Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome in Young Adults. a Retrospective Study on Behalf of the Chronic Malignancies Working Party of the EBMT
Authors: Jimenez Jimenez Antonio M. , Eikema Dirk-Jan , Koster Linda , Tuffnell Joe , Kulagin Alexander , Vydra Jan , Kröger Nicolaus , Halahleh Khalid , Parovichnikova Elena , Huang He , Potter Victoria , Gedde-Dahl Tobias , Reményi Péter Pál , Passweg Jakob , Koc Yener , Clesham Katherine , Cerretti Raffaella , Rabitsch Werner , Onida Francesco , Gurnari Carmelo , Scheid Christof , Drozd-Sokolowska Joanna , Raj Kavita K , Robin Marie , McLornan Donal P 
Published: December 2024

Background
Myelodysplastic syndromes (MDS), primarily a disease of the elderly, can sporadically affect younger adults and pediatric patients. Available data suggest distinct pathophysiologic and molecular features in younger MDS patients. Although allogeneic hematopoietic cell transplantation (alloHCT) is the only curative treatment for MDS, there is limited data on the clinical outcomes of younger patients following alloHCT.
Methods
The outcomes of young adults (18-40 years) with MDS who received their first alloHCT between 2016 and 2021 in 220 participating centers reporting to the EBMT were analyzed. Individuals were stratified by age at HCT (18-29 vs. 30-40), Revised International Prognostic Scoring System (R-IPSS) cytogenetic risk, and conditioning intensity, among other factors. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and acute and chronic graft-versus-host disease (a/cGVHD).
Results
Overall, 697 patients met the inclusion criteria for the study. The median age was 31.1 years (IQR 25.9-36), and 52% of the cohort (N=364) were male; the majority had high (&gt;90%) Karnofsky Performance Status (75%, N=492) and low Hematopoietic Cell Transplantation-Comorbidity Index (61%, N=385). The most common MDS subtype was MDS with increased blasts (IB) 1-2 (47%, N=312). Cytogenetic information was available for 82% of patients, with low-risk per R-IPSS being the most common group (49%, N=279). A myeloablative conditioning regimen was used in 68% of patients, and 83% received a peripheral blood graft. Notably, 28% of patients received treatment prior to HCT, the most common being a hypomethylating agent-based regimen (47% of those treated). Overall, 40% of patients (N=261) received a graft from a matched unrelated donor, followed by a matched sibling donor (MSD) (29%, N=190). The majority (52.7%, N=362) received GVHD prophylaxis with an anti-thymocyte globulin-based regimen. The median time from diagnosis to transplant was 6 months (4-12).
With a median follow-up of 2.8 years (2.5-3), OS was 77% and 69% at 1 and 3 years, respectively. The leading causes of death following HCT were infection (N=63, 36%), GVHD (N=51, 29%), and disease relapse/progression (N=31, 17%). PFS was 71% and 62% at 1 and 3 years, respectively. CIR and NRM were 13% and 16% at 1 year and 20% and 18% at 3 years. The cumulative incidence of grade II-IV aGVHD at day +100 and extensive cGVHD at 3 years were 28% and 18%, respectively.
There were no significant differences between younger and older age groups in OS (73% vs. 66% at 3 years, p=0.2), NRM (15% vs. 17% at 1 year, p=0.3), CIR (16% vs. 22% at 3 years, p=0.08), grade II-IV aGVHD (27% vs. 29% at 100 days, p=0.4), or cGVHD (39% vs. 38% at 3 years, p&gt;0.99). PFS was better at 1 year (74% vs. 69%) and at 3 years (68% vs. 58%) for those younger than 30 (p=0.039). Patients with very-poor risk cytogenetics had higher relapse rates at 3 years (40% vs. 15% for those with low-risk disease, p=0.002), resulting in lower PFS (32% vs. 72%, p&lt;0.001) and OS (43% vs. 79%, p&lt;0.001). Additionally, cytogenetics influenced NRM (11% for good risk vs. 28% for very-high risk, p=0.03). Cytogenetics did not affect the incidence or severity of GVHD.
On multivariable analysis, very-poor versus good risk cytogenetics (hazard ratio [HR] 3.18 [1.96-5.16], p&lt;0.001), IB1-2 vs other MDS subtypes (HR 1.65 [1.22-2.25], p=0.001), haploidentical donor versus MSD (HR 2.54 [1.64-3.93], p=0.001), and reduced-intensity conditioning (RIC) vs myeloablative conditioning (HR 1.66 [1.23-2.24], p=0.001) were associated with worse OS. PFS was similarly affected by very-poor risk cytogenetics (HR 2.82 [1.79-4.45], p&lt;0.001), MDS disease subtype (HR 1.83 [1.37-2.43], p&lt;0.001), haploidentical donor (HR 1.72 [1.15-2.57], p=0.009), and RIC (HR 1.48 [1.12-1.95], p=0.006), as well as older age (HR 1.03 [1.01-1.05], p=0.01).
Conclusion
AlloHCT is an effective curative strategy for young patients with MDS, with most experiencing favorable long-term OS and PFS. Outcomes are primarily influenced by cytogenetic risk, disease subtype, and conditioning intensity. Patients younger than 30 exhibited better PFS, whereas those with very poor risk cytogenetics had notably higher relapse rates, resulting in poorer OS and PFS. Reduction of relapse rates in this high-risk group represents an unmet clinical need.