Unrelated Donors Are Associated with Improved Relapse Free Survival Compared to Related Donors in Patients with Myelodysplastic Syndrome Undergoing Reduced Intensity Conditioned Allogeneic Stem-Cell Transplantation
Authors: Yam Clinton , Crisalli Lisa , Luger Selina , Loren Alison , Hexner Elizabeth O , Frey Noelle , Mangan James , Gao Amy , Stadtmauer Edward A. , Porter David , Reshef Ran 
Published: October 2019

Abstract
Background: Reduced intensity conditioned allogeneic stem-cell transplantation (RIC alloSCT) is a potentially curative approach for the treatment of myelodysplastic syndrome (MDS). The median age of onset of MDS is typically greater than 65 and prognosis is related to disease-specific variables such as the IPSS score and WHO classification. We have previously shown that young unrelated donors might be better than older related donors in the setting of RIC alloSCT, possibly due to age-related differences in graft CD8 T-cell content (Reshef et al, JCO 2015). Here we report results of a multi-variable analysis aimed at determining the optimal donor for patients (pts) with MDS.
Methods: We retrospectively studied 53 consecutive pts who underwent RIC alloSCT conditioned with Flu/Bu from April 2007 - June 2014. Cumulative incidence and Cox regression analyses were used to evaluate associations between donor type and outcomes. Multivariable models were adjusted for significant covariates. Death was considered a competing risk for relapse and graft versus host disease (GVHD) outcomes.
Results:
Patients: Median age at transplant was 63 (range 50-72). Pts were allografted from HLA matched related donors (36%) or unrelated donors (64%). Median time from diagnosis to transplant was 11.7 months (range 4.5-135.8). There were no differences in median age at transplant, IPSS score at diagnosis and WHO classification at diagnosis/transplant (Table 1). Median time from diagnosis to transplant for pts receiving allografts from unrelated donors was 14.9 months (range 5.0-135.8) versus 9.2 months (range 4.5-98.0) in pts who had a related donor. This difference was of borderline statistical significance (p=0.0504).
Outcomes: Pts who received grafts from unrelated donors had a decreased risk of relapse (adjusted hazard ratio [aHR]=0.36, 95% CI [0.15-0.86], p=0.02) and improved relapse free survival (aHR=0.45, 95% CI [0.23-0.88], p=0.02) (Fig 1). The 1-year survival rates were 41% (95% CI [24.8-56.9]) for unrelated allografts and 17% (95% CI [3.5-38.8]) for related allografts. Pts who had HLA mismatched unrelated donors had a significantly higher risk of developing acute grade 2-4 GVHD (aHR=5.7, 95% CI [2.0-16.3], p=0.001) as compared to those who had related donors. Having an HLA matched unrelated donor was also associated with an increased risk of acute grade 2-4 GVHD (aHR=2.8, 95% CI [1.1-7.1], p=0.03). Rates of severe (grade 3-4) GVHD and chronic GVHD were not significantly different between donor types.
Donors: Median donor age at the time of transplantation was 39 (range 19-72). Unrelated donors were significantly younger than related donors (p<0.001, Table 1). We then analyzed whether donor age and type affected graft T-cell content. Donor age correlated inversely with CD8 cell doses (r=-0.39, p = 0.01, Fig 2) but did not have a significant association with CD34 (r=-0.19, p=0.19) or CD4 cell doses (r=-0.11, p=0.49). Unrelated and related donors provided a mean CD8 cell dose of 0.69 x 108/kg (95% CI 0.53-0.85) and 0.42 x 108/kg (95% CI 0.26-0.59) respectively (p=0.030). In contrast, there were no significant differences in mean CD34 (p=0.28) and CD4 cell doses (p=0.14) between grafts from unrelated and related donors.
Conclusion: In this study, pts with MDS who received allografts from unrelated donors had a lower risk of relapse and improved relapse free survival when compared to pts who received allografts from related donors in the setting of an RIC alloSCT. Unrelated donors were younger and provided grafts with higher CD8 cell doses. Confirmation of these findings in a prospective study is warranted.
Table 1. Baseline characteristics of patients and donors Unrelated donor (n=34) Related donor (n=19) p value Median recipient age at transplant - yrs (range) 64 (50-72) 60 (52-70) 0.15 Median donor age at transplant - yrs (range) 32 (19-53) 60.5 (42-72) <0.001 Median time from diagnosis to transplant - mths (range) 14.9 (5.0-135.8) 9.2 (4.5-98.0) 0.05 IPSS score at diagnosis Low/Int-1 - no. (%) 12 (35) 8 (42) 1.00 Int-2/High - no. (%) 15 (44) 9 (47) Unknown - no. (%) 7 (21) 2 (11) WHO classification at diagnosis RAEB1/2 - no. (%) 14 (41) 10 (53) 0.58 Other - no. (%) 18 (53) 9 (47) Unknown - no. (%) 2 (6) 0 WHO classification at transplant RAEB1/2 - no. (%) 6 (18) 4 (21) 0.72 Other - no. (%) 26 (77) 13 (68) Unknown - no. (%) 2 (6) 2 (11)
Figure 1. Impact of donor type on relapse free survival Figure 1. Impact of donor type on relapse free survival Figure 2. Effect of donor age and relatedness on CD8 cell dose Figure 2. Effect of donor age and relatedness on CD8 cell dose

Disclosures
Loren: Merck: Research Funding. Frey:Novartis Pharmaceuticals Corporation: Research Funding. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Other: Spouse employment; Novartis: Other: IP interest, Research Funding.