abexinostat and Lymphoma--Non-Hodgkin

Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat is an orally available hydroxamate-containing histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concentrations required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between October 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade 3 or over adverse events and any serious adverse events were reported in 88% and 73% of patients, respectively. The most frequently reported grade 3 or over treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response 5%), with highest responses observed in patients with follicular lymphoma (overall response rate 56%), T-cell lymphoma (overall response rate 40%), and diffuse large B-cell lymphoma (overall response rate 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less dose-intense week-on-week-off schedule is warranted. (

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Remission Induction; Thrombocytopenia; Treatment Outcome

Background We determined the safety, pharmacokinetics, pharmacodynamics, and antitumour activity of abexinostat in B-cell lymphoma or chronic lymphocytic leukaemia. Patients and methods Thirty-five patients received oral abexinostat 30, 45, or 60 mg/m(2) bid in a 3 + 3 design in three 21-day schedules: 14 days on treatment in schedule 1 (D1-14); 10 days in schedule 2 (D1-5 and D8-12); and 12 days in schedule 3 (D1-4, D8-11, and D15-18). Safety, tumour response, plasma concentration, and histone H3 acetylation were measured. Results Two dose-limiting toxicities occurred in each schedule (one grade 3 febrile neutropenia; five grade 4 thrombocytopenia) at 60 mg/m(2) bid (maximal tolerated dose). The recommended dose was 45 mg/m(2) bid; schedule 1 was considered optimal. Non-haematological drug-related toxicities included grade 1 or 2 diarrhoea (43%), nausea (23%), and vomiting (11%); haematological toxicities included thrombocytopenia (31% grade 3, and 26% grade 4), which remained manageable and reversible on withdrawal. Of 29 evaluable patients, there were 2 complete and 6 partial responses; median duration of response was 14.6 months (range 3-16.5 months) (1 cycle is equivalent to 0.75 months). There was no evidence for nonlinear pharmacokinetics. There was a correlation between dose and histone acetylation. Conclusion Abexinostat has manageable toxicity and induced some durable complete and partial responses in B-cell lymphoma or chronic lymphocytic leukaemia. Our results suggest most favourable responses in patients with follicular lymphoma, though further research would be needed to confirm this finding.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Hydroxamic Acids; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Male; Maximum Tolerated Dose; Middle Aged

We investigated the cytotoxicity and mechanisms of cell death of the broad-spectrum histone deacetylase (HDAC) inhibitor PCI-24781, alone and combined with bortezomib in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines and primary lymphoproliferative (CLL/SLL) cells.. Apoptosis, mitochondrial membrane potential, cell cycle analysis, and reactive oxygen species (ROS) were measured by flow cytometry, whereas caspase activation was determined by Western blot. Nuclear factor kappaB (NF-kappaB)-related mRNAs were quantified by reverse transcription-PCR, NF-kappaB-related proteins by Western blotting, and NF-kappaB DNA-binding activity by electromobility shift assay. Finally, gene expression profiling was analyzed.. PCI-24781 induced concentration-dependent apoptosis that was associated with prominent G(0)/G(1) arrest, decreased S-phase, increased p21 protein, and increased ROS in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. Dose-dependent apoptosis with PCI-24781 was also seen among primary CLL/SLL cells. PCI-24781-induced apoptosis was shown to be ROS- and caspase-dependent. Combined PCI-24781/bortezomib treatment resulted in strong synergistic apoptosis in all non-Hodgkin lymphoma lines (combination indices, 0.19-0.6) and was additive in Hodgkin lymphoma and primary CLL/SLL cells. Further, PCI-24781/bortezomib resulted in increased caspase cleavage, mitochondrial depolarization, and histone acetylation compared with either agent alone. Gene expression profiling showed that PCI-24781 alone significantly down-regulated several antioxidant genes, proteasome components, and NF-kappaB pathway genes, effects that were enhanced further with bortezomib. Reverse transcription-PCR confirmed down-regulation of NF-kappaB1 (p105), c-Myc, and IkappaB-kinase subunits, where NF-kappaB DNA binding activity was decreased.. We show that PCI-24781 results in increased ROS and NF-kappaB inhibition, leading to caspase-dependent apoptosis. We also show that bortezomib is synergistic with PCI-24781. This combination or PCI-24781 alone has potential therapeutic value in lymphoma.

Topics: Aged; Antineoplastic Agents; Apoptosis; Benzofurans; Blotting, Western; Boronic Acids; Bortezomib; Caspases; Cell Cycle; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Female; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lymphoma; Lymphoma, Non-Hodgkin; Male; Membrane Potential, Mitochondrial; Middle Aged; NF-kappa B; Pyrazines; Reactive Oxygen Species; Tumor Cells, Cultured