counts of 286 (±276) on d+30, 196 (±194) on d+60, and 165 (±124) on d+100 (P=N.S. for haplotype B vs. A). As a whole, median CD56+ cell counts peaked at d+30 post HCT, a phenomenon more pronounced in haplotype B (fig. 1), and then declined at d+60 and d+100. There was no correlation between CD56 and CD3 at d+60. Survival was superior in patients who had CD56+ cell count > median for the entire cohort (227 µL−1) on d+60 (p= .039) (fig. 2); ROC-AUC analysis confirmed the deleterious effect of low NK cell counts, with a higher mortality rate observed in those with CD56+ cell count of Conclusions The magnitude of NK cells reconstitution at d+60 may override the effect of KIR Haplotype on survival in patients with myeloid and lymphoid malignancies, as well as play an important role in controlling viral reactivation. Our data demonstrates that poor NK cell recovery does not necessarily imply delayed T cell reconstitution; suggesting that the adverse survival effect may be NK cell mediated. Ongoing work is examining relationship between NK- and T-cell reconstitution as well as KIR-KIR ligand interactions, and clinical outcomes.