An analysis of genetic targets for guiding clinical management of follicular lymphoma

ABSTRACT

Introduction: Follicular lymphoma (FL) is one of the most common non‐Hodgkin lymphoma (NHL) types, where genomic studies have accumulated potentially useful information about frequently mutated genes and deregulated pathways, which has allowed to a better understanding of the molecular pathogenesis of this tumor and the complex interrelationship between the tumoral cells and the stroma.

Areas covered: The results of the molecular studies performed on Follicular Lymphoma have been here reviewed, summarizing the results of the clinical trials so far developed on this basis and discussing the reasons for the successes and failures. Searches were performed on June 1^st, 2020, in PubMed and ClinicalTrials.gov.

Expert opinion: Targeted therapy for follicular lymphoma has multiple opportunities including the use of epigenetic drugs, PI3K inhibitors, modifiers of the immune stroma and others.

Data currently known on FL pathogenesis suggest that combining these treatments with immunotherapy should be explored in clinical trials, mainly for patients with clinical progression or adverse prognostic markers. Association of targeted trials with dynamic molecular studies of the tumor and serum samples is advised. Chemotherapy-free approaches should also be explored as first-line therapy for FL patients.

KEYWORDS:

• BCL2 inhibitors
• BCL6 inhibitors
• epigenetic therapy
• follicular lymphoma
• targeted therapy

Article highlights box

• Follicular lymphoma genesis and progression is driven by a combination between chromosomal translocations leading to a deregulated Bcl2 protein expression with mutations in chromatin modifiers, always in the context of a close relationship with follicular dendritic cells and TFH lymphocytes.

• Clinical studies have shown a distinct clinical benefit for patients with EZH2 mutations treated with EZH2 inhibitors. The treatment using other epigenetic drugs lacks specific molecular markers predicting response.

• Different PI3K inhibitors have been approved for the treatment of multiple-relapsed FL and shown that they can induce durable remissions. At least some of the clinical benefits of the use of PI3K inhibitors depend on their action on the TFH cells that support tumor growth.

• Taken this complexity in consideration, it seems unlikely that therapy focused to individual targets may reach the level of clinical benefit enough for replacing the currently used chemo-immunotherapy.

• Progress in the introduction of targeted therapy for Follicular Lymphoma requires an effort for the integration of clinical and molecular studies. Samples of patients enrolled in clinical trials, using these drug combinations, should be analyzed for mutational and gene expression signatures that may allow performing a dynamic correlation with either clinical response or progression.

Declaration of interest

MA Piris declares to have received research funding, advisory board and/or lecture fees from the companies: Millenium/Takeda, Celgene, Gilead, Jansen, Nanostring, Kyowa Kirin, EUSA and Kura. RCordoba declares to have received research funding, advisory board and/or lecture fees from the companies: Roche, Janssen, Abbvie, Celgene, BMS, Gilead, Takeda, Roche, Janssen, Celgene, Gilead, Kite, Kyowa-Kirin, Pfizer. DMorillo declares to have received research funding, advisory board and/or lecture fees from the companies: AbbVie, Amgen, Janssen-Cilag, Celgene, Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.