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A growing understanding of follicular lymphoma pathogenesis is resulting in new drug candidates and approaches to clinical treatment.
The slow growing and frequently asymptomatic 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 follicular lymphoma pathogenesis is resulting in new drug candidates and approaches to clinical treatment.
Therapeutic options available for the treatment of follicular lymphoma, beyond conventional radiation and chemotherapy, include immunomodulatory agents such as idiotypic vaccines, monoclonal antibodies, and kinase inhibitors. In July 2014, the FDA approved idelalisib (Zydelig) in combination with rituximab (Rituxan) 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 (ORR) with idelalisib was 54% (95% CI, 0.42-0.66). For patients with SLL, the ORR was 61% (95% CI, 0.41-0.79). For the entire population, the median time to response was 1.9 months, with a median duration of response of 12.5 months. The median progression-free survival (PFS) was 11 months and the median OS was 20.3 months.
Deleterious mutations of the B cell receptor (BCR) are selected against in patients with follicular lymphoma, suggesting that intact BCR signaling is important for the survival of the malignant cells. This approach is targeted by idelalisib through inhibition of PI3K. Additionally, the BTK inhibitor ibrutinib also affects BCR signaling.
The combination of R-CHOP and ibrutinib resulted in an ORR of 94% in patients with CD20-positive non-Hodgkin lymphoma. The established dose for ibrutinib in this setting is 560 mg. A phase III clinical trial to assess the combination in newly diagnosed patients with non-germinal center B-cell-like diffuse large B-cell lymphoma is ongoing (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.
In a paper in Nature Genetics published online in December 2013, researchers sought to catalogue the genetic changes that occurred in patients’ lymphoma as it progressed from an indolent to an aggressive stage using whole genome and whole-exome sequencing.
The authors identified a large degree of epigenetic pathway involvement, which they termed epigenetic addiction. Recurrent alterations were found in B-cell development genes, the JAK-STAT pathway, and nuclear factor kappa B (NF-κB) signaling. Longitudinal analyses identified early driver mutations in CREBBP, EZH2, and MLL2. However, no single mutation or aberration was identified in disease progression.
In other studies, the most frequent molecular abnormality observed in follicular lymphoma cells (85%) is a translocation of chromosomes 14 and 18, t(14;18), which results in the activation of the B-cell CLL/lymphoma 2 (BCL-2) gene.
A phase I study exploring the BCL-2 inhibitor ABT-199 was presented at the 2014 ASCO Annual Meeting. For patients with follicular lymphoma treated with doses ≥600 mg of ABT-199, the ORR was 28%. Dose escalation and further study of this treatment in patients with follicular lymphoma is ongoing.
B cells from patients with follicular lymphoma, like many other malignant cell types, demonstrate a rich variety of somatic mutations accumulated over time in addition to t(14;18). There are therefore numerous additional gene mutations with potential relevance to the development and progression of follicular lymphoma.
A large number of genetic abnormalities contributing to the pathogenesis of follicular lymphoma include genes that affect the epigenetic status of B cells. Gain-of-function mutations affecting the histone methyltransferases EZH2 and MLL2 are observed in 27% and 89% of patients, respectively. These histone-modifying genes affect the epigenetic regulation of other genes, and it has been shown that EZH2 protein contributes to the silencing of antiproliferative genes in healthy B cells.
Histone deacetylases inhibitors have been explored in follicular lymphoma, including the agent mocetinostat. The ORR with this therapy in patients with follicular lymphoma was 11%, with 1 complete response. The disease control rate was 61%. A phase II study exploring the HDAC inhibitor panobinostat is currently enrolling patients with non-Hodgkin lymphoma (NCT01261247).
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. CD70 expression by the malignant cells can signal through CD27 on effector T cells to induce FoxP3 expression. This induces their conversion to regulatory T (Treg) cells11 and suppresses the immune response.
To explore checkpoint inhibition further, researchers looked at the PD-1 inhibitor pidilizumab in combination with rituximab in patients with follicular lymphoma in a phase II open-label clinical trial. In the study, the ORR was 66%, with a complete response in 52% of patients. Moreover, no autoimmune or treatment related adverse events of grade 3/4 were noted.
Clinical trials are currently assessing PD-1 inhibitors as treatments for patients with follicular lymphoma and other B-cell lymphomas. A phase II study is assessing nivolumab in patients with follicular lymphoma following progression on CD20 (NCT02038946).