Follicular Lymphoma Therapy Based on Biological Insights and Novel Concepts

The majority of patients with follicular lymphoma experience a protracted course with survival estimates measured in decades. However, there are several critical unmet needs, including pre-emptive identification of high-risk patients, management of early relapse, and treatment of patients with multiply relapsed or rituximab-refractory disease. While exact numbers are not known, approximately 15-20% of patients will have early relapse and the bulk of patients will become rituximab-refractory with time; since there are 30,000 newly diagnosed patients with follicular lymphoma annually in The United States, this constitutes a substantial cancer and societal burden. Unfortunately, the overall possibility for widespread cure remains elusive. Clinical prognostic tools including the FLIPI and FLIPI-2 are difficult to apply at an individual level, and, to date, there are no prospectively validated biologic tools capable of identifying the highest risk groups. The M7-FLIPI, which integrates seven gene mutations (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, CARD11) with performance status and the FLIPI, is prognostic in patients receiving chemoimmunotherapy, and merits further study. There are currently no pathobiologic predictors of outcome in patients treated with monoclonal antibodies or non-cytotoxic therapies. While prognostication in treatment-naïve patients remains elusive, there are now several time-to-event based observations following initial therapy that define a high-risk subset of patients with inferior survival; these include CR30 and EFS24 which will be further described. As discussed by the previous speakers, a provocative emerging theme is that many somatic mutations and epigenetic and genetic changes occur relatively early in the evolution of the disease and could potentially shape the subsequent clinical course. The possibility that early progression (as defined by EFS24, for example) is directly related to these events affords the exciting prospect of identifying high-risk patients before they receive standard treatment; furthermore, if confirmed, these aberrations are ripe targets for new agents. Moving from prognostication to prediction of response to individual agents or regimens is badly needed in this disease, particularly since there are a plethora of new drugs and new targets being identified. An important and poorly understood component of FL biology that is likely to impact clinical behavior is the tumor microenvironment. The non-malignant milieu of follicular lymphoma is comprised of several cell types, and their composition and interaction with the malignant compartment probably evolves with the disease course. The relationship between the microenvironment and the malignant cell is also a valid target, with both immunomodulatory agents and immunotherapy drugs actively being tested. Overall, the incorporation of biologic insights into treatment of follicular lymphoma will drive the next generation of clinical investigations and move to limit the impact of unmet needs in this disease.