Higher-risk myelodysplastic syndromes
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.
Overview
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.
State of the art
- Azacitidine remains the only drug shown to lengthen life without transplant, fifteen years after AZA-001.
- Every phase 3 add-on to azacitidine, including venetoclax in VERONA, magrolimab and sabatolimab, has failed.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- Allogeneic transplant doubles three-year survival for patients who can reach it.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowDifferentiation syndrome
Fever, cough or breathlessness, rapid weight gain or swelling, bone pain, low blood pressure or reduced urine; the labels say to start steroids and monitor at the first suspicion, and the syndrome has been fatal.
- Emergency services nowTumour lysis syndrome
Nausea, vomiting, muscle cramps, palpitations, seizures, confusion or passing much less urine in the first days of a new dose; the label requires hydration, anti-hyperuricaemic drugs and blood tests around each ramp-up step.
- Check before combiningIvosidenib with Revumenib: major interaction
QT: both Ivosidenib and Revumenib prolong the QT interval (known and known risk).. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
- Check before combiningFood and drink: Venetoclax
Take with a meal and water. Avoid grapefruit, Seville oranges and starfruit.
- Check before combiningHeart rhythm (QT): Ivosidenib
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
See all on the product pages:AzacitidineDecitabineDecitabine + cedazuridine (oral)IvosidenibRevumenibVenetoclax·Printable cards in the navigator
Anatomy and lymph node drainage
- Bone marrow (leukaemia, MDS, MPN, myeloma)
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- Nodes: cervical
- Nodes: axillary
- Nodes: mediastinal
- Nodes: para-aortic and mesenteric
- Nodes: inguinal
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
- Bone marrow (leukaemia, MDS, MPN, myeloma)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
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- cervical
- axillary
- mediastinal
- para-aortic and mesenteric
- inguinal
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Smouldering multiple myeloma, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Relapsed or refractory chronic lymphocytic leukaemia, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- 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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Allogeneic stem cell transplant after donor search, usually with azacitidine or decitabine to bridge and reduce blasts; reduced-intensity conditioning in older patients.
Azacitidine (AZA-001) or decitabine, or oral decitabine-cedazuridine, continued until progression; trials of hypomethylating agent combinations.
Clinical trial; venetoclax combinations off-label in selected patients; genotype-directed drugs where IDH, FLT3 or KMT2A targets exist; best supportive care.
Subtypes & biomarkers
top- 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
- 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
How often this target appears
- 2004Azacitidine approved for MDS in the United States
- 2009AZA-001: azacitidine lengthens survival in higher-risk MDS
- 2020Oral decitabine-cedazuridine approved
- 2021BMT CTN 1102: transplant improves survival in 50 to 75 year olds
- 2023Magrolimab and sabatolimab combinations fail
- 2024VERONA: venetoclax plus azacitidine does not lengthen life
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 7 changes by month →- 2026-09-17This recordHigher-risk myelodysplastic syndromesFacts on this page last checked
When this page itself was last checked or edited.
- 2024MilestoneVenetoclaxVERONA: venetoclax plus azacitidine does not lengthen life
A milestone in how this cancer is treated.
- 2023MilestoneMagrolimabMagrolimab and sabatolimab combinations fail
A milestone in how this cancer is treated.
- 2021MilestoneAllogeneic stem cell transplantationBMT CTN 1102: transplant improves survival in 50 to 75 year olds
A milestone in how this cancer is treated.
- 2020MilestoneDecitabine + cedazuridine (oral)Oral decitabine-cedazuridine approved
A milestone in how this cancer is treated.
- 2009MilestoneAzacitidineAZA-001: azacitidine lengthens survival in higher-risk MDS
A milestone in how this cancer is treated.
What is in development for Higher-risk myelodysplastic syndromes, drawn from the whole corpus: 7 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Drugs in phase 2 · 2
Technologies being tested · 3
Trials under way · 2
- A Study of CTX-712 in Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes · phase 1/2 · Chordia Therapeutics, Inc.
- Trial of Orca-T Following Reduced Intensity or Nonmyeloablative Conditioning in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome · phase 2 · Orca Biosystems, Inc.
Open problems and what is being done
Nothing has beaten azacitidine alone in a phase 3 trial.
TP53 multi-hit disease relapses after transplant and responds to no drug durably.
and how the field plans to fix it →What is being done about thisRecurrence and residual diseaseAvailable nowNothing recorded yet.
In trialsIdeas and roadmapsNothing recorded yet.
Also on OnCo: Treatment journeys · Survivorship planner.
Post-transplant maintenance to prevent relapse is unproven.
and how the field plans to fix it →What is being done about thisRecurrence and residual diseaseAvailable nowNothing recorded yet.
In trialsIdeas and roadmapsNothing recorded yet.
Also on OnCo: Treatment journeys · Survivorship planner.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Los Angeles, CA · cancer center | United States | 0 | 318 | 3,917 | - | ||
Melbourne · research institute | Australia | none recorded | 0 | 298 | 3,639 | - | |
Indianapolis, IN · cancer center | United States | 0 | 159 | 4,238 | - | ||
Hamilton, ON · cancer center | Canada | none recorded | 0 | 103 | 1,158 | - | |
Baltimore, MD · cancer center | United States | 0 | 101 | 2,306 | - | ||
Omaha, NE · cancer center | United States | 0 | 37 | 4,159 | - | ||
Rotterdam · consortium | Netherlands | none recorded | 0 | 8 | 207 | - | |
Minneapolis, MN · cancer center | United States | 0 | not matched | - | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Higher-risk myelodysplastic syndromes but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about Higher-risk myelodysplastic syndromes
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example IPSS-R and IPSS-M scores, Marrow blast percentage, Karyotype: complex, monosomy 7, del, TP53 mutation and allelic state, ASXL1, RUNX1, EZH2 and spliceosome mutations), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include MDS with increased blasts, MDS with biallelicTP53 inactivation, MDS with complex or monosomal karyotype.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Transplant candidate
- For my situation (transplant candidate), which of the standard options do you recommend and why?Why: Guideline options include: Allogeneic stem cell transplant after donor search, usually with azacitidine or decitabine to bridge and reduce blasts; reduced-intensity conditioning in older patients.
- Am I a candidate for Azacitidine, Decitabine, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of Trial of Orca-T Following Reduced Intensity or Nonmyeloablative Conditioning in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Not a transplant candidate
- For my situation (not a transplant candidate), which of the standard options do you recommend and why?Why: Guideline options include: Azacitidine (AZA-001) or decitabine, or oral decitabine-cedazuridine, continued until progression; trials of hypomethylating agent combinations.
- Am I a candidate for Azacitidine, Decitabine, Decitabine + cedazuridine (oral), and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of A Study Comparing Treatment Preference Between Oral Decitabine/Cedazuridine and Azacitidine in Myelodysplastic Syndrome, Low-Blast Acute Myeloid Leukemia, or Chronic Myelomonocytic Leukemia apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Failure of hypomethylating therapy
- For my situation (failure of hypomethylating therapy), which of the standard options do you recommend and why?Why: Guideline options include: Clinical trial; venetoclax combinations off-label in selected patients; genotype-directed drugs where IDH, FLT3 or KMT2A targets exist; best supportive care.
- Am I a candidate for Venetoclax, Ivosidenib, Revumenib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of A Study of CTX-712 in Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Any stage
- Are there clinical trials I could join, for example of Allogeneic stem cell transplantation, Venetoclax, Revumenib, Tuspetinib?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Nothing has beaten azacitidine alone in a phase 3 trial”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “TP53 multi-hit disease relapses after transplant and responds to no drug durably”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with Higher-risk myelodysplastic syndromes, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
11targets
6drugs
10companies
11terms
5trials
3Latest papers
topQuery for this cancer: (TITLE:"Higher-risk myelodysplastic syndromes" OR ABSTRACT:"Higher-risk myelodysplastic syndromes" OR TITLE:"High-risk MDS" OR ABSTRACT:"High-risk MDS" OR TITLE:"IPSS-R high and very high MDS" OR ABSTRACT:"IPSS-R high and very high MDS" OR TITLE:"MDS with increased blasts" OR ABSTRACT:"MDS with increased blasts" OR TITLE:"Higher-risk myelodysplastic neoplasms" OR ABSTRACT:"Higher-risk myelodysplastic neoplasms") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Higher-risk myelodysplastic syndromes, not a curated reading list.
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