Active idiotypic vaccination versus control immunotherapy for follicular lymphoma

Abstract

Purpose: Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF.

Patients and methods: Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n=287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy.

Results: At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n=195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy.

Conclusion: This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study.

Trial registration: ClinicalTrials.gov NCT00017290.

Fig 1.

CONSORT diagram. Of patients with tumor progression before random assignment (n = 189), 52 received < eight cycles of CVP (cyclophosphamide 1 g/m² on day 1, vincristine 1.4 mg/m² on day 1, and prednisone 100 mg per day on days 1 to 5) chemotherapy, 20 had progressive disease (PD) immediately after chemotherapy, and 117 achieved response but had PD between postchemotherapy assessment and random assignment. Of those randomly assigned, nine patients in MyVax arm were not immunized because of PD before planned first immunization; one patient in control immunotherapy arm erroneously received single injection of MyVax but was nonetheless considered among those in control immunotherapy arm in intent-to-treat analyses. GM-CSF, granulocyte macrophage colony-stimulating factor; Id, idiotype; Id-KLH, idiotype conjugated to keyhole limpet hemocyanin.

Fig 2.

Comparison of treatment arms for (A) primary end point (progression-free survival [PFS]) and (B) prespecified secondary end point (time to subsequent antilymphoma therapy [SALT]). Kaplan-Meier curves show patients randomly assigned to MyVax versus control immunotherapy, with corresponding end points measured from time of random assignment for intent-to-treat population (n = 287). (A) Steep drop in PFS at 6 months reflects timing of first radiographic response assessment. SALT was administered in blinded fashion. Neither end point was significantly different between study arms. Exp, expected; HR, hazard ratio; Obs, observed.

Fig 3.

Superior outcomes among patients mounting humoral immune response (IR) to idiotypic vaccination. Patients randomly assigned to receive MyVax were assessed for anti-idiotypic antibody responses and stratified into IR-positive (IR+) and IR-negative (IR−) designations based on prespecified criteria on serial serologic assessments, solely considering seroconversion before prespecified landmark for such evaluation. Kaplan-Meier curves show (A) progression-free survival and (B) subsequent antilymphoma therapy (SALT) –free survival of IR-positive versus IR-negative patients treated with MyVax. Exp, expected; HR, hazard ratio; Obs, observed.