panobinostat and Hematologic-Neoplasms

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.. 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.. 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.

Topics: Administration, Oral; Antineoplastic Agents; Apoptosis; Cell Cycle; Clinical Trials, Phase II as Topic; Disease Progression; Drug Administration Schedule; Hematologic Neoplasms; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Panobinostat

Over the last 5 years, a plethora of histone deacetylase inhibitors (HDACi) have been evaluated in clinical trials. These drugs have in common the ability to hyperacetylate both histone and nonhistone targets, resulting in a variety of effects on cancer cells, their microenvironment, and immune responses. To date, responses with single agent HDACi have been predominantly observed in advanced hematologic malignancies including T-cell lymphoma, Hodgkin lymphoma, and myeloid malignancies. Therefore, in this review we focus upon hematologic malignancies. Generally HDACi are well tolerated with the most common acute toxicities being fatigue, gastrointestinal, and transient cytopenias. Of note, few patients have been treated for prolonged periods of time and little is known about long-term toxicities. The use of the biomarker of histone hyperacetylation has been useful as a guide to target specificity, but generally does not predict for response and the search for more clinically relevant biomarkers must continue.

Topics: Antibiotics, Antineoplastic; Benzamides; Clinical Trials as Topic; Depsipeptides; Drug Therapy, Combination; Enzyme Inhibitors; Hematologic Neoplasms; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Panobinostat; Pyridines; Pyrimidines; Sulfonamides; Vorinostat

The study aimed to characterize the population pharmacokinetics of panobinostat, a pan-deacetylase inhibitor that has demonstrated efficacy in combination with bortezomib and dexamethasone in patients with multiple myeloma.. A nonlinear mixed-effect model was used to fit plasma panobinostat concentration-time data collected from patients across 14 phase 1 and phase 2 trials following either oral or intravenous (IV) administration. The model was used to estimate bioavailabilities of the two oral formulations and the effects of demographic and clinical covariates on the central volume of distribution and clearance of panobinostat.. A total of 7834 samples from 581 patients were analyzed. Panobinostat pharmacokinetic parameters were best characterized by a three-compartment model with first-order absorption and elimination. Bioavailability was 21.4 %. Median clearance was 33.1 L/h. Interindividual variability in clearance was 74 %. For Caucasian patients of median age 61 years, area under the curve (AUC) decreased from 104 to 88 ng · h/mL as body surface area (BSA) increased from the first to third quartiles, 1.8 to 2.1 m(2). For Caucasian patients of median BSA 1.9 m(2), AUC decreased from 102 to 95 ng · h/mL as age increased from the first to third quartiles, 51 to 70 years. For patients of median BSA and median age, AUC ranged across the four race categories from 80 to 116 ng · h/mL. Covariate analysis showed no impact on panobinostat clearance and volume by patients' sex, tumor type, kidney function, liver markers, or coadministered medications. However, separate analyses of dedicated studies have demonstrated effects of liver impairment and CYP3A4 inhibition.. Although covariate analyses revealed significant effects of body size, age, and race on panobinostat pharmacokinetics, these effects were minor compared to the interindividual variability and therefore not clinically relevant when dosing panobinostat in populations similar to those studied.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Biological Availability; Female; Hematologic Neoplasms; Humans; Hydroxamic Acids; Indoles; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Panobinostat; Young Adult

Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.

Topics: Acetylation; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Administration Schedule; Female; Hematologic Neoplasms; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Panobinostat; Treatment Outcome; Young Adult

Drug-induced thrombocytopenia often results from dysregulation of normal megakaryocytopoiesis. In this study, we investigated the mechanisms responsible for thrombocytopenia associated with the use of Panobinostat (LBH589), a histone deacetylase inhibitor with promising anti-cancer activities. The effects of LBH589 were tested on the cellular and molecular aspects of megakaryocytopoiesis by utilizing an ex vivo system in which mature megakaryocytes (MK) and platelets were generated from human primary CD34(+) cells. We demonstrated that LBH589 did not affect MK proliferation or lineage commitment but inhibited MK maturation and platelet formation. Although LBH589 treatment of primary MK resulted in hyperacetylation of histones, it did not interfere with the expression of genes that play important roles during megakaryocytopoiesis. Instead, we found that LBH589 induced post-translational modifications of tubulin, a nonhistone protein that is the major component of the microtubule cytoskeleton. We then demonstrated that LBH589 treatment induced hyperacetylation of tubulin and alteration of microtubule dynamics and organization required for proper MK maturation and platelet formation. This study provides new insights into the mechanisms underlying LBH589-induced thrombocytopenia and provides a rationale for using tubulin as a target for selective histone deacetylase inhibitor therapies to treat thrombocytosis in patients with myeloproliferative neoplasms.

Topics: Acetylation; Blood Platelets; Cell Proliferation; Cells, Cultured; Hematologic Neoplasms; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Megakaryocytes; Myeloproliferative Disorders; Panobinostat; Protein Processing, Post-Translational; Thrombocytopenia; Thrombopoiesis; Tubulin

Topics: Dose-Response Relationship, Drug; Hematologic Neoplasms; Humans; Hydroxamic Acids; Indoles; Long QT Syndrome; Panobinostat