Follicular lymphoma (FL) is a common type of non-Hodgkin lymphoma which requires a complex treatment regimen involving both chemotherapy and immunotherapy. Oftentimes, adequate treatment leads to remission and helps patients enjoy a more fulfilling life. However, despite the best efforts of treaters, FL can recur or become resistant to therapy, which is known as relapsed/refractory FL. New therapies have recently emerged that have shaped the path towards personalised care for FL patients. In this article, we will explore FL, current, and novel treatment options.

Overview of Follicular Lymphoma

What is Lymphoma?

Lymphomas are a group of malignant tumours originating from lymphatic tissue. Lymphomas can develop both in lymph nodes (nodal lymphomas) and other lymphoid organs (extranodal lymphomas). Lymphatic tissue consists of lymphocytes, which are divided into three main types: B cells, T cells, and NK cells. These cells are produced in primary lymphoid organs, such as the thymus and bone marrow, and mature in secondary lymphoid organs, including the lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT).¹ Lymphomas arise from mutations in lymphocytes causing them to divide out of control, forming masses (tumours) of lymphoid tissue that can cause enlargement of lymph nodes, obstruct or compress vital organs such as the intestines and spinal cord, and even crowd out normal white blood cells, red blood cells and platelets, leading to impaired immunity, anaemia, and blood clotting disorders. Most lymphomas are derived from B cells and are called B cell lymphomas. On the other hand, T cell lymphomas are less frequent and are derived from T cells.¹

To better understand how lymphomas develop, we need to cut open a lymph node and see how and where this disease can occur. Lymph nodes are small bean-shaped clumps of lymphoid tissue that are connected to one another via lymphatic ducts. Lymph nodes contain multiple cavities, called sinuses, where lymph full of infectious microbes is carried into via the lymphatic ducts. Lymph nodes act as microbial filters, cleaning the lymph from infections. Each lymph node is connected to the lymphatic ducts via an outer capsule. Under the capsule, there are three layers of lymphoid tissue - the medulla, inner cortex and outer cortex. The medulla contains mature lymphocytes (both B and T cells) and other immune cells such as macrophages that actively fight off microbes. The inner and outer cortex are rich in naive T cells and naive B cells, respectively. When immune cells in the medulla encounter a pathogen, they take a sample and show it to the naive T cells in the inner cortex (basically calling for reinforcement), causing them to differentiate into mature T cells. The latter activate naive B cells from the outer cortex causing them to differentiate as well into so-called plasma cells that aid in the fight by producing antibodies against the invaders.²

As this article discusses FL, which is a type of B cell lymphoma, we will deep dive just a bit more into the anatomy of the outer cortex, where all B cell lymphomas originate from.

The outer cortex is composed of multiple clumps of B cells of varying maturity known as follicles. A follicle consists of three distinct zones:

• Germinal centre: the innermost part of a follicle where plasma cells are formed from naive B cells and migrate to the medulla
• Mantle zone: the middle part of a follicle that surrounds the germinal centre. It acts as a reservoir for naive B cells waiting to get activated
• Marginal zone: the outermost part of a follicle that surrounds the mantle zone and is adjacent to the inner cortex. The marginal zone is where naive B cells establish their first contact with mature T cells in the inner cortex. When a B cell in the marginal zone is activated, it differentiates into an intermediate cell type known as a centroblast that migrates to the germinal centre and starts dividing and maturing rapidly, producing centrocytes and subsequently plasma cells

B cell lymphomas can originate anywhere in the follicles - the germinal centre, the mantle zone and the marginal zone as well. Follicles are also found in other lymphoid organs, which is the reason why B cell lymphomas can form and spread inside the spleen, MALT, thymus, etc.²

Classification of Lymphomas

Lymphomas are generally classified into Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL). They can be further classified into smaller groups based on the aggressiveness of the tumour and tumour microenvironment, i.e. the cells (incl. Healthy cells) surrounding the tumour mass.

• HL is named after Thomas Hodgkin, who first described this disease in the 19th century.³ HL differs from NHL by the presence of Reed-Sternberg or RS cells which are malignant B cells with an abnormally large size and an oddly-shaped nucleus resembling the eyes of an owl. RS cells originate from the germinal centre of lymph node follicles and usually represent a very small population of the total cell mass in lymphoid tissue, while the majority of the tissue is composed of the tumour microenvironment. HL is divided into subgroups - the predominant classical HL, and the rare nodular lymphocyte-predominant hodgkin lymphoma (NLPHL) that is characterised by the presence of a second type of abnormal tumour cells known as “popcorn cells” due to the characteristic fragmented appearance of their nucleus⁴

Classical HL is further divided into many subtypes depending not on the malignant cell types, but rather the type of healthy immune cells surrounding the tumour.¹ While HL is pretty straightforward to remember (just look for the owl’s eyes), NHL represents a highly diverse group of lymphomas differing in aggressiveness, organ distribution, and prognosis. Some major NHL types include:

• Diffuse large B-cell lymphoma (DLBCL): the most commonly observed type of NHL. Tumour cells are diffusely spread out throughout multiple lymph nodes, the gastrointestinal tract, bone marrow, and/or central nervous system. The malignant cells have a distinctive large size compared to healthy B cells. This is an aggressive lymphoma with a poor prognosis¹
• Follicular lymphoma (FL): This is the second most common type of NHL. Unlike DLBCL, FL is located primarily inside lymph nodes and originates from follicles. This is an indolent lymphoma with slow disease progression¹
• Mantle cell lymphoma (MCL): MCL is named after the mantle zone where it originates from in lymph nodes¹
• Marginal zone lymphoma (MZL): named after the marginal zone where it originates from in lymph nodes⁵
• Burkitt lymphomas: last but not least, Burkitt lymphomas, first described by Dennis Burkitt, differ from other types of NHL in their specific connection to the Epstein Barr virus⁶

How is FL different from other Lymphomas?

Similar to HL, FL tumours originate in the germinal centres; however, unlike HL there are no RS cells present in lymph nodes. Large numbers of cells resembling normal centroblasts and centrocytes are observed in FL. Unlike the more common DLBCL, FL affects only lymph nodes and has a slower progression rate, but can with time transform into a more aggressive form like DLBCL.⁷

Approximately 90% of FL cases are associated with a specific chromosomal translocation between chromosomes 14 and 18. As a result, the BCL2 oncogene located normally on chromosome 18 moves to chromosome 14 in close proximity to a specific transcription promoter. Mutated cells start overproducing the Bcl-2 protein –an important inhibitor of the natural cell death process apoptosis– making the affected cell practically immortal.⁷ Tumour cells start proliferating inside the primary lymph node, then spread to adjacent lymph nodes, and in the aggressive disease phase - leak into the bloodstream and infest organs all over the body.

Importance of addressing relapsed/refractory FL

FL is generally treated with a combination of chemotherapy (cyclophosphamide, doxorubicin, vincristine), corticosteroids (prednisolone), and immunotherapy (rituximab) - a therapeutic regimen known as chemoimmunotherapy. Rituximab acts by attacking cells bearing the CD20 protein on their surfaces, which is present both on normal B cells, and almost all tumour cells in NHL, and rarely in HL. Rituximab in combination with chemotherapy and corticosteroids reduces the size of tumour cell colonies and shrinks enlarged lymphoid organs.⁸

In some cases, patients with FL can experience refractory or relapsed disease. These two terms should be differentiated:

• Refractory disease means that the treatment stops working after a period of time and the tumour starts growing again⁷
• Relapsed disease means that the tumour comes back after significant treatment progression has already been made⁷

Both refractory and relapsed FL cases are considered treatment failures, as patients go back to their previous disease state or may even worsen. One major reason why FL can become refractory or relapse is that the FL tumour itself is indolent, i.e. it grows slowly. Despite this being associated with a slower disease progression compared to aggressive tumours like DLBCL, this makes tumour cells less sensitive to chemotherapy which preferentially acts on rapidly dividing, more aggressive cells.⁹

Management of relapsed/refractory FL

CAR-T

CAR-T cell therapies use the patient’s own white blood cells to treat lymphomas. Healthy cells are first extracted, and then genetically modified in a lab in a way that makes them express a protein known as CAR that allows immune cells to more effectively find and kill tumour cells. Finally, CAR-modified cells are infused back into the same patient’s blood. Different CAR-T technologies target different tumour antigens.¹⁰ CAR-T that are used to treat relapsed/refractory FL incorporate a CAR protein targeting CD19 which like CD20 is expressed on the surface of healthy B cells and malignant NHL cells. Currently, there are several CAR-T therapies approved by the FDA and EC, and available to affected patients. The names of these therapeutics are a mouthful to remember, so scientists have come up with nicknames for each one of them. Examples of anti-CD19 CAR-T therapies indicated for relapsed/refractory FL are axi-cel, tisa-cel, and liso-cel.^11,12,13

BiTEs

BiTEs is an innovative class of antibody-based medications named bispecific T-cell engagers. Like classical monoclonal antibodies (rituximab being one such example), BiTEs bind to a specific target protein on tumour cells on one end but also bind to a second protein, usually expressed on a healthy immune cell. This way BiTEs link immune cells to tumour cells, allowing them to more effectively recognise and kill them.¹⁴ Examples of BiTEs used for relapsed/refractory FL are mosunetuzumab and epcoritamab. Both of them simultaneously target the CD20 protein expressed on malignant NHL cells, and the CD3 protein expressed on T cells.^15,16

Predictors of relapse

Despite the disease outcome being generally unpredictable, there are some factors that are associated with a greater risk for relapsed/refractory FL.

• Transformation from an indolent form to a more aggressive form like DLBCL - patients with transformed DLBCL experience the formation of new tumour masses and a sudden and rapid increase in the size of affected lymph nodes. Cells become larger and start spreading to other lymphoid organs. New symptoms or worsening of old symptoms may develop, like a persistent fever, night sweats, and unintentional weight loss¹⁷
• Mutations in specific genes are associated with a higher risk of relapsed/refractory FL. Examples include MYD88, STAT6, and CREBBP¹⁸
• Early relapse - this is when FL progresses within 2 years of immunochemotherapy initiation or within 1 year of rituximab monotherapy initiation. Early relapse is associated with a worse overall survival for FL patients⁷
• High FLIPI score - this is an abbreviation for The Follicular Lymphoma International Prognostic Index. This is a tool used to predict the prognosis in patients with FL. A higher FLIPI score at diagnosis is associated with a higher risk of relapsed/refractory FL. FLIPI includes factors such as the patient’s age, number and distribution of affected lymph nodes, haemoglobin levels, and LDH levels¹⁹

Summary

The management of relapsed/refractory FL includes a thorough assessment of each patient’s unique disease profile and choosing the most effective treatment. Novel FL therapeutic options have emerged throughout the last few years that have helped shape a brighter future for patients.