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Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin lymphoma in western countries. Despite the addition of rituximab to chemotherapy, the prognosis is still poor and almost one-third of patients fail or relapse after first-line treatment. Gene expression profiling has identified three main signatures related to subgroups with different biological characteristics and responses to treatment. Novel agents targeting the oncogenic drivers of these subsets are currently under investigation with the aim of providing a tailored approach and avoiding unnecessary toxicity. Herein, we review the emerging therapies for DLBCL with a focus on preclinical and early clinical trials as well as future directions.
Financial & competing interests disclosure
A Younes has received research support from Novartis, Johnson & Johnson and Curis. A Younes has also received honoraria from Bayer, Bristol-Myers Squibb, Celgene, Incyte, Janssen R&D, Sanofi, Seattle Genetics and Takeda Millenium. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Molecular analyses identified distinct subsets of diffuse large B-cell lymphoma (DLBCL) with different underlying oncogenic processes providing an opportunity for the development of precision therapy.
Novel molecular antibodies against B-cell epitope (such as anti-CD20, CD-19, CD22) have been demonstrated to be more active than rituximab and are currently under evaluation.
Immuno-based therapy with T cells expressing a chimeric antigen receptor and antibodies anti-PD1 are emerging as new therapeutic strategies.
Small molecules targeting various components of PI3K/AKT/mTOR pathway have shown an antitumor activity and are currently under evaluation within combination treatments.
Novel compounds targeting B-cell receptor and Bcl-2 are being tested in DLBCL with promising results. Combination strategies with front-line R-CHOP regimens are being evaluated.
Bortezomib and lenalidomide have shown high single agent activity in activated B-cell DLBCL, thanks to their ability to block the NF-kB pathway. Even more relevant were the results obtained combining each of these molecules with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. No difference in prognosis was revealed between activated B-cell like and germinal center B-cell like, suggesting that these two drugs are able to overcome negative risks related to DLBCL subtypes.
Aberrant MYC expression is a negative prognostic factor in DLBCL, therefore targeting this oncogene may result in an increased cure rate. However, reducing its expression using histone deacetylase inhibitors or bromodomain inhibitors demonstrated only a modest activity. Nevertheless, their effectiveness has proven to be significantly increased in combination with other molecules.
Genetic testing of tumor specimens will likely identify biomarkers that may aid in future selection of patients for therapy.