Teaching pack: Myelodysplastic syndromes / neoplasms (MDS)

MDS are clonal myeloid neoplasms with ineffective haematopoiesis, cytopenias, dysplasia and variable risk of transformation to AML. Risk is stratified by IPSS-R and, since 2022, the molecular IPSS-M, which incorporates mutations (TP53 multi-hit, ASXL1, RUNX1, SF3B1 among 31 genes). The WHO 2022 and ICC classifications define genetically specified entities (SF3B1-mutant, del(5q), biallelic TP53) and renamed the group 'myelodysplastic neoplasms'.

Lower-risk disease is treated for anaemia: erythropoiesis-stimulating agents, lenalidomide for del(5q), luspatercept (MEDALIST 2020, COMMANDS 2023 first line), and imetelstat (IMerge, 2024) after ESA failure. Higher-risk disease is treated with hypomethylating agents (azacitidine, decitabine, oral decitabine-cedazuridine) and, for the fit with a donor, allogeneic transplant, the only cure. Three large phase 3 additions to azacitidine failed in 2023-24 (magrolimab ENHANCE, sabatolimab STIMULUS-MDS2, venetoclax VERONA), leaving azacitidine alone as the higher-risk standard.

• IPSS-M (2022) reclassifies about half of patients relative to IPSS-R and is now the recommended risk model.
• Two new drugs for lower-risk anaemia in four years: luspatercept and imetelstat, both reducing transfusion dependence.
• Higher-risk MDS has had no new drug since azacitidine: the 2023-24 failures of magrolimab, sabatolimab and venetoclax combinations were a field-wide setback.
• Allogeneic transplant remains the only cure; reduced-intensity conditioning extends it to older patients.

1. 1982FAB classification of MDS
2. 1997IPSS risk score
3. 2004Azacitidine approved
4. 2005Lenalidomide for del(5q)
5. 2012IPSS-R
6. 2020Luspatercept approved
7. 2022IPSS-M and WHO5/ICC
8. 2023Higher-risk combinations fail
9. 2024Imetelstat approved

• Imetelstat (treatment)
• Luspatercept (treatment)
• Allogeneic stem cell transplantation (technology)
• Tuspetinib (treatment)
• Bexmarilimab (treatment)
• Spartalizumab (treatment)
• Sabatolimab (treatment)
• ARD103 (treatment)

• AZA-001 (phase 3, n=358): Overall survival: 24.5 months vs 15 months, HR 0.58
• COMMANDS (phase 3, n=363): Transfusion independence >=12 weeks with haemoglobin rise >=1.5 g/dL, weeks 1-24 (interim analysis): 59% vs 31%
• MEDALIST (phase 3, n=229): Transfusion independence >=8 weeks, weeks 1-24: 38% vs 13%
• BMT CTN 1102 (phase 2, n=384): Overall survival at 3 years (intention to treat, adjusted): 47.9% vs 26.6%
• IMerge (phase 2/3, n=289): Red blood cell transfusion independence >=8 weeks: 40% vs 15%
• Precision-T: A Randomized Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies (phase 3, n=187): Event-free at 12 Months for Moderate or Severe Chronic Graft-versus-Host-Disease-free Survival (cGFS) Per Endpoint Adjudication Committee (EAC): 78% vs 38.4%, HR 0.26

• No drug has beaten azacitidine in higher-risk MDS.
• TP53-mutant and complex-karyotype disease: median survival about a year even after transplant.
• Clonal cytopenia of undetermined significance (CCUS): who to watch, who to treat.
• Post-HMA failure has no standard.

1. Why does venetoclax work in leukaemia?
   Answer

   It blocks BCL-2, the protein that stops leukaemia cells from self-destructing, so the built-in death programme (apoptosis) can run; used in CLL (fixed duration with obinutuzumab) and AML (with azacitidine).

• IPSS-M (NEJM Evidence 2022): https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200008
• NCI PDQ: MDS: https://www.cancer.gov/types/myeloproliferative/patient/myelodysplastic-treatment-pdq
• Wikipedia: https://en.wikipedia.org/wiki/Myelodysplastic_syndrome
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446