title: Rationale for combination therapy in myelofibrosis.
abstract: Agents targeting the JAK-STAT pathway have dominated the investigational therapeutic portfolio over the last five years resulting in the first and only approved agent for the treatment of patients with myelofibrosis (MF). However, chromatin modifying agents, anti-fibrosing agents, and other signaling pathway inhibitors have also demonstrated activity and offer the potential to improve upon the clinical success of JAK2 inhibition. Due to the complex pathobiological mechanisms underlying MF, it is likely that a combination of biologically active therapies will be required to target the MF hematopoietic stem cell in order to achieve significant disease course modification. Ruxolitinib in partnership with panobinostat, decitabine, and LDE225 are being evaluated in current combination therapy trials based on pre-clinical studies that provide strong scientific rationale. The rationale of combination of danazol or lenalidomide with ruxolitinib is mainly based on mitigation of anti-JAK2-mediated myelosuppression. Combination trials of ruxolitinib and novel anti-fibrosing agents such as PRM-151 represent an attempt to address therapeutic limitations of JAK2 inhibitors such as reversal of bone marrow fibrosis. Ruxolitinib is also being incorporated in novel treatment strategies in the setting of hematopoietic stem cell transplantation for MF. As the pathogenetic mechanisms are better understood, potential drug combinations in MF will increase dramatically and demonstration of biologic activity in effective preclinical models will be required to efficiently evaluate the most active combinations with least toxicity in future trials. This manuscript will address the proposed goals of combination therapy approach and review the state of the art in combination experimental therapy for MF.
authors.affiliation: Myeloproliferative Disorder Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY, USA. Electronic address: john.mascarenhas@mssm.edu.
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D000077209:Decitabine; D004359:Drug Therapy, Combination; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D009154:Mutation; D009570:Nitriles; D000077767:Panobinostat; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines; D011994:Recombinant Proteins / Q000627:therapeutic use; D000683:Serum Amyloid P-Component / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D001713:Biphenyl Compounds; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; D007211:Indoles; D009570:Nitriles; C552898:PRM-151; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011994:Recombinant Proteins; D000683:Serum Amyloid P-Component; C561435:sonidegib; D000077209:Decitabine; C540383:ruxolitinib; D000077767:Panobinostat; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D001374:Azacitidine
keywords: LDE225; PRM-151; combination therapy; decitabine; myelofibrosis; panobinostat; ruxolitinib