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Immune Modulation in Follicular Lymphoma
Is Immune Modulation the Future of Therapy in Follicular Lymphoma?

Released: February 11, 2015

Expiration: February 10, 2016

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In the pre-rituximab era, the overall survival for patients with indolent non-Hodgkin’s lymphoma was 8-10 years, a result that had not significantly changed with the evolution of therapy from single-agent chlorambucil to multiagent chemotherapy. Treatment with a 4-week course of the unmodified, chimeric, monoclonal antibody rituximab demonstrated an overall response rate of approximately 50% in patients with relapsed and refractory follicular lymphoma. Subsequent studies demonstrated a response rate of approximately 70% in untreated patients with a median progression-free survival of approximately 18 months, the latter of which could be extended to 36 months with 4 additional doses on an extended schedule. A meta-analysis of rituximab in combination with conventional regimens such as cyclophosphamide, vincristine, and prednisone (CVP) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) demonstrated that addition of rituximab to first-line therapy resulted in an overall survival advantage.

Lenalidomide and Rituximab
The pathology of follicular lymphoma demonstrates extensive infiltration by T cells. However, the infiltrating T cells are impaired in their ability to form immunologic synapses with the follicular lymphoma cells, which is thought to be a mechanism of active immunosuppression in this disease. The immune synapse can be restored by treatment with mixtures of T cells and follicular lymphoma cells in the presence of lenalidomide. Lenalidomide is a potent immunomodulatory drug with multiple mechanisms of action, all centrally related to the degradation of the critical transcription factors IKZF1 and IKZF3 in both B cells and T cells. Lenalidomide has significant single agent activity in relapsed/refractory follicular lymphoma. However, the quality of response and the response duration are improved by the addition of rituximab. This finding prompted the study of combination rituximab and lenalidomide in untreated patients. The overall and complete response rates in patients with follicular lymphoma were extremely high, 72% and 87%, in 2 studies. These highly favorable results prompted the international randomized phase III RELEVANCE study, which compares conventional immunochemotherapy with combination rituximab and lenalidomide. This study has completed accrual, but analysis is several years on the horizon given the expected favorable outcomes for both arms of the study.

Checkpoint Blockade
Another approach to modulating the immune response and tumors is the use of checkpoint blockade with antibodies directed at PD-1 and PD-L1. Two anti–PD-1 monoclonal antibodies, nivolumab and pembrolizumab, have been approved for the treatment of metastatic melanoma based on their significant clinical activity. At the 2014 annual meeting of the American Society of Hematology (ASH), high response rates in phase I results of nivolumab and pembrolizumab as single agents for the treatment of relapsed/refractory Hodgkin’s lymphoma stole the headlines. Nivolumab also demonstrated single-agent activity in diffuse large B-cell lymphoma and follicular lymphoma, achieving an overall response rate of 40% with a 10% complete response rate in patients with follicular lymphoma. All responders to nivolumab demonstrated an incremental response improvement over time and several patients experienced disease stability for > 6 months. Although highly preliminary, these results demonstrate another avenue for immune modulation in follicular lymphoma. One can speculate that the impact of lenalidomide on enhancement of antibody-dependent drug-mediated cytotoxicity and direct immune synapse formation between T cells and follicular lymphoma cells could be significantly augmented by combination with checkpoint inhibitors. These combinations have the potential for significant immune modulation and therefore have significant adverse events. Further studies will be needed to determine the safety and efficacy of the combination of immunomodulatory drugs with checkpoint inhibitors.

Impact on the Natural History of Follicular Lymphoma
Immunotherapy with rituximab has dramatically altered the natural history of follicular lymphoma. The expected median survival of patients with follicular lymphoma is now approximately 16 years. A recent analysis presented at ASH 2014 suggests that overall survival of patients diagnosed with follicular lymphoma is similar to age-matched controls. Furthermore, patients presenting with significant tumor bulk and symptoms requiring therapy have overall survival similar to age-matched controls if they remain event free at 12 months. Another analysis from the National Lymphocare study demonstrated a poor-risk group accounting for approximately 20% of patients who had progression within 24 months of the completion of R-CHOP chemotherapy but with excellent outcomes for the remaining 80% of patients. It remains to be seen if the intriguing results with immune modulation are able to address the adverse prognosis of the 20% of patients with poor-risk disease. Nonetheless, immunomodulatory therapy holds promise for high-quality durable remissions in patients with follicular lymphoma without the need for cytotoxic chemotherapy.

In Clinical Practice
While participating in the phase III RELEVANCE trial, I was very impressed by the rapid responses that I observed in previously untreated patients who received rituximab and lenalidomide. However, as we await published results for this combination, I continue to use immunochemotherapy as frontline therapy for patients with follicular lymphoma. In many cases, I use bendamustine and rituximab. If I am concerned about concurrent transformation based on very hot lesions on a pretreatment PET, I select R-CHOP. I currently reserve rituximab and lenalidomide for the treatment of patients with relapsed disease.

Your Thoughts?
Do you see potential for incorporating immunotherapies into the treatment of patients with follicular lymphoma? I invite readers to post their thoughts in the comments section below.

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Which immunotherapeutic strategy would you most confidently incorporate into your treatment approach for patients with follicular lymphoma?
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