FCgamma Receptor Polymorphisms Do Not Influence the Outcome of Treatment with Rituximab Followed by Active Immunotherapy with Mitumprotimut-T (FavId®, Id-KLH).
Authors: Maloney David G. , Pender Barbara , McCarthy Erin , Gold Daniel P. 
Published: October 2019

Background: Patient specific active idiotype immunotherapy with immunoglobulin idiotype is a promising new therapy for follicular NHL. Response to therapy may include both humoral and cellular anti-idiotypic immunity, but it is not clear which is most important. Prior studies have suggested that immunoglobulin FCgammaRIIIa (FCgRIIIa) polymorphisms at position 158 valine (V) or phenylalanine (F) effect the response to treatment with rituximab as well as outcomes from idiotype immunotherapy following objective response to chemotherapy. Here we present data assessing the correlation of FCgRIIIa polymorphisms and outcomes from idiotype immunotherapy following treatment with rituximab.

Treatment: We determined the FCgRIIIa genotype using a SSCP method with genomic DNA isolated from 55 rituximab-naïve patients treated on a Phase II trial of mitumprotimut-T (FavId®, Id-KLH) (Koc et al, Blood, 2006; 108: #691). Four patients who progressed following rituximab and therefore did not receive mitumprotimut-T were excluded from this analysis. All 55 patients in this analysis had follicular NHL with a median age of 55 years. Thirty five patients were treatment naïve and 20 had relapsed following prior chemotherapy. Patients received rituximab (375mg/m2 i.v. weekly x 4) and those with stable or responding disease assessed at Week 11 received Id-KLH (1 mg s.q. monthly x 6) starting on Week 12 along with Leukine® (sargramostim, GM-CSF, 250 mcg, s.q.) on Days 1–4. Pts continued to receive booster injections on a reduced schedule, every other month x6 then quarterly thereafter, until disease progression. Radiological scans were performed every 3 months for the first 2 years of follow up, then every 6 months thereafter and reviewed centrally. Objective response and time to tumor progression (TTP) were assessed using modified IWG criteria (Cheson et al, J Clin Oncol1999; 17:1244). Response at 3 months, best response, TTP and progression free survival (PFS) at 1 year and 3.5 years were all assessed with respect to FCgRIIIa genotypes.

Results: DNA was isolated from all 55 patients and successfully analyzed by SSCP for polymorphisms at position 158 of FCgRIIIa. Nine of 55 patients were V/V (16%), 27 were F/F (49%) and 19 were heterozygous V/F (35%). Overall, the 3 month response rate CR+PR) was 31/55 (56%) and the best overall response rate was 39/55 (71%). The 3 month response (post rituximab) was 5/9 (56%) for V/V, 9/19 (47%) for V/F and 17/27 (63%) for F/F patients. Best response was 6/9 (67%) for V/V, 12/19 (63%) for V/F and 21/27 (78%) for F/F patients. Median TTP was 19.5 months for V/V, 22.3 months for V/F and 18 months for F/F patients. The PFS at 1 year post initiation of rituximab was 57% for V/V, 61% for VF and 68% for FF patients while at the median follow-up of 3.5 years the PFS was 31% for V/V, 42% for V/F and 31% for F/F patients.

Conclusions: FCgRIIIa polymorphisms were not associated with response rate or time to progression following a treatment program consisting of single agent rituximab followed by idiotype vaccination with mitumprotimut-T in rituximab-naïve patients. Results from an ongoing randomized Phase III study will assess the efficacy of this combined therapy, but these data suggest that long term PFS in patients receiving an idiotype vaccine following rituximab may rely more on a cell mediated immune response rather than a humoral response to idiotype.