Current and new targets in the treatment of MPNs
| . | Aim of therapy . | Target—therapeutic mechanism of action . | Agent . |
|---|---|---|---|
| Where we are now | Reduce myeloproliferation | Ribonucleoside diphosphate reductase inhibition | Hydroxyurea |
| Reduce symptom burden, splenomegaly, and myeloproliferation. | JAK1/JAK2 inhibition | Ruxolitinib | |
| Reduce symptom burden, splenomegaly, and myeloproliferation; reduce allele burden and fibrosis (in early disease). | Apoptosis and immune modulation | Interferons | |
| Alleviating anemia | EPO receptor - early erythroid maturation | Darbepoetin, EPO | |
| Suppression of inflammatory cytokines and angiogenesis; enhancement of erythropoietin signaling. | Lenalidomide, thalidomide | ||
| Androgen, mechanism unknown. | Danazol | ||
| Reduce malignant clone | DNA methylation | Azacitidine, decitabine | |
| Maintenance-free remission (cure) | Alloreactive T cells eliminating the malignant clone | Allo-HCT | |
| Just ahead | Alleviating anemia | Activin receptor IIA ligand trap—late erythroid maturation | Luspatercept, sotatercept |
| Reduce symptom burden and splenomegaly and alleviate anemia | JAK2/ACVR1—reduction in hepcidin levels | Momelotinib | |
| Reduce symptom burden and splenomegaly in the setting of thrombocytopenia | JAK2/FLT3 inhibition | Pacritinib | |
| Reduce symptom burden and splenomegaly after ruxolitinib | JAK2/FLT3 inhibition | Fedratinib | |
| Down the road | Reverse fibrosis | Differentiation of monocytes into fibrocytes | PRM-151 |
| TGF-β ligand trap | AVID200 | ||
| Reverse fibrosis and clonal hematopoiesis | Hedgehog-smoothened inhibitor | Glasdegib, sonidegib | |
| Reduce symptom burden, splenomegaly, and myeloproliferation. | PI3K—suppress neoplastic clonal hematopoiesis via cell cycle arrest and apoptosis | Buparlisib, parsaclisib | |
| Reduce clonal hematopoiesis and potentially fibrosis | SMAC (activation)—increase apoptosis | LCL161 | |
| MDM2—increase apoptosis | Idasanutlin, KRT-232 | ||
| Aurora kinase A—increase apoptosis | Alisertib | ||
| Telomerase | Imetelstat | ||
| Bromodomain and extraterminal proteins—reduction in inflammatory cytokine production | CPI-0610 | ||
| LSD1—epigenetic reprogramming | Bomedemstat (IMG-7289) | ||
| On the horizon | Reduction in mutant allele burden | JAK2—type II inhibitor | CHZ868 |
| Reduction in myeloproliferation | Mutant CALR trap | ? | |
| Clonal eradication | CAR T cells | ? | |
| Delay of progression in early disease | ? | ? | |
| Cure without allo-HCT | ? | ? |
| . | Aim of therapy . | Target—therapeutic mechanism of action . | Agent . |
|---|---|---|---|
| Where we are now | Reduce myeloproliferation | Ribonucleoside diphosphate reductase inhibition | Hydroxyurea |
| Reduce symptom burden, splenomegaly, and myeloproliferation. | JAK1/JAK2 inhibition | Ruxolitinib | |
| Reduce symptom burden, splenomegaly, and myeloproliferation; reduce allele burden and fibrosis (in early disease). | Apoptosis and immune modulation | Interferons | |
| Alleviating anemia | EPO receptor - early erythroid maturation | Darbepoetin, EPO | |
| Suppression of inflammatory cytokines and angiogenesis; enhancement of erythropoietin signaling. | Lenalidomide, thalidomide | ||
| Androgen, mechanism unknown. | Danazol | ||
| Reduce malignant clone | DNA methylation | Azacitidine, decitabine | |
| Maintenance-free remission (cure) | Alloreactive T cells eliminating the malignant clone | Allo-HCT | |
| Just ahead | Alleviating anemia | Activin receptor IIA ligand trap—late erythroid maturation | Luspatercept, sotatercept |
| Reduce symptom burden and splenomegaly and alleviate anemia | JAK2/ACVR1—reduction in hepcidin levels | Momelotinib | |
| Reduce symptom burden and splenomegaly in the setting of thrombocytopenia | JAK2/FLT3 inhibition | Pacritinib | |
| Reduce symptom burden and splenomegaly after ruxolitinib | JAK2/FLT3 inhibition | Fedratinib | |
| Down the road | Reverse fibrosis | Differentiation of monocytes into fibrocytes | PRM-151 |
| TGF-β ligand trap | AVID200 | ||
| Reverse fibrosis and clonal hematopoiesis | Hedgehog-smoothened inhibitor | Glasdegib, sonidegib | |
| Reduce symptom burden, splenomegaly, and myeloproliferation. | PI3K—suppress neoplastic clonal hematopoiesis via cell cycle arrest and apoptosis | Buparlisib, parsaclisib | |
| Reduce clonal hematopoiesis and potentially fibrosis | SMAC (activation)—increase apoptosis | LCL161 | |
| MDM2—increase apoptosis | Idasanutlin, KRT-232 | ||
| Aurora kinase A—increase apoptosis | Alisertib | ||
| Telomerase | Imetelstat | ||
| Bromodomain and extraterminal proteins—reduction in inflammatory cytokine production | CPI-0610 | ||
| LSD1—epigenetic reprogramming | Bomedemstat (IMG-7289) | ||
| On the horizon | Reduction in mutant allele burden | JAK2—type II inhibitor | CHZ868 |
| Reduction in myeloproliferation | Mutant CALR trap | ? | |
| Clonal eradication | CAR T cells | ? | |
| Delay of progression in early disease | ? | ? | |
| Cure without allo-HCT | ? | ? |
allo-HCT, allogeneic hematopoietic cell transplantation; CAR, chimeric antigen receptor; EPO, erythropoietin; MDM2, mouse double minute 2 homolog; SMAC, second mitochondria-derived activator of caspases; ?, unknown.