panobinostat and Neutropenia

Patients with relapsed or refractory multiple myeloma who have received several lines of therapy have no satisfactory treatment options. High-dose corticosteroid therapy or a combination of low-dose dexamethasone and pomaildomide may be proposed. Panobinostat is the first histone deacetylase (HDAC) inhibitor to be authorised in the European Union for use in this indication. A randomised, double-blind, placebo-controlled trial evaluated panobinostat in 768 patients with relapsed or refractory multiple myeloma who were also receiving bortezomib + dexamethasone. Panobinostat did not prolong survival. The median time to myeloma progression, relapse, or death was prolonged by about 3 months with the panobinostat-containing combination, and by a median of about 8 months in the subgroup of patients who had received at least two lines of chemotherapy including bortezomib and an "immunomodulatory" drug. There was no statistically significant increase in survival, however. In this trial, adverse events led one in six patients to discontinue panobinostat and resulted in numerous hospital admissions. The proportion of patients who died from causes unrelated to myeloma was 6.8% in the panobinostat group versus 3.2% In the placebo group. The toxicity of panobinostat affects most vital functions, resulting in a risk of infections as well as haematological, gastrointestinal, cardiac, renal, hepatic and thyroid disorders. These adverse effects are often severe and sometimes fatal. Panobinostat is subject to pharmacokinetic interactions via cytochrome P450 enzymes and P-glycoproteln, and also to pharmacodynamic Interactions. Panobinostat was teratogenic in animal studies. In practice, even when several previous lines of treatment have failed, panobinostatis more toxic than useful In patients with myeloma. It should therefore not be used.

Topics: Antineoplastic Agents; Arrhythmias, Cardiac; Chemical and Drug Induced Liver Injury; Cost-Benefit Analysis; Diarrhea; Drug Interactions; Gastrointestinal Diseases; Hemorrhage; Humans; Hypothyroidism; Infections; Mortality; Multiple Myeloma; Myocardial Ischemia; Neutropenia; Panobinostat; Progression-Free Survival; Renal Insufficiency; Survival Rate; Thrombocytopenia

This phase-I/phase-II study evaluated panobinostat in combination with ifosfamide, carboplatin, etoposide (P-ICE) in relapsed/refractory classical Hodgkin lymphoma. During phase I, panobinostat was given daily on Monday/Wednesday/Friday starting one week prior to Cycle 1 (C1) of ICE and during two weeks of C1-2 of ICE (Schedule A). No DLT was observed at 30 mg. However, frequent (84%) grade-4 thrombocytopenia during second week prompted us to omit the second week of panobinostat 30 mg (Schedule B) for phase II, where this regimen was compared to ICE. In the randomized phase-II study, CR was seen in 9/11 (82%) and 8/12 (67%) for P-ICE and ICE, respectively (p = .64). Grade-4 neutropenia (55% vs. 8%) and thrombocytopenia (100% vs. 33%) were more common in P-ICE. In summary, combination therapy using panobinostat produced high CR rate at the cost of greater bone marrow toxicity. Investigation of panobinostat with less myelosuppressive agents is of interest.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carboplatin; Drug Administration Schedule; Drug Resistance, Neoplasm; Etoposide; Female; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Ifosfamide; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Panobinostat; Survival Rate; Thrombocytopenia; Treatment Outcome; Young Adult

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hematopoietic Stem Cell Transplantation; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Nausea; Neoplasm Recurrence, Local; Neutropenia; Panobinostat; Prospective Studies; Risk Factors; Transplantation, Autologous; Young Adult

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Diarrhea; Humans; Hydroxamic Acids; Indoles; Induction Chemotherapy; Middle Aged; Multiple Myeloma; Nausea; Neutropenia; Panobinostat; Preoperative Period; Stem Cell Transplantation; Thrombocytopenia; Transplantation, Autologous; Treatment Outcome; Vomiting

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Boronic Acids; Bortezomib; Diarrhea; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Lenalidomide; Male; Metabolic Clearance Rate; Middle Aged; Multiple Myeloma; Nausea; Neutropenia; Panobinostat; Pyrazines; Recurrence; Remission Induction; Thalidomide; Thrombocytopenia; Treatment Outcome

The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Hydroxamic Acids; Indoles; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Neutropenia; Panobinostat; Prednisone; Recurrence; Thalidomide; Thrombocytopenia; Time Factors; Treatment Outcome