Humoral Immune Response and Immunoglobulin G Fc Receptor Genotype Are Associated with Better Clinical Outcome Following Idiotype Vaccination in Follicular Lymphoma Patients Regardless of Their Response to Induction Chemotherapy.
Authors: Weng Wen-Kai , Czerwinski Debra , Levy Ronald 
Published: April 2020

Abstract
Recently, we found that anti-idiotype humoral immune response and FcγRIIIa 158 Valine/Valine (V/V) correlated with clinical outcome in follicular lymphoma patients receiving idiotype vaccination (JCO 22:4717). This result highlighted the importance of developing anti-tumor antibodies and hosting an efficient ADCC machinery. In the previous study, all 136 patients received induction chemotherapy and were in clinical remission at the time of idiotype vaccination. One important question is whether the outcome of these patients was correlated with their clinical response to induction chemotherapy. We, therefore, analyzed the impact of chemotherapy response on clinical outcome to determine if the better outcome associated with humoral immune response and V/V genotype applies to patients with different chemotherapy response. Induction cheomtherapies included chlorambucil, CVP, an adriamycin-containing regimen, or alternating CVP and fludarabine. Ninety patients (66%) achieved complete response or unconfirmed complete response (CR/CRu) and 46 patient (34%) achieved partial response (PR). The progression free survival at 4 years was 59% for CR/CRu patients and 41% for PR patients. The median time to progression (TTP) of 5.21 for CR/CRu patients was significantly longer than the 1.62 years for PR patients (p=0.004). Multi-variant analysis using the Cox Proportional Hazards Model showed that humoral IR, V/V genotype and CR/CRu were three independent positive predictors for progression free survival, while FcγRIIa genotype, FcγRIIb genotype, cellular IR, gender, age, B symptoms, time from diagnosis to therapy, use of adriamycin or use of fludarabine during induction chemotherapy had no impact. The relative benefit was 2.26 (95% CI, 1.36–3.76, p=0.0016) for humoral IR, 5.03 (95% CI, 2.06–12.25, p=0.0004) for V/V genotype and 2.01 (95% CI, 1.22–3.29, p=0.0057) for CR/CRu. The impact of humoral immune response and V/V genotype on CR/CRu or PR patients were then examined. In CR/CRu patients, the progression free survival at 4 years was 74% for patients with humoral immune response and/or V/V genotype while only 45% for patients without either, with median TTP not reached and of 3.46 years for the two groups, respectively (p=0.007). In PR patients, the benefit of having humoral immune response and/or V/V genotype was even more pronounced. The progression free survival at 4 years was 63% for patients with humoral immune response and/or V/V genotype and 21% for patients without either, with median TTP not reached after 8 years and of 1.31 years for the two groups, respectively (p=0.0004). This result suggests that having humoral immune response and/or V/V genotype was associated with longer TTP regardless of their response to induction chemotherapy. In fact, there is no difference in the TTP between CR/CRu and PR patients if they had humoral immune response and/or V/V genotype (TTP not reached in both groups, p=0.338). In contrast, in the group with neither humoral immune response nor V/V genotype, CR/CRu patients enjoyed much longer TTP than PR patients (TTP 3.46 year vs 1.31 years, p=0.0005). This result further confirms the strong association of clinical outcome with humoral immune response and with the functional activity of Fc receptor bearing cells in patients receiving idiotype vaccination. Our results also argue for the inclusion of PR as well as CR patients in idiotype vaccine trials, since the apparent benefit of immune response is even greater in PR patients.