Alternative-Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Pediatric Patients: A Systematic Review and Meta-Analysis
Authors: Elsabbagh Eman M. , Abunar Osama , Habbal Ammar , Tanbour Mohammad , Mansour Ahmed , Sarhan Mohamed , Elkaryoni Ahmed , Badawy Sherif M. 
Published: October 2019

Abstract
Background
Allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched sibling donor for patients with sickle cell disease (SCD) provides excellent curative potential with acceptable rates of graft rejection and other common post transplant complications. However, in the United States, only 18% of patients with SCD have an HLA-matched sibling donor. Hence, multiple studies adopted various strategies to figure out alternative donors with favorable outcomes. Poor engraftment, graft versus host disease (GVHD) and regimen related toxicities are the main obstacles following alternative-donor transplant. To overcome these complications, different modalities had been experimented targeting the source of the stem cell, CD34 and TNC cell counts, pre-transplant conditioning regimens and adding immunosuppressive drugs pre/post transplant. However, so far there is no worldwide consensus about robust strategy for alternative donor HSCT.
Aim
The aim of this review is to systematically evaluate the outcomes of alternative-donor HSCT in patients with SCD in pediatric population, and correlate the outcomes with experimented interventional regimens.
Methods
We searched PubMed, SCOPUS, Embase, Cochrane and Clinical trials.gov from 2000 till February 2018. We utilized the Systematic Reviews and Meta-Analyses guidelines for Preferred Reporting Results (PRISMA). Two reviewers independently screened titles/abstracts, assessed full-text articles, extracted data from included articles, and assessed their quality. Risk of bias in the included studies was assessed using ROBINS-I tool. Data of platelet/neutrophil recovery, acute/chronic GvHD incidence and overall survival were pooled in a single-arm meta-analysis approach.
Results
Of the 2886 records examined, 19 met predefined criteria. 16 studies were included in the meta-analysis. 12 clinical trials, 5 cohort observational studies and 2 case reports. All studies had a sample size <50. The pooled times of platelet and neutrophil recovery were 31.55 and 20.15 days, respectively. The pooled incidences of acute and chronic GvHD were 36.1% and 21.7, respectively (Figure 1). The pooled one-year overall survival was 90.3% and two-years was 88.3%. Neutrophil engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 16 days (7-32) compared to 23 days (12-42) after Myelo-ablative Conditioning, (P=0.013). Platelet engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 29 days (15-204) in comparison to 62 days (18-123) after Myelo-ablative Conditioning, (P=0.026). The median duration of neutrophil engraftment after mismatched related donors was 14 days (14-17), after unrelated donors was 14 days (9-25) , after haplo-identical transplantation was 14 days (12-16), after umbilical cord blood transplantation (UCBT) was 23 days (7-42), (P=0.001). The median duration of platelet engraftment after haplo-identical and mismatched related transplantation was 19 days, after matched unrelated donors was 19 days (18-24), after mismatched unrelated donors was 22 day (19-37) and after UCBT was 47 days (15-204), (P=.001). There was no significant difference in acute/chronic GvHD between different types of alternative donors but acute GvHD was significantly less in Myelo-ablative Conditioning compared to Reduced Intensity Conditioning (P=.036)
Conclusion
Our systematic review showed better outcomes with using Myelo-ablative Conditioning and post transplant cyclophosphamide in haplo-identical transplantation compared to using Reduced Intensity Conditioning. Adding pre-transplant immunosuppressive drugs in haplo-identical transplantation didn't significantly improve the outcomes. In unrelated donor no significant difference between Myelo-ablative Conditioning and Reduced Intensity Conditioning but adding Mesenchymal Stem Cell to the reduced intensity regimen improved the outcomes. In UCBT and mismatched related donors, Reduced Intensity Conditioning had better outcomes especially with high doses of TNC and CD34 cell counts and with applying Mesenchymal Stem Cell or adequate dose of Alemtuzumab. Randomized controlled trials are mandated to generate standardized regimen in the setting of alternative-donor HSCT.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.