Panobinostat in lymphoid and myeloid malignancies

摘要

Introduction: Histone deacetylase inhibitors (HDACIs) are a class of antineoplastic agent targeting the epigenome, specifically chromatin remodelling, resulting in modulation of genes responsible for apoptosis and cell cycle regulation, and also hyperacetylation of many non-histone proteins. Panobinostat is a potent pan-histone inhibitor of HDAC enzymes implicated in cancer development and progression. Activity has been demonstrated in hematological diseases, such as cutaneous T-cell lymphoma (CTCL), Hodgkin lymphoma (HL), myeloma and myeloid malignancies. Areas covered: We discuss basic pharmacology, followed by early phase trial results and analyse recent large Phase II trials in HL, CTCL, myeloid malignancies and Waldenstrom's macroglobulinemia (WM). Future directions for drug development including potential predictive biomarkers are considered. Expert opinion: The results of Phase II trials prove that oral panobinostat is deliverable with dosing regimens of three times per week, either weekly or biweekly. The major hematologic side-effect of myelosuppression, in particular thrombocytopenia, is transient and manageable, as are the non-hematologic side-effects. Encouraging responses are observed in HL, CTCL, myelofibrosis and WM. The safety and efficacy results from studies of combination therapy with azacitidine in acute myeloid leukemia and myelodysplastic syndromes suggest that this agent may find a place in the management of a range of hematologic cancers.