abexinostat and Lymphoma--Mantle-Cell

Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N = 55) with single-agent abexinostat in relapsed/refractory lymphoma.. In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m(2) twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/refractory follicular lymphoma or mantle cell lymphoma.. The recommended phase II dose was 45 mg/m(2) twice daily (90 mg/m(2) total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigator-assessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2-22.3+). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1-11.5). Grade 3-4 treatment-related adverse events (phase II) with ≥ 10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths.. The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Disease-Free Survival; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Recurrence

Mantle cell lymphoma (MCL) is a rare lymphoma caused by the t(11:14) juxtaposing the cyclin D1 (CCND1) locus on chromosome 11 and the immunoglobulin heavy chain (IgH) locus on chromosome 14. Several new treatments are proposed for MCL, including histone deacetylase inhibitors (HDACi). We have studied gene expression and chromatin organization in the translocated 11q13 locus in MCL cells as compared to lymphoblastoid cell lines as well as the effect of HDACi abexinostat on chromatin organization and gene expression in the 11q13 locus. We have identified a cluster of genes overexpressed in the translocation region on chromosome 11 in MCL cells. Abexinostat provokes a genome-wide disaggregation of heterochromatin. The genes upregulated after the t(11;14) translocation react to the HDACi treatment by increasing their expression, but their gene promoters do not show significant alterations in H3K9Ac and H3K9me2 levels in abexinostat-treated cells.

Topics: B-Lymphocytes; Benzofurans; Cell Line, Tumor; Chromatin; Chromatin Assembly and Disassembly; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lymphoma, Mantle-Cell; Promoter Regions, Genetic; Transcription, Genetic; Translocation, Genetic