Unmet needs in the first-line treatment of follicular lymphoma

Abstract

For the majority of patients with newly diagnosed follicular lymphoma (FL), current treatments, while not curative, allow for long remission durations. However, several important needs remain unaddressed. Studies have consistently shown that ∼20% of patients with FL experience disease progression within 2 years of first-line treatment, and consequently have a 50% risk of death in 5 years. Better characterization of this group of patients at diagnosis may provide insight into those in need of alternate or intensive therapies, facilitate a precision approach to inform clinical trials, and allow for improved patient counseling. Prognostic methods to date have employed clinical parameters, genomic methods, and a wide assortment of biological and biochemical markers, but none so far has been able to adequately identify this high-risk population. Advances in the first-line treatment of FL with chemoimmunotherapy have led to a median progression-free survival (PFS) of approximately 7 years; creating a challenge in the development of clinical trials where PFS is a primary end point. A surrogate end point that accurately predicts PFS would allow for new treatments to reach patients with FL sooner, or lessen toxicity, time, and expense to those patients requiring little to no therapy. Quality of response to treatment may predict PFS and overall survival in FL; as such complete response rates, either alone or in conjunction with PET imaging or minimal residual disease negativity, are being studied as surrogates, with complete response at 30 months after induction providing the strongest surrogacy evidence to date. A better understanding of how to optimize quality of life in the context of this chronic illness is another important focus deserving of further study. Ongoing efforts to address these important unmet needs are herein discussed.

Keywords: follicular lymphoma; indolent lymphoma; progression-free survival; surrogate end point.

Figure 1.

Overall survival from risk-defining event after diagnosis in patients treated with R-CHOP in (A) the National LymphoCare Study Group, and (B) a validation set of patients with first-line FL treated with R-CHOP. Early progression of disease (POD) was defined as progression within 24 months of diagnosis. Reprinted with permission. ©2015 American Society of Clinical Oncology. All rights reserved. Casulo, C et al: J Clin Oncol 33(23), 2015: 2516–2522 [9].

Figure 2.

Reclassification of risk category by m7-FLIPI. (A) Migration plot showing reclassification of patients by m7-FLIPI in both cohorts. (B) m7-FLIPI score for all high-risk FLIPI patients from the GLSG2000 cohort, along with the ECOG PS and molecular predictors. Boxes indicate high-risk FLIPI, an ECOG performance status of more than 1, or a mutation in the indicated gene, and the color code indicates the coefficient of the individual m7-FLIPI predictor. (C) Relative frequencies of molecular predictors by m7-FLIPI category in high-risk FLIPI patients from the BCCA and GLSG2000 cohorts are shown. Reprinted from The Lancet Oncology, 16/9, Pastore et al., Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry, 1111–1122, ©2015, with permission from Elsevier [14].