{"entity":{"id":"mds-higher-risk","kind":"cancer","name":"Higher-risk myelodysplastic syndromes","aka":["High-risk MDS","IPSS-R high and very high MDS","MDS with increased blasts","Higher-risk myelodysplastic neoplasms"],"tldr":"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.\n\nAzacitidine 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.\n\nThe 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Myelodysplastic_syndrome","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Myelodysplastic_syndrome"},{"label":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}],"tags":["subtype-page"],"related":[],"cancers":[],"sections":[],"technologies":["allogeneic-hsct","cd47-blockade","tim3-blockade"],"targets":["tp53","cd47","tim3"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["hma","tp53-mutated","staging-systems","allogeneic-transplant","conditioning-regimen"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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"],"standardOfCare":[{"setting":"Transplant candidate","approach":"Allogeneic stem cell transplant after donor search, usually with azacitidine or decitabine to bridge and reduce blasts; reduced-intensity conditioning in older patients.","refs":["allogeneic-hsct","azacitidine","decitabine","conditioning-regimen","nct07216443"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Not a transplant candidate","approach":"Azacitidine (AZA-001) or decitabine, or oral decitabine-cedazuridine, continued until progression; trials of hypomethylating agent combinations.","refs":["azacitidine","decitabine","decitabine-cedazuridine","hma","nct05883956"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Failure of hypomethylating therapy","approach":"Clinical trial; venetoclax combinations off-label in selected patients; genotype-directed drugs where IDH, FLT3 or KMT2A targets exist; best supportive care.","refs":["venetoclax","ivosidenib","revumenib","transfusion-support","nct05732103"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}}],"stateOfArt":["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."],"history":[{"year":2004,"title":"Azacitidine approved for MDS in the United States","refs":["azacitidine"]},{"year":2009,"title":"AZA-001: azacitidine lengthens survival in higher-risk MDS","refs":["azacitidine"]},{"year":2020,"title":"Oral decitabine-cedazuridine approved","refs":["decitabine-cedazuridine"]},{"year":2021,"title":"BMT CTN 1102: transplant improves survival in 50 to 75 year olds","refs":["allogeneic-hsct"]},{"year":2023,"title":"Magrolimab and sabatolimab combinations fail","refs":["magrolimab","sabatolimab"]},{"year":2024,"title":"VERONA: venetoclax plus azacitidine does not lengthen life","refs":["venetoclax","azacitidine"]}],"pipeline":["allogeneic-hsct","venetoclax","revumenib","tuspetinib","nct05732103","nct07216443","tregzi"],"openProblems":["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."],"parent":"mds"},"route":"/cancers/mds-higher-risk/","neighbours":{"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"cd47-blockade","kind":"technology","name":"CD47 and SIRP-alpha blockade","route":"/technologies/cd47-blockade/"},{"id":"tim3-blockade","kind":"technology","name":"TIM-3 blockade","route":"/technologies/tim3-blockade/"},{"id":"transfusion-support","kind":"technology","name":"Transfusion support and anaemia management","route":"/technologies/transfusion-support/"}],"target":[{"id":"cd47","kind":"target","name":"CD47","route":"/targets/cd47/"},{"id":"tim3","kind":"target","name":"TIM-3","route":"/targets/tim3/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"term":[{"id":"allogeneic-transplant","kind":"term","name":"Allogeneic stem cell transplant (allo-SCT)","route":"/terms/allogeneic-transplant/"},{"id":"conditioning-regimen","kind":"term","name":"Conditioning regimen (myeloablative, reduced-intensity)","route":"/terms/conditioning-regimen/"},{"id":"staging-systems","kind":"term","name":"Disease-specific staging and risk systems (FIGO, Ann Arbor, IPI, R-ISS, ELN, IMDC)","route":"/terms/staging-systems/"},{"id":"hma","kind":"term","name":"Hypomethylating agents (azacitidine, decitabine)","route":"/terms/hma/"},{"id":"tp53-mutated","kind":"term","name":"TP53-mutated (p53-abnormal)","route":"/terms/tp53-mutated/"}],"drug":[{"id":"tregzi","kind":"drug","name":"Allogeneic regulatory T cell immunotherapy with HSPC and T cells-vldq","route":"/drugs/tregzi/"},{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/"},{"id":"decitabine","kind":"drug","name":"Decitabine","route":"/drugs/decitabine/"},{"id":"decitabine-cedazuridine","kind":"drug","name":"Decitabine + cedazuridine (oral)","route":"/drugs/decitabine-cedazuridine/"},{"id":"ivosidenib","kind":"drug","name":"Ivosidenib","route":"/drugs/ivosidenib/"},{"id":"magrolimab","kind":"drug","name":"Magrolimab","route":"/drugs/magrolimab/"},{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"sabatolimab","kind":"drug","name":"Sabatolimab","route":"/drugs/sabatolimab/"},{"id":"tuspetinib","kind":"drug","name":"Tuspetinib","route":"/drugs/tuspetinib/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"trial":[{"id":"nct05883956","kind":"trial","name":"A Study Comparing Treatment Preference Between Oral Decitabine/Cedazuridine and Azacitidine in Myelodysplastic Syndrome, Low-Blast Acute Myeloid Leukemia, or Chronic Myelomonocytic Leukemia","route":"/trials/nct05883956/"},{"id":"nct05732103","kind":"trial","name":"A Study of CTX-712 in Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes","route":"/trials/nct05732103/"},{"id":"nct07216443","kind":"trial","name":"Trial of Orca-T Following Reduced Intensity or Nonmyeloablative Conditioning in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome","route":"/trials/nct07216443/"}],"cancer":[{"id":"mds","kind":"cancer","name":"Myelodysplastic syndromes / neoplasms (MDS)","route":"/cancers/mds/"}]}}