Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study

O’Connor, Owen A.; Falchi, Lorenzo; Lue, Jennifer K.; Marchi, Enrica; Kinahan, Cristina; Sawas, Ahmed; Deng, Chao; Montanari, Francesca; Amengual, Jennifer E.; Kim, Hye A.; Rada, Aishling M.; Khan, Karen; Jacob, Alice T.; Malanga, Michelle; Francescone, Mark M.; Nandakumar, Renu; Soderquist, Craig; Park, David C.; Bhagat, Govind; Cheng, Bin; Risueño, Alberto; Menezes, Daniel L.; Shustov, Andrei R.; Sokol, Lubomir; Scotto, Luigi

doi:10.1182/blood.2019001285

Cited by 113 publications

(79 citation statements)

References 23 publications

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“…Experimentally, HDAC inhibitor chidamide significantly inhibited the growth of EP300-mutated T-lymphoma cells and KMT2D-mutated T-lymphoma cells when combined with the hypomethylating agent decitabine [12]. Clinically, a phase 1 study of HDAC inhibitor romidepsin and hypomethylating agent 5azacytidine exhibited marked activity in patients with PTCL, with ORR and CR of 73% and 55%, respectively [32]. Therapeutic efficacy of novel small molecules like IDH2 inhibitors targeting IDH2, or modulators of the SWI/SNF chromatin complex targeting ARID1B could also be explored in PTCL.…”

Section: Discussionmentioning

confidence: 99%

CEOP/IVE/GDP alternating regimen compared with CEOP as the first-line therapy for newly diagnosed patients with peripheral T cell lymphoma: results from a phase 2, multicenter, randomized, controlled clinical trial

et al. 2020

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Background: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy is widely used in peripheral T cell lymphoma (PTCL). Here we conducted a phase 2, multicenter, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in newly diagnosed PTCL. Methods: PTCL patients, except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, were 1:1 randomly assigned to receive CEOP/IVE/GDP (CEOP, cyclophosphamide 750 mg/m 2 , epirubicin 70 mg/m 2 , vincristine 1.4 mg/m 2 [maximum 2 mg] on day 1, and prednisone 60 mg/m 2 [maximum 100 mg] on days 1-5 every 21 days, at the first and fourth cycle; IVE, ifosfamide 2000 mg/m 2 on days 1-3, epirubicin 70 mg/m 2 on day 1, and etoposide 100 mg/m 2 on days 1-3 every 21 days, at the second and fifth cycle; and GDP, gemcitabine 1000 mg/m 2 on days 1 and 8, cisplatin 25 mg/m 2 on days 1-3, and dexamethasone 40 mg on days 1-4 every 21 days, at the third and sixth cycle) and CEOP (every 21 days for 6 cycles). Analysis of efficacy and safety was of the intent-to-treatment population. The primary endpoint was a complete response rate at the end of treatment. Meanwhile, whole exome

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Section: Discussionmentioning

confidence: 99%

CEOP/IVE/GDP alternating regimen compared with CEOP as the first-line therapy for newly diagnosed patients with peripheral T cell lymphoma: results from a phase 2, multicenter, randomized, controlled clinical trial

et al. 2020

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“…Benigno C. Valdez et al reported that the combination of a hypomethylating agent, decitabine (DAC), a PARP inhibitor and an HDAC synergistically inhibited cell proliferation and induced apoptosis in human leukaemia and lymphoma cells [ 138 ]. A phase I study investigated oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with PTCL and showed that combination epigenetic modifying drug therapy exhibited marked activity in patients with PTCL [ 139 ]. The PTCL responses to the combination proved durable.…”

Section: Dna Methylationmentioning

confidence: 99%

“…Therefore, novel epigenetic combination treatments based on biological pathophysiology, preclinical data, and clinical efficacy are needed to challenge front-line conventional chemotherapy in the future. 5-Azacytidine and romidepsin combination regimens still suit those patients scheduled for SCT, as reported in a phase I study [ 139 ]. The combination of epigenetic drugs and immune checkpoint inhibitors such as anti-PD1 mAb and lenalidomide are expected to have a good therapeutic effect.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

Zhang

2020

Clin Epigenet

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Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of clinically aggressive diseases associated with poor prognosis. Except for ALK + anaplastic large-cell lymphoma (ALCL), most peripheral T-cell lymphomas are highly malignant and have an aggressive disease course and poor clinical outcomes, with a poor remission rate and frequent relapse after first-line treatment. Aberrant epigenetic alterations play an important role in the pathogenesis and development of specific types of peripheral T-cell lymphoma, including the regulation of the expression of genes and signal transduction. The most common epigenetic alterations are DNA methylation and histone modification. Histone modification alters the level of gene expression by regulating the acetylation status of lysine residues on the promoter surrounding histones, often leading to the silencing of tumour suppressor genes or the overexpression of proto-oncogenes in lymphoma. DNA methylation refers to CpG islands, generally leading to tumour suppressor gene transcriptional silencing. Genetic studies have also shown that some recurrent mutations in genes involved in the epigenetic machinery, including TET2, IDH2-R172, DNMT3A, RHOA, CD28, IDH2, TET2, MLL2, KMT2A, KDM6A, CREBBP, and EP300, have been observed in cases of PTCL. The aberrant expression of miRNAs has also gradually become a diagnostic biomarker. These provide a reasonable molecular mechanism for epigenetic modifying drugs in the treatment of PTCL. As epigenetic drugs implicated in lymphoma have been continually reported in recent years, many new ideas for the diagnosis, treatment, and prognosis of PTCL originate from epigenetics in recent years. Novel epigenetic-targeted drugs have shown good tolerance and therapeutic effects in the treatment of peripheral T-cell lymphoma as monotherapy or combination therapy. NCCN Clinical Practice Guidelines also recommended epigenetic drugs for PTCL subtypes as second-line therapy. Epigenetic mechanisms provide new directions and therapeutic strategies for the research and treatment of peripheral T-cell lymphoma. Therefore, this paper mainly reviews the epigenetic changes in the pathogenesis of peripheral T-cell lymphoma and the advancement of epigenetic-targeted drugs in the treatment of peripheral T-cell lymphoma (PTCL).

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“…In addition to these agents, there are drugs in development with some evidence of activity in MTCL, including PI3K inhibitors (duvalisib); proteasome inhibitors (bortezomib and carfilzomib); a host of biologics targeting CD37, CD70, and CD47; and bispecific NK engagers. Figure 4 116,[119][120][121][122][123] shares some data regarding these combinations, recognizing that much of this information has not yet been published in peer-reviewed journals and is available only in abstract form.…”

Section: Development Of Novel:novel Backbonesmentioning

confidence: 99%

“…In a phase 2 study, patients were treated with pembrolizumab at pralatrexate; Romi, romidepsin. 116,[119][120][121][122][123] 200 mg every 21 days. Of 18 patients enrolled, 13 were evaluable for the primary endpoint.…”

Section: Possible New Drugs In Developmentmentioning

confidence: 99%

The rapidly changing landscape in mature T‐cell lymphoma (MTCL) biology and management

Marchi

O’Connor

2019

CA A Cancer J Clinicians

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Historical advances in the care of patients with non-Hodgkin lymphoma (NHL) have been restricted largely to patients with B-cell lymphoma. The peripheral T-cell lymphomas (PTCLs), which are rare and heterogeneous in nature, have yet to experience the same degree of improvement in outcome over the past 20 to 30 years. It is estimated that there are approximately 80,000 and 14,000 cases, respectively, of NHL and Hodgkin lymphoma per year in the United States. As a subgroup of NHL, the PTCLs account for 6% to 10% of all cases of NHL, making them exceedingly rare. In addition, the World Health Organization 2017 classification describes 29 distinct subtypes of PTCL. This intrinsic diversity, coupled with its rarity, has stymied progress in the disease. In addition, most subtypes carry an inferior prognosis compared with their B-cell counterparts, an outcome largely attributed to the fact that most treatment paradigms for patients with PTCL have been derived from B-cell neoplasms, a radically different disease. In fact, the first drug ever approved for patients with PTCL was approved only a decade ago. The plethora of recent drug approvals in PTCL, coupled with a deeper understanding of the molecular pathogenesis of the disease, has stimulated the field to pursue new avenues of research that are now largely predicated on the development of novel, targeted small molecules, which include a host of epigenetic modifiers and biologics. There is an expectation these advances may begin to favorably challenge the chemotherapy paradigms that have been used in the T-cell malignancies.

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Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study

Abstract: The authors report a phase 1 study of romidepsin combined with oral 5-azacytidine in patients with relapsed/refractory lymphomas, including complete remissions in 3 patients with angioimmunoblastic T-cell lymphoma.

Cited by 113 publications

References 23 publications

CEOP/IVE/GDP alternating regimen compared with CEOP as the first-line therapy for newly diagnosed patients with peripheral T cell lymphoma: results from a phase 2, multicenter, randomized, controlled clinical trial

CEOP/IVE/GDP alternating regimen compared with CEOP as the first-line therapy for newly diagnosed patients with peripheral T cell lymphoma: results from a phase 2, multicenter, randomized, controlled clinical trial

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

The rapidly changing landscape in mature T‐cell lymphoma (MTCL) biology and management

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