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Journal of Clinical Oncology : Official... Jan 2022Romidepsin, a histone deacetylase inhibitor, has demonstrated activity in relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single agent. Cyclophosphamide,... (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
Romidepsin, a histone deacetylase inhibitor, has demonstrated activity in relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single agent. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used as first-line treatment of PTCL; however, it has limited efficacy. Results from a phase Ib and II study showed the feasibility of combining romidepsin with CHOP (Ro-CHOP).
METHODS
This study is a randomized phase III study of Ro-CHOP versus CHOP in adult patients with previously untreated PTCL. All patients received CHOP in 3-week cycles for six cycles. Romidepsin, 12 mg/m, was administered intravenously over a 4-hour period on days 1 and 8 of each 3-week cycle for six cycles. The primary end point was progression-free survival (PFS) according to International Working Group 1999 criteria.
RESULTS
Between January 2013 and December 2017, 421 patients were enrolled (Ro-CHOP, n = 211; CHOP, n = 210). The median PFS for Ro-CHOP versus CHOP was 12.0 months (95% CI, 9.0 to 25.8) versus 10.2 months (95% CI, 7.4 to 13.2) with a hazard ratio of 0.81 ( = .096). In the Ro-CHOP versus CHOP arms, the median overall survival was 51.8 versus 42.9 months and the objective response rate was 63% versus 60% with complete response plus unconfirmed complete response rates of 41% versus 37% ( > .1 in all comparisons), respectively. Grade 3 or 4 treatment-emergent adverse events occurring in ≥ 30% of patients in the Ro-CHOP arm included thrombocytopenia (50% 10% in the Ro-CHOP CHOP arms, respectively), neutropenia (49% 33%), anemia (47% 17%), and leukopenia (32% 20%).
CONCLUSION
The addition of romidepsin to CHOP did not improve PFS, response rates, nor overall survival and increased the frequency for grade ≥ 3 treatment-emergent adverse events. Ro-CHOP does not represent a significant advance in the standard of care for patients with previously untreated PTCL.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asia; Australia; Cyclophosphamide; Depsipeptides; Disease Progression; Doxorubicin; Europe; Female; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Prednisone; Progression-Free Survival; Time Factors; Vincristine
PubMed: 34843406
DOI: 10.1200/JCO.21.01815 -
Blood Apr 2021Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA...
Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.
Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; DNA Methylation; Depsipeptides; Female; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Mutation; Treatment Outcome
PubMed: 33171487
DOI: 10.1182/blood.2020009004 -
Expert Opinion on Drug Discovery Aug 2017Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a... (Review)
Review
Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34-35% and 25-38%, with complete response (CR) rates of 6% and 15-18%, respectively. Areas covered: This review summarizes the development of romidepsin, the mechanisms behind its antineoplastic action and its pharmacology. It also covers its pharmacokinetic and pharmacodynamic properties, as well as the preclinical and clinical data on its activity in T-cell lymphoma. Expert opinion: Since there are only few effective therapies available for T-cell lymphomas, romidepsin is a valuable option for relapsed/refractory patients with both CTCL and PTCL. It's also generally well tolerated, and gives potentially durable responses for patients with advanced and symptomatic disease. Combinations of romidepsin with other antineoplastic agents may also further improve drug response and outcomes in T-cell lymphoma.
Topics: Animals; Antibiotics, Antineoplastic; Depsipeptides; Drug Design; Drug Evaluation, Preclinical; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell; Treatment Outcome
PubMed: 28641053
DOI: 10.1080/17460441.2017.1341487 -
Expert Opinion on Investigational Drugs 2015Patients with relapsed or refractory lymphoma remain a population with unmet medical needs. Histone deacetylase inhibitors (HDACIs) represent a novel class of anticancer... (Review)
Review
INTRODUCTION
Patients with relapsed or refractory lymphoma remain a population with unmet medical needs. Histone deacetylase inhibitors (HDACIs) represent a novel class of anticancer drugs currently in development in several malignancies. Inhibition of HDACs leads to acetylation of histone and non-histone proteins, which in turn results in epigenetic modification of gene expression that leads to a plethora of effects, such as cell cycle arrest, apoptosis and inhibition of angiogenesis. Romidepsin is a novel HDACI that has demonstrated preclinical and clinical activity.
AREAS COVERED
This review discusses the different HDACs and epigenetic regulation with a particular focus on the preclinical and clinical development of romidepsin in lymphoma. The review of romidepsin includes: the mechanism of action, its synergistic interaction with novel agents, pivotal clinical trials that lead to its US FDA approval in cutaneous T-cell lymphoma and peripheral T-cell lymphoma as well as active combinations currently in clinical trials.
EXPERT OPINION
Romidepsin is a potent HDACI with clinical activity in T-cell lymphoma where novel agents and combinations are desperately needed. A deeper understanding of the molecular characteristics of this class of agents will allow the design of more potent drugs with improved toxicity profiles and future rational combinations that will expand the indication and benefit from these novel agents.
Topics: Animals; Antibiotics, Antineoplastic; Depsipeptides; Histone Deacetylase Inhibitors; Humans; Lymphoma, Non-Hodgkin
PubMed: 25936363
DOI: 10.1517/13543784.2015.1041586 -
The Oncologist Sep 2015Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis in most subtypes. Diagnosis of this rare disease by... (Review)
Review
UNLABELLED
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis in most subtypes. Diagnosis of this rare disease by expert hematopathologists improves accuracy of subtyping, and referral to academic or specialty centers is recommended. Many patients, however, will receive treatment in the community, and knowledge of approved agents is key to optimizing therapeutic approaches for all patients. There is no current standard of care for patients with PTCL and no approved therapies for first-line treatment. Although many patients initially respond to induction chemotherapy, responses are often brief, and many patients relapse or become treatment refractory. For patients with relapsed or refractory PTCL, achievement of durable responses is challenging, and there are few treatment options. Romidepsin is a histone deacetylase inhibitor approved by the U.S. Food and Drug Administration for the treatment of patients with cutaneous T-cell lymphoma who have received one prior systemic therapy or more and patients with PTCL who have received one prior therapy or more. Approval of romidepsin for PTCL was based on a pivotal phase II study of patients with relapsed or refractory PTCL (n = 131) that demonstrated an objective response rate of 25% including 15% with complete response; responses lasted a median of >2 years. Long-term responses to romidepsin were achieved in patients regardless of baseline characteristics, including subtype, heavy pretreatment, response to prior therapy, or advanced disease. Common adverse events included hematologic abnormalities, gastrointestinal or asthenic conditions, and infections; romidepsin was not correlated with clinically meaningful QT prolongation or electrocardiogram abnormalities.
IMPLICATIONS FOR PRACTICE
Due to the rarity, severity, and heterogeneous nature of peripheral T-cell lymphoma (PTCL), diagnosis by expert hematopathologists is preferred, and referral to specialty centers is recommended. Many patients, however, will receive treatment in the community, and community oncologists play a key role in the recognition and treatment of PTCL. Knowledge of approved agents is key for optimizing therapeutic approaches. This review provides an overview of PTCL and an in-depth examination of romidepsin, a histone deacetylase inhibitor approved for the treatment of relapsed or refractory PTCL, and highlights difficulties of diagnosis and optimization of treatment modalities for patients with PTCL.
Topics: Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Depsipeptides; Humans; Lymphoma, T-Cell, Peripheral; Prognosis; Treatment Outcome
PubMed: 26099743
DOI: 10.1634/theoncologist.2015-0043 -
American Journal of Health-system... Jul 2013The pharmacology, pharmacokinetic and pharmacodynamic properties, and clinical data on a novel therapy for the treatment of cutaneous or peripheral T-cell lymphoma... (Review)
Review
PURPOSE
The pharmacology, pharmacokinetic and pharmacodynamic properties, and clinical data on a novel therapy for the treatment of cutaneous or peripheral T-cell lymphoma (CTCL, PTCL) are summarized.
SUMMARY
Romidepsin is the only bicyclic histone deacetylase (HDAC) inhibitor to undergo clinical development. A potent and specific inhibitor of class 1 HDACs, romidepsin has linear pharmacokinetics and is primarily metabolized by cytochrome P-450 isoenzyme 3A4. In two Phase II studies involving patients with relapsed or refractory CTCL, romidepsin therapy produced overall response rates of 34-35% (including patients with advanced and heavily pretreated disease), with a complete response seen in about 6% of patients in both studies; romidepsin responses were seen across all evaluated disease sites (skin, blood, lymph, viscera). In two Phase II studies in patients with relapsed or refractory PTCL, romidepsin produced overall response rates of 25-38%, and 15-18% of patients experienced a complete response; therapeutic responses were seen across major PTCL subtypes regardless of the number or types of previous therapies or refractoriness to the last prior therapy. In clinical trials to date, romidepsin therapy was generally well tolerated, with nausea, fatigue, and vomiting reported as the most common nonhematologic adverse events. However, thrombocytopenia and neutropenia are relatively common events, especially in patients with PTCL.
CONCLUSION
Romidepsin, a class 1-specific HDAC inhibitor, induces durable responses, with a manageable toxicity profile, in patients with relapsed or refractory CTCL or PTCL who have few therapeutic options.
Topics: Antibiotics, Antineoplastic; Clinical Trials, Phase II as Topic; Depsipeptides; Drug Resistance, Neoplasm; Fatigue; Humans; Lymphoma, T-Cell; Nausea; Remission Induction; Treatment Outcome; Vomiting
PubMed: 23784158
DOI: 10.2146/ajhp120163 -
Leukemia May 2023
Topics: Humans; Depsipeptides; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36906714
DOI: 10.1038/s41375-023-01873-5 -
Current Medicinal Chemistry 2021Human HDACs represent a group of enzymes able to modify histone and non-histone proteins, which interact with DNA to generate chromatin. The correlation between... (Review)
Review
BACKGROUND
Human HDACs represent a group of enzymes able to modify histone and non-histone proteins, which interact with DNA to generate chromatin. The correlation between irregular covalent modification of histones and tumor development has been proved over the last decades. Therefore, HDAC inhibitors are considered as potential drugs in cancer treatment. Romidepsin (FK228), Belinostat (PXD-101), Vorinostat (SAHA), Panobinostat (LBH-589) and Chidamide were approved by FDA as novel antitumor agents.
OBJECTIVE
The aim of this review article is to highlight the structure-activity relationships of several FK228 analogues as HDAC inhibitors. In addition, the synergistic effects of a dual HDAC/PI3K inhibition by some derivatives have been investigated.
MATERIALS AND METHODS
PubMed, MEDLINE, CAPLUS, SciFinder Scholar database were considered by selecting articles which fulfilled the objectives of this review, dating from 2015 till present time.
RESULTS
HDAC inhibitors have a significant role in cancer pathogenesis and evolution. Class I HDAC isoforms are expressed in many tumor types, therefore, potent and selective Class I HDAC inhibitors are of great interest as candidate therapeutic agents with limited side effects. By structurebased optimization, several FK228 analogues [15 (FK-A5), 22, 23 and 26 (FK-A11)] were identified, provided with significant activity against Class I HDAC enzymes and dose dependent antitumor activity. Compound 26 was recognized as an interesting HDAC/PI3K dual inhibitor (IC against p110α of 6.7 μM while for HDAC1 inhibitory activity IC was 0.64 nM).
CONCLUSION
Romidepsin analogues HDAC inhibitors have been confirmed as useful anticancer agents. In addition, dual HDAC/PI3K inhibition showed by some of them exhibited synergistic effects in inducing apoptosis in human cancer cells. Further studies on FK228 analogues may positively contribute to the availability of potent agents in tumor treatment.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Depsipeptides; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Neoplasms
PubMed: 32013816
DOI: 10.2174/0929867327666200203113926 -
Biomedicine & Pharmacotherapy =... Aug 2023Romidepsin, also known as NSC630176, FR901228, FK-228, FR-901228, depsipeptide, or Istodax®, is a natural molecule produced by the Chromobacterium violaceum bacterium... (Review)
Review
Romidepsin, also known as NSC630176, FR901228, FK-228, FR-901228, depsipeptide, or Istodax®, is a natural molecule produced by the Chromobacterium violaceum bacterium that has been approved for its anti-cancer effect. This compound is a selective histone deacetylase (HDAC) inhibitor, which modifies histones and epigenetic pathways. An imbalance between HDAC and histone acetyltransferase can lead to the down-regulation of regulatory genes, resulting in tumorigenesis. Inhibition of HDACs by romidepsin indirectly contributes to the anticancer therapeutic effect by causing the accumulation of acetylated histones, restoring normal gene expression in cancer cells, and promoting alternative pathways, including the immune response, p53/p21 signaling cascades, cleaved caspases, poly (ADP-ribose) polymerase (PARP), and other events. Secondary pathways mediate the therapeutic action of romidepsin by disrupting the endoplasmic reticulum and proteasome and/or aggresome, arresting the cell cycle, inducing intrinsic and extrinsic apoptosis, inhibiting angiogenesis, and modifying the tumor microenvironment. This review aimed to highlight the specific molecular mechanisms responsible for HDAC inhibition by romidepsin. A more detailed understanding of these mechanisms can significantly improve the understanding of cancer cell disorders and pave the way for new therapeutic approaches using targeted therapy.
Topics: Humans; Histones; Depsipeptides; Apoptosis; Neoplasms; Histone Deacetylases; Histone Deacetylase Inhibitors; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37224749
DOI: 10.1016/j.biopha.2023.114774 -
Expert Opinion on Investigational Drugs Aug 2011Romidepsin is a novel histone deacetylase (HDAC) inhibitor, with a recent approval for treatment of cutaneous T-cell lymphoma (CTCL). HDAC inhibitors represent a novel... (Review)
Review
INTRODUCTION
Romidepsin is a novel histone deacetylase (HDAC) inhibitor, with a recent approval for treatment of cutaneous T-cell lymphoma (CTCL). HDAC inhibitors represent a novel approach to anti-tumor therapy. In contrast to traditional cytotoxic chemotherapy, HDAC inhibitors target underlying epigenetic changes leading to malignant transformation. Further study of romidepsin and similar agents in solid and hematologic malignancies is ongoing.
AREAS COVERED
This review discusses the development of romidepsin, its mechanism of action, pivotal clinical trials, drug toxicity and its recent approval for CTCL treatment. Key clinical trials covered include Phase I/II testing of romidepsin in solid and hematologic malignancies. In addition, the Phase II trial in CTCL leading to FDA approval of romidepsin is reviewed in detail. Literature search was performed using PubMed; keywords and concepts used included romidepsin, T-cell lymphoma and HDAC inhibitors.
EXPERT OPINION
Romidepsin is a potent HDAC inhibitor with demonstrable activity in T-cell lymphoma. In contrast to vorinostat, romidepsin is approved as second-line therapy. Current approval only includes CTCL; promising results have been demonstrated in Phase II testing of peripheral T-cell lymphoma subtypes. Future directions include expanded indications in T-cell lymphomas as well as novel combinations with other HDAC inhibitors and other therapeutic agents.
Topics: Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Depsipeptides; Histone Deacetylase Inhibitors; Humans; Neoplasms
PubMed: 21699444
DOI: 10.1517/13543784.2011.594437