New directions in treating peripheral T-cell lymphomas (PTCL): leveraging epigenetic modifiers alone and in combination

ABSTRACT

Introduction: The peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous group of non-Hodgkin lymphomas originating from mature T- and NK-cells. They are aggressive diseases often resistant to chemotherapy.

Areas Covered: The methodology of this review involves a literature search of data published on PubMed, abstracts from international conferences, and our own research. Recent evidence suggests that PTCL are ‘epigenetic’ driven diseases, an observation underscored by a series of clinical and biological observations. First, recurring mutations in genes that drive genome methylation are commonly seen across the major subtypes of the disease. Second, murine models predicated on TET2 deletions produce follicular T-helper cell subtypes of PTCL, including angioimmunoblastic T-cell lymphoma, underscoring the driver role of these epigenetic lesions in the pathogenesis of the disease. Finally, histone deacetylase inhibitors have unique activity in PTCL with four approved globally for patients with relapsed/refractory PTCL. Collectively, these findings support a fundamental role for targeting this underlying biology as a potential new direction in the development of novel platforms for the disease.

Expert Opinion: In this review, we discuss the spectrum of novel therapies in PTCL, with a specific focus on epigenetic approaches, and how we aim to develop new strategies in PTCL care.

KEYWORDS:

• Peripheral T-cell lymphomas
• epigenetic modifiers
• histone deacetylase inhibitors
• hypomethylating agents

Article Highlights

• Peripheral T-cell lymphomas are treated with CHOP-based chemotherapy that is as not effective in the management of these diseases as B-cell lymphomas.

• As a whole, PTCL exhibits marked epigenetic dysregulation that makes combinations of epigenetic modifiers such as HDAC inhibitors and hypomethylating agents ideal treatment options that show clinical benefit.

• Preclinical data suggest that epigenetic priming may activate the host immune system to induce long-lasting responses.

• Currently, our group has ongoing clinical trials studying various combinations of epigenetic therapies and immunotherapies with promising results and allow us to treat patients without harsh chemotherapy regimens.

Declaration of interest

E Marchi receives research support from Spectrum and Verastem. O O’Connor receives research support from Affimed, Agensys, Celgene, Merck, Seattle Genetics, Spectrum, TG Therapeutics and Trillium Pharmaceuticals. O O’Connor has also held scientific advisory roles for Celgene (Data Safety Monitoring Committee) Millennium, Mundipharma and TG Pharmaceuticals (travel support only). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded in part by the Columbia University Lymphoma Research Fund and the American Cancer Society.