Myelodysplastic syndromes (MDS), commonly seen in elderly patients, represent a heterogeneous group of clonal hematopoietic stem cell disorders caused by the accumulation of gene mutations. By contrast, congenital bone marrow failure syndromes and genetic predispositions associated with MDS are known in pediatric patients. However, little is known about the pathogenesis of MDS in adolescent and young adult (AYA) patients. Previous reports showed the patients with MDS aged under 40 or 41.5 years at allo-HSCT were associated with good survival compared to those among the older population (N Engl J Med. 2017;376:536-547, Blood. 2017;129:2347-2358). However, AYA-MDS is rare, and its clinical features and genetic abnormalities have not been analyzed enough. It is suspected that the clinical and genetic features of AYA-MDS patients might be different from those of elderly patients or pediatric patients. Therefore, we investigated the gene abnormalities of AYA-MDS patients and aimed to elucidate the genetic characteristics associated with the good outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We analyzed the patients younger than 50 years of age in order to reduce the variation of patient-related factors.


We analyzed the outcomes of all consecutive patients aged under 50 years who were diagnosed with MDS or acute myeloid leukemia evolving from MDS in our hospital between January 2005 and July 2018. The study was approved by the institutional review board, and patients gave written informed consent for the study, according to the Declaration of Helsinki. Cytogenetic analysis and genomic DNA extraction were carried out using diagnostic bone marrow samples. We performed targeted next-generation sequencing to identify mutations in 68 driver genes using AmpliSeq for Illumina Myeloid Panel and On-Demand Panel on the MiniSeq system (Illumina). Gene variants were detected by in-house analysis pipeline. Overall survival (OS) was analyzed for all patients, and the Kaplan-Meier survival curve was used to assess OS using the log-rank test. Additionally, the cumulative incidence of relapse (CIR) was analyzed for patients who underwent allo-HSCT. Gray's test was used to evaluate the CIR.


A total of 85 patients with MDS aged under 50 years (U40 between 15 and 39 years old: N=37, 40s between 40 and 49 years old: N=48) were analyzed. The median follow-up time of survivors was 2,041 days (range 176-5,085). There were no significant differences in patient characteristics between U40 and 40s. The 3-year OS of U40 were superior to 40s (79.9% vs. 58.1%, P=0.018), especially lower risk IPSS categories (3-year OS, 95.5% vs. 50.8%, P=0.002).

In total, 69 of 85 patients (U40: N=31, 40s: N=38) had undergone allo-HSCT. U40 patients had lower percentage of bone marrow blasts at just before HSCT than 40s patients (over 10%, 12.9% vs. 36.8%, P=0.048), and better 3-year OS from HSCT in lower-IPSS (88.8% vs. 53.8%, P=0.024); but not in higher-IPSS (45.0% vs. 43.2%, P=0.834).

In this cohort, at least one driver mutation was detected in 61% of allo-HSCT recipients. Frequently mutated genes (more than 10%) were ASXL1 and RUNX1; however, both of the genes did not have significant impact on the outcomes. While, only one patient in 40s had TP53 mutation. We detected 0.8 (range 0-3) and 1.8 (range 0-6) mutations at average in U40 and 40s, respectively (P=0.06). The proportions of the patients without any gene mutations were 52% in U40 and 30% in 40s. Transplanted patients with 0 or 1 mutation showed lower relapse rate than those with 2 or more mutations (3-year CIR, 23.3% vs. 45.2%, P=0.049).


The clinical outcomes of U40 patients with MDS were favorable than those in the 40s, especially in lower disease risk. The number of driver mutations in U40 tended to be lower than that in 40s. MDS in adult is regarded as a stem-cell aging disease with gene mutations; however, MDS-associated mutations were not detected in the half of U40. Moreover, TP53 mutation that is associated with extremely poor posttransplant survival was not detected in U40 patients. MDS patients with less than 2 mutations showed lower relapse rate, which maybe indicate genetic mutations have a great impact on transplant outcomes between 15 and 49 years old.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.