OS and PFS were calculated from the date of registration until death from any cause (OS), or until disease progression or death from any cause (PFS)

OS and PFS were calculated from the date of registration until death from any cause (OS), or until disease progression or death from any cause (PFS). Iodine I-131 tositumomab on protocols S9800 and S9911, n=30 and 42, respectively) was analyzed. DNA was extracted and assayed for Fc gamma receptor 3A V158F and 2A R131H polymorphisms using a TaqMan SNP assay. Stratified Coxs regression was used to assess association with overall survival. == Results == Tafamidis (Fx1006A) For Fc gamma receptor 3A, there was an association with overall survival in Tafamidis (Fx1006A) the combination therapy Tafamidis (Fx1006A) trials but not in the chemotherapy-only trial. Having at least one Fc gamma receptor 3A V allele was associated with improved overall survivalversusF/F (HR=0.33, 95% CI, 0.11, 0.96,P=0.042). For overall survival, there was evidence of a statistical conversation between the use of mAb and the number of V alleles (0, 1, or 2) (P=0.006). There was no such association for Fc gamma receptor 2A. == Conclusions == Fc gamma receptor 3A polymorphism status may be predictive of survival in follicular lymphoma patients receiving treatments made up of an anti-CD20 antibody but not treatment with chemotherapy alone. Thus, Fc gamma receptor 3A polymorphisms may be important to consider in designing new follicular lymphoma trials and new anti-CD20 monoclonal antibodies. Keywords:follicular lymphoma, SWOG, FCGR, combined monoclonal antibody, chemotherapy == Introduction == Rituximab is usually a Tafamidis (Fx1006A) monoclonal IgG1 antibody against CD20 with human gamma1 and kappa constant regions and murine variable domains, approved for use by the FDA in non-Hodgkins lymphoma (NHL), chronic lymphocytic leukemia (CLL), and rheumatoid arthritis.1The exact mechanism of rituximab activity is not completely understood. Possible mechanisms of action include apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), opsonization-phagocytosis, and a vaccinal effect.2ADCC is thought to be a particularly prominent mechanism of action of rituximab in follicular lymphoma (FL),3the most common indolent NHL type. ADCC requires activation of a receptor for the Fc portion of IgG (Fc gamma receptor, FCGR) on a leukocyte such as an NK cell or macrophage. There are three classes of FCGR (1, 2 and 3) with polymorphisms that impart different IgG-binding properties. In particular, FCGR3A (CD16), expressed on NK cells and macrophages, has a polymorphism encoding phenylalanine (F) or valine (V) at aminoacid position 158 (V158F). Position 158 on FCGR3A interacts with the lower hinge region of IgG1,4and IgG1 binds strongest to NK cells with 158V/V.5It is therefore plausible that having 158V/V may result in stronger NK activation and increased benefit from rituximab. Indeed, patients with FCGR3A 158V/V, and to a lesser degree with 158V/F, genotype have been reported to have better overall response rate (ORR), progression-free survival (PFS), Splenopentin Acetate or event-free survival (EFS) when treated with single agent rituximab for follicular lymphoma.3,6,7However, other studies failed to confirm the association between FCGR polymorphisms and outcome when FL patients were treated with rituximab and CHOP chemotherapy.810However, these studies did not compare outcomes with chemotherapy alone which would have helped to delineate the contribution of anti-CD20 monoclonal therapy, since any effects of FcR polymorphisms on outcome could be overwhelmed by the effect of chemotherapy. Furthermore, it is not known if there is an impact of FcR polymorphisms on overall survival (OS) which would be the outcome of best importance. Therefore, we investigated the association between FCGR3A polymorphism and survival outcome in FL patients treated with a combination of chemotherapy and an anti-CD20 monoclonal antibody (mAb) in the context of large multi-institutional trials conducted by the Southwest Oncology Group (SWOG). In particular, we tested whether the 158V-made up of genotype was predictive of survival following all treatment regimens, or just regimens made up of mAb. In addition to FCGR3A V158F, we also assessed the prognostic importance of FCGR2A R131H polymorphism, since 131 H/H (histidine) binds human IgG2 stronger than 131R/R, and was correlated with a more favorable outcome in a previous study of FL by Weng and Levy.3 == Design and Methods == == Patients == All patients had previously untreated advanced-stage (bulky II, III or IV) follicular lymphoma (grades 1, 2 or 3 3). The patients were enrolled on one of three trials: prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide (ProMACE) plus mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), with randomization of responders to interferon maintenance (SWOG 8809: 19881994); CHOP followed by 4 doses of rituximab (SWOG 9800: 1998) and CHOP followed by tositumomab and iodine I 131 tositumomab (BEXXAR therapeutic regimen) (SWOG 9911: 19992000). Specimens had to be excisional biopsies with sufficient remaining tissue. All patients gave informed consent for the use of remaining tissue for.