Molecular subtypes of MDSs and relevant targeted compounds in development
| Molecular subtype . | Potential therapeutic compound . | Mechanism of action . | Phase . | Route . | Ongoing/recent trials . | References . |
|---|---|---|---|---|---|---|
| DNA maintenance and repair | ||||||
| HRD mutations and altered expression | Olaparib, talazoparib, veliparib, temozolomide | Synthetic lethality in absence of functional HRD | 1/2 | Oral | Decitabine + talazoparib for untreated or R/R AML | NCT02878785 |
| Telomerase dysfunction | ||||||
| Telomerase overexpression | Imetelstat | Telomerase inhibitor | 2/3 | IV | Imetelstat for ESA-resistant LR MDS (IMerge) | NCT0259866132 |
| Defective apoptosis | ||||||
| TP53 mutations or MDMX/MDM2 alterations | ALRN-6924 | Targets p53 through MDMX/MDM2 antagonism | 1 | IV | ALRN-6924 alone or with AraC for AML/MDS | NCT02909972 |
| Decitabine, 10-d course | DNMT inhibitor | 2 | IV | Decitabine for HR MDS/AML | 105 | |
| APR-246 | Refolds/restores wild-type p53 | 1/2 | IV | APR-246 + azacitidine for mutated TP53 MDS | NCT03072043 | |
| BCL-2 overexpression | Venetoclax | Decreases BCL-2 expression, proapoptotic | 1b | Oral | Venetoclax + azacitidine for untreated HR MDS | NCT02942290 |
| Epigenetic abnormalities | ||||||
| IDH1/2 mutations | Ivosidenib (AG-120) | Inhibits mutant IDH1 | 1 | Oral | Ivosidenib for mutated IDH1 MDS/AML | 59 |
| Enasidenib (AG-221) | Inhibits mutant IDH2 | 2 | Oral | Denasidenib alone or with azacitidine for mutated IDH2 HR MDS | 58 | |
| DNMT3A, TET2, ASXL1 mutations | 5-Azacitidine | DNMT inhibitor | 2 | Oral | Azacitidine alone or with durvalumab in HMA R/R MDS | NCT03019003 |
| ASTX727 decitabine w/CDA inhibitor | DNMT inhibitor | 2 | Oral | ASTX727 vs decitabine (IV) for Int/HR MDS, CMML | NCT03306264 | |
| Guadecitabine (SGI-110) | DNMT inhibitor | 3 | SC | Guadecitabine vs treatment of choice for HMA R/R MDS | NCT02907359 | |
| HDAC abnormalities | Mocetinostat | HDAC inhibitor | 1/2 | Oral | Mocetinostat + azacitidine for HR MDS | NCT02018926106 |
| Pracinostat | HDAC inhibitor | 2 | Oral | Pracinostat + azacitidine for HR MDS | NCT0187370362 | |
| Vorinostat | HDAC inhibitor | 2/3 | Oral | Azacitidine + vorinostat vs lenalidomide for HR MDS | NCT0152297660 | |
| Entinostat | HDAC inhibitor | 3 | Oral | Azacitidine + entinostat vs azacitidine for MDS and AML | 107 | |
| Abnormal signal transduction | ||||||
| CK1α | Lenalidomide | Degradation in del(5q) of CK1α by E3 ubiquitin ligase cereblon | 3 | Oral | lenalidomide vs placebo for LR del(5q) | 78 |
| Pim kinase/PLK-1 | LGH447 | Pan-PIM kinase inhibition | 1 | Oral | LGH447 for R/R HR MDS, AML | NCT02078609 |
| Volasertib | PLK-1 inhibitor | 1 | IV | Volasertib for untreated HR MDS | NCT01957644 | |
| MEK1/2 | Binimetinib (MEK162) | MEK, Ras inhibition | 1b | Oral | Binimetinib with or without BYL719 (PI3K inhibitor) for HR MDS | NCT01449058 |
| Ras mutations | Rigosertib | Inhibition of PI3K/AKT pathway and cell cycle checkpoint proteins | 3 | IV | Rigosertib vs placebo for R/R HR MDS (INSPIRE trial) | NCT01926587 |
| 2 | Oral | Rigosertib + azacitidine for untreated HR MDS | ||||
| Hedgehog pathway | Sonidegib (erismodegib) | Inhibits Hh signaling | 1b | Oral | Sonidegib + azacitidine in R/R HR MDS | NCT02129101 |
| BET pathway | Mivebresib (ABBV-075) | Disrupts chromatin remodeling, Myc inhibitor | 1 | Oral | Mivebresib in subjects with cancer, including AML/MDS | NCT02391480 |
| Spliceosome dysregulation | ||||||
| SF3B1, U2AF1, SRSF2, ZRSR2 mutations | H3B-8800 | Modulator of SF3b complex | 1 | Oral | H3B-8800 for LR/HR MDS, AML, CMML | NCT02841540 |
| Immune dysregulation | ||||||
| PD-1/PD-L1 axis | Ipilimumab | CTLA-4 inhibitor | 2 | IV | Nivolumab + ipilimumab + azacitidine for HR MDS | NCT02530463 |
| Atezolizumab | PD-L1 inhibitor | 1/2 | IV | Atezolizumab alone or with azacitidine for R/R MDS | NCT02508870 | |
| Durvalumab | PD-1 inhibitor | 2 | IV | Durvalumab alone or with oral azacitidine for HMA R/R MDS | NCT02281084 | |
| Pembrolizumab | PD-1 inhibitor | 2 | IV | Pembrolizumab + azacitidine for HR MDS | NCT03094637 | |
| Inhibitory cytokine effects | ||||||
| TGF-β superfamily ligands | Luspatercept | Binds GDF-11 | 3 | SC | Luspatercept for LR MDS-RS, ESA refractory | NCT02631070 |
| Sotatercept | Binds GDF-11 | 1/2 | SC | Sotatercept for LR MDS | 89 | |
| Molecular subtype . | Potential therapeutic compound . | Mechanism of action . | Phase . | Route . | Ongoing/recent trials . | References . |
|---|---|---|---|---|---|---|
| DNA maintenance and repair | ||||||
| HRD mutations and altered expression | Olaparib, talazoparib, veliparib, temozolomide | Synthetic lethality in absence of functional HRD | 1/2 | Oral | Decitabine + talazoparib for untreated or R/R AML | NCT02878785 |
| Telomerase dysfunction | ||||||
| Telomerase overexpression | Imetelstat | Telomerase inhibitor | 2/3 | IV | Imetelstat for ESA-resistant LR MDS (IMerge) | NCT0259866132 |
| Defective apoptosis | ||||||
| TP53 mutations or MDMX/MDM2 alterations | ALRN-6924 | Targets p53 through MDMX/MDM2 antagonism | 1 | IV | ALRN-6924 alone or with AraC for AML/MDS | NCT02909972 |
| Decitabine, 10-d course | DNMT inhibitor | 2 | IV | Decitabine for HR MDS/AML | 105 | |
| APR-246 | Refolds/restores wild-type p53 | 1/2 | IV | APR-246 + azacitidine for mutated TP53 MDS | NCT03072043 | |
| BCL-2 overexpression | Venetoclax | Decreases BCL-2 expression, proapoptotic | 1b | Oral | Venetoclax + azacitidine for untreated HR MDS | NCT02942290 |
| Epigenetic abnormalities | ||||||
| IDH1/2 mutations | Ivosidenib (AG-120) | Inhibits mutant IDH1 | 1 | Oral | Ivosidenib for mutated IDH1 MDS/AML | 59 |
| Enasidenib (AG-221) | Inhibits mutant IDH2 | 2 | Oral | Denasidenib alone or with azacitidine for mutated IDH2 HR MDS | 58 | |
| DNMT3A, TET2, ASXL1 mutations | 5-Azacitidine | DNMT inhibitor | 2 | Oral | Azacitidine alone or with durvalumab in HMA R/R MDS | NCT03019003 |
| ASTX727 decitabine w/CDA inhibitor | DNMT inhibitor | 2 | Oral | ASTX727 vs decitabine (IV) for Int/HR MDS, CMML | NCT03306264 | |
| Guadecitabine (SGI-110) | DNMT inhibitor | 3 | SC | Guadecitabine vs treatment of choice for HMA R/R MDS | NCT02907359 | |
| HDAC abnormalities | Mocetinostat | HDAC inhibitor | 1/2 | Oral | Mocetinostat + azacitidine for HR MDS | NCT02018926106 |
| Pracinostat | HDAC inhibitor | 2 | Oral | Pracinostat + azacitidine for HR MDS | NCT0187370362 | |
| Vorinostat | HDAC inhibitor | 2/3 | Oral | Azacitidine + vorinostat vs lenalidomide for HR MDS | NCT0152297660 | |
| Entinostat | HDAC inhibitor | 3 | Oral | Azacitidine + entinostat vs azacitidine for MDS and AML | 107 | |
| Abnormal signal transduction | ||||||
| CK1α | Lenalidomide | Degradation in del(5q) of CK1α by E3 ubiquitin ligase cereblon | 3 | Oral | lenalidomide vs placebo for LR del(5q) | 78 |
| Pim kinase/PLK-1 | LGH447 | Pan-PIM kinase inhibition | 1 | Oral | LGH447 for R/R HR MDS, AML | NCT02078609 |
| Volasertib | PLK-1 inhibitor | 1 | IV | Volasertib for untreated HR MDS | NCT01957644 | |
| MEK1/2 | Binimetinib (MEK162) | MEK, Ras inhibition | 1b | Oral | Binimetinib with or without BYL719 (PI3K inhibitor) for HR MDS | NCT01449058 |
| Ras mutations | Rigosertib | Inhibition of PI3K/AKT pathway and cell cycle checkpoint proteins | 3 | IV | Rigosertib vs placebo for R/R HR MDS (INSPIRE trial) | NCT01926587 |
| 2 | Oral | Rigosertib + azacitidine for untreated HR MDS | ||||
| Hedgehog pathway | Sonidegib (erismodegib) | Inhibits Hh signaling | 1b | Oral | Sonidegib + azacitidine in R/R HR MDS | NCT02129101 |
| BET pathway | Mivebresib (ABBV-075) | Disrupts chromatin remodeling, Myc inhibitor | 1 | Oral | Mivebresib in subjects with cancer, including AML/MDS | NCT02391480 |
| Spliceosome dysregulation | ||||||
| SF3B1, U2AF1, SRSF2, ZRSR2 mutations | H3B-8800 | Modulator of SF3b complex | 1 | Oral | H3B-8800 for LR/HR MDS, AML, CMML | NCT02841540 |
| Immune dysregulation | ||||||
| PD-1/PD-L1 axis | Ipilimumab | CTLA-4 inhibitor | 2 | IV | Nivolumab + ipilimumab + azacitidine for HR MDS | NCT02530463 |
| Atezolizumab | PD-L1 inhibitor | 1/2 | IV | Atezolizumab alone or with azacitidine for R/R MDS | NCT02508870 | |
| Durvalumab | PD-1 inhibitor | 2 | IV | Durvalumab alone or with oral azacitidine for HMA R/R MDS | NCT02281084 | |
| Pembrolizumab | PD-1 inhibitor | 2 | IV | Pembrolizumab + azacitidine for HR MDS | NCT03094637 | |
| Inhibitory cytokine effects | ||||||
| TGF-β superfamily ligands | Luspatercept | Binds GDF-11 | 3 | SC | Luspatercept for LR MDS-RS, ESA refractory | NCT02631070 |
| Sotatercept | Binds GDF-11 | 1/2 | SC | Sotatercept for LR MDS | 89 | |
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.