Polymorphisms of FcγRIIA, FcγRIIB, and FcγRIIIA and Therapeutic Response to Rituximab Combination Therapy in Patients with Waldenstrom's Macroglobulinemia.

The efficacy of rituximab is dependent on a number of host immune interactions, including binding through excitatory (FcγRIIA, FcγRIIIA) as well as inhibitory (FcγRIIB) Fcγ receptors. In previous studies, we showed that polymorphisms in FcγRIIIA-158 predicted outcome to single agent rituximab therapy. Patients displaying L/H or L/R at FcγRIIIA-48 or at least one valine (V/V or V/F) at FcγRIIIA-158 demonstrated greater responses to rituximab versus those patients who expressed FcγRIIIA-48-L/L or FcγRIIIA-158 F/F, respectively (JCO 23:474). The predictive role of FcγRIIIA polymorphisms in patients receiving combination therapy with rituximab has not been addressed to date in WM. We therefore investigated the predictive role of FcγRIIIA-48, -158, as well as other important polymorphisms implicated in modulating IgG antibody binding and activation: FcγRIIA-27, -131, and FcγRIIB-187 in 65 patients with WM who received combination rituximab therapy.

Sixty-four WM patients with a median age of 61, prior therapies of 0, IgM of 3,540 mg/dL, Hct of 32.3%, B2M of 2.7 g/L, who participated on a clinical study and whose outcomes have previously been reported were included in this analysis. Treatment included rituximab in combination with cyclophosphamide (n=43), thalidomide (n=14), or lenalidomide (n=7). Categorical responses for all patients were as follows: CR/VGPR 7 (11%); PR (n=30; 46.2%); MR (n=18; 27.7%); Non-Responders (n=9; 14.1%) for an overall response rate of 86%. Twenty seven patients have progressed with a median follow-up of 19.4 months. Polymorphic variants at FcγRIIA-27, -131, FcγRIIB-187, and FcγRIIIA-48, -158 were determined by Taq Man real time PCR analysis and sequencing, and impact on overall response, categorical response rates, and progression free survival determined.

The expression of H/H at FcγRIIA-131, or at least one valine (V/V or V/F) at FcγRIIIA-158 was associated with improved categorical response, particularly the attainment of CR/VGPR. For FcγRIIA-131, H/H was expressed in 2/9 (22.22%) WM patients who were non-responders; 13/38 (34.2%) patients attaining a major (≥ PR) response, and 4/7 (57.14%) patients who attained a CR/VGPR. For FcγRIIIA-158, the expression of at least one valine was observed in 3/9 (33.3%) WM patients who were non-responders; 20/38 (52.62%) patients attaining a major (≥ PR) response, and 5/7 (71.42%) patients who attained a CR/VGPR. Polymorphisms at FcγRIIA-27, and FcγRIIB-187 showed no association with response. The expression of L/H or L/R at FcγRIIIA-48 was observed in 3/7 (42.86%) patients with CR/VGPR, whereas 2/9 (22.22%) of patients who were non-responders expressed this polymorphism. Subset analysis showed that among patients who received cyclophosphamide based therapy, no differences in polymorphic variation for FcγRIIA-131, FcγRIIIA-48, and -158 were observed between non-responders, major responders and those achieving CR/VGPR.

Taken together, the results of this study support a role for the use of FcγRIIA-131, FcγRIII-158, and possibly FcγRIIA-48 as determinants of better categorical responses in WM patients receiving combination therapy with an immunomodulatory agent. The combined use of cyclophosphamide with rituximab therapy appears to negate the inferior outcomes predicted by polymorphic variants in FcγRIIA-131, FcγRIIIA-48, and -158 which have previously been shown to be associated with lower response rates to single agent rituximab therapy.

No relevant conflicts of interest to declare.