Topline Presentation Points 

Goals of therapy should reflect goals of patient 

Definitions and the Notion of Risk 

  • A heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell  
  • Characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis  
  • MDS is a Cancer!!! 
  • Mutation Risk 
    • Driver genes can be classified into molecular subtypes differentially associated with disease severity 

Lower risk MDS   

  • Ameliorating Anemia 
    • Lower risk MDS  Del (5q) and non Del (5q) – LEN(Fenaux et al. Blood 2011;118:3765-76.)
      (List et al. Leukemia 2014;28:1033)
      (Santini et al. JCO 2016;34:2988)
    • Imetelstat in HTB Lower-risk MDS (Steensma et al. JCO 2020)
  • Tackling Thrombocytopenia
  • Modifying Multilineage DysplasiaRegimens:  
    • DAC 20 mg/m2 IV D1-3 every 4 weeks 
    • AZA 75 mg/m2 IV/SC D1-3 every 4 weeks (Jabbour et al. for MDS CRC Blood 2017;130:1514)

The Higher-risk Hurdle 

  • Hypomethylating Agent (HMA) and Human Clinical Trials (HCT)

(Sekeres and Cutler Blood 2014;123:829)

  • Specific HMAs Options 
    • Azacitidine (AZA)(Fenaux P, et al. Lancet Oncology 2009;10:223-232.)
    • Decitabine (DAC) (Lubbert et al. JCO 2011;29:1987.)
    • Decitabine (DAC) + Cedazuridine (CED)  – Phase 2 In Int-1, Int-2, High, CMML(Garcia-Manero  et al. Blood 2020.)
  • Higher-risk MDS Combinations 
    • AZA 
    • AZA+ LEN 
    • AZA+Vorin 
    • AZA +/- PevonedistatNCT02610777: Phase 2, randomized, open-label, global, multicenter study [proof of concept]