New Therapies in T-cell Lymphoma

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Chemotherapy regimens containing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) have typically been used for the treatment of peripheral T-cell lymphoma (PTCL); however, outcomes have been poor.

As a result, new agents like antimetabolites, histone deacetylase (HDAC) inhibitors, immunomodulatory agents, monoclonal antibodies, proteasome inhibitors, and tyrosine kinase inhibitors (TKIs) have developed for the treatment of patients with PTCL.

HDAC inhibitors, such as panobinostat, romidepsin, and vorinostat, have demonstrated effectiveness for the treatment of PTCL, as well as cutaneous T-cell lymphoma (CTCL).

Romidepsin is the only agent approved by the U.S. Food and Drug Administration (FDA) for both diseases with an indicated dose of 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Vorinostat is to be given at a dose of 400 mg by mouth daily with food for refractory CTCL.

Brentuximab vedotin, a monoclonal antibody, is approved by the FDA for the treatment of refractory systemic anaplastic large cell lymphoma (sALCL) at a dose of 1.8 mg/kg IV on day 1 of a 3-week cycle. Its main adverse effects include neutropenia and peripheral neuropathy.

The antimetabolite pralatrexate is approved by the FDA for PTCL at a dose of 30 mg/m2 IV weekly of a 7-week cycle. It should be administered in combination with folate and B12 supplementation.

Biomarker-driven chemotherapeutics is becoming a critical part of the state-of-the-art treatment in T-cell lymphoma.
Biomarker-driven chemotherapeutics is becoming a critical part of the state-of-the-art treatment in T-cell lymphoma.

ABSTRACT: T-cell lymphomas represent 10–12% of all patients with non-Hodgkin lymphoma (NHL) in the Western world. When cutaneous T-cell lymphoma (CTCL) is excluded, peripheral T-cell lymphoma—not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL) represent the overwhelming majority of patients in this population.

These diseases remain a great challenge to treat. They are characterized by an aggressive presentation, extranodal disease, paraneoplastic phenomena, and resistance to standard chemotherapeutics. With the rapid development of new molecular gene profiling techniques, it is highly likely that these diseases will be subclassified by molecular abnormalities in the future.

An evolving understanding of the tumor molecular pathogenesis will undoubtedly lead to further novel targeted therapies.

Immunoconjugates, such as brentuximab vedotin (BV), have provided outstanding responses in relapsed, refractory CD30-positive ALCL. Histone deacetylase (HDAC) inhibitors have shown activity in PTCL and are potentially synergistic with proteasome inhibitors. Denileukin diftitox is an interesting recombinant DNA fusion protein linking fragments of the diphtheria toxin to interleukin-2 (IL-2) that is tested in clinical trials.

Crizotinib, a highly specific anaplastic lymphoma kinase (ALK) inhibitor, has shown great promise in small number of patients with ALK-positive ALCL; the future of patients with this disorder looks very promising. Biomarker-driven chemotherapeutics is becoming a critical part of the state-of-the-art treatment in early- and late-phase clinical trials.

It is crucial that future trials include sensible biomarker-based designs when future treatments are used in these challenging disorders. 

KEYWORDS: T cell lymphoma, angioimmunoplastic lymphoma, anaplastic large cell lymphoma, brentuximab, crizotinib

CITATION: Collins et al. new therapies in t-cell Lymphoma. Lymphoma and Chronic Lymphocytic Leukemias 2014:4 1–8 doi:10.4137/LCLL.s13716. 

RECEIVED: February 25, 2014. RESUBMITTED: June 2, 2014. ACCEPTED FOR PUBLICATION: June 3, 2014. 

ACADEMIC EDITOR: Mitchell Smith, Editor in Chief 

TYPE: Review 

FUNDING: authors disclose no funding sources. 

COMPETING INTERESTS: GPC has received honoraria for advisory work and as a speaker, from Takeda Pharmaceuticals, and research grants from Celgene and Onyx. Other authors  disclose no potential conflicts of interest.

COPYRIGHT: © the authors, publisher and licensee Libertas cademica Limited. This is an open-access article distributed under the terms of the Creative Commons CC-BY-NC 3.0 License.

CORRESPONDENCE: graham.collins@ouh.nhs.uk

This paper was subject to independent, expert peer review by a minimum of two blind peer reviewers. All editorial decisions were made by the independent academic editor. All authors have provided signed confirmation of their compliance with ethical and legal obligations including (but not limited to) use of any copyrighted material, compliance with ICMJE authorship and competing interests disclosure guidelines and, where applicable, compliance with legal and ethical guidelines on human and animal research participants. Provenance: the authors were invited to submit this paper.

Introduction

Peripheral T-cell lymphomas (PTCLs) are a rare group of clonal, mature post-thymic T-cell lymphoproliferative disorders that arise predominantly in lymphoid tissue. They represent a particular treatment challenge as they are frequently poorly responsive to treatment and prone to relapse with a five year overall survival (OS) of only 30%. Novel therapies for PTCL are being investigated in an effort to improve their frequently dismal prognosis.

PTCL represents 10–12% of all non-Hodgkin lymphomas (NHLs) in Europe, America, and Australasia. Generally, T-cell lymphomas are more common in the Far East where they account for up to 20% of NHLs.1

In Europe, the three most common subtypes of PTCL are peripheral T-cell lymphoma—not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL). Together, these make up approximately 80% of all T-cell lymphoma diagnoses.2

T-cell lymphoma subtypes have distinct clinical and pathological characteristics. These divisions have been helped by advances in molecular diagnostics, and refinement of the WHO classification has further improved diagnostic accuracy.

Diagnosis remains a challenging field, and the International T-cell Lymphoma Project (ITLP) review of more than 1300 cases published in 2008 using centralized expert review found misclassification occurring in more than 10% of the cases.2

PTCLs frequently present with extranodal disease, advanced stage compared to B-cell lymphoid malignancies, paraneoplastic phenomena, and are more resistant to standard chemotherapy.A large retrospective series has highlighted the poor prognoses of patients with PTCL. Typically, PTCL and AITL have a five-year failure free survival of 20% and OS of 30%.2

This International T-cell Lymphoma (ITCL) project also displayed the relatively limited efficacy of anthracycline-based treatment. Given the historical disappointing results, novel treatments are desperately needed. Improved understanding of the different subtypes of T-cell lymphoma is helping to lay the foundations for novel therapies and improve survival.

 
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