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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.
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.
Averages across everyone diagnosed, often years ago. A median is the middle of a group: half the people counted lived longer than the figure shown, and some lived far longer. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
Averages across everyone diagnosed, often years ago. A median is the middle of a group: half the people counted lived longer than the figure shown, and some lived far longer. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
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.
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: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma), Mediastinal grey zone lymphoma, Primary effusion lymphoma, Plasmablastic lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, EBV-positive diffuse large B-cell lymphoma, Primary large B-cell lymphoma of the testis, Gastric MALT lymphoma, Ocular adnexal MALT lymphoma, Extranodal NK/T-cell lymphoma, Adult T-cell leukaemia/lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous anaplastic large cell lymphoma, Lymphomatoid papulosis, Mycosis fungoides, Enteropathy-associated T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Splenic marginal zone lymphoma, Nodal marginal zone lymphoma, Primary cutaneous marginal zone lymphoma, Primary cutaneous follicle centre lymphoma, Sezary syndrome, Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma), Hepatosplenic T-cell lymphoma, Intravascular large B-cell lymphoma, Lymphomatoid granulomatosis, T-cell prolymphocytic leukaemia, Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant), T-cell large granular lymphocytic leukaemia, Mixed-phenotype acute leukaemia, Myeloid leukaemia of Down syndrome, Burkitt leukaemia, 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, Standard-risk B-cell acute lymphoblastic leukaemia in children, High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL), Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL), Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL), Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year), Relapsed and refractory acute lymphoblastic leukaemia in children, Acute myeloid leukaemia in children, Erdheim-Chester disease, Rosai-Dorfman-Destombes disease, Single-system Langerhans cell histiocytosis (bone, skin or one other organ), Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement), Indolent and smouldering systemic mastocytosis, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Early-stage classical Hodgkin lymphoma (stage I to II), Advanced-stage classical Hodgkin lymphoma (stage III to IV), Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma), Relapsed and refractory classical Hodgkin lymphoma
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.
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Trial eligibility and risk stratification in AML and MDS often refer to this classification alongside the WHO edition; the two overlap heavily but not completely.
Sequencing at diagnosis now changes the risk group, and therefore the transplant discussion, for a large fraction of patients. Trials and guidelines are adopting the IPSS-M in place of the IPSS-R.
The names and definitions on a marrow report (for example MDS with biallelic TP53 inactivation, or AML myelodysplasia-related) come from this document or from the parallel International Consensus Classification.
Allogeneic transplant should be included in the management plan of fit older adults with higher-risk myelodysplastic syndrome; donor search should start at diagnosis.
Azacitidine (and decitabine) became the standard for higher-risk MDS in patients not going straight to transplant, and the backbone for combination trials that have so far failed to beat it.
Query 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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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
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.
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.
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.
Take with a meal and water. Avoid grapefruit, Seville oranges and starfruit.
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
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