benzofurans 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

In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed.. Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 microg/m2. A total of 140 patients were entered and a total of 285 courses were administered.. In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen.. At this dose and schedule carzelesin did not yield activity in the types of tumors studied.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Breast Neoplasms; Colorectal Neoplasms; Duocarmycins; Female; Head and Neck Neoplasms; Humans; Indoles; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Male; Melanoma; Middle Aged; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Prodrugs; Stomach Neoplasms

Patients with indolent non-Hodgkin lymphomas (NHL) may often be followed up only with observation, reserving chemotherapy in case of spread. Patients with chronic HCV infection and B cell NHL frequently undergo regression of lymphoproliferative disease once HCV infection is eradicated by treatment. Interferon (IFN)-based therapy has been the treatment of choice for years, remaining unclear whether it is effective in B cell NHL directly or through HCV eradication, since IFN is effective in both HCV infection and B cell NHL. IFN therapy for HCV infection became obsolete with the advent of the well tolerated direct-acting antiviral agents (DAAs), whose excellent efficacy in treating patients with chronic HCV infection and B cell NHL has been recently highlighted. We treated a 53-year-old woman with chronic HCV infection and marginal zone lymphoma (MZL) with elbasvir plus grazoprevir in 2018, with complete remission and persisting excellent results: sustained virological response 24 weeks after treatment (SVR24). The exclusive role of HCV eradication in B cell NHL regression is also underlined.

Topics: Antiviral Agents; Benzofurans; Female; Genotype; Hepatitis C, Chronic; Humans; Imidazoles; Lymphoma, Non-Hodgkin; Middle Aged; Sustained Virologic Response

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

Since 1971, a municipal solid waste incinerator (MSWI) with high dioxin emission levels has been in operation in Besançon, France. We recently found a 2.3-fold risk of non-Hodgkin's lymphoma in the highest exposure zone using a Gaussian-type dispersion model as a proxy for dioxin exposure. However, the sources of PCDD/Fs in this area are a matter of controversy. The aim of this survey was therefore to examine the nature of the PCDD/F soil contamination in the surroundings of the MSWI to characterize whether more than one potential emission source could explain the presence of the PCDD/Fs. PCDD/F congener profiles were determined in 75 soil samples collected in the vicinity of the MSWI. They were compared according to the most environmentally impacted zones and to various spatial contrasts. PCDD/F concentrations ranged from 0.25 to 28.06 pg WHO-TEQ g(-1). Two different clustering algorithms identified the same main cluster (consisting of 73 samples). The remaining two soil samples composed either one, or two clusters. All clusters showed similar congener profiles. Moreover, no contrast was observed for congener distributions between complex and simple topographies, inside and outside the city boundary, the two most and the two least exposed areas, reflecting a common fingerprint. Congener profiles indicate that the area under influence of the MSWI is not subject to other point sources of PCDD/Fs. Since, the most polluting combustion chambers were recently shut down and replaced by a new one with up-to-date pollution control, slowly decreasing dioxin concentrations in the soils are to be expected.

Topics: Benzofurans; Dibenzofurans, Polychlorinated; Environmental Monitoring; Epidemiological Monitoring; France; Humans; Incidence; Incineration; Lymphoma, Non-Hodgkin; Polychlorinated Dibenzodioxins; Soil Pollutants; Waste Products

A rapid increase in the incidence of non-Hodgkin lymphoma (NHL) has been reported in many countries. Exposure to certain pesticides or organochlorines has been shown to be a risk factor. Epstein-Barr virus (EBV) is a human herpesvirus that has been associated with some subgroups of NHL, such as Burkitt lymphoma and lymphomas related to severe immunosuppression. In this study we measured concentrations of dioxins and dibenzofurans in 33 NHL cases and 39 surgical controls. For 23 of the cases and 32 of the controls EBV titers were also available. Median titer of antibodies to EBV early antigen (EA) IgG was higher in patients than in controls. Concentrations of dioxins and dibenzofurans were divided into two groups according to the median concentration for the controls. Unconditional logistic regression analysis was performed adjusting for sex, age, and body mass index. For several higher chlorinated congeners increased risk was found for patients in the high-concentration and high-titer group. For toxic equivalency factor >27.79 and EA>80 an odds ratio of 2.8 with 95% confidence interval 0.52-18 was calculated. These results indicated that current exposure to certain organochlorines in combination with EBV might increase the risk for NHL.

Topics: Adipose Tissue; Adult; Aged; Antibodies, Viral; Antigens, Viral; Benzofurans; Case-Control Studies; Dioxins; Environmental Exposure; Epstein-Barr Virus Infections; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Regression Analysis; Risk Assessment