Impact of Natural Killer Cells Reconstitution on Outcomes after Allogenic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis
Authors: Shahzad Moazzam , Shah Amna Y , Zafar Muhammad Usman , Tariq Ezza , Hamid Anam , Serwat Ayna , Anwar Iqra , Chaudhary Sibgha Gull , Balusu Ramesh , Bansal Rajat , Ahmed Nausheen , Shune Leyla , McGuirk Joseph P. , Mushtaq Muhammad Umair 
Published: November 2021

Abstract
Background:
Natural killer (NK) cells are the first cells to recover following allogeneic hematopoietic stem cell transplant (HSCT) and play a crucial role in enabling engraftment, preventing post-transplant infection and tumor relapse. In addition, NK cells also reduce the risk of graft versus host disease (GvHD) and increase the graft versus leukemia effect (GVL). The purpose of this systematic review and meta-analysis is to know the impact of NK cells reconstitution on outcomes of allogeneic HSCT.

Methods:
Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane Library, and ClinicalTrials.gov through January 2021. We used MeSH terms and keywords for "hematologic malignancies" OR "hematopoietic stem cell transplantation" AND "natural killer cells." No filters or publication time limits were applied for the search. A total of 13 studies were included after screening 988 records and excluding duplicates, review, and non-relevant articles. An arbitrary value of NK cell count of 22.2 cell/ul was set as a cut-off to divide between high and low groups of NK where applicable. Quality evaluation was done using the NIH quality assessment tool and Inter-study variance was calculated using Der Simonian-Laird Estimator. Pooled analysis was done using the 'meta' package (Schwarzer et al. R programming language), and proportions with 95% confidence intervals (CI) were computed.

Results:
A total of 1623 patients were evaluated from 13 studies. (Table 1) The median age of patients was 44 (8.6-63) years and 33.5% were males. The median duration of follow-up was 18 (0.3-122) months. The median 2-year overall survival (OS) for high NK cohort and low NK cohort was 77% (95%CI 0.70-0.83, I 2 =82%, n=982) and 52%(95%CI 0.38-0.67, I 2 =95%, n=982), respectively. The pooled rate of relapse in high NK group was 8% (95%CI 0.01-0.19, I 2 =83%, n=226) and it was 20% (95%CI 0.06-0.39, I 2 =90%, n=226) for low NK group. The pooled incidence of acute GvHD was 24% (95%CI 0.09-0.42, I 2 =91%, n=336) and 44% (95%CI 0.26-0.62, I 2 =91%, n=336) for high and low NK cohorts, respectively. The pooled incidence for viral infection for high NK group was 17% (95%CI 0.01-0.47, I 2 =98%, n=508) while it was 29% (95%CI 0.04-0.65, I 2 =98%, n=508) for low NK group, respectively.

Conclusion:
Higher reconstitution of NK cells after allogeneic hematopoietic stem cell transplant has a favorable impact on outcomes, including better overall survival and low incidence of relapse, acute GvHD, and viral infections. Our findings suggest the need for further prospective studies to investigate utility of NK cells infusion early post-transplant to improve clinical outcomes and survival.
Figure 1 Figure 1.

Disclosures
McGuirk: Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Astelllas Pharma: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding.