Lenalidomide Overcomes FcγRIIIa-Mediated Resistance to Rituximab In Patients with Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma (NHL): A Correlative Analysis of a Phase 2 Study

One of several mechanisms attributed to the antitumor activity of rituximab is antibody-dependent cellular cytotoxicity (ADCC), which depends on the affinity between the FcγRIIIa receptor (CD16) and human immunoglobulin G1 (IgG1). A genetic polymorphism at position 158 of the FcγRIIIa gene, which places either a phenylalanine (F) or a valine (V), results in an Fc receptor with high or low affinity. It has recently been reported that FL patients with the high affinity 158V/V genotype appear to have significantly higher objective response rates (ORR) and progression-free survival (PFS) compared to patients with at least one low affinity 158F allele when treated with rituximab monotherapy: ORR was 75% for patients with V/V compared with 23% and 30% for patients with V/F and F/F, respectively (Weng et al JCO 2003). Lenalidomide is an immunomodulatory agent that has been shown to enhance rituximab-mediated ADCC and to induce CD16 expression on NK cells (Zhang et al Am J Hematol 2009). In lymphoma cell lines and animal models, combining lenalidomide and rituximab (R2) resulted in improved antitumor activity relative to treatment with either agent alone. In a clinical setting, we previously reported on the activity and safety profile of the R2 regimen in patients with relapsed or refractory (rel/ref) indolent NHL. In this abstract, we update the efficacy data and report on whether the FcγRIIIa polymorphism affects the clinical outcome in the subset of patients with follicular lymphoma (FL) treated with R2.

Enrolled patients had rel/ref indolent NHL with measurable disease, ≥1 prior therapy, and ECOG Performance Status ≤2. Lenalidomide 25 mg/day was initially administered on days 1–21 of a 28-day cycle and continued until disease progression, while rituximab 375 mg/m² IV was administered on day 15 of cycle 1, and repeated weekly for a total of 4 doses. A second 4-weekly course of rituximab was permitted after cycle 2 for patients achieving less than a CR. After 2 of the first 4 patients developed Gr. 3 tumor lysis syndrome, the protocol was amended to reduce the lenalidomide starting dose to 20 mg, and prophylaxis with allopurinol was initiated. The primary endpoint was ORR. Secondary endpoints included response duration, overall survival, PFS, and safety. The FcγRIIIa genotype was determined in DNA isolated from peripheral blood cells by PCR amplification followed by allele-specific restriction enzyme digestion.

Of the 18 patients enrolled on study, 14 had FL, 2 had marginal zone lymphoma and 2 had chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (1 patient with CLL/SLL was taken off study during cycle 1 due to transformation to Hodgkin's lymphoma). Median patients age was 60 years (range 50–91), median number of prior therapies was 3 (range 1–11), and 7 out of 16 (44%) patients were considered refractory to rituximab (defined as no response to, or progression within 6 months of receiving rituximab). The median number of cycles received was 10 (range 2-–24). The most common grade 3 and 4 toxicities were lymphopenia (23%), neutropenia (23%), fatigue (17%) and hyponatremia (11%). FcγRIIIa genotype data was available for 11 patients with FL: 1 patient had V/V, 6 patients were F/V heterozygotes, and 4 patients had F/F. For the 17 evaluable patients, the ORR (CR+PR) was 76%, which included 7 patients (41%) with a CR, and 6 patients (35%) with a PR, and additionally 2 patients (11%) had stable disease. At median follow-up of 21 months, median PFS was 12.4 months. Since all 7 patients with a CR had FL we investigated their polymorphism status. When grouped according to the genotype, the ORR was 100% in the V/V type, 100% in the V/F type, and 50% in the F/F type. Median PFS could not be calculated in the V/V type due to small number of patients, but it was 14.85 months in the V/F type and 8.31 months in the F/F type.

The R2 regimen has considerable activity in patients with rel/ref indolent NHL, and particularly in patients with FL. In addition, the number of higher responses and longer PFS among patients with the F/V heterozygotes suggest that lenalidomide can potentially overcome the previously reported lower activity of single-agent rituximab in patients with the low affinity type FcγRIIIa receptor. This signal is currently being confirmed with additional patients receiving R2 and is anticipated for presentation at the meeting.

Off Label Use: Lenalidomide use in NHL is off-label.