Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma

Marcus, Robert; Imrie, Kevin; Solal‐Céligny, Philippe; Catalano, John; Dmoszyńska, Anna; Raposo, João; Offner, Fritz; Gómez-Codina, José; Belch, Andrew R.; Cunningham, David; Wassner-Fritsch, Elisabeth; Stein, G.

doi:10.1200/jco.2007.13.5376

Cited by 533 publications

(334 citation statements)

References 13 publications

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“…The CVP chemotherapy used during the time these samples were collected is no longer the standard of care. The monoclonal antibody rituximab (45) is now used with current chemotherapy strategies (46,47). CD20, the rituximab target, tends to be underexpressed on the LNP cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

Irish

Myklebust

Alizadeh

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

151

185

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Human tumors contain populations of both cancerous and host immune cells whose malignant signaling interactions may define each patient's disease trajectory. We used multiplexed phospho-flow cytometry to profile single cells within human follicular lymphoma tumors and discovered a subpopulation of lymphoma cells with impaired B cell antigen receptor (BCR) signaling. The abundance of BCR-insensitive cells in each tumor negatively correlated with overall patient survival. These lymphoma negative prognostic (LNP) cells increased as tumors relapsed following chemotherapy. Loss of antigen receptor expression did not explain the absence of BCR signaling in LNP tumor cells, and other signaling responses were intact in these cells. Furthermore, BCR signaling responses could be reactivated in LNP cells, indicating that BCR signaling is not missing but rather specifically suppressed. LNP cells were also associated with changes to signaling interactions in the tumor microenvironment. Lower IL-7 signaling in tumor infiltrating T cells was observed in tumors with high LNP cell counts. The strength of signaling through T cell mediator of B cell function CD40 also stratified patient survival, particularly for those whose tumors contained few LNP cells. Thus, analysis of cell–cell interactions in heterogeneous primary tumors using signaling network profiles can identify and mechanistically define new populations of rare and clinically significant cells. Both the existence of these LNP cells and their aberrant signaling profiles provide targets for new therapies for follicular lymphoma.

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Section: Discussionmentioning

confidence: 99%

B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

Irish

Myklebust

Alizadeh

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

151

185

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“…On the contrast, patients with asymptomatic advanced‐stage FL do not need to be treated immediately 1, 5, 6, 7. Once they develop symptoms, chemotherapies with rituximab are suggested as frontline treatments 1, 4, 8, 9, 10, 11…”

Section: Introductionmentioning

confidence: 99%

“…Rituximab combined with cytotoxic chemotherapies is superior to chemotherapies alone, regardless of frontline treatments or in relapse and/or refractory FL 8, 9, 10, 12, 13, 14, 15. Several prospective trials tried to address the clinical benefits of rituximab maintenance in the patients with FL, but rituximab maintenance only improves progression‐free survival instead of overall survival 16, 17, 18, 19.…”

Section: Introductionmentioning

confidence: 99%

Rituximab maintenance improves overall survival in follicular lymphoma: A retrospective nationwide real‐world analysis from Taiwan Cancer Registry Database

et al. 2018

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Follicular lymphoma (FL) is the most frequent indolent lymphoma in Western countries, but it is less frequent in Asia. Several trials have demonstrated the progression‐free benefit of rituximab maintenance for FL patients in Western countries. However, the overall survival (OS) benefits and effectiveness of rituximab maintenance in Asian FL patients remain uncertain. We utilized the Taiwan Cancer Registry Database and the National Health Insurance Research Database to investigate the roles of rituximab maintenance for newly diagnosed FL patients in Taiwan. Among 836 patients with newly diagnosed FL during 2009‐2012, we enrolled patients with stage II‐IV diseases receiving 4‐8 cycles of rituximab‐containing induction chemotherapies (R‐induction). We excluded those who died or received additional chemotherapy within 180 days after R‐induction. Among the 396 enrolled patients, 260 underwent rituximab maintenance (R‐maintenance group), and 136 served as the observation group. The R‐maintenance group received less anthracycline and fewer cycles of R‐induction than the observation group, but they exhibited a significantly better OS both in the univariate and multivariate analyses [hazard ratio, 0.42; 95% confidence interval, 0.19‐0.91] after adjusting for age, sex, and Ann Arbor stages. Meanwhile, we also found more patients required further therapies in the first 6 months after the cease of rituximab maintenance. In the subgroup analysis, patients older than 60 years or with stage IV diseases benefited more from rituximab maintenance. Conclusively, our nationwide study is the first one to demonstrate the OS benefit of rituximab maintenance after induction therapies in newly diagnosed FL patients from Asian populations.

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“…Frontline targeted therapy with the antibody rituximab produces an overall response rate of 72%, with a 36% complete remission rate, in patients with advanced-stage grade I FL (Witzig et al, 2005). Adding rituximab to chemotherapy has consistently enhanced response rates (Marcus et al, 2008). However, the availability of numerous therapies for early-stage low-grade B-cell lymphomas and a lack of adherence to one single treatment plan make the best treatment recommendations unclear.…”

mentioning

confidence: 99%

⁹⁰Y‐ibritumomab tiuxetan radiotherapy as first‐line therapy for early stage low‐grade B‐cell lymphomas, including bulky disease

et al. 2014

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Summary 90Y-ibritumomab-tiuxetan ( 90 YIT) was used as a first-line therapy for patients with early-stage follicular lymphoma (FL) or marginal zone B-cell lymphoma (MZL). Thirty-one patients were treated, with an overall 3-month response rate of 100% (68% complete response, 29% unconfirmed complete response and 3% partial response). At a median follow-up of 56 months, ten patients (32%) had disease relapse or progression. The progression-free rates at 3 and 5 years were lower in males, patients with FL, stage II diseaseand non-bulky disease, although they did not reach statistical significance. Grade 3-4 neutropenia, thrombocytopenia and anaemia were 61%, 35%, and 3%, respectively. 90YIT was well tolerated, including in those patients over 60 years old, and achieved high response rates in patients with earlystage low-grade B-cell lymphomas. Bulky disease did not adversely affect tumour response.Keywords: zevalin, myelosuppression, radiation, follicular, marginal zone.Low-grade B-cell lymphomas include the histological types of follicular lymphoma (FL), marginal zone lymphoma (MZL), splenic MZL and lymphoplasmacytic lymphoma. Because these lymphomas are clinically unaggressive and progress slowly, the optimal treatment for stage I-II low-grade B-cell lymphomas has not yet been determined and they are unlikely to be included in clinical trials. Frontline targeted therapy with the antibody rituximab produces an overall response rate of 72%, with a 36% complete remission rate, in patients with advanced-stage grade I FL (Witzig et al, 2005). Adding rituximab to chemotherapy has consistently enhanced response rates (Marcus et al, 2008). However, the availability of numerous therapies for early-stage low-grade B-cell lymphomas and a lack of adherence to one single treatment plan make the best treatment recommendations unclear.The mouse anti-cluster of differentiation (CD) 20 antibody, which targets the same epitope as rituximab, has been conjugated with the radioisotope complex yttrium-90-ibritumomab tiuxetan ( 90 YIT), which has shown clinical benefit in lymphoma therapy. An initial randomized clinical trial with patients with relapsed FL, including transformed lymphoma, showed response rates of 80% in the 90 YIT group and 56% in the rituximab group; the complete response (CR) rates were 30% and 16%, respectively (Witzig et al, 2002). The second type of radiotherapy, YIT as consolidation therapy after various frontline chemotherapies for FL was shown to increase the PFS rate at 8 years from 32% to 48% (Morschhauser et al, 2013).Although the benefits of 90 YIT as treatment for advancedstage FL in the frontline and relapse settings are well documented, little data exist that document whether individuals with early-stage low-grade B-cell lymphomas benefit from 90 YIT therapy.

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Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma

Abstract: Analysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL.

Cited by 533 publications

References 13 publications

B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

Rituximab maintenance improves overall survival in follicular lymphoma: A retrospective nationwide real‐world analysis from Taiwan Cancer Registry Database

⁹⁰Y‐ibritumomab tiuxetan radiotherapy as first‐line therapy for early stage low‐grade B‐cell lymphomas, including bulky disease

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Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma

Abstract: Analysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL.

Cited by 533 publications

References 13 publications

B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

Rituximab maintenance improves overall survival in follicular lymphoma: A retrospective nationwide real‐world analysis from Taiwan Cancer Registry Database

90Y‐ibritumomab tiuxetan radiotherapy as first‐line therapy for early stage low‐grade B‐cell lymphomas, including bulky disease

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Product

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⁹⁰Y‐ibritumomab tiuxetan radiotherapy as first‐line therapy for early stage low‐grade B‐cell lymphomas, including bulky disease