DRUG EVALUATION For reprint orders, please contact: [email protected]
Belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma
Armin Rashidi1 & Amanda F Cashen*,1
ABSTRACT 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. Peripheral T-cell lymphomas (PTCL) are a rare group of hematologic malignancies with an incidence of less than one case per 100,000 persons in the USA. With currently available therapies, 5-year overall survival for patients with PTCL is poor at only 25–35% [1] . The three most common subtypes of PTCL are PTCL-not otherwise specified, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma. The preferred initial treatment for PTCL continues to be controversial. The most popular frontline therapies are anthracycline-based regimens such as CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) and CHOEP (etoposide in addition to CHOP) [2] . A comparison between CHOP and CHOEP showed superiority of CHOEP in terms of 3-year event-free survival (75% with CHOEP, 51% for CHOP) among patients younger than 60 years of age, with no significant difference among older patients [3] . Consolidation with autologous stem cell transplantation (auto-SCT) is often performed for chemosensitive disease with variable outcomes [4,5] , best when performed in first complete remission (CR) [6] . While frontline therapy for PTCL is usually with curative intent, treatment of relapsed/refractory disease remains palliative, with the exception of allogeneic stem cell transplantation (allo-SCT). The available treatment options include traditional platinum-based salvage chemotherapy, pralatrexate, brentuximab vedotin, allo-SCT and, most recently, histone deacetylase (HDAC) inhibitors [7] . The purpose of the present article is to review the pharmacology and clinical experience with belinostat, a recently approved HDAC inhibitor for the treatment of relapsed/refractory PTCL.
KEYWORDS
• belinostat • histone
deacetylase inhibitor • T-cell lymphoma
Overview of the market of HDAC inhibitors in T-cell lymphomas The acetylation status of histones, determined by the balance between the action of histone acetyltransferase and HDACs, determines the binding between DNA and histones. This in turn alters DNA accessibility for gene transcription and ultimately protein expression. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and a number of other proteins such as transcription factors, signaling molecules and chaperons. Disrupted regulation of these processes Division of Oncology, Washington University School of Medicine, 660 S Euclid Avenue, Campus Box 8007, St Louis, MO 63110, USA *Author for correspondence: Tel.: +1 314 454 8306; Fax: +1 314 454 7551; [email protected] 1
10.2217/FON.15.62 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(11), 1659–1664
part of
ISSN 1479-6694
1659
Drug Evaluation Rashidi & Cashen is a mechanism for malignant transformation in a variety of human tumors. HDAC inhibitors reverse the inhibitory effect of histone deacetylation and chromatin compacting on gene expression. The rationale behind the use of HDAC inhibitors is the frequent aberrant expression of HDACs in cancer cells [8,9] . In addition, many HDAC inhibitors also modulate nonhistone proteins by lysine deacetylation and hence regulate gene expression [10] . A total of 18 members of the HDAC have been described and can be classified in two major groups: zinc-dependent HDACs (class I: HDACs 1, 2, 3 and 8; class IIa: HDACs 4, 5, 7 and 9; class IIb: HDACs 6 and 10; class IV: HDAC 11); and nicotinamide adenine dinucleotide (NAD)-dependent (class III or sirtuins 1–7) [11,12] . In a study of 45 patients with PTCL, HDAC 1, 2 and 6 were overexpressed compared with normal lymphoid tissues [13] . Vorinostat, an oral class I–II HDAC inhibitor, was approved in 2006 for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL). This was based on two singlearm, Phase II studies. The first study included patients with relapsed/refractory CTCL with a median of five prior therapies and demonstrated an overall response rate (ORR) of 24% (no CR) with a median duration of response of about 4 months [14] . The second study demonstrated an ORR of 30% and a median duration of response of longer than 6 months in patients with CTCL after at least two prior systemic therapies [15] . Diarrhea, nausea, fatigue and thrombocytopenia are the most common side effects with vorinostat. The recommended dose of vorinostat is 400 mg daily. Romidepsin (primarily a class I HDAC inhibitor) was approved by the US FDA in 2009 for the treatment of patients with PTCL who have received at least one prior therapy. Approval was based on two single-arm Phase II studies. In the first study, including 45 patients with relapsed/refractory PTCL and a median of three prior therapies, an ORR of 38% (CR: 18%) was achieved with a median duration of response of 9 months [16] . Another large international Phase II study on 130 patients with relapsed/refractory PTCL and a median of two prior therapies achieved an ORR of 25% (CR: 15%), with a median duration of response of 17 months [17] . Nausea, fatigue, thrombocytopenia and neutropenia are the most common side effects, and QTc prolongation is a rare but potentially serious adverse effect. Romidepsin is
1660
Future Oncol. (2015) 11(11)
administered intravenously at 14 mg/m2 on days 1, 8 and 15 on 28-day cycles. The drug is not yet licensed in Europe. Belinostat has now joined vorinostat and romidepsin as HDAC inhibitors approved for the treatment of relapsed/refractory T-cell lymphoma. Belinostat was structurally designed by TopoTarget (merged in 2014 with BioAlliance Pharma to form Onxeo) and was previously known as PXD101. Following an agreement between TopoTarget and Spectrum Pharmaceuticals in 2010, and a subsequent amendment in 2013, Spectrum is now responsible for manufacturing of belinostat. Belinostat chemistry, pharmacokinetics & pharmacodynamics Belinostat (Beleodaq), (2E)-N-hydroxy-3-[3(phenylsulfamoyl)phenyl]prop-2-enamide, is a pan-HDAC inhibitor with a sulfonamidehydroxamide structure and high affinity for the class I, II and IV HDACs (Figure 1) . In vitro exposure to belinostat results in the accumulation of acetylated histones, restoration of the expression of epigenetically silenced tumor suppressor genes (e.g., TGF-β receptor II) [18] , repression of survivin expression (a protein involved in mitosis and with antiapoptotic effects) [18] , and ultimately cell cycle arrest and apoptosis of malignant cells. Belinostat is active at nanomolar concentrations (
Belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma
Armin Rashidi1 & Amanda F Cashen*,1
ABSTRACT 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. Peripheral T-cell lymphomas (PTCL) are a rare group of hematologic malignancies with an incidence of less than one case per 100,000 persons in the USA. With currently available therapies, 5-year overall survival for patients with PTCL is poor at only 25–35% [1] . The three most common subtypes of PTCL are PTCL-not otherwise specified, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma. The preferred initial treatment for PTCL continues to be controversial. The most popular frontline therapies are anthracycline-based regimens such as CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) and CHOEP (etoposide in addition to CHOP) [2] . A comparison between CHOP and CHOEP showed superiority of CHOEP in terms of 3-year event-free survival (75% with CHOEP, 51% for CHOP) among patients younger than 60 years of age, with no significant difference among older patients [3] . Consolidation with autologous stem cell transplantation (auto-SCT) is often performed for chemosensitive disease with variable outcomes [4,5] , best when performed in first complete remission (CR) [6] . While frontline therapy for PTCL is usually with curative intent, treatment of relapsed/refractory disease remains palliative, with the exception of allogeneic stem cell transplantation (allo-SCT). The available treatment options include traditional platinum-based salvage chemotherapy, pralatrexate, brentuximab vedotin, allo-SCT and, most recently, histone deacetylase (HDAC) inhibitors [7] . The purpose of the present article is to review the pharmacology and clinical experience with belinostat, a recently approved HDAC inhibitor for the treatment of relapsed/refractory PTCL.
KEYWORDS
• belinostat • histone
deacetylase inhibitor • T-cell lymphoma
Overview of the market of HDAC inhibitors in T-cell lymphomas The acetylation status of histones, determined by the balance between the action of histone acetyltransferase and HDACs, determines the binding between DNA and histones. This in turn alters DNA accessibility for gene transcription and ultimately protein expression. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and a number of other proteins such as transcription factors, signaling molecules and chaperons. Disrupted regulation of these processes Division of Oncology, Washington University School of Medicine, 660 S Euclid Avenue, Campus Box 8007, St Louis, MO 63110, USA *Author for correspondence: Tel.: +1 314 454 8306; Fax: +1 314 454 7551; [email protected] 1
10.2217/FON.15.62 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(11), 1659–1664
part of
ISSN 1479-6694
1659
Drug Evaluation Rashidi & Cashen is a mechanism for malignant transformation in a variety of human tumors. HDAC inhibitors reverse the inhibitory effect of histone deacetylation and chromatin compacting on gene expression. The rationale behind the use of HDAC inhibitors is the frequent aberrant expression of HDACs in cancer cells [8,9] . In addition, many HDAC inhibitors also modulate nonhistone proteins by lysine deacetylation and hence regulate gene expression [10] . A total of 18 members of the HDAC have been described and can be classified in two major groups: zinc-dependent HDACs (class I: HDACs 1, 2, 3 and 8; class IIa: HDACs 4, 5, 7 and 9; class IIb: HDACs 6 and 10; class IV: HDAC 11); and nicotinamide adenine dinucleotide (NAD)-dependent (class III or sirtuins 1–7) [11,12] . In a study of 45 patients with PTCL, HDAC 1, 2 and 6 were overexpressed compared with normal lymphoid tissues [13] . Vorinostat, an oral class I–II HDAC inhibitor, was approved in 2006 for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL). This was based on two singlearm, Phase II studies. The first study included patients with relapsed/refractory CTCL with a median of five prior therapies and demonstrated an overall response rate (ORR) of 24% (no CR) with a median duration of response of about 4 months [14] . The second study demonstrated an ORR of 30% and a median duration of response of longer than 6 months in patients with CTCL after at least two prior systemic therapies [15] . Diarrhea, nausea, fatigue and thrombocytopenia are the most common side effects with vorinostat. The recommended dose of vorinostat is 400 mg daily. Romidepsin (primarily a class I HDAC inhibitor) was approved by the US FDA in 2009 for the treatment of patients with PTCL who have received at least one prior therapy. Approval was based on two single-arm Phase II studies. In the first study, including 45 patients with relapsed/refractory PTCL and a median of three prior therapies, an ORR of 38% (CR: 18%) was achieved with a median duration of response of 9 months [16] . Another large international Phase II study on 130 patients with relapsed/refractory PTCL and a median of two prior therapies achieved an ORR of 25% (CR: 15%), with a median duration of response of 17 months [17] . Nausea, fatigue, thrombocytopenia and neutropenia are the most common side effects, and QTc prolongation is a rare but potentially serious adverse effect. Romidepsin is
1660
Future Oncol. (2015) 11(11)
administered intravenously at 14 mg/m2 on days 1, 8 and 15 on 28-day cycles. The drug is not yet licensed in Europe. Belinostat has now joined vorinostat and romidepsin as HDAC inhibitors approved for the treatment of relapsed/refractory T-cell lymphoma. Belinostat was structurally designed by TopoTarget (merged in 2014 with BioAlliance Pharma to form Onxeo) and was previously known as PXD101. Following an agreement between TopoTarget and Spectrum Pharmaceuticals in 2010, and a subsequent amendment in 2013, Spectrum is now responsible for manufacturing of belinostat. Belinostat chemistry, pharmacokinetics & pharmacodynamics Belinostat (Beleodaq), (2E)-N-hydroxy-3-[3(phenylsulfamoyl)phenyl]prop-2-enamide, is a pan-HDAC inhibitor with a sulfonamidehydroxamide structure and high affinity for the class I, II and IV HDACs (Figure 1) . In vitro exposure to belinostat results in the accumulation of acetylated histones, restoration of the expression of epigenetically silenced tumor suppressor genes (e.g., TGF-β receptor II) [18] , repression of survivin expression (a protein involved in mitosis and with antiapoptotic effects) [18] , and ultimately cell cycle arrest and apoptosis of malignant cells. Belinostat is active at nanomolar concentrations (
