Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma

Abstract

Purpose: To evaluate patient-specific immunotherapy with mitumprotimut-T (idiotype keyhole limpet hemocyanin [Id-KLH]) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in CD20(+) follicular lymphoma.

Patients and methods: Patients with treatment-naive or relapsed/refractory disease achieving a complete response (CR), partial response (PR), or stable disease (SD) with four weekly rituximab infusions were randomly assigned to mitumprotimut-T/GM-CSF or placebo/GM-CSF, with doses given monthly for six doses, every 2 months for six doses, and then every 3 months until disease progression (PD). Randomization was stratified by prior therapy (treatment-naive or relapsed/refractory) and response to rituximab (CR/PR or SD). The primary end point was time to progression (TTP) from randomization.

Results: A total of 349 patients were randomly assigned; median age was 54 years, 79% were treatment naive, and 86% had stage III/IV disease. Median TTP was 9.0 months for mitumprotimut-T/GM-CSF and 12.6 months for placebo/GM-CSF (hazard ratio [HR] = 1.384; P = .019). TTP was comparable between the two arms in treatment-naive patients (HR = 1.196; P = .258) and shorter with mitumprotimut-T/GM-CSF in relapsed/refractory disease (HR = 2.265; P = .004). After adjusting for Follicular Lymphoma International Prognostic Index (FLIPI) scores, the difference in TTP between the two arms was no longer significant. Overall objective response rate, rate of response improvement, and duration of response were comparable between the two arms. Toxicity was similar in the two arms; 76% of adverse events were mild or moderate, and 94% of patients had injection site reactions.

Conclusion: TTP was shorter with mitumprotimut-T/GM-CSF compared with placebo/GM-CSF. This difference was possibly due to the imbalance in FLIPI scores.

Fig 1.

Patient disposition. GM-CSF, granulocyte-macrophage colony-stimulating factor; Id-KLH, idiotype keyhole limpet hemocyanin; PD, progressive disease.

Fig 2.

Time to progression: intent-to-treat population. Mitumprotimut-T:placebo hazard ratio of 1.384 (95% CI, 1.053 to 1.819; P = .019). GM-CSF, granulocyte-macrophage colony-stimulating factor.

Fig 3.

Time to progression by prior therapy: (A) treatment-naive patients and (B) patients with relapsed/refractory disease. Mitumprotimut-T:placebo hazard ratio (HR) = 1.196;P = .258 for treatment-naive patients. Mitumprotimut-T:placebo HR = 2.265, P = .004 for patients with relapsed/refractory disease. GM-CSF, granulocyte-macrophage colony-stimulating factor.

Fig 4.

Time to progression by disease response to rituximab based on investigator's assessment: (A) objective response and (B) stable disease. Mitumprotimut-T:placebo hazard ratio (HR) = 1.352; P = .142 for patients having complete response/partial response. Mitumprotimut-T:placebo HR = 1.412; P = .068 for patients with stable disease. GM-CSF, granulocyte-macrophage colony-stimulating factor.