The Treatment of Diffuse Large B-cell Lymphoma with Poor Prognosis in the Rituximab Era – State of the Art and Future Perspectives

European Haematology, 2010;4:75-9

Abstract:

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma. The International Prognostic Index, gene profiling and early positron-emission tomography (PET) evaluation are important prognostic factors, each with a different role in predicting outcome. The addition of rituximab to standard chemotherapy – cyclophosphamide, doxorubicine, vincristine and prednisone (CHOP) – improved the outcome in elderly newly diagnosed DLBCL patients and in young patients with favourable prognostic profiles. The best treatment of young poor-prognosis patients affected by DLBCL is controversial. Several phase II trials have demonstrated that the addition of rituximab to dose-dense chemotherapy CHOP14 or the addition of rituximab to high-dose chemotherapy (HDC) with peripheral stem cell transplantation were feasible and effective. The question of whether rituximab–HDC may be more effective compared with rituximab–dose-dense chemotherapy is under investigation in randomised phase III trials by major international groups. Novel therapeutic options should be investigated to increase the outcome in poor-prognosis DLBCL patients, both as single agents and in combination with standard therapy. Radioimmunotherapy, immunomodulating agents (IMiDs), dacetuzumab (SGN-40), mammalian target of rapamycin (mTOR) inihibitors, proteasome inhibitors, histone deacetylase inhibitors and anti-angiogenetic agents (anti-vascular endothelial growth factor [VEGF]) are under evaluation in clinical trials. The results will provide new insights into the treatment of DLBCL following poor prognosis.
Keywords: Diffuse large B-cell lymphoma, poor prognosis, rituximab, high-dose chemotherapy, novel drugs
Disclosure: Umberto Vitolo has received lecture fees from Roche and Celgene. Annalisa Chiappella, Chiara Frairia and Barbara Botto have no conflicts of interest to declare.
Received: September 24, 2009 Accepted February 22, 2010 Citation European Haematology, 2010;4:75-9
Correspondence: Umberto Vitolo, SC Ematologia 2, Azienda Ospedaliera e Universitaria San Giovanni Battista, Corso Bramante 88 10126 Torino, Italy. E: uvitolo@molinette.piemonte.it

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma (NHL), accounting for 30% of all newly diagnosed cases and >80% of aggressive lymphomas.
The cyclophosphamide, doxorubicine, vincristine and prednisone (CHOP) regimen has been the mainstay of therapy for several decades, but a marked improvement in the outcome was demonstrated with the development of the anti-CD20 monoclonal antibody rituximab. Several studies have reported a significant advantage of adding rituximab to CHOP (R-CHOP) in elderly newly diagnosed DLBCL patients and young patients with a favourable prognostic profile.1–3 Although the combination of rituximab with CHOP as the standard regimen has led to improved outcomes, there is a group of poor-risk patients who have a lower chance of being cured with standard R-CHOP and who need alternative treatment strategies.
Prognostic Factors
Clinical and molecular models were devised to better discriminate patients with poor prognosis at presentation.
The International Prognostic Index (IPI) has become the primary clinical tool to predict outcome for patients with aggressive NHL.4 Based on the number of negative prognostic features (>60 years of age, stage III–IV, lactate dehydrogenase (LDH) level, performance status (PS) >1 and more than one extranodal site), four distinct risk groups were identified, with a five-year overall survival (OS) ranging from 26 to 73%. Recently, on the basis that risk assessment is a moving target, a Revised International Prognostic Index (R-IPI) was retrospectively applied to patients with DLBCL treated with R-CHOP, and in so doing distinguished between three separate prognostic groups with different four-year OS rates: very good risk 94%, good risk 79% and poor risk 55%.5
Gene-expression-profiling models defined molecular subgroups of DLBCL, i.e. germinal B cell (GBC) and activated B cell (ABC), with different prognosis: GBC seems to have a more favourable outcome than ABC regardless of rituximab use.6,7 There is clear evidence that DLBCL subtypes are different diseases with distinct oncogenic pathways. Recently, two gene-expression signatures – stromal-1 and stromal-2 – were identified: stromal-1 includes genes that are expressed in fibronectin, suggesting the fibrotic nature of many DLBCLs, while the stromal-2 signature is accompanied by new blood vessel formation and is associated with adverse outcomes (see Figure 1).8
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Keywords: Diffuse large B-cell lymphoma, poor prognosis, rituximab, high-dose chemotherapy, novel drugs