Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II study

Abstract

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. (Trial registered at: EudraCT-2009-013691-47)

Phase 1 dose-escalation study of oral abexinostat for the treatment of patients with relapsed/refractory higher-risk myelodysplastic syndromes, acute myeloid leukemia, or acute lymphoblastic leukemia

“…[38] ECG changes including QTc prolongation have been reported with other HDAC inhibitors and a potential class effect has been suggested. [39,40] However, in this study and others of abexinostat, [31,32,41] treatment with abexinostat did not result in clinically relevant ECG changes. The MTD was not identified.…”

The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance

“…125 The significant hematological and infectious toxicity observed with the latter regimen, both during and after therapy, was deemed too high in this patient population. 125 As shown in Table 4, [126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144] new targeted agents have been poorly studied in MALT lymphomas: only 3 studies 127,129,133 were restricted to this entity and included .10 patients.…”

Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia

“…Although specifically treatment with NSC3852 suggested a potential for therapeutic applications in pediatric AML, future studies are required to further investigate the molecular mechanisms underlying these effects by transcriptomic and epigenomic analysis. In addition, more insights into toxicity, both hematological, including thrombocytopenia and anemia, and nonhematological, are needed in order to move forward to clinical studies …”