The EBMT Score Predicts Transplant Related Mortality and Overall Survival after Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes
Authors: Lozano Sara , Olavarria Eduardo , Iacobelli Simona , van Biezen Anja , Beelen Dietrich W. , Finke Jurgen , Mufti Ghulam J , Niederwieser Dietger , Ehninger Gerhard , Ganser Arnold , Stuhler Gernot , Maertens Johan , Bacigalupo Andrea , Volin Liisa , Nagler Arnon , Kobbe Guido , Schönland Stefan , de Witte Theo , Kröger Nicolaus , Robin Marie 
Published: October 2019

Abstract
Introduction: Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) is still the only curative treatment for myelodysplastic syndromes (MDS). However, the so far perceived high transplant related mortality (TRM) limits the number of patients referred for alloSCT.
Materials (or patients) and methods: We retrospectively analyzed 9741 consecutive patients diagnosed with primary or secondary MDS aged 18 or older undergoing allogeneic transplantation at EBMT centers between 1997 and 2013. Cord blood and haploidentical donors and second or further transplants were excluded.
Results: Patients´ characteristics: Median age at time of transplant was 54.9 years (18-79) with 5804 patients (60%) being male. WHO classification at transplant (available from 2009) in 4033 patients showed: 634 (16%) patients with RA/RARS/del5q, 406 (10%) with RCMD (+/-RS), 964 (24%) with RAEB-1, 1707 (42%) with RAEB-2 and 322 (8%) with secondary AML. A total of 1437 (19%) patients had secondary MDS.
Transplant characteristics: Peripheral blood was the preferred source of stem cells (82.5%).The conditioning was reduced intensity in 4987 (53%) and myeloablative in 4492 (47%). The reasons for RIC included institutional protocol (44%), patient age (38%) and co-morbidities (14%).Donor was unrelated in 5475 (56%) patients and an HLA-identical sibling in 4266 (44%). GvHD prophylaxis consisted of cyclosporine and short-course MTX with (1585 patients - 16%) or without (1906- 20%) in vivo T-cell depletion with alemtuzumab or ATG. In addition, MMF was used instead of MTX in 1320 (14%) and 751 (8%) patients respectively. The EBMT risk score reported by Gratwohl et al. was calculated in our cohort (Table 1). The EBMT score separated patients into 3 groups: low risk (0-2 points, n=1949, 22%), intermediate risk (3-4 points, n=4795, 53%) and poor risk (5-7 points, n=2229, 25%).
Primary and secondary graft failure was reported in 419 (4%) and 71 (0.7%) patients respectively. Grade 0-I GvHD developed in 6314 (69%) and grade II-IV in 2789 (31%). 2270 (23%) patients relapsed during follow-up. At time of analysis, 4390 (45%) patients were alive without relapse and 4902 (50%) of patients had died, of whom 3081 (32%) never relapsed. We analyzed the cause of death of this latter population: 1004 (33%) died of GvHD, 996 (32%) due to infections, 86 (3%) of haemorrhages, 130 (4%), due to multi-organ failure, 69 (2%) of secondary malignancies and 796 (26%) from other causes.
The overall survival was 60% at 12 months and 41% at 5 years. The EBMT score strongly separated patients with good (50%), intermediate (41%) and poor (31%) survival at 5 years (p<0.001). TRM was 27% at 12 months and 37% at 5 years. TRM for patients with a low EBMT score was 20% at 12 months compared with 26% and 35% for intermediate and poor-risk EBMT scores respectively (p<0.001). No differences in the cumulative incidence of relapse among the three EBMT score risk groups (CI at 3 years for low was 27%, intermediate 25% and poor risk 26%). For patients with RA/RARS/del5q and low-risk EBMT score, the TRM was 23% at 5 years.
We found small but statistically significance differences in TRM in favor of patients who received reduced intensity vs myeloablative conditionings (p=0). In addition, the overall TRM at 12 months has slightly improved (p=0.008): 1997-2001 (32%), 2002-2006 (27%) and 2007-2013 (26%).
Conclusion: The EBMT Score accurately predicts OS and TRM but does not correlate with the relapse risk. The TRM for MDS patients after alloHSCT is lower than previously described and this should no longer be an obstacle for referring patients for transplantation. Patients with low risk MDS (RA/RARS/del5q) who are otherwise candidates for alloHSCT, should expect a low TRM of 23% at 5 years from transplant if their EBMT score is low.
Table 1. EBMT Risk Score RISK FACTOR POINTS PATIENTS (%) AGE OF PATIENT (years) <20 0 129 (1%) 20-40 1 1542 (16%) >40 2 8070 (83%) DISEASE STATUS Early (first CR, untreated) 0 5575 (62%) Intermediate (second CR, PR) 1 1163 (13%) Late (other) 2 2283 (25%) TIME INTERVAL DIAGNOSIS-TRANSPLANT (months)* Does not apply if CR <12 0 6154 (63%) >12 1 3587 (37%) DONOR TYPE HLA-identical sibling 0 4266 (44%) Unrelated, other 1 5475 (56%) DONOR RECIPIENT SEX COMBINATION All other 0 7679 (81%) Female donor, male recipient 1 1847 (19%)
Figure 1. OS by EBMT Score Figure 1. OS by EBMT Score Figure 2. NRM by EBMT Score Figure 2. NRM by EBMT Score

Disclosures
Niederwieser: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Schönland:Janssen, Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.