It is conceivable that alterations in the B-cell receptor signaling pathway or in the metabolic regulatory pathway may affect the efficacy of agents targeting those pathways

It is conceivable that alterations in the B-cell receptor signaling pathway or in the metabolic regulatory pathway may affect the efficacy of agents targeting those pathways. and should incorporate the patients goals. Preserving quality of life for these patients is essential, Ac-LEHD-AFC given the likelihood of years to decades of survival and the possibility of multiple lines of therapy. The current landscape is likely to continue evolving rapidly with other effective agents emerging (notably bispecific antibodies and other targeted therapies), and multiple combinations being evaluated. It is hoped that new treatments under development will achieve longer progression-free intervals and minimize toxicity. A better understanding of disease biology and the mechanisms of these different agents should provide further insights to select the optimal therapy at each stage of disease. Introduction While the median overall survival (OS) of patients with follicular lymphoma (FL) was under 10 years over two decades ago, the vast majority (~80%) of patients diagnosed today are likely to be alive 10 years after their initial diagnosis, and their expected median OS may exceed 20 years.1 This remarkable progress reflects the improved efficacy of first-line therapeutic interventions with the introduction of anti-CD20 antibodies, and our ability to deliver active therapies in subsequent lines for those patients experiencing disease progression. Several important challenges should be considered regarding the treatment Ac-LEHD-AFC of patients with disease progression after first-line therapy, who are still generally considered to have an incurable disease after the lymphoma recurrence. The first challenge is the possibility of histological transformation C the leading cause of death of patients with FL.2 Transformation can occur any time during the disease course, although some data suggest an increased risk in the early years after diagnosis which decreases thereafter.2-4 This feared event should always be anticipated, and a new tumor biopsy performed whenever lymphoma progresses or does not respond to therapy. The use of positron emission tomography/computed tomography to guide the site of biopsy in the nodal area with the highest glucose uptake is recommended. The detailed management of transformed FL has been recently reviewed5 and is beyond the scope of this paper. The second consideration is the optimal sequencing of available therapies.6 While some clinical trials were conducted in specific populations of patients, such as those with disease refractory to rituximab or to rituximab and alkylating agents (double refractory), there are few randomized clinical trials to guide our choice of a given therapy at a precise time. This is in part due to the broad array of options available after diagnosis, with a variety of mechanisms of action (Figure 1), and to the heterogeneity of patients entering clinical trials evaluating new agents in the relapsed/refractory setting. However, not all available drugs or regimens have similar clinical efficacy – both in terms of response rate, and more importantly, response duration. A third key element is the patients quality of life, including short-term Ac-LEHD-AFC treatment-related side effects and convenience of therapeutic administration, as well as long-term and cumulative toxicities, which may result in cardiac, hematopoietic, infectious, or neurological comorbidities, or increase the risk of potentially fatal secondary malignancies.7 Attractive oral therapies have emerged, although they have their own toxicity profiles, and are often administered for indefinite periods, presenting unique challenges. Overall, these different elements should be discussed with every patient, with transparency regarding the benefits and risks of each strategy, keeping in mind our goals (prolongation of OS while preserving quality of life) as well as patients own priorities, which might differ according to their age and their personal history.8 Figure 1. Open in a separate window Mechanisms of action and opportunities for synergy in follicular lymphoma-directed therapies. From top left, clockwise: Autologous chimeric antigen receptor T cells are engineered Ac-LEHD-AFC to target the CD19 epitope on follicular lymphoma (FL) cells, with co-stimulatory domains activating T-cell anti-tumor responses. Bispecific antibodies bind both CD20 on the lymphoma cells and CD3 on the surface of cytotoxic T cells, activating anti-tumor cytotoxicity. Tazemetostat inhibits EZH2- mediated suppression of differentiation genes in FL cells, and inhibits suppression of MHC expression, allowing for greater immune recognition of lymphoma cells. PI3K inhibitors block key Plat molecular signal pathways for the growth and survival of lymphoma cells, and also inhibit T regulatory cell function, which may facilitate immune activation against FL cells. Lenalidomide functions via cereblon-mediated ubiquitination and degradation of transcriptional factors, which is directly cytotoxic Ac-LEHD-AFC to lymphoma cells, and potentiates the immune synapse, improving T-cell- and NK-cell-mediated recognition and killing of lymphoma cells. Lenalidomide is synergistic with monoclonal antibodies (rituximab and tafasitamab), which together promote antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity. Antibody-drug conjugates bind to the cell.