Expression of Inhibitory Fc Receptor (FcγRIIB) Is a Marker of Poor Response to Rituximab Monotherapy in Follicular Lymphoma (FL).

Single-agent immunotherapy with rituximab is a viable treatment option for low risk FL, with limited toxicity and a long duration of response in some patient subsets. We have previously shown that high expression of FcγRIIB promotes rituximab internalisation on various B cell targets, including FL (Blood 2011 118:2530–2540), something not seen with type II anti-CD20 antibodies. The SAKK 35/98 trial examined rituximab monotherapy in FL and now has long-term follow-up data of almost 10 years (JCO 2010 28:4480–4484). We analysed diagnostic tumour samples from this trial to determine the relationship of FcγRIIB expression to responses and clinical outcomes after rituximab treatment in FL.

202 patients (pts) with newly diagnosed or relapsed FL received induction treatment with rituximab 375 mg/m² weekly for 4 weeks. Pts with stable or responding disease at week 12 were randomized into 2 groups: no further treatment or prolonged treatment with single infusions of rituximab 375 mg/m² at weeks 12, 20, 28 and 36. Archived tissue samples from 135 evaluable pts were stained using an anti-human FcγRIIB antibody (clone EP888Y, Abcam) at a dilution of 1:3000 on a Dako autostainer. The samples were pretreated with the Dako EnVisionFLEX target retrieval solution high pH and detection using the Dako AS-Link 48 with Dako EnVision flex plus detection kit. Positive samples were graded into negative/low intensity staining (n=120) versus medium/high (n=13) by an expert lymphoma histopathologist blinded to the clinical outcomes. Data from 2 slides and response at week 12 data for 4 pts were unavailable (1 of whom also has missing slide data), resulting in 130 pts available for analysis. Failure-free survival (FFS) was defined as time from registration until failure to achieve complete/partial response at week 12, progression, relapse, a second cancer or death from any cause. Objective response rate (ORR) was associated with intensity staining levels using Fisher's exact test. All time-to-event endpoints were evaluated using the Kaplan-Meier method; groups were compared using the log-rank test. The hazard ratio (HR) was assessed using Cox proportional hazards models.

Registered and randomised pts had very similar baseline characteristics; previously untreated pts had slightly more favourable characteristics but were balanced between the 2 treatment arms. Pts expressing medium/high levels of FcγRIIB were less likely to respond to rituximab by week 12 (ORR 58.1% vs 23.1%, Fisher's exact test, p=0. 02), a finding independent of prior therapy. For FFS, there was a statistically significant difference (p=0.001; HR=0.42; 95% confidence interval (C.I.): 0.23–0.77) between the negative/low staining group (median: 21.4 months; 95% C.I.: 7.0–34.2) and the medium/high staining group (median: 7.0 months; 95% C.I.: Not calculable). The interaction between staining levels and randomised treatment groups for FFS was not statistically significant. There was a non-significant trend towards better overall survival in the low/negative group (median: 140.0 vs 50.0 months; p=0.15; HR=0.57; 95% C.I.: 0.27–1.23); however the event rate was lower (36.8% vs 61.5%).

Elevated FcγRIIB expression level is associated with poor response to rituximab in pts with FL. This group may show better results with non-internalising type II antibodies, a hypothesis for validation in future prospective clinical trials.

Ghielmini:Roche: Honoraria, Speakers Bureau. Johnson:Roche: Honoraria.