Targeted Therapy in Follicular Lymphoma: Towards a Chemotherapy-Free Approach

SIMPLE SUMMARY: Follicular lymphoma (FL)—a common, indolent, and usually non-curable B-cell non-Hodgkin lymphoma—is frequently treated with cytotoxic chemotherapy with anti-CD20 therapy. The downsides of this approach include cumulative toxicities that limit the total duration of treatment and may be prohibitive in unfit patients, as well as chemotherapy-refractory disease that develops over time. Targeted therapies in FL show promise by inhibiting key molecular pathways responsible for cancer proliferation and survival, reducing toxicity, and potentially circumventing chemotherapy refractoriness. In this review, we investigate, summarize, and critique the sentinel studies underpinning the use of targeted therapies currently available for FL in both the front-line and relapsed–refractory setting. We also detail the role of molecular markers in FL as well as future directions in targeted treatment for follicular lymphoma. ABSTRACT: Background: The treatment of follicular lymphoma (FL) has previously centered on chemoimmunotherapy, which can be disadvantageous due to patient intolerance, cumulative toxicities, and disease refractoriness. Targeted therapies can produce deep responses and improve progression-free and overall survival with more tolerable adverse event profiles. Methods: We summarize the current literature and key clinical trials regarding targeted therapies in follicular lymphoma both in the front-line and in the relapsed-refractory setting. Results: Targeted therapies studied in FL include immune modulators, anti-CD20 antibodies, Bruton’s tyrosine kinase (BTK) inhibitors, enhancers of zeste homolog 2 (EZH2) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL-2) inhibitors. Chimeric antigen receptor (CAR-T) therapy and bispecific T-cell engager (BiTE) therapies also show promise in monotherapy and in combination with targeted therapies. These therapies exhibit high overall response rates and substantial progression-free survival and overall survival, even in high-risk patients or patients previously refractory to chemotherapy or rituximab. Adverse events vary substantially but are generally manageable and compare favorably to the cumulative toxicities of chemotherapy. Conclusion: Targeted therapies represent a paradigm shift in the treatment of FL. Further studies are needed to directly compare these targeted therapies and their combinations, as well as to investigate biomarkers predictive of response.