**5. Treatment of diffuse large B-cell lymphoma**

The treatment protocol in DLBCL did not witness significant changes during the last two decades. The widespread adoption of rituximab as an important adjuvant to standard chemotherapy protocol in CD20+ cases was a notable exception, which provided significant improvement in disease-free survival, overall survival, and complete remission rates, with limited toxicity. However, no less than 20% of patients diagnosed with DLBCL exhibit relapse after the initial response to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, while more than 15% of the patients exhibit primary refractory disease [27]. All these factors required the search for alternative therapeutic regimens, such as R-CHOEP (rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone), R-miniCHOP (adjusted short-term R-CHOP therapy), R-ACVBP (adriamycin-cytoxan-vindesine-bleomycin-prednisonerituximab), etc., that are strictly codified by several therapeutic protocols, such as the 2015 ESMO guidelines [10].

The choice for any of these regimens should be adapted to the specific clinical status of each patient, as the exact therapy depends on a number of factors, such as the stage of the disease, age, and biological status. However, despite numerous attempts, no clear recommendation has been published thus far.

The association of radiation therapy to chemotherapy offered conflicting results. While some studies showed some benefits for the combined therapy, most of the authors did not find any real advantages, especially in the case of localized disease without bulky mass [28]. There were some suggestions of a combined therapeutic algorithm, involving four R-CHOP cycles followed by either local radiation therapy or two more cycles of R-CHOP, in the case of complete remission. Armitage et al. pleaded for mandatory radiation therapy after six cycles of R-CHOP in the case of bulky disease [29]. More recently MInT (MabThera International Trial) study recommended the same therapeutic algorithm for localized bulky disease [30].

In the case of localized disease, the therapeutic protocol varies with the specific organ involvement. For primary DLBCL of the testis, R-CHOP should be associated with radiotherapy and methotrexate or intrathecal cytarabine, due to the potential risk of CNS involvement. In case of documented CNS involvement before the onset of therapy, then high-dose intravenous and intrathecal methotrexate is advised. Conversely, cytarabine should be used instead of methotrexate for lymphomatous meningitis [31]. R-CEOP can be advised for patients with an altered cardiac function.

In the case of advanced stage DLBCL, the therapeutic options varied greatly since the early 1980s. The third-generation regimens, ProMACE/CytaBOM

(cyclophosphamide, doxorubicin, etoposid, Cytosar, bleomycin, vincristine, methotrexate, prednisone) and M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), showed no benefits for complete remission or disease-free survival when compared to CHOP. However, a lower toxicity for CHOP was observed [32].

The R-ACVBP regimen, consisting of rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone, for induction of remission, and consolidation with methotrexate, doxorubicin, and cyclophosphamide, was tested by the GELA (Groupe d'Etude des Lymphomes de l'Adulte) study on 379 patients. This regimen showed some advantages over the R-CHOP-21 but at the price of significantly higher toxicity [33].

Given these circumstances, there is a growing need for new therapeutic alternatives, fitted for the morphologic, immunohistochemical, and genetic profile of each patient selected for individualized treatment protocol.

The role of immunophenotype variability for the therapeutic outcome has long been the cornerstone for DLBCL management strategy, largely because the treatment of lymphomas evolves toward new therapies (immunotherapy, targeted therapy), which is made possible by analyzing the biology and the signaling pathways of this disease [34, 35]. Furthermore, a growing number of biological agents are available, varying from interferon to rituximab or radiolabeled antibodies, but also the more recent acquisitions in targeted therapy, such as ibrutinib, acalabrutinib, and daratumumab [36–38].
