Follicular Lymphoma: a Focus on Current and Emerging Therapies

Abstract

Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.

FIGURE 1.. Genomic Hallmarks of FL

BCL2 rearrangement with t(14;18) and mutations in epigenetic regulators are key molecular features in FL. BCL2 rearrangement is necessary, but not sufficient for lymphomagenesis. Founder mutations in FL often involve chromatin modifying proteins such as histone methyltransferases and acetyltransferases. Abnormal DNA methylation programming cooperates with somatic mutations to drive lymphomagenesis, while the acquisition of additional mutations contribute to disease progression and the risk of transformation to diffuse large B-cell lymphoma. FL, follicular lymphoma.

FIGURE 2.. A Proposed Treatment Approach for Advanced-Stage FL

Unless there is an indication for treatment based on GELF or NCCN criteria, patients may be observed. When treatment is indicated, clinical trials should always be considered. Standard therapy includes chemoimmunotherapy with BR, which is the most common, and has improved PFS with less toxicity compared to R-CHOP. Lenalidomide with rituximab is an excellent first-line or second-line option, but this combination requires longer treatment duration than R-CHOP or BR. Rituximab monotherapy is also effective in the frontline and relapsed/refractory setting, especially with low disease burden. Patients with early relapse within 24 months (POD24) are a high-risk subset. Salvage chemoimmunotherapy includes bendamustine or CHOP with an anti-CD20 agent, followed by auto-SCT. Targeted agents such as PI3K inhibitors and tazemetostat may also be used. The optimal sequence of subsequent-line agents is unknown, and there are multiple options that can be used prior to CAR T-cell therapy, which is approved after 2 or more lines of therapy. auto-SCT, autologous stem cell transplant; BEAM, BCNU (carmustine), etoposide, cytarabine, and melphalan; BR, bendamustine and rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, complete remission; FL, follicular lymphoma; R-CHOP, rituximab with CHOP.

FIGURE 3.. Approved and Investigational Targeted Agents in FL

Several FDA-approved targeted therapies(*) exist, as well as many other investigational agents that are changing the treatment landscape of FL. Given the significant genetic heterogeneity and complex interactions with the tumor microenvironment, the cure for FL will likely require a biomarker-based subset-specific approach. Ab, antibody; BCR, B-cell receptor; BTK, Bruton tyrosine kinase; FL, follicular lymphoma.