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Journal of Oncology Pharmacy Practice :... Mar 2017Peripheral T-cell lymphoma is a heterogenous non-Hodgkin Lymphoma with historically poor outcomes. Currently, response rates remain poor with traditional chemotherapy... (Review)
Review
Peripheral T-cell lymphoma is a heterogenous non-Hodgkin Lymphoma with historically poor outcomes. Currently, response rates remain poor with traditional chemotherapy and many of those responding to initial therapy will relapse. Belinostat (Beleodaq, Spectrum Pharmaceuticals) is a histone deacetylase inhibitor (HDACi) approved for use in relapsed or refractory peripheral T-cell lymphoma (PTCL). Belinostat is metabolized hepatically through cytochrome P-450 enzymes 3A4, 2C9, and 2A6; however, no empiric dosage adjustments of belinostat are recommended during concurrent use of inhibitors or inducers of these enzymes. Belinostat's efficacy has been evaluated in a clinical trial showing an overall response rate (ORR) of 25.8% and a median duration of response of 8.4 months. Belinostat is generally well tolerated, with the most common adverse reactions (>25%) being nausea, vomiting, fatigue, pyrexia, and anemia in patients with relapsed or refractory PTCL. Belinostat is a safe and effective treatment option for relapsed and refractory peripheral T-cell lymphoma, with many future applications currently being investigated.
Topics: Antineoplastic Agents; Blood Cell Count; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Practice Guidelines as Topic; Sulfonamides; Treatment Outcome
PubMed: 26921086
DOI: 10.1177/1078155216634178 -
Journal of Clinical Oncology : Official... Aug 2015Peripheral T-cell lymphomas (PTCLs) represent a diverse group of non-Hodgkin lymphomas with a poor prognosis and no accepted standard of care for patients with relapsed...
PURPOSE
Peripheral T-cell lymphomas (PTCLs) represent a diverse group of non-Hodgkin lymphomas with a poor prognosis and no accepted standard of care for patients with relapsed or refractory disease. This study evaluated the efficacy and tolerability of belinostat, a novel histone deacetylase inhibitor, as a single agent in relapsed or refractory PTCL.
PATIENTS AND METHODS
Patients with confirmed PTCL who experienced progression after ≥ one prior therapy received belinostat 1,000 mg/m(2) as daily 30-minute infusions on days 1 to 5 every 21 days. Central assessment of response used International Working Group criteria. Primary end point was overall response rate. Secondary end points included duration of response (DoR) and progression-free and overall survival.
RESULTS
A total of 129 patients were enrolled, with a median of two prior systemic therapies. Overall response rate in the 120 evaluable patients was 25.8% (31 of 120), including 13 complete (10.8%) and 18 partial responses (15%). Median DoR by International Working Group criteria was 13.6 months, with the longest ongoing patient at ≥ 36 months. Median progression-free and overall survival were 1.6 and 7.9 months, respectively. Twelve of the enrolled patients underwent stem-cell transplantation after belinostat monotherapy. The most common grade 3 to 4 adverse events were anemia (10.8%), thrombocytopenia (7%), dyspnea (6.2%), and neutropenia (6.2%).
CONCLUSION
Monotherapy with belinostat produced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across the major subtypes, irrespective of number or type of prior therapies. These results have led to US Food and Drug Administration approval of belinostat for this indication.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Infusions, Intravenous; Kaplan-Meier Estimate; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Neoplasm Recurrence, Local; Sulfonamides; Treatment Outcome
PubMed: 26101246
DOI: 10.1200/JCO.2014.59.2782 -
Biomedicine & Pharmacotherapy =... Sep 2023Cancer progression is strongly affected by epigenetic events in addition to genetic modifications. One of the key elements in the epigenetic control of gene expression... (Review)
Review
Cancer progression is strongly affected by epigenetic events in addition to genetic modifications. One of the key elements in the epigenetic control of gene expression is histone modification through acetylation, which is regulated by the synergy between histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are thought to offer considerable potential for the development of anticancer medications, particularly when used in conjunction with other anticancer medications and/or radiotherapy. Belinostat (Beleodaq, PXD101) is a pan-HDAC unsaturated hydroxamate inhibitor with a sulfonamide group that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory or relapsed peripheral T-cell lymphoma (PTCL) and solid malignancies or and other hematological tissues. This drug modifies histones and epigenetic pathways. Because HDAC and HAT imbalance can lead to downregulation of regulatory genes, resulting in tumorigenesis. Inhibition of HDACs by belinostat indirectly promotes anti-cancer therapeutic effect by provoking acetylated histone accumulation, re-establishing normal gene expressions in cancer cells and stimulating other routes such as the immune response, p27 signaling cascades, caspase 3 activation, nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) degradation, cyclin A (G2/M phase), cyclin E1 (G1/S phase) and other events. In addition, belinostat has already been discovered to increase p21 in a number of cell lines (melanoma, prostate, breast, lung, colon, and ovary). This cyclin-dependent kinase inhibitor actually has a role in processes that cause cell cycle arrest and apoptosis. Belinostat's clinical effectiveness, comprising Phase I and II studies within the areas of solid and hematological cancers, has been evidenced through several investigative trials that have supported its potential to be a valuable anti-cancer drug. The purpose of this research was to provide insight on the specific molecular processes through which belinostat inhibits HDAC. The ability to investigate new therapeutic options employing targeted therapy and acquire a deeper understanding of cancer cell abnormalities may result from a better understanding of these particular routes.
Topics: Male; Female; Humans; Hydroxamic Acids; Antineoplastic Agents; Sulfonamides; Histone Deacetylase Inhibitors; Histones; Apoptosis; Neoplasms; Histone Deacetylases; Cell Line, Tumor
PubMed: 37541175
DOI: 10.1016/j.biopha.2023.115212 -
Pharmacological Research Mar 2016Certain genetic polymorphisms of UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) can reduce gene expression (*28, *60, *93) or activity (*6), thereby... (Review)
Review
Certain genetic polymorphisms of UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) can reduce gene expression (*28, *60, *93) or activity (*6), thereby altering the pharmacokinetics, pharmacodynamics, and the risk of toxicities of UGT1A1 substrates, of which irinotecan is a widely-described example. This review presents an overview of the clinical effects of UGT1A1 polymorphisms on the pharmacology of UGT1A1 substrates, with a special focus on the novel histone deacetylase inhibitor belinostat. Belinostat, approved for the treatment of peripheral T-cell lymphoma, is primarily glucuronidated by UGT1A1. Recent preclinical and clinical data showed that UGT1A1*28 was associated with reduced glucuronidation in human liver microsomes, while in a retrospective analysis of a Phase I trial with patients receiving belinostat UGT1A1*60 was predominantly associated with increased belinostat plasma concentrations. Furthermore, both UGT1A1*28 and *60 variants were associated with increased incidence of thrombocytopenia and neutropenia. Using population pharmacokinetic analysis a 33% dose reduction has been proposed for patients carrying UGT1A1 variant alleles. Clinical effects of this genotype-based dosing recommendation is currently prospectively being investigated. Overall, the data suggest that UGT1A1 genotyping is useful for improving belinostat therapy.
Topics: Animals; Antineoplastic Agents; Genotyping Techniques; Glucuronosyltransferase; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lymphoma, T-Cell, Peripheral; Pharmacogenetics; Polymorphism, Genetic; Sulfonamides
PubMed: 26773202
DOI: 10.1016/j.phrs.2016.01.002 -
Journal of the Advanced Practitioner in... Mar 2016
Review
PubMed: 28090369
DOI: 10.6004/jadpro.2016.7.2.6 -
Future Oncology (London, England) 2015The prognosis of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) remains poor and current treatments are typically of limited benefit. Histone... (Review)
Review
The prognosis of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) remains poor and current treatments are typically of limited benefit. Histone deacetylase (HDAC) inhibitors have proven effective for the treatment of relapsed/refractory PTCL. To date approved HDAC inhibitors for patients with T-cell lymphoma are vorinostat, romidepsin and, recently, belinostat. Here we review the pharmacology and the clinical activity of belinostat. Belinostat is a well-tolerated HDAC inhibitor that has shown activity in heavily pretreated patients with relapsed/refractory PTCL. Several clinical trials are currently investigating the use of belinostat in different cancers and in combination with other chemotherapeutic agents.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Hydroxamic Acids; Lymphoma, T-Cell, Peripheral; Recurrence; Retreatment; Sulfonamides
PubMed: 26043217
DOI: 10.2217/fon.15.62 -
Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: a perspective review.Therapeutic Advances in Hematology Aug 2015Peripheral T-cell lymphoma (PTCL) is a disease with poor prognosis and limited treatment options. Recent advances in cancer biology suggest that PTCL may be... (Review)
Review
Peripheral T-cell lymphoma (PTCL) is a disease with poor prognosis and limited treatment options. Recent advances in cancer biology suggest that PTCL may be characterized by gross epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors. HDAC inhibitors have demonstrated significant activity in T-cell neoplasms and recently, the BELIEF trial evaluated belinostat leading to its approval in the US. This review discusses the development of belinostat, its mechanism of action, pivotal clinical trials, drug toxicity and its recent approval for patients with relapsed or refractory PTCL. Key clinical trials covered include phase I/II evaluation of belinostat in hematologic malignancies, cutaneous T-cell lymphoma (CTCL) and PTCL. In addition, the BELIEF trial in PTCL leading to FDA approval of belinostat is reviewed in detail.
PubMed: 26288714
DOI: 10.1177/2040620715592567 -
The Medical Letter on Drugs and... Apr 2015
Review
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Hydroxamic Acids; Lymphoma, T-Cell, Peripheral; Sulfonamides
PubMed: 25988963
DOI: No ID Found