Background High-risk myelodysplastic syndromes (MDS)—those falling into IPSS Int-2/High or IPSS-R High/Very-High categories—still confer a bleak prognosis: most patients survive barely 16 months after diagnosis. Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) remains the only treatment with curative potential, while hypomethylating agents (HMAs) provide, at best, brief disease control. Deciding how and when to deploy these therapies has therefore become a central, and still unsettled, issue in the care of adults with high-risk MDS.

Methods Following PRISMA-2020 guidance, we searched MEDLINE, EMBASE and Cochrane (2012-2025) for studies that compared upfront allo-HSCT with non-transplant therapy in adults with higher-risk MDS. After dual screening of 425 records and risk-of-bias assessment (RoB-2 or Newcastle–Ottawa), nine studies met inclusion criteria: one randomised controlled trial, two prospective donor-versus-no-donor cohorts, one biologic-assignment trial (BMT CTN 1102), four retrospective cohorts and one decision-analytic model (total = 3,287 patients; median age 60–71 years). Owing to design heterogeneity we synthesised results narratively.

Results Overall survival (OS). All five prospective studies reported a durable OS advantage when a donor was available. In BMT CTN 1102, 3-year OS was 47.9 % with a donor versus 26.6 % without (P < 0.001). Two European donor-versus-no-donor cohorts showed similar benefits at 2–4 years. Retrospective series and a decision model predicted an 8–12-month life-expectancy gain with immediate HSCT.

Leukaemia-free survival (LFS) and relapse. Upfront HSCT roughly halved the cumulative risk of relapse and produced 3–4-year LFS rates of 33–36 %. No long-term disease-free survivors were reported with HMA-only therapy.

Key subgroups. The survival edge for transplantation held steady across key groups. Patients aged ≥ 65 years, those with complex or adverse cytogenetics (including TP53 mutation), and participants from varied racial or ethnic backgrounds and genders gained similar benefit once a matched donor was located.Observed disparities stemmed mainly from donor availability, not treatment efficacy.

Timing. Delaying HSCT beyond 4–6 HMA cycles increased attrition due to progression and lowered 5-year OS (34–43 % with delay vs 56–64 % with upfront HSCT).

Safety. Modern reduced-intensity HSCT carries a 1-year non-relapse mortality of 15–20 % and acute GVHD rates of 30–55 %. Despite this early hazard, survival curves consistently favoured HSCT after year 2.

Conclusions Across nine contemporary studies, immediate allo-HSCT offers the greatest chance of long-term survival and cure for medically fit adults with higher-risk MDS, approximately doubling 3- to 5-year OS compared with HMA-only strategies despite higher early mortality. Chronological age alone should not exclude patients from transplant consideration. We recommend initiating donor search and transplant referral at diagnosis. A short HMA bridge (≤ 4 cycles) can be useful for cytoreduction or while awaiting a donor, but longer delays compromise outcomes.

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2025
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