Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020.¹² Lymphoma is one of the common cancers that involves the cells of the lymphatic system, namely, the B-cells and the T-cells. Lymphomas can further be classified into different subtypes based on the type of immune cells involved. Among them, one prominent type of lymphoma is the Marginal Zone Lymphoma (MZL).
MZL is a type of lymphoma that involves B cells and typically develops in the lymphoid tissue. It usually occurs in the lymph nodes but may affect organs like the stomach, small intestine, salivary glands, thyroid, eyes, and lungs. There are many treatment regimens available for better management of MZL.
This article discusses in detail the genetic and molecular basis of MZL along with the therapy methods available for its treatment. It focuses on targeted therapy for MZL, its benefits and the approved drugs.

Introduction

Overview of lymphoma

Lymphoma is considered a type of cancer that originates in the lymphatic system due to the excessive proliferation of those cells involved in fighting infections.. It primarily involves the lymphoid organs like lymph nodes, spleen, thymus, and bone marrow. Lymphomas can be classified into: Hodgkin lymphoma which is characterised by the presence of Reed-Sternberg cells and Non-Hodgkin lymphoma. These further include a diverse group of subtypes. Early detection and advances in treatment have improved outcomes significantly.¹ 

Overview of MZL

Marginal Zone Lymphoma is the second most common subtype of Non-Hodgkin lymphoma that originates in the marginal zone of lymphoid tissues. MZL typically affects older adults and is often slow-growing. Symptoms vary based on the subtype and can include painless swelling of lymph nodes, fatigue, fever, and weight loss. It involves three subtypes: extranodal MZL (MALT lymphoma), nodal MZL, and splenic MZL.² 

Subtypes of MZL

Extranodal MZL (MALT lymphoma)

Extranodal MZL primarily occurs in the mucosa-associated lymphoid tissue (MALT) of certain organs like the stomach, thyroid, salivary glands and lungs. Hence it is also named MALT lymphoma. It can be caused by certain chronic infections like Helicobacter pylori infection that leads to gastric MALT lymphoma. Symptoms usually depend on the organ where the lymphoma is spreading. In gastric MALT lymphoma, one of the common symptoms is abdominal pain, indigestion and bleeding. Diagnosis can be done by techniques like endoscopy, biopsy and imaging methods. Treatment involves antibiotics in case of H. pylori infection along with radiation therapy, chemotherapy and surgery.³ 

Nodal MZL

Nodal Marginal Zone lymphoma occurs in the lymph nodes present across the body. The exact cause of this type of MZL is unknown yet. It typically presents itself as painless swelling of the lymph nodes. General symptoms like fever, night sweats, and weight loss can also occur. Diagnosis and treatment strategies are similar to extranodal MZL.³

Splenic MZL

As the name suggests, this type of MZL typically occurs in the spleen and sometimes involves the blood and bone marrow. Splenic MZL is associated with hepatitis C infection and involves symptoms like splenomegaly (enlarged spleen), cytopenias (reduced blood cell counts), fatigue, and abdominal discomfort. Imaging studies, blood tests, bone marrow biopsy and sometimes splenectomy (removal of spleen) are used for diagnostic and therapeutic purposes. Treatment includes antiviral therapy for hepatitis C along with other common cancer treatment methods.³

Pathophysiology of Marginal Zone Lymphoma

Genetic and molecular basis of MZL

Understanding the genetic and molecular basis of MZL is essential for developing targeted therapies and improving patient outcomes.

Chromosomal Aberrations

Translocations

Chromosomal translocation refers to a genetic modification where one part of a chromosome breaks and attaches itself to a broken piece of another chromosome. This leads to the translocation of the genetic information and thereby causing a mutation. Many such translocations are also seen in patients with MZL. One such example is t(11;18)(q21;q21) which is commonly seen in extranodal MZL. It causes the fusion of two genes namely BIRC3 and MALT1 that results in tumour proliferation. Other such translocations include t(14;18)(q32;q21) that fuses IGH and MALT1 genes and t(1;14)(p22;q32) that involves the BCL10 and IGH genes.⁴ 

Gene mutations

Certain genes are often modified into variants and are seen in different subtypes of MZL. In splenic MZL, NOTCH2 and KLF2 genes are the most frequently mutated genes. The NOTCH2 mutation causes dysregulation of the NOTCH signalling, affecting cell differentiation and survival. Another such mutation is seen in the MYD88 in cases involving the spleen and bone marrow. Inactivating mutations like TNFAIP3 are also common in MZL which inactivate a signalling pathway that leads to tumour growth.⁵ 

Signalling pathways

Signalling pathways are the way in which the cells in a body communicate with each other. They release certain chemicals that help in cell-to-cell communication. Two major signalling pathways are involved in MZL development, namely, NF-kB and BCR signalling pathways. Aberrant activation of the NF-kB pathway is the hallmark of MZL. This pathway plays a crucial role in promoting the survival and proliferation of tumour cells. Chronic active B-cell receptor (BCR) signalling is implicated in MZL pathogenesis. Mutations and translocations affecting components of the BCR signalling pathway can lead to continuous activation and survival of malignant B-cells. Other relevant pathways also involved in MZL pathogenesis include PI3K-AKT, JAK/STAT and apoptosis signalling pathways.⁶ 

Overview of targeted therapies for MZL

Traditional treatment methods

Traditional treatment methods used for Marginal Zone Lymphoma depend on the subtype. (extranodal, nodal or splenic) along with patient factors. One of the most commonly used treatments is radiation therapy mainly used in cases of localised extranodal MZL, particularly MALT lymphoma. Radiation therapy provides high cure rates for early-stage disease. Chemotherapy regimens like CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) are also utilised in cases of advanced-stage disease. Antibiotic therapy can be employed among patients who have MALT lymphoma associated with Helicobacter pylori infection. This is because inhibiting bacterial growth helps in lymphoma regression. Gastrectomy is also considered as a first-line treatment in cases of gastric MALT lymphoma.⁷ 

Definition and mechanism of targeted therapy

Targeted therapy is a treatment method that uses medicines to recognise and attack the specific cancer cells whilst preventing damage to non-cancerous cells. Targeted therapies can be classified into two subtypes, namely, monoclonal antibodies and small molecule inhibitors. The mechanism of action of targeted therapy involves the following:

• Molecular Targets: they interfere with specific molecules like receptors, genes or enzymes that are responsible for the aggressive growth of the tumour
• Blockage of Signals: As discussed in the genetic basis of MZL, certain signalling pathways play an important role in the progression of the lymphoma. Inhibiting such signalling pathways blocks the growth signals from reaching the cancer cell nucleus
• Inducing Apoptosis: agents that directly trigger programmed cell death (apoptosis) in cancer cells
• Immune Modulation: Immunotherapy is a form of targeted therapy that utilises certain drugs called monoclonal antibodies (eg: Rituximab). These antibodies target antigens on cancer cells, marking them for destruction by the patient’s immune system⁸ 

Approved targeted therapies for MZL

Rituximab

Rituximab is an approved monoclonal antibody that is used in the treatment of many B-cell-related malignancies, including Marginal Zone Lymphoma. It exclusively binds to the CD20 antigen that is present on the surface of B-cells. Such rituximab-bound B-cells are easily recognised and destroyed by the patient’s immune cells. It can also directly activate the programmed cell death (apoptosis) pathway for such cancerous B-cells. However, it does have certain side effects that can range from mild (fever, chills and infections) to more serious like affecting the cardiovascular system.⁹

Ibrutinib

Ibrutinib, also called Bruton’s Tyrosine Kinase (BTK) inhibitor is a small molecule inhibitor that is given orally as a form of targeted therapyL BTK is an essential enzyme that is required for B-cell activation, proliferation, and survival. Inhibiting this enzyme inactivates the BCR signalling pathway and thereby preventing tumour progression. Common and mild side effects involve nausea, diarrhoea and fatigue. It also has an infection risk and occurrence of cardiovascular events as severe side effects.¹⁰ 

Future directions in targeted therapy for MZL

Potential targeted therapy in the treatment of Marginal Zone Lymphoma involves developing novel drugs and combination strategies that improve patient outcomes whilst having less side effects. Research is exploring next-generation BTK inhibitors, such as acalabrutinib, offering potentially fewer side effects. Additionally, immunotherapies, including CAR-T cells and immune checkpoint inhibitors, are under investigation for their potential of achieving long-term remission. Personalised medicine approach is another area that is extensively being researched as it helps in devising treatment regimens tailor-made for every patient. This will drastically improve patient outcomes and longevity.¹¹ 

FAQ’s

What is the best treatment for marginal zone lymphoma?

Ans: The best treatment options for MZL, especially in the advanced stages of the disease are immunotherapy and chemotherapy.

What are the new drugs for MZL?

Ans: The newly approved drug by the U.S. Food and Drug Administration (FDA) is called umbralisib (UKONIQ) which is an orally administered small kinase inhibitor.

Can lymphoma be 100% cured?

Ans: Usually lymphomas can be fast-growing or slow-growing in nature. MZL is a slow-growing type of lymphoma. Treatment can potentially put lymphoma into remission or cure it.

Summary 

• Marginal zone lymphoma is a non-Hodgkin type of lymphoma that can be categorised into extranodal (MALT lymphoma), nodal and splenic MZL
• There are many genetic modifications like chromosomal translocations, gene mutations and signalling pathways involved in the pathogenesis of MZL
• Targeted therapy helps in specifically attacking the cancer cells and preventing damage to normal cells. It involves two types of drugs: monoclonal antibodies and small molecule inhibitors
•  Rituximab and Ibrutinib are the approved and most commonly used drugs for targeted therapy for MZL