Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial

Vitolo, Umberto; Chiappella, Annalisa; Franceschetti, Silvia; Carella, Angelo Michele; Baldi, Ileana; Inghirami, Giorgio; Spina, Michele; Pavone, Vincenzo; Ladetto, Marco; Liberati, Anna Marina; Molinari, Anna Lia; Zinzani, Pier Luigi; Salvi, Flavia; Fattori, Pier Paolo; Zaccaria, Alfonso; Dreyling, Martin; Botto, Barbara; Castellino, Alessia; Congiu, Angela Giovanna; Gaudiano, Marcello; Zanni, Manuela; Ciccone, Giovannino; Gaïdano, Gianluca; Rossi, Giuseppe

doi:10.1016/s1470-2045(14)70191-3

Cited by 166 publications

(115 citation statements)

References 29 publications

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“…[74][75][76][77] First-line R2 plus cyclophosphamide, doxorubicin, vincristine, prednisone (R2CHOP) produced encouraging response rates and progression-free survival times in patients with DLBCL and FL in several clinical trials, particularly when compared with historical data for R-CHOP alone. [78][79][80] Notably, patients with GCB and non-GCB DLBCL phenotypes achieved similar objective response rates with R2CHOP. 79 The combination of R2 with bendamustine is being explored as a first-line option in elderly patients with MCL (Table 2).…”

Section: 59-61mentioning

confidence: 99%

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Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

Gribben

Fowler

Morschhauser

2015

JCO

243

188

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Lenalidomide is an orally active immunomodulatory drug that has direct antineoplastic activity and indirect effects mediated through multiple types of immune cells found in the tumor microenvironment, including B, T, natural killer (NK), and dendritic cells. Recently, the E3 ubiquitin ligase cereblon was identified as a molecular target that may underlie the effects of lenalidomide on tumor cells, as well as on cells in the tumor microenvironment. Decreases in cereblon attenuate these effects and also confer resistance to lenalidomide. Tumoricidal effects of lenalidomide are associated with reduced interferon regulatory factor 4, a downstream target of cereblon. Lenalidomide stimulates proliferation and activation of NK cells, thereby enhancing NK cell–mediated cytotoxicity and antibody-dependent cellular cytotoxicity. These effects appear to be secondary to cytokine production from T cells. Lenalidomide has been shown to produce synergistic effects in experimental models when evaluated in combination with rituximab, dexamethasone, bortezomib, and B-cell receptor signaling inhibitors, consistent with mechanisms complementary to these agents. These experimental findings have translated to the clinic, where single-agent use displays durable responses in relapsed/refractory non-Hodgkin lymphoma, and combination with rituximab and other agents leads to improved responses at first line and in relapsed/refractory disease. The activity of lenalidomide is evident across multiple lymphoma subtypes, including indolent and aggressive forms. The interaction among cell types in the immune microenvironment is increasingly recognized as important to tumor cell recognition and destruction, as well as to protection of normal immune cells, as reflected by lenalidomide studies across multiple types of B-cell lymphomas.

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Section: 59-61mentioning

confidence: 99%

“…[78][79][80] Notably, patients with GCB and non-GCB DLBCL phenotypes achieved similar objective response rates with R2CHOP. 79 The combination of R2 with bendamustine is being explored as a first-line option in elderly patients with MCL (Table 2). 81 Studies of R2 with multiple combination partners are ongoing in phase I and II trials.…”

Section: 59-61mentioning

confidence: 99%

Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

Gribben

Fowler

Morschhauser

2015

JCO

243

188

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“…Early clinical data showed preferential activity in refractory/relapsed ABC vs. GCB DLBCL, with an overall response rate (ORR) of 53% and 9%, respectively [47]. Given these results, two studies adding lenalidomide to R-CHOP in newly diagnosed DLBCL have recently been completed [48,49]. Ibrutinib is an inhibitor of the Bruton Tyrosine Kinase (BTK), an important component of the B-cell receptor (BCR) pathway.…”

Section: Antiviral Therapy In Combination With Ebv Lytic Phase Inductionmentioning

confidence: 99%

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

et al. 2016

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Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) of the elderly is a provisional entity included in the 2008 WHO classification of lymphoid neoplasms. It is a disease typically seen in the elderly and thought to be associated with chronic EBV infection and severe immunosuppression with a component of immunosenescence. Recent research, however, has suggested that EBV‐positive DLBCL can be seen in younger, immunocompetent patients.The diagnosis of EBV‐positive DLBCL of the elderly is made through a careful pathological evaluation. The differential diagnosis includes infectious mononucleosis (specifically in younger patients), lymphomatoid granulomatosis, Hodgkin lymphoma, and gray zone lymphoma, among others. Detection of EBV‐encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for positivity has not been defined.The International Prognostic Index (IPI), and the Oyama score can be used for risk‐stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 is emerging as a potential adverse, and targetable, prognostic factor.Patients with EBV‐positive DLBCL should be staged and managed following similar guidelines than patients with EBV‐negative DLBCL. It has been suggested, however, that EBV‐positive patients have a worse prognosis than EBV‐negative counterparts in the era of chemoimmunotherapy. There is an opportunity to study and develop targeted therapy in the management of patients with EBV‐positive DLBCL. Am. J. Hematol. 91:530–537, 2016. © 2016 Wiley Periodicals, Inc.

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“…30 The Fondazione Italiana Linfomi group also reported that there was no difference in 2-year PFS (81% vs. 71%; p = 0.705) and OS (94% vs. 88%; p = 0.58) in patients with stage II-IV disease, 60-80 years of age, treated with 6 cycles of R2-CHOP between the non-GCB type and GCB type, with a median follow-up in survivors of 28 mon (REAL07). 31 Several clinical trials, such as phase III trials comparing R-CHOP and R2CHOP and trials consisting of lenalidomide maintenance therapy, have been conducted on untreated DLBCL.…”

Section: Immunomodulatory Drugsmentioning

confidence: 99%

Treatment of Diffuse Large B-Cell Lymphoma

Miyazaki

2016

JCEH

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Diffuse large B-cell lymphoma (DLBCL) comprises a heterogeneous group with pathophysiological, genetic and clinical features. Many patients can be cured with R-CHOP therapy, which is the current standard regimen. Despite recent progress in improving patient survival, the 40% survival of DLBCL patients remains poor. Therefore, the most important issue for patients with DLBCL remains the development of a new front-line therapy. Several studies have reported that intensified chemotherapy with dose-adjusted EPOCH-R or R-ACVBP was superior to R-CHOP. Gene expression profiling has identified two distinct forms of DLBCL: activated B cell-like (ABC) and germinal center B-cell-like (GCB) types. ABC DLBCL exhibits a worse prognosis than GCB DLBCL by molecular diagnosis after R-CHOP therapy. Next-generation sequencing has identified unique oncogenic mechanisms and genetic complexity, which has provided rational therapeutic targets. There are also a number of biomarkers, including CD5, and prognostic factors. Efforts to distinguish many biomarkers will be crucial for individualized treatment in the future. 〔J Clin Exp Hematop 56(2):79-88, 2016〕

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Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial

Cited by 166 publications

References 29 publications

Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

Treatment of Diffuse Large B-Cell Lymphoma

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