Abstract
Background
First-line rituximab therapy together with chemotherapy is the standard care for patients with advanced follicular B-cell lymphoma, as rituximab together with chemotherapy prolongs progression-free and overall survival (Herold et al. 2007; Marcus et al. 2005). However, as not all patient subgroups benefit from combined immuno-chemotherapy, we asked whether the microenvironment may predict benefit from rituximab-based therapy.
Design
To address this question, we performed a retrospective immunohistochemical analysis on pathological specimens of 18 patients recruited into a randomized clinical trial, where patients with advanced follicular lymphoma were randomized into either chemotherapy or immuno-chemotherapy with rituximab (Herold et al. 2007).
Results
We show here that rituximab exerts beneficial effects, especially in the subgroup of follicular lymphoma patients with low intrafollicular CD3, CD5, CD8, and ZAP70 and high CD56 and CD68 expression.
Conclusion
Rituximab may overcome immune-dormancy in follicular lymphoma in cases with lower intrafollicular T-cell numbers and higher CD56 and CD68 cell counts. As this was a retrospective analysis on a small subgroup of patients, these data need to be corroborated in larger clinical trials.
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Introduction
Follicular lymphoma (FL) is the most frequent indolent lymphoma diagnosed. In limited stages, radiation-based therapy is thought to have curative potential. In advanced stages, when patients lack symptoms, watch and wait strategy is applied, whereas chemotherapy is the therapy of choice when treatment is needed (Yuda et al. 2016). Over decades, no progress had been seen in the therapy of advanced FL. The introduction of rituximab has changed the therapy of follicular lymphomas (FL) significantly, in that the combined immuno-chemotherapy not only prolongs progression- and event-free survival, but more importantly, overall survival (Herold et al. 2007; Marcus et al. 2008). Transformation into high-grade diffuse large B-cell lymphoma is observed in approx. 4% after 5 years in rituximab-treated patients, which seems lower than in the pre-rituximab era (Janikova et al. 2018).
Predictive factors that discriminate patients who might have a higher benefit from anti-CD20 therapy are not known. Serum concentration of APRIL or low recovery of IgG has been associated with poor survival (Kusano et al. 2018; Li et al. 2008; Taskinen et al. 2007). In contrast, Blaker et al. found that a higher number of intrafollicular CD68-positive macrophages was associated with a higher likelihood of transformation of follicular lymphoma patients into aggressive B-cell lymphoma (Blaker et al. 2016). In their study, all patients had been treated with rituximab-based protocols. However, our study addressed the difference between a small cohort of follicular lymphoma patients treated with rituximab-based chemotherapy and compared this with the cohort treated with chemotherapy only. Both studies thus focused on different issues.
Our study suffers from small numbers, and we used a criterion of p < 0.05 for nominal statistical significance. Therefore, the data presented in this paper need to be interpreted with caution. However, the patients were balanced between the two arms of the original protocol, and the clinical outcome of the 18 patients analyzed here reflected the original trial. As the numbers are small, the data need to be confirmed in larger trials. For such future trials, we propose that the levels as determined for each antigen in the present study (see suppl. Table 3) may be applied as cut-off values since we here demonstrated that the cohort of 18 patients analyzed was representative for the whole trial (see Fig. 1). Naturally, as the chemotherapy given in this trial is not used any more (MCP), we cannot rule out that the herein observed rituximab-based immune activating effect would also be observed when using other chemotherapy regimens such as CHOP or bendamustine. It would also be interesting to apply—in addition to the markers analyzed here—the mutational load of the respective samples, as given in the m7-FLIPI (Pastore et al. 2015).
Taken together, we show here that rituximab exerts beneficial effects especially in the subgroup of follicular lymphoma patients with low intrafollicular CD3, CD5, ZAP70 and CD8, and high CD56 and CD68 expression. Although the study by Dave et al. did not use immunohistology (Dave et al. 2004), they showed that lower T cell and higher macrophage cell signature were both associated with worse prognosis in advanced follicular lymphoma. Our study, therefore, suggests that rituximab therapy could overcome the worse prognostic feature of lower T-cell and higher macrophage infiltration in follicular lymphoma. As this was a retrospective analysis on a small subgroup of patients, these data need to be corroborated in larger clinical trials. Whether rituximab resistance may be overcome by higher dosages of CD20-specific antibodies must be addressed in prospective trials. A hint could be the so-called GADOLIN trial, in which rituximab-resistant patients with indolent lymphomas were randomly assigned to either bendamustine alone or bendamustine plus obinutuzumab that was given at a significant increased dosage as compared to the previously applied rituximab (Sehn et al. 2016).
Notes
The study had been registered as East German Study Group Hematology and Oncology Trial 39 and at ClinicalTrials.gov (http://www.clinicaltrials.gov/) under ID 00269113.
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Funding
Supported by the Deutsche Forschungsgemeinschaft (KFO210; Ne310/14-1; Ne310/14-2 to AN and AB) and the German José Carreras Leukämie Stiftung (AH06-01, AN).
Funding
Andreas Neubauer and Christian Wilhelm designed the research study. Laura Budau and Roland Moll performed the research. Konstantin Strauch did the statistical analysis. Jörg Jäkel, Carsten Hirt, Gottfried Dölken, Georg Maschmeyer, Ellen Neubauer, Andreas Burchert and Michael Herold contributed essential reagents or tools. Laura Budau and Andreas Neubauer wrote the paper. All authors analyzed the data and agreed on the manuscript.
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Georg Maschmeyer reports personal fees from Celgene, personal fees from Novartis, personal fees from Bristol-Myers Squibb, personal fees from Janssen-Cilag, not related to the current paper. Andreas Neubauer has received honoraria from Medupdate GmbH, not related to the current paper.
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Budau, L., Wilhelm, C., Moll, R. et al. Low number of intrafollicular T cells may predict favourable response to rituximab-based immuno-chemotherapy in advanced follicular lymphoma: a secondary analysis of a randomized clinical trial. J Cancer Res Clin Oncol 145, 2149–2156 (2019). https://doi.org/10.1007/s00432-019-02961-9
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DOI: https://doi.org/10.1007/s00432-019-02961-9