Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma

Abstract

Purpose: Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) -specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial.

Patients and methods: Treatment-naive patients with advanced stage FL achieving complete response (CR) or CR unconfirmed (CRu) after chemotherapy were randomly assigned two to one to receive either Id vaccine (Id-KLH + GM-CSF) or control (KLH + GM-CSF). Primary efficacy end points were disease-free survival (DFS) for all randomly assigned patients and DFS for randomly assigned patients receiving at least one dose of Id vaccine or control.

Results: Of 234 patients enrolled, 177 (81%) achieved CR/CRu after chemotherapy and were randomly assigned. For 177 randomly assigned patients, including 60 patients not vaccinated because of relapse (n = 55) or other reasons (n = 5), median DFS between Id-vaccine and control arms was 23.0 versus 20.6 months, respectively (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.16; P = .256). For 117 patients who received Id vaccine (n = 76) or control (n = 41), median DFS after randomization was 44.2 months for Id-vaccine arm versus 30.6 months for control arm (HR, 0.62; 95% CI, 0.39 to 0.99; P = .047) at median follow-up of 56.6 months (range, 12.6 to 89.3 months). In an unplanned subgroup analysis, median DFS was significantly prolonged for patients receiving IgM-Id (52.9 v 28.7 months; P = .001) but not IgG-Id vaccine (35.1 v 32.4 months; P = .807) compared with isotype-matched control-treated patients.

Conclusion: Vaccination with patient-specific hybridoma-derived Id vaccine after chemotherapy-induced CR/CRu may prolong DFS in patients with FL. Vaccine isotype may affect clinical outcome and explain differing results between this and other controlled Id-vaccine trials.

Fig 1.

(A) Clinical trial schema. Previously untreated patients with advanced stage follicular lymphoma underwent lymph node biopsy (LN Bx) after enrollment and were treated with prednisone (60 mg/m² orally daily on days 1 to 14), doxorubicin (25 mg/m² intravenously [IV] on days 1 and 8), cyclophosphamide (650 mg/m² IV on days 1 and 8), and etoposide (120 mg/m² IV on days 1 and 8; PACE) chemotherapy (chemo) every 28 days. Patients achieving complete response (CR)/CR unconfirmed (CRu) were stratified according to International Prognostic Index (IPI) and number of chemotherapy cycles and randomly assigned two to one to receive five injections of hybridoma-derived autologous tumor immunoglobulin idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF; Id-KLH + GM-CSF) or control vaccine (KLH + GM-CSF), respectively. (*) Low, low-intermediate or high-intermediate, high groups. (†) < eight or ≥ eight cycles. (B) CONSORT diagram of enrollment, randomization, and treatment. Two hundred thirty-four patients were enrolled and 117 patients were randomly assigned to receive at least one dose of the blinded vaccine; 76 received Id vaccine and 41 received control vaccine. Patients receiving fewer than five immunizations either (*) withdrew from the study or (†) relapsed before completion.

Fig 2.

Disease-free survival (DFS) and overall survival (OS) according to treatment group for all randomly assigned patients (n = 177) and randomly assigned patients who received blinded vaccinations (n = 117). (A) Kaplan-Meier survival curves for DFS for all randomly assigned patients are shown according to treatment group: hybridoma-derived autologous tumor immunoglobulin idiotype (Id) vaccine (n = 118) and control vaccine (n = 59). Kaplan-Meier survival curves for (B) DFS and (C) OS for randomly assigned patients who received at least one dose of Id vaccine (n = 76) or control (n = 41).

Fig 3.

Disease-free survival (DFS) according to tumor immunoglobulin (Ig) heavy chain isotype for randomly assigned patients who received blinded vaccination. Randomly assigned patients who received at least one dose of the hybridoma-derived autologous tumor immunoglobulin idiotype (Id) vaccine or control vaccine were grouped according to isotype of their tumor Ig heavy chain. Kaplan-Meier survival curves for DFS for Id vaccine and control groups according to (A) IgM and (B) IgG isotype.

Fig A1.

Distribution of randomized patients that received blinded vaccination according to days from randomization to first vaccination. (A) Days from randomization to first vaccination shown for randomly assigned patients that received at least one dose of hybridoma-derived autologous tumor immunoglobulin idiotype (Id) vaccine (N = 76) or control vaccine (N = 41). (B) Days from randomization to first vaccination shown for randomized patients according to heavy chain isotype: IgM-Id vaccine (N = 35), IgG-Id vaccine (N = 40), IgM control (N = 25), and IgG control (N = 15). The median for each group is indicated by a line. The p-values were calculated using two-sided Wilcoxon rank sum test of the days from randomization to first vaccine for the vaccine and the respective control group.

Fig A2.

Disease-free survival (DFS) according to treatment group for randomized patients who did not receive vaccination (N = 60). Kaplan-Meier survival curves for DFS for randomized patients who did not receive vaccination are shown according to treatment group: hybridoma-derived autologous tumor immunoglobulin idiotype (Id) vaccine (N = 42; yellow); control (N = 18; blue). The number of events, median DFS, and 95% confidence intervals for each group are also presented. (*) Five patients who remained in complete response/complete response unconfirmed did not receive vaccination because of study closure (n = 4) or noncompliance (n = 1).

Fig A3.

Disease-free survival (DFS) for the randomized patients that received IgM-Id vaccine vs all controls. Kaplan-Meier survival curves for DFS for the IgM-Id vaccinated patients (N = 35; yellow) and all patients in the control arm (N = 41; blue) are shown. The number of events, median DFS, and 95% confidence intervals for each group are also presented. Id, hybridoma-derived autologous tumor Ig idiotype; Ig, immunoglobulin; NA, not applicable.