benzofurans and Lymphoproliferative-Disorders

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

Concentrations of dioxins (PCDD) and dibenzofurans (PCDF) were analysed in adipose tissue from seven patients with malignant lymphoproliferative diseases and 12 surgical patients without a malignant disease. All cases in the first group had reported potential exposure to PCDD and PCDF. Of the analysed congeners significantly higher concentrations of 1,2,3,7,8-pentachlorodioxin, 1,2,3,6,7,8-hexachlorodioxin, and 2,3,4,7,8-pentachlorodibenzofuran were found in the cases with lymphoproliferative diseases compared with the patients in the other group. Higher mean concentration of 2,3,7,8-TCDD was also found in the first group but not significantly so. Toxic equivalents of PCDD and PCDF were significantly higher in the first group (mean 64.7 pg/g, range 19.9-187) than in the second group (mean 29.7 pg/g, range 12.9-53.4). Even if the cases with lymphoproliferative diseases in this case series were potentially exposed to PCDD/PCDF in contrast to the other group, the observed differences may be of may be of interest in relation to the aetiology of these malignancies. Immunosuppression increases the risk for malignant lymphoproliferative diseases, and PCDD/PCDF have established immunotoxic properties.

Topics: Adipose Tissue; Adult; Aged; Benzofurans; Dioxins; Female; Humans; Lymphoproliferative Disorders; Male; Middle Aged