Table 1.

Molecular subtypes of MDSs and relevant targeted compounds in development

Molecular subtypePotential therapeutic compoundMechanism of actionPhaseRouteOngoing/recent trialsReferences
DNA maintenance and repair
 HRD mutations and altered expressionOlaparib, talazoparib, veliparib, temozolomideSynthetic lethality in absence of functional HRD1/2OralDecitabine + talazoparib for untreated or R/R AMLNCT02878785
Telomerase dysfunction
 Telomerase overexpressionImetelstatTelomerase inhibitor2/3IVImetelstat for ESA-resistant LR MDS (IMerge)NCT0259866132
Defective apoptosis
TP53 mutations or MDMX/MDM2 alterationsALRN-6924Targets p53 through MDMX/MDM2 antagonism1IVALRN-6924 alone or with AraC for AML/MDSNCT02909972
Decitabine, 10-d courseDNMT inhibitor2IVDecitabine for HR MDS/AML105
APR-246Refolds/restores wild-type p531/2IVAPR-246 + azacitidine for mutated TP53 MDSNCT03072043
 BCL-2 overexpressionVenetoclaxDecreases BCL-2 expression, proapoptotic1bOralVenetoclax + azacitidine for untreated HR MDSNCT02942290
Epigenetic abnormalities
IDH1/2 mutationsIvosidenib (AG-120)Inhibits mutant IDH11OralIvosidenib for mutated IDH1 MDS/AML59
Enasidenib (AG-221)Inhibits mutant IDH22OralDenasidenib alone or with azacitidine for mutated IDH2 HR MDS58
DNMT3A, TET2, ASXL1 mutations5-AzacitidineDNMT inhibitor2OralAzacitidine alone or with durvalumab in HMA R/R MDSNCT03019003
ASTX727 decitabine w/CDA inhibitorDNMT inhibitor2OralASTX727 vs decitabine (IV) for Int/HR MDS, CMMLNCT03306264
Guadecitabine (SGI-110)DNMT inhibitor3SCGuadecitabine vs treatment of choice for HMA R/R MDSNCT02907359
 HDAC abnormalitiesMocetinostatHDAC inhibitor1/2OralMocetinostat + azacitidine for HR MDSNCT02018926106
PracinostatHDAC inhibitor2OralPracinostat + azacitidine for HR MDSNCT0187370362
VorinostatHDAC inhibitor2/3OralAzacitidine + vorinostat vs lenalidomide for HR MDSNCT0152297660
EntinostatHDAC inhibitor3OralAzacitidine + entinostat vs azacitidine for MDS and AML107
Abnormal signal transduction
 CK1αLenalidomideDegradation in del(5q) of CK1α by E3 ubiquitin ligase cereblon3Orallenalidomide vs placebo for LR del(5q)78
 Pim kinase/PLK-1LGH447Pan-PIM kinase inhibition1OralLGH447 for R/R HR MDS, AMLNCT02078609
VolasertibPLK-1 inhibitor1IVVolasertib for untreated HR MDSNCT01957644
 MEK1/2Binimetinib (MEK162)MEK, Ras inhibition1bOralBinimetinib with or without BYL719 (PI3K inhibitor) for HR MDSNCT01449058
Ras mutationsRigosertibInhibition of PI3K/AKT pathway and cell cycle checkpoint proteins3IVRigosertib vs placebo for R/R HR MDS (INSPIRE trial)NCT01926587
2OralRigosertib + azacitidine for untreated HR MDS
 Hedgehog pathwaySonidegib (erismodegib)Inhibits Hh signaling1bOralSonidegib + azacitidine in R/R HR MDSNCT02129101
 BET pathwayMivebresib (ABBV-075)Disrupts chromatin remodeling, Myc inhibitor1OralMivebresib in subjects with cancer, including AML/MDSNCT02391480
Spliceosome dysregulation
SF3B1, U2AF1, SRSF2, ZRSR2 mutationsH3B-8800Modulator of SF3b complex1OralH3B-8800 for LR/HR MDS, AML, CMMLNCT02841540
Immune dysregulation
 PD-1/PD-L1 axisIpilimumabCTLA-4 inhibitor2IVNivolumab + ipilimumab + azacitidine for HR MDSNCT02530463
AtezolizumabPD-L1 inhibitor1/2IVAtezolizumab alone or with azacitidine for R/R MDSNCT02508870
DurvalumabPD-1 inhibitor2IVDurvalumab alone or with oral azacitidine for HMA R/R MDSNCT02281084
PembrolizumabPD-1 inhibitor2IVPembrolizumab + azacitidine for HR MDSNCT03094637
Inhibitory cytokine effects
 TGF-β superfamily ligandsLuspaterceptBinds GDF-113SCLuspatercept for LR MDS-RS, ESA refractoryNCT02631070
SotaterceptBinds GDF-111/2SCSotatercept for LR MDS89
  • BCL-2, B-cell lymphoma 2; CDA, cytidine deaminase; CK1α, casein kinase 1α; CMML, chronic myelomonocytic leukemia; DNMT, DNA methyl transferase; ESA, erythroid-stimulating agent; GDF-11, growth and differentiation factor-11; HDAC, histone deacetylase; Int, intermediate; LR, lower risk; MDS-RS, MDS with ring sideroblasts; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PI3K, phosphatidylinositol 3-kinase; PLK-1, polo-like kinase 1; R/R, refractory relapsed; SC, subcutaneously; TGF-β, transforming growth factor β.