Investigation of FcγR Polymorphisms and Response to IL-2 (Proleukin®) and Rituximab Treatment in Rituximab-Resistant NHL Patients: Importance of the F/F Polymorphism at Position 158 of the Fcγ.

Background: Antibody-dependent cellular cytotoxicty (ADCC) is an important mechanism of rituximab activity. Genetic polymorphisms in FcγRIIIa have been reported to influence response to rituximab in follicular non-Hodgkin’s lymphoma (NHL) patients, and the F/F polymorphism at position 158 has been associated with decreased response (Cartron, et al. Blood 2004). IL-2 induces expansion and activation of FcR bearing cells, enhancing ADCC (Gluck, et al. Clin Cancer Res 2004).

Methods: The combination therapy of IL-2 and rituximab (IL-2+R) was evaluated in low grade NHL patients who were rituximab-resistant by standard criteria. Rituximab was administered weeks (wks) 1–4 at 375 mg/m² IV; IL-2 was administered SC 3 times/wk at 14 MIU wks 2–5 and at 10 MIU wks 6–9.

Results: 57 patients (pts) were enrolled. Twenty-nine pts are evaluable with at least week 8 response data, all of whom have been genotyped. Best response to date: 4 responders (1 CR, 3 PR), 22 patients with stable disease (SD), and 3 pts have progressed (PD) on therapy. Follow-up is on-going. FcγRIIIa polymorphism analysis at position 158 from 36 pts typed to date shows a frequency of 53% F/F, 36% V/F, and 11% V/V as compared to 35%F/F, 45%V/F and 20% V/V in previously untreated pts (Cartron et al, 2004). To date, the data has shown a higher response rate for the F/F pts (4/17; 24%) than the overall population (4/29; 14%). Best response to date for 17 F/F pts: 4 responders and 13 SD; for the 9 V/F pts: 0 responders, 7 SD, and 2 PD; for the 3 V/V pts: 0 responders, 2 SD, and 1PD. In addition, 9 pts had responses lasting = 4 months with 6/9 being F/F and 3/9 being V/F. Patients will be followed periodically up to 2 years or until disease progression. The regimen was well tolerated and the majority of adverse events (AEs) were CTC grade 0, 1, or 2 (flu like symptoms, injection site reactions and rash). No grade 3 or 4 AEs occurred in 10% or more of pts.

Conclusions: These data support an association of the genetic polymorphism of FcγRIIIa 158F/F with prior failure to respond to rituximab. Immunotherapy with IL-2+R may achieve a critical threshold to drive ADCC more effectively in patients carrying the low affinity F/F IgG FcR polymorphism, restoring their response to monoclonal antibody therapy. All pts with this F/F polymorphism either responded to therapy or achieved SD as their best response to date. This outpatient regimen was generally well tolerated. The role of the FcγRIIIa F/F polymorphism is currently being evaluated in a prospective randomized trial comparing rituximab to rituximab + IL-2 in patients with follicular lymphoma.