Maintenance Rituximab After Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 Study

Hochster, Howard S.; Weller, Edie; Gascoyne, Randy D.; Habermann, Thomas M.; Li, Gordon; Ryan, Theresa; Zhang, Lijun; Colocci, Natalia; Frankel, Stanley R.; Horning, Sandra J.

doi:10.1200/jco.2008.17.1561

Cited by 253 publications

(149 citation statements)

References 24 publications

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“…Other randomized trials also failed to directly demonstrate a translation from improved outcome in terms of EFS to a prolonged OS. 23 However, recent cross-trial comparisons indicated steady progress in OS for patients with FL in part due to improved front-line therapies. [11][12][13] This clearly suggests that phase III trials with a PFS or EFS end point, such as the FL2000 study, were likely underpowered to demonstrate a significant OS prolongation.…”

Section: Discussionmentioning

confidence: 99%

Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

Bachy¹,

Houot²,

Morschhauser³

et al. 2013

Haematologica

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Section: Discussionmentioning

confidence: 99%

Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

Bachy¹,

Houot²,

Morschhauser³

et al. 2013

Haematologica

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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.

153

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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“…Several schedules have been proposed for maintenance therapy, with either 4 weekly infusions every 6 months (one, two or four times) or one infusion every 2 or 3 months [20]. The benefits in terms of progression-free survival and overall survival of rituximab maintenance were shown in several trials [17,18,21,22] and in a recent meta-analysis [23]. Rituximab was therefore approved by the FDA in 2011 for first-line maintenance treatment of patients with advanced FL who responded to initial treatment with rituximab.…”

Section: Introductionmentioning

confidence: 99%

Model‐based design of rituximab dosage optimization in follicular non‐Hodgkin's lymphoma

Ternant

Cartron

Hénin

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The concentration-effect relationship of rituximab in follicular lymphoma (FL) was previously described using pharmacokinetic-pharmacodynamic (PK-PD) modelling.• The influence of genetic polymorphism of FCGR3A on rituximab efficacy in FL patients was included in this PK-PD model.• Previous studies suggest that increasing the dose of rituximab and/or the number of infusions may lead to a better clinical response in FL. WHAT THIS STUDY ADDS• The previously validated PK-PD model can be used to design an optimized rituximab dose regimen in FL patients.• Clinical trial simulation shows the potential clinical benefits of changes in rituximab dose.• Optimization of the rituximab dose regimen cannot compensate for the lower response of FCGR3A-158F carriers compared with that of FCGR3A-158VV patients. AIMSRituximab has dramatically improved the survival of patients with non-Hodgkin's lymphoma (NHL). However, studies have suggested that the dose regimen currently used (i.e. 375 mg m -2) could be optimized. The aims of this study were to quantify the benefits of the new dose regimen for rituximab in follicular NHL (FL) patients using a previously validated PK-PD model and to design clinical trials investigating optimization of rituximab dosage. METHODSA PK-PD model was used to predict progression-free survival (PFS) of FL patients treated by rituximab alone in asymptomatic FL, and those treated by rituximab combined with chemotherapy (R-CHOP) in relapsed/resistant FL. This model accounts for the influence of a polymorphism in FCGR3A, the gene encoding the FcgRIIIa receptor, on clinical efficacy. Several induction and maintenance dose regimens using rituximab alone or in combination with conventional chemotherapy (CHOP) were tested. The benefits of rituximab dose adjustment for F carriers were investigated. The numbers of subjects required for the design of two-armed clinical trials were calculated using model-predicted PFS at a power of 80%. RESULTSThe model predicted a potential benefit of 1500 mg m -2 maintenance doses of rituximab for both rituximab monotherapy and R-CHOP. The model shows that the PFS of FCGR3A-F carriers remains lower than that of homozygous FCGR3A-VV patients, even with markedly increased rituximab doses. CONCLUSIONOur results suggest a benefit of increasing doses of rituximab in FL, both during induction and maintenance. These results need to be confirmed in controlled clinical trials.

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Maintenance Rituximab After Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 Study

Abstract: The E1496 study provides the first phase III data in untreated indolent lymphoma that MR after chemotherapy significantly prolongs PFS.

Cited by 253 publications

References 24 publications

Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

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

Model‐based design of rituximab dosage optimization in follicular non‐Hodgkin's lymphoma

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