Optimization of Rituximab for the Treatment of Diffuse Large B-Cell Lymphoma (II): Extended Rituximab Exposure Time in the SMARTE-R-CHOP-14 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group

Pfreundschuh, Michael; Poeschel, Viola; Zeynalova, Samira; Hänel, Mathias; Held, Gerhard; Schmitz, Norbert; Viardot, Andreas; Dreyling, Martin; Hallek, Michael; Mueller, Carolin; Wiesen, Martin H. J.; Witzens-Harig, Mathias; Truemper, Lorenz; Keller, Ulrich; Rixecker, Torben; Zwick, Carsten; Murawski, Niels

doi:10.1200/jco.2013.54.6861

Cited by 81 publications

(72 citation statements)

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“…10 These results are attributed to higher rituximab clearance in males who are undertreated without rituximab maintenance. 11 The risk of relapse at onset (age-adjusted International Prognostic Index) or disease status after induction (CR or PR) would also affect the applicability of rituximab maintenance and should be clarified.…”

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confidence: 89%

Efficacy of rituximab maintenance therapy for aggressive B-cell lymphoma depends on use of rituximab in induction therapy: a meta-analysis of randomized controlled trials

et al. 2015

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Contrary to the established role of rituximab maintenance therapy for advanced follicular lymphoma with a high tumor burden, 1 it remains controversial as to whether rituximab confers advantageous effects for aggressive lymphoma when used as maintenance therapy. Recently, a cardinal study from an Austrian group reported the results of the randomized NHL13 trial, which demonstrated no significant prolongation in event-free survival (EFS) by adding rituximab maintenance for patients with aggressive lymphoma who achieved CR/CRu with R-CHOP-like regimens.2 The interpretation of this study and previous trials featuring rituximab maintenance for aggressive lymphoma, suffers from the problem of inconsistent results, which are probably attributable to the different study designs among trials. Therefore, we conducted a meta-analysis to inquire into those features connected to the benefits associated with rituximab maintenance.We extracted studies by searching Medline (years dating from 1960 to May 2015), The Cochrane Library, and ongoing and unpublished trials.3,4 The terms "rituximab", "maintenance", and "lymphoma" were cross-searched. Out of the 739 candidate papers and clinical study registries, we extracted prospective randomized controlled trials where case cohorts were administered with single-agent rituximab as maintenance therapy for responding patients (PR or better) to induction treatments, with or without consolidative autologous stem-cell transplantation (ASCT), and were compared with control cohorts who were followed with observation alone. Studies focusing mainly on mantle cell lymphoma were excluded as the basic treatment scheme for mantle cell lymphoma differs to that for aggressive lymphoma. As a result, we extracted 4 relevant reports.2-5-7 The details of these studies are shown in Table 1. Three studies targeted untreated patients and the other targeted patients with relapsed/refractory status. Induction regimens included rituximab in two studies, and not in one. The remaining study had randomized patients into two arms of those receiving rituximab-containing and non-rituximab containing regimens before maintenance therapy, thus patients in this study were divided into rituximabnaïve or not in the subgroup analysis.6 The pooled estimates of the effect were calculated using the random effects model using the DerSimonian-Laird method with inverse-variance weighting. Hazard ratio (HR) was selected to measure responses, and adverse effects were evaluated by using risk difference (RD). Three of the studies examined event-free survival (EFS) and one examined failure-free survival (FFS), and we used these parameters to estimate treatment effects, considering the similarity of endpoints. When HR was not available for a given study, data measurement was estimated using methods described by Tierney et al. 8 We assessed the heterogeneity of the trial results using a chi-squared test of heterogeneity and the I 2 measure of inconsistency. We analyzed the data for the 1546 patients with aggressive lymphoma from the...

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confidence: 89%

Efficacy of rituximab maintenance therapy for aggressive B-cell lymphoma depends on use of rituximab in induction therapy: a meta-analysis of randomized controlled trials

et al. 2015

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“…Die Optimierung der Gaben von Rituximab wird zurzeit von der DSHNHL untersucht [45]. Durch Genexpressionsanalyse konnten 2 Subtypen des DLBCL identifiziert …”

Section: Introductionunclassified

Lymphome bei rheumatischen Erkrankungen

2017

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“…We further demonstrated that FcgRIIIA-158VF polymorphism influenced the rituximab pharmacokinetics/ pharmacodynamics relationship, homozygous VV NK cells needing 4 times lower RTX concentration compared with homozygous FF NK cells to obtain a comparable in vitro effect, 40 suggesting that certain subsets of patients may benefit from increased dosing. Further studies demonstrated that PK-guided RTX dosing to maintain sufficient RTX concentrations in indolent non-Hodgkin lymphomas (iNHLs), 41 or an increased number of RTX infusions in DLBCL, 42 failed to demonstrate any clinical advantage. As suggested in a murine model, 43 antigen burden is probably, at least in DLBCL, the main parameter affecting RTX exposure.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

“…44 The theoretical dose of RTX according to tumor burden could be calculated, demonstrating that the optimal dose was close to the approved dose, probably explaining the lack of significant difference in a dose-dense trial. 42 The correlation of total metabolic volume before treatment with distribution volumes (V D ) without modification of clearance could suggest a "sponge effect," tumor cells trapping RTX before release of the antibody after exerting its cytotoxic effect. 44 In CLL patients, the standard dose of RTX is higher than in non-Hodgkin lymphoma (NHL) patients (500 mg/m 2 instead 375 mg/m 2 ), justified by a faster RTX clearance observed in the first phase 2 trial, 37,39 leading to low RTX exposure and a worse outcome.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

Obinutuzumab: what is there to learn from clinical trials?

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2017

Blood

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Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL). Rituximab (RTX) is frequently considered as its "ancestor" and OBZ clinical development was justified by the importance of FcgRIIIAmediated mechanisms in RTX clinical activity. However, RTX differs from OBZ in 2 critical independent properties: being a type I anti-CD20 mAb and not being Fcoptimized. Moreover, the use of a different dosing regimen for RTX and OBZ further complicates any interpretation of clinical results. The results obtained for OBZ in CLL provide new arguments for FcgRIIIAmediated mechanisms when the target antigen is expressed at a low density. Results of OBZ in FL confirm the interest for FcgRIIIA-mediated mechanisms, with some limitations, some of them being possibly due to lack of OBZ-induced complement activation. The situation in diffuse large B-cell lymphoma is deceiving, as the possible gains of activity of OBZ appear to be annihilated by the lack of complement activation. Although RTX was by chance an anti-CD20 mAb with equilibrated pharmacodynamic properties, the reinforcement of some of these properties, which has been done at the expense of complement activation, has conferred an advantage in some B-cell disorders while restricting OBZ indications. The OBZ story nicely demonstrates that the future of naked mAbs is to design agents with optimized and tailored properties, and that this must be done step by step, with a full clinical validation. (Blood. 2017;130(5):581-589) Introduction Obinutuzumab (OBZ) is the first recombinant type II anti-CD20 and immunoglobulin G1 (IgG1) Fc-optimized monoclonal antibody (mAb) approved by the US Food and Drug Administration (FDA) and European Medicines Agency. It is currently labeled in first-line chronic lymphocytic leukemia (CLL) patients in association with chlorambucil, and in combination with bendamustine followed by OBZ monotherapy for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab (RTX)-containing regimen. RTX was the first anti-CD20 mAb approved and largely contributed to establish the therapeutic value of anti-CD20 strategies in almost all CD201 malignancies. Experimental studies demonstrated that RTX is able to induce CD20 1 cell death by several mechanisms.1 RTX is sometimes presented as the "ancestor" of OBZ. First of all, OBZ is in no way a RTX biosimilar: not only are their variable domains totally different but also, in addition, RTX does not recognize the same CD20 epitope as OBZ and is a human IgG1 non-Fc-optimized antibody, 2 characteristics independent from each other and having functional and pharmacological consequences that need to be taken into consideration when trying to compare the 2 drugs. OBZ development was largely based on the presumed importance of FcgRIIIA-mediated mechanisms in RTX clinical activity, this being mainly supported by the influ...

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Optimization of Rituximab for the Treatment of Diffuse Large B-Cell Lymphoma (II): Extended Rituximab Exposure Time in the SMARTE-R-CHOP-14 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group

Cited by 81 publications

References 15 publications

Efficacy of rituximab maintenance therapy for aggressive B-cell lymphoma depends on use of rituximab in induction therapy: a meta-analysis of randomized controlled trials

Efficacy of rituximab maintenance therapy for aggressive B-cell lymphoma depends on use of rituximab in induction therapy: a meta-analysis of randomized controlled trials

Lymphome bei rheumatischen Erkrankungen

Obinutuzumab: what is there to learn from clinical trials?

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