Treatments for Follicular Lymphoma Continue to Evolve

The frequently asymptomatic and slow-growing nature of follicular lymphoma presents a significant obstacle to clinical identification in the early stages, and thereby obscures the mechanisms that cause disease initiation and progression. Despite the challenges, a growing understanding of how follicular lymphoma develops is resulting in potential new drugs and approaches to treatment.

Treatment options for follicular lymphoma, beyond conventional radiation and chemotherapy, include immunomodulatory agents such as vaccines, monoclonal antibodies and kinase inhibitors. In July 2014, the Food and Drug Administration (FDA) approved Zydelig (idelalisib) in combination with Rituxan (rituximab) for patients with high-risk relapsed or refractory chronic lymphocytic leukemia (CLL) and as a single-agent for follicular lymphoma and small lymphocytic lymphoma (SLL).

In follicular lymphoma, the overall response rate with Zydelig was 54 percent. For patients with SLL, the response rate was 61 percent. For the entire population, the median duration of response was 12.5 months. Median progression-free survival was 11 months and survival was 20.3 months. It's believed that B cell receptor (BCR) signaling is important for the survival of these malignant cells. This approach is targeted by Zydelig through inhibition of PI3K, an enzyme involved in a cancer cell growth pathway that has been the focus of new cancer drugs. Additionally, the targeted drug Imbruvica (ibrutinib) also affects BCR signaling.

The combination of Rituxan and chemotherapy, a regimen called R-CHOP that is standard treatment for this group, with the addition of Imbruvica resulted in a response rate of 94 percent in patients with CD20-positive non-Hodgkin lymphoma. A phase 3 clinical trial to assess the combination in newly diagnosed patients with a type of diffuse large B-cell lymphoma is ongoing and accepting new participants (http://clinicaltrials.gov/show/NCT01855750).

These approved and investigational agents have improved outcomes for patients with follicular lymphoma; however a growing understanding of the origins and progression of the disease might offer further insights for future clinical development.

A phase 1 study exploring the BCL2 inhibitor ABT-199, which was presented at the annual meeting of the American Society for Clinical Oncology this past summer, found promising efficacy. For patients with follicular lymphoma treated with ABT-199, the response rate was 28 percent. Dose escalation and further study of this treatment in patients with follicular lymphoma is ongoing.

Studies have demonstrated that malignant B cells achieve functional immune suppression through a variety of mechanisms. By expressing programmed death-ligand 1 (PD-L1) on their surface, follicular lymphoma cells can activate PD-1 receptors on effector T cells, thereby suppressing their function to attack cancer cells. To explore this "checkpoint inhibition" further, researchers looked at the PD-1 inhibitor pidilizumab in combination with Rituxan in patients with follicular lymphoma in a phase 2 clinical trial. In the study, the response rate was 66 percent, with a complete response in 52 percent of patients. Moreover, no autoimmune or treatment-related adverse events of grade 3/4 were reported. Clinical trials are currently assessing other PD-1 inhibitors as treatments for patients with follicular lymphoma and other B-cell lymphomas, including a phase 2 study assessing nivolumab in patients following progression on a previous therapy (http://clinicaltrials.gov/show/NCT02038946).