Follicular lymphoma: are we ready for a risk-adapted approach?

Abstract

Follicular lymphoma is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. The natural history of FL appears to have been favorably impacted by the introduction of rituximab after randomized clinical trials demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Yet, the disease is biologically and clinically heterogeneous with wide variations in outcomes for individual patients. The ability to accurately risk-stratify patients and then tailor therapy to the individual is an area of ongoing research. Historically, tumor grade, tumor burden, and the FL international prognostic index (version 1 and version 2) have been used to distinguish low-risk from high-risk patients. Biologic factors such as mutations in key genes can identify patients at high risk for poor outcomes to first-line therapy (mutational status of 7 genes [EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, and CARD11] with Follicular Lymphoma International Prognostic Index). More recently, the quality of the response to initial therapy, as measured by either PET imaging or by remission duration, has been show to identify individuals at high risk. However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation.

Figure 1.

(A) Individual coefficient of risk for high-risk FLIPI; ECOG performance status; and mutations in EP300, FOX01, CREBBP, CARD11, MEF2B, ARID1A, and EZH2. Mutations in MEF2B, ARID1A, and EZH2 are all “favorable” findings. (B) Mutational frequency of the various genes in the training set and in the validation cohort. (C) Failure-free survival by FLIPI risk and by m7-FLIPI risk in the training cohort. (D) Failure-free survival by FLIPI risk and by m7-FLIPI risk in the validation cohort.

Figure 2.

The schema of S1608 is depicted. Patients with POD24 after bendamustine-rituximab induction therapy will be randomized to either the phosphatidylinositol 3-kinase inhibitor TG1202 plus obinutuzumab (Arm A), lenalidomide-obinutuzumab (Arm B), or R-CHOP (Arm C).

Figure 3.

The accuracy of 3 pretreatment risk models to predict POD24 status is represented in bar graphs. (A) FLIPI. (B) m7-FLIPI. (C) POD24 prognostic index (POD24-PI).