Prospects in the management of patients with follicular lymphoma beyond first-line therapy

Abstract

The management of patients with relapsed or refractory follicular lymphoma has evolved markedly in the last decade, with the availability of new classes of agents (phosphoinositide 3-kinase inhibitors, immunomodulators, epigenetic therapies, and chimeric antigen receptor T cells) supplementing the multiple approaches already available (cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants). The diversity of clinical scenarios, the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies preclude firm recommendations and require personalized decisions. Patients with early progression require specific attention given the risk of histological transformation and their lower response to standard therapies. In sequencing therapies, one must consider prior treatment regimens and the potential need for future lines of therapy. Careful evaluation of risks and expected benefits of available options, which vary depending on location and socioeconomics, should be undertaken, and should incorporate the patient's goals. Preserving quality of life for these patients is essential, 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.

Figure 1.

Mechanisms of action and opportunities for synergy in follicular lymphoma-directed therapies. From top left, clockwise: Autologous chimeric antigen receptor T cells are engineered 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 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 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 expressing the target antigen, are internalized, and deliver their cytotoxic payload directly in the cytoplasm. CD47 on FL interacts with SIRPα on macrophages to inhibit phagocytosis of cancer cells. Anti-CD47 antibodies block this checkpoint interaction, promoting macrophage phagocytosis. CAR: chimeric antibody receptor; TCR: T-cell receptor; IgG: immunoglobulin G; MHC: major histocompatibility complex; BCR: B-cell receptor; Ag: antigen; PI3K: phosphoinositide 3-kinase; TILs: tumor-inflitrating lymphocytes; NK: natural killer.

Figure 2.

Epigenetic dynamics in follicular lymphoma. Frequent epigenetic mutations in follicular lymphoma result in repression of mature B-cell differentiation factors and cell regulators, preventing terminal differentiation and exit from the cell cycle. This allows a germinal center phenotype, genomic instability, and cellular proliferation to persist. (A) Activating mutations in EZH2 result in aberrant trimethylation of lysine 27 in histone 3 (H3K27me3), resulting in transcriptional silencing and lymphomagenesis. Tazemetostat inhibits EZH2, restoring normal H3K27 methylation. (B) Loss-of-function mutations in the histone acetyltransferases CREBBP and EP300 result in decreased acetylation of histones H3K27 and H3K18, shifting the balance toward histone deacetylation by HDAC3. Histone deacetylase inhibitors prevent this deacetylation. (C) KMT2D is a histone methyltransferase and is frequently inactivated in follicular lymphoma, favoring demethylation of H3K4 and repression of key differentiation genes. Inhibitors of the demethylase KDM5 restore normal H3K4 methylation and gene expression in KMT2D-mutant lymphoma. HDAC: histone deacetylase.

Figure 3.

Schema for treatment choice at the time of first disease progression. After ruling out histological transformation, the choice of agent depends on prior therapy, the timing of relapse, tumor burden, and patients’ ability to tolerate therapy. R: rituximab; O: obinutuzumab; CHOP: cyclophosphamide, adriamycin, vincristine, prednisone; CVP: cyclophosphamide, vincristine, prednisone: ASCT: autologous stem cell transplantation.

Figure 4.

Schema for treatment choice in third-line and subsequent settings. Given the paucity of randomized data and large number of effective therapies in this setting, treatment is highly personalized, dependent on disease characteristics, prior therapies, and patients’ ability to tolerate treatment. Clinical trials should always be strongly considered. ASCT: autologous stem cell transplantation; HCT: hematopoietic cell transplantation; R2: rituximab and lenalidomide; PI3K: phosphoinositide 3-kinase; mut: mutated; WT: wild-type.