Outcomes with Mismatched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis
Authors: Mushtaq Muhammad Umair , Shahzad Moazzam , Zafar Muhammad Usman , Arslan Muhammad , Tariq Ezza , Fatima Naira , Bokhari Syeda Sadia , Shahani Javeria , Anwar Iqra , Chaudhary Sibgha Gull , Singh Anurag K. , Abhyankar Sunil , Callander Natalie S. , Hematti Peiman , McGuirk Joseph P. 
Published: November 2021

Abstract
Background
Allogeneic hematopoietic stem cell transplantation (HCT) is the optimal and potentially curative therapy in various high-risk hematologic malignancies. Although a human leukocyte antigen (HLA)-matched sibling or unrelated donor is a clinically preferred stem cell source, the use of haploidentical family donors and umbilical cord blood HCT now offers the option of HCT in patients lacking a matched donor. However, many patients lack an appropriate donor, in particular the ethnic minorities. Mismatched unrelated donors (MMUD) have historically been utilized as alternative donor source for these patients due to ease of donor availability but is associated with increased risk of graft versus host disease (GVHD) and non-relapse mortality (NRM). In this systematic review and meta-analysis, we aimed to assess the outcomes with MMUD HCT.

Methods:
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was performed on three databases (PubMed, Cochrane Library, and ClinicalTrials.gov) from date of inception through February 2021 using the MeSH and entry terms for "hematopoietic stem cell transplantation", OR "hematologic neoplasms", AND unrelated donors" AND "treatment outcome". A total of 2477 records were identified and primary and secondary screening was done. After excluding review, duplicate, and non-relevant articles, we included 13 studies (11 retrospective, 2 prospective) reporting outcomes following MMUD HCT. The Joanna Briggs Institute (JBI) critical appraisal checklist for studies reporting prevalence data and randomized control trial was used for quality assessment, and all studies were reported as good. Proportions along with a 95% confidence interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). The variance between the studies was calculated using Der Simonian-Laird Estimator.

Results:
We identified 2588 patients from 13 included studies who had MMUD HCT. (Table 1) Median age was 51.7 (18-76) years and 52% (n=1347) were males. Source of primary graft was bone marrow (BM) in 19% (n=478/2508) and peripheral blood (PB) in 81% (n=2030/2508) HCT recipients. Median time to transplant was 10.45 (1.5-139.6) months and median follow up was 41.5 (0.4-136.5) months. Reduced intensity conditioning (RIC) conditioning was used for 73% (n=1884) of the patients while 27.2% (n= 704) patients received myeloablative conditioning (MAC). We estimated a pooled overall survival (OS) of 59% (95% CI 0.52-0.66, I 2 = 92%, n=2563) at one year and 44% (0.36-0.53, I 2=92%, n=1972) at three years. The pooled incidence of acute GVHD (grade II-IV), acute GVHD (grade III-IV), and chronic GVHD were 39% (95% CI 0.33-0.44, I 2=84%, n=2282), 19% (95% CI 0.15-0.23, I 2=65%, n=1417), and 38% (95% CI 0.32-0.47, I 2=93%, n=2477) respectively. Progression free survival (PFS) was 39.5% (95% CI 0.31-0.48, I 2=94% n=2505). The pooled incidence of relapse rate (RR) and NRM were 31% (95% CI 0.25-0.38, I 2=90%, n=2482) and 27% (95% CI 0.21-0.34, I 2 =90% n=2448) respectively.

Conclusion:
Mismatched unrelated donor HCT has shown favorable outcomes with acceptable toxicity profile. MMUD HCT represents a promising option for patients lacking an HLA-matched donor and has expanded access to HCT in patients with ethnic minorities who often lack a matched donor.
Figure 1 Figure 1.

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