# Higher-risk myelodysplastic syndromes

Source: https://onco.cc/cancers/mds-higher-risk/  
OnCo record `mds-higher-risk` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Higher-risk myelodysplastic syndromes behave like a slow leukaemia and often become one. Azacitidine lengthens life and a donor stem cell transplant is the only cure; every attempt to improve on azacitidine in a large trial, including the venetoclax combination tested in VERONA, has so far failed.

## Summary

Higher-risk disease is IPSS-R above 3.5 (intermediate with adverse features, high and very high) or IPSS-M moderate-high and above: excess blasts (5 to 19 percent), adverse cytogenetics including complex karyotype and chromosome 7 loss, deep cytopenias and mutations such as TP53, ASXL1, RUNX1 and EZH2. Multi-hit TP53 disease is the worst group and is now classified separately by both WHO and ICC. The goal shifts from managing cytopenias to changing the natural history, and the first question at diagnosis is whether the patient can reach an allogeneic transplant.

Azacitidine is the standard for those who cannot: AZA-001 (2009) showed median survival of 24.5 months against 15 months with conventional care, the first drug to lengthen life in MDS, and decitabine and the oral decitabine-cedazuridine combination (2020) are equivalents. For fit patients up to about 75, allogeneic transplant is the only cure; the BMT CTN 1102 donor-versus-no-donor study (2021) found three-year survival of 47.9 percent with a donor against 26.6 percent without, and most centres give hypomethylating therapy to bridge and debulk before transplant. Relapse after transplant remains common in TP53-mutated disease.

The failures are as important as the standards. Adding venetoclax to azacitidine produced high response rates in phase 1b but VERONA, the phase 3, did not lengthen survival when it reported in 2024 and 2025; magrolimab (ENHANCE) stopped for futility in 2023, sabatolimab (STIMULUS-MDS2) and pevonedistat (PANTHER) were negative, and eprenetapopt failed in TP53-mutated disease. Hypomethylating agents plus a partner remain unproven, and trials now test menin inhibitors for KMT2A- or NPM1-driven disease, IDH inhibitors, post-transplant maintenance and better conditioning to reduce relapse.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: High-risk MDS; IPSS-R high and very high MDS; MDS with increased blasts; Higher-risk myelodysplastic neoplasms
- Tags: subtype-page
- Group: haematologic
- Burden: About a third of myelodysplastic syndromes are higher risk; without treatment median survival is around a year and a half or less, and most progress to acute myeloid leukaemia.
- Subtypes: MDS with increased blasts (IB1, 5 to 9 percent; IB2, 10 to 19 percent); MDS with biallelic (multi-hit) TP53 inactivation; MDS with complex or monosomal karyotype; Therapy-related higher-risk MDS; Higher-risk MDS eligible for allogeneic transplant; Higher-risk MDS in patients unfit for transplant
- Biomarkers: IPSS-R and IPSS-M scores; Marrow blast percentage; Karyotype: complex, monosomy 7, del(7q); TP53 mutation and allelic state; ASXL1, RUNX1, EZH2 and spliceosome mutations; Donor availability and HCT comorbidity index; Measurable residual disease before and after transplant

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/mds-higher-risk/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/mds-higher-risk/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/mds-higher-risk/#what-it-is [6 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/mds-higher-risk/#finding-it [7 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/mds-higher-risk/#treating-it [3 settings, 3 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/mds-higher-risk/#evidence [9 trials, 5 key papers, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/mds-higher-risk/#science [6 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/mds-higher-risk/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/mds-higher-risk/#living-with-it [18 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/mds-higher-risk/coming/ [11 medicines, 9 trials, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/mds-higher-risk/data/ [62 connected records]

## Standard of care

- Transplant candidate: Allogeneic stem cell transplant after donor search, usually with azacitidine or decitabine to bridge and reduce blasts; reduced-intensity conditioning in older patients. ([Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Azacitidine](https://onco.cc/drugs/azacitidine/), [Decitabine](https://onco.cc/drugs/decitabine/), [Conditioning regimen (myeloablative, reduced-intensity)](https://onco.cc/terms/conditioning-regimen/), [Trial of Orca-T Following Reduced Intensity or Nonmyeloablative Conditioning in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome](https://onco.cc/trials/nct07216443/))
- Not a transplant candidate: Azacitidine (AZA-001) or decitabine, or oral decitabine-cedazuridine, continued until progression; trials of hypomethylating agent combinations. ([Azacitidine](https://onco.cc/drugs/azacitidine/), [Decitabine](https://onco.cc/drugs/decitabine/), [Decitabine + cedazuridine (oral)](https://onco.cc/drugs/decitabine-cedazuridine/), [Hypomethylating agents (azacitidine, decitabine)](https://onco.cc/terms/hma/), [A Study Comparing Treatment Preference Between Oral Decitabine/Cedazuridine and Azacitidine in Myelodysplastic Syndrome, Low-Blast Acute Myeloid Leukemia, or Chronic Myelomonocytic Leukemia](https://onco.cc/trials/nct05883956/))
- Failure of hypomethylating therapy: Clinical trial; venetoclax combinations off-label in selected patients; genotype-directed drugs where IDH, FLT3 or KMT2A targets exist; best supportive care. ([Venetoclax](https://onco.cc/drugs/venetoclax/), [Ivosidenib](https://onco.cc/drugs/ivosidenib/), [Revumenib](https://onco.cc/drugs/revumenib/), [Transfusion support and anaemia management](https://onco.cc/technologies/transfusion-support/), [A Study of CTX-712 in Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes](https://onco.cc/trials/nct05732103/))

## State of the art

- Azacitidine remains the only drug shown to lengthen life without transplant, fifteen years after AZA-001.
- Allogeneic transplant doubles three-year survival for patients who can reach it.
- Every phase 3 add-on to azacitidine, including venetoclax in VERONA, magrolimab and sabatolimab, has failed.

## Open problems

- Nothing has beaten azacitidine alone in a phase 3 trial.
- TP53 multi-hit disease relapses after transplant and responds to no drug durably.
- Post-transplant maintenance to prevent relapse is unproven.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Myelodysplastic_syndrome
- Wikipedia: https://en.wikipedia.org/wiki/Myelodysplastic_syndrome
- NCCN Guidelines: Myelodysplastic Syndromes: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446

## Connected records

- cancers: [Lower-risk myelodysplastic syndromes](https://onco.cc/cancers/mds-lower-risk/), [Myelodysplastic syndromes / neoplasms (MDS)](https://onco.cc/cancers/mds/)
- technologies: [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [CD47 and SIRP-alpha blockade](https://onco.cc/technologies/cd47-blockade/), [TIM-3 blockade](https://onco.cc/technologies/tim3-blockade/), [Transfusion support and anaemia management](https://onco.cc/technologies/transfusion-support/)
- targets: [CD47](https://onco.cc/targets/cd47/), [TIM-3](https://onco.cc/targets/tim3/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Allogeneic regulatory T cell immunotherapy with HSPC and T cells-vldq](https://onco.cc/drugs/tregzi/), [Azacitidine](https://onco.cc/drugs/azacitidine/), [Decitabine](https://onco.cc/drugs/decitabine/), [Decitabine + cedazuridine (oral)](https://onco.cc/drugs/decitabine-cedazuridine/), [Ivosidenib](https://onco.cc/drugs/ivosidenib/), [Magrolimab](https://onco.cc/drugs/magrolimab/), [Pevonedistat](https://onco.cc/drugs/pevonedistat/), [Revumenib](https://onco.cc/drugs/revumenib/), [Sabatolimab](https://onco.cc/drugs/sabatolimab/), [Tuspetinib](https://onco.cc/drugs/tuspetinib/), [Venetoclax](https://onco.cc/drugs/venetoclax/)
- terms: [Allogeneic stem cell transplant (allo-SCT)](https://onco.cc/terms/allogeneic-transplant/), [Conditioning regimen (myeloablative, reduced-intensity)](https://onco.cc/terms/conditioning-regimen/), [del(5q) (5q- syndrome and lenalidomide response)](https://onco.cc/terms/del5q/), [Disease-specific staging and risk systems (FIGO, Ann Arbor, IPI, R-ISS, ELN, IMDC)](https://onco.cc/terms/staging-systems/), [Hypomethylating agents (azacitidine, decitabine)](https://onco.cc/terms/hma/), [IPSS-R and IPSS-M (myelodysplastic syndrome risk scores)](https://onco.cc/terms/ipss-m-ipss-r/), [TP53-mutated (p53-abnormal)](https://onco.cc/terms/tp53-mutated/)
- trials: [A Study Comparing Treatment Preference Between Oral Decitabine/Cedazuridine and Azacitidine in Myelodysplastic Syndrome, Low-Blast Acute Myeloid Leukemia, or Chronic Myelomonocytic Leukemia](https://onco.cc/trials/nct05883956/), [A Study of CTX-712 in Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes](https://onco.cc/trials/nct05732103/), [AZA-001](https://onco.cc/trials/aza-001/), [BMT CTN 1102](https://onco.cc/trials/bmt-ctn-1102/), [First-in-human Study Aiming to Characterize the Safety, Tolerability, Pharmacokinetic and Preliminary Signs of Activity of ABD-3001 in Refractory or Relapsed AML and High Risk MDS Adult Patients](https://onco.cc/trials/nct05601726/), [Magrolimab + Azacitidine Versus Azacitidine + Placebo in Untreated Participants With Myelodysplastic Syndrome (MDS)](https://onco.cc/trials/nct04313881/), [Study to Evaluate Imetelstat in Patients With High-Risk MDS or AML Failing HMA-based Therapy](https://onco.cc/trials/nct05583552/), [Trial of Orca-T Following Reduced Intensity or Nonmyeloablative Conditioning in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome](https://onco.cc/trials/nct07216443/), [VERONA](https://onco.cc/trials/verona/)
- key papers: [AZA-001: azacitidine versus conventional care in higher-risk myelodysplastic syndromes](https://onco.cc/key-papers/paper-aza-001-fenaux-lancet-oncol-2009/), [BMT CTN 1102: biologic assignment trial of reduced-intensity transplant by donor availability in patients aged 50 to 75 with advanced myelodysplastic syndrome](https://onco.cc/key-papers/paper-bmt-ctn-1102-transplant-older-mds-nakamura-jco-2021/), [International Consensus Classification of myeloid neoplasms and acute leukaemias (2022)](https://onco.cc/key-papers/paper-icc-2022-arber-blood-2022/), [IPSS-M: the molecular international prognostic scoring system for myelodysplastic syndromes](https://onco.cc/key-papers/paper-ipss-m-bernard-nejm-evidence-2022/), [WHO classification of haematolymphoid tumours, fifth edition: myeloid and histiocytic neoplasms](https://onco.cc/key-papers/paper-who-2022-myeloid-khoury-leukemia-2022/)
- people: [Amer M. Zeidan](https://onco.cc/people/amer-zeidan/)

---
JSON: https://onco.cc/api/v1/entities/mds-higher-risk.json