Novel treatment avenues for peripheral T-cell lymphomas.

INTRODUCTION: Peripheral T-cell lymphomas (PTCLs) and natural killer (NK) or T-cell non-Hodgkin's lymphomas (NHLs) are a rare and heterogeneous class of diseases with generally poor prognosis. This work intends to provide a focused primer on clinical diagnosis, current treatment regimens, and novel therapeutic approaches. The recent WHO classification has defined 18 different subtypes of PTCL and NK T-cell lymphomas. Diagnosis is mainly based on histology, flow-cytometric analysis of surface molecules in the blood and bone marrow, cytogenetics/fluorescence in situ hybridization (FISH), and T-cell receptor (TCR) rearrangement. Staging as well as follow-up diagnostic procedures rely on imaging techniques such as computerized tomography (CT) and positron emission tomography (PET). Current chemotherapeutic regimens such as CHOP result in a 60 - 70% response rate; however, 5-year survival is only around 30%. Therefore, new treatment strategies are urgently needed. Currently, different drug classes are under scrutiny. AREAS COVERED: The authors discuss substances that directly target the tumor cells. The article includes such substances as antimetabolites, antibodies, histone deacetylase inhibitors, tyrosine kinase inhibitors, and immunomodulatory substances such as lenalidomide. EXPERT OPINION: In the future a close collaboration of geneticists, biochemists, and clinicians together with new technologies such as deep sequencing will allow the refinement of treatment strategies in many diseases including PTCLs and NHLs. This refinement will allow treatments to be prepared according to the need of the individual patient.

Novel therapeutic options in anaplastic large cell lymphoma: molecular targets and immunological tools.

Anaplastic large cell lymphoma (ALCL) is a CD30-positive, aggressive T-cell lymphoma, and about half of the patients with this disease harbor the t(2;5)(p21;q35) translocation. This chromosomal aberration leads to fusion of the NPM gene with the ALK tyrosine kinase, leading to its constitutive activation. To date, treatment options include polychemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone), which is sometimes combined with radiation in the case of bulky disease, leading to remission rates of ∼80%. However, the remaining patients do not respond to therapy, and some patients experience chemo-resistant relapses, making the identification of new and better treatments imperative. The recent discovery of deregulated ALK in common cancers such as non-small cell lung cancer and neuroblastoma has reinvigorated industry interest in the development of ALK inhibitors. Moreover, it has been shown that the ALK protein is an ideal antigen for vaccination strategies due to its low expression in normal tissue. The characterization of microRNAs that are deregulated in ALCL will yield new insights into the biology of ALCL and open new avenues for therapeutic approaches in the future. Also, CD30 antibodies that have been tested in ALCL for quite a while will probably find a place in forthcoming treatment strategies.

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK- anaplastic large-cell lymphoma.

Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK(+) from ALK(-) subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK(+) and ALK(-) ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK(+) ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK(-) ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK(+) and not in ALK(-) cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.