Reduced-Intensity Conditioning Versus Myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis of Randomized Trials
Authors: Kamal Ahmad , Abu Zar Muhammad , Fazeel Hafiz Muhammad , Durer Seren , Durer Ceren , Hassan Syed Shabee , Malik Mustafa Nadeem , Rafae Abdul , Ijaz Faiqa , Aslam Shehroz , Anwer Faiz , Hamadani Mehdi 
Published: October 2019

Abstract
Background:
Allogenic hematopoietic cell transplantation (alloHCT) is a curative option for patients with high-risk myelodysplastic syndrome (MDS). The benefit of higher conditioning intensity in MDS is controversial. While myeloablative conditioning (MAC) regimens can mitigate the risk of relapse, they are associated with higher non-relapse mortality (NRM). In contrast, the reduced intensity conditioning (RIC) regimens are associated with higher risk of relapse. And owing to the lower NRM, they are feasible in patients with advanced age or comorbidities.
Methods:
We report here a systematic review and meta-analysis of randomized controlled trials (RCTs) that directly compared the safety and efficacy of MAC vs RIC regimens in MDS. The efficacy was evaluated in terms of overall survival (OS), relapse-free survival (RFS) and relapse incidence (RI). The safety was evaluated in terms of non-related mortality (NRM) and incidence of acute (a) and chronic (c) graft-versus-host disease (GVHD). A systematic search of databases using PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed on May 6th, 2018 with no restrictions of language or time period. RCTs comparing MAC with RIC regimens that include MDS patients were considered eligible for inclusion. After duplicates removal, a total of 683 articles were scrutinized for relevance by screening the abstracts and/or full length articles. Based on the eligibility criteria, only two randomized studies (BMT CTN 0901 Trial Scott, B. et al. 2017 & EBMT RICMAC Trial Kroger, N. et al. 2017) qualified for inclusion and quantitative synthesis. The quality assessment was done using the Cochrane tool regarding the bias in study selection, performance, detection, attrition and reporting of the clinical trials.
Results:
Out of total 392 MDS and acute myeloid leukemia (AML) patients enrolled in these two trial, 169 patients had MDS (N=115 in Kroger et al and N=54 cases in Scott et al). Eighty one patients received MAC and 88 patients received RIC followed by either a related or unrelated alloHCT. The median age range at the time of transplant was 50-54 years and these patients were followed for a period of 18-24 months. There were no statistically significant differences in the baseline patient characteristics between two regimen groups in the both trials. The use of RIC regimen was associated with a statistically non-significant trend towards improved OS (OR 1.52: 95% CI: 0.93-2.5, p-value= 0.097), along with a significantly reduced risk of NRM (OR 0.39: 95% CI: 0.16-0.94, p-value= 0.04). The RIC alloHCT was not associated with a higher risk of disease relapse (OR: 4.24, 95% CI: 0.34-52.22, p-value= 0.26) or inferior RFS (OR: 0.64, 95% CI: 0.196-2.06, p-value= 0.45). There was no difference between the two conditioning intensities in terms of risk of developing aGVHD (OR: 0.51, 95% CI: 0.11-2.27, p-value= 0.37) or cGVHD (OR: 0.50, 95% CI: 0.18-1.40, p-value= 0.19). The meta-analysis results are shown in figure-1. The Infectious complications were comparable for both groups in Scott, et al. But Kroger et al reported significantly lower overall infections rate at day 100 (4.3 vs. 6.9, p=0.002) and at total follow up (1.4 vs. 2.0, p= 0.002) for RIC.
Conclusion:
In adult patients with MDS undergoing alloHCT, RIC regimens were associated with a significantly lower risk of NRM, without increased risk of relapse, mortality or GVHD. It is unknown if any specific poor risk groups regarding clinical indicators (e.g. IPSS score) or genomic predictors (e.g. p53 mutations or RAS pathway mutations) may benefit from higher conditioning intensity and warrants further investigation.

Disclosures
Hamadani: Sanofi Genzyme: Research Funding, Speakers Bureau; ADC Therapeutics: Research Funding; Ostuka: Research Funding; Janssen: Consultancy; Merck: Research Funding; MedImmune: Consultancy, Research Funding; Cellerant: Consultancy; Celgene Corporation: Consultancy; Takeda: Research Funding.