Follicular lymphoma (FL) is typically an indolent disease, with many newly diagnosed patients followed without active therapy and a median overall survival likely well over 2 decades with modern therapies.1 With a median age at diagnosis of >60 years, the majority of patients can receive intermittent courses of therapy and have lifespans that rival their prediagnosis life expectancy. However, the high efficacy of recently approved therapies in relapsed/refractory (R/R) disease (eg, chimeric antigen receptor [CAR] T cells and bispecific antibodies) and the increasingly constrained regulatory landscape have dampened enthusiasm for developing new drugs in FL. On the surface, it is tempting to think of FL as a solved problem or at least as close enough to solved, making it not worth the investment to pursue much further.
Nonetheless, below this surface lie many highly challenging questions: (1) Given a long lag time to clinical diagnosis and identified possible precursor states, such as t(14;18)2 or CREBBP mutation,3 can we intercept FL before it even becomes malignant? (2) In light of a large and expanding range of possible frontline therapies having substantially different efficacy and toxicity, who are the patients with high-risk FL at diagnosis who could benefit from earlier treatment or from more aggressive treatments, and who are those best treated with low-intensity or no therapy? (3) When is the best time and what is the best population for more expensive or toxic therapies such as CAR T cells? (4) How can we rigorously and accurately evaluate the toxicities of our therapies, especially using the patients’ own experience, and can that ever become a regulatory end point? (5) What does “cure” mean in FL and is it even a definable and desirable goal? (6) Finally, how can we prevent and appropriately treat histologic transformation (HT), which eventually affects a sizable minority of patients with FL and leads to outcomes that are invariably worse than untransformed FL and frequently fatal?4
This review series is dedicated to some of those questions.
In “Biology as vulnerability in follicular lymphoma: genetics, epigenetics, and immunogenetics,” Ferran Araujo-Ayala and Wendy Béguelin describe recent advances in the biological investigation of FL. This understanding will be fundamental to efforts to successfully intercept or cure FL, which will require identifying the evolutionary pathway to FL as well as the therapeutic vulnerabilities of both precursor cells and posttreatment residual disease.
In “Frontline treatment of follicular lymphoma: what will it take to change current practice?,” Emmanuel Bachy and Kim Linton review the challenges of clinical trials for frontline treatment before describing and proposing strategies to conduct such trials in the modern era.
In “Treatment of relapsed and refractory follicular lymphoma: which treatment for which patient for which line of therapy?,” Carla Casulo and Laurie H. Sehn suggest an approach for the personalized treatment of patients with R/R FL, using a range of currently available therapies.
In “The future of follicular lymphoma management: strategies on the horizon,” Erin Mulvey, Sarah C. Rutherford, and John P. Leonard peer into the near future of new assays and treatments that may reshape the treatment landscape in the next few years.
In “End points and outcomes in follicular lymphoma: what should we measure, how, and why?,” Mengyang Di, Matthew J. Maurer, and Christopher R. Flowers consider the unique challenge of FL research from the point of view of clinical trial design, which must account for the long duration of benefits of many therapies and the central importance of quality of life as an outcome in FL treatment.
Finally, in “An updated understanding of follicular lymphoma transformation,” Erin M. Parry and Jessica Okosun review the modern understanding of the biology of HT and the clinical approach to those patients, which remains perhaps one of the most challenging aspects of FL care.
In conclusion, we hope that these reviews not only provide our readers with a useful summary of the present state of scientific and clinical understanding of FL at all stages of the disease, but also convince our readers of the value of continued rigorous, thoughtful, biologically informed, and patient-centered research in a disease that is far from a solved problem and extremely likely to be just as far from an insoluble one.
Conflict-of-interest disclosure: P.A. received consultancy fees from Merck, Bristol Myers Squibb/Celgene, Genmab, Enterome, Genentech/Roche, ATB Therapeutics, Regeneron, and Pfizer; reports research funding from Kite; and institutional research funding from Merck, Bristol Myers Squibb/Celgene, Adaptive Biotechnologies, Genentech, IGM Biosciences, and AstraZeneca.
