Introduction

Marginal zone lymphoma (MZL) is a type of non-Hodgkin lymphoma which is usually slow-growing. It affects a type of white blood cell called B-lymphocytes and develops within lymphoid tissue. There are three main types of lymphomas:

1. Mucosa-associated lymphoid tissue (MALT)
2. Nodal or
3. Splenic MZL

Some cases of MZL can be cured with treatment; however, some may return after treatment. Exactly what the treatment is varies depending on how widespread the disease is, the type, and if there is an underlying cause.¹ Relapse occurs when a patient’s disease returns after a period of remission, whereas refractory disease indicates the MZL is not responding to treatment. Both relapsed and refractory MZL can be harder to treat, and may involve more intensive or different treatments.² 

Marginal zone lymphoma prognosis

Prognosis after initial diagnosis of MZL varies depending on multiple factors, including type, patient health and any underlying causes. The relapse rate is high, but treatment is often successful. 

MALT MZL

This is the most common type seen in around 70% of cases. The five-year survival rate for MALT lymphoma is approximately 88%, indicating that about 9 out of 10 patients are expected to be alive five years after diagnosis.¹ It is often slow-growing, and many patients live for years without any clinical signs. Many patients do relapse; however, treatment is often successful again.³

Nodal MZL

Nodal MZL has the lowest five-year survival at around 76.5%.¹ It is also slow-growing and often managed well with treatment.⁵ Nodal MZL is the rarest form, accounting for around 1 in 10 cases of MZL. 

Splenic MZL

The five-year survival time is around 79% for splenic MZL, indicating that 8 out of every 10 patients are expected to be alive five years after diagnosis.¹  Again, splenic MZL is often slow growing, and patients can live for a long time with the disease under control. When relapse occurs, treatment is often successful at managing the cancer once again. Rarely, splenic MZL can transform into a faster-growing cancer which requires more intensive treatment.⁴    

Treatment strategies 

Treatment for MZL depends on multiple factors and may involve different modalities. Because MZL is a slow-growing lymphoma, sometimes a ‘watch and wait’ approach is taken when patients have no treatment but are regularly monitored for signs of disease progression. If there is an underlying cause, for example, hepatitis C infection with MALT lymphoma, then treatment with antivirals may be enough to induce remission. Similarly, antibiotics to treat H.pylori in gastric MALT MZL can induce remission in around 75% of patients. These treatments are often used first line due to their small side effect profile when compared to other anti-cancer drugs.⁶

Radiotherapy

If no underlying cause is identified or there is no response to first-line treatment, targeted radiotherapy may be used. This is often successful in patients with very localised disease and is not often used in advanced systemic disease. Radiotherapy can also be used as a salvage therapy in cases with localised relapse.⁷

Rituximab

Rituximab is a targeted drug called a monoclonal antibody. This means it targets a specific protein that sits on the surface of a cell. In this case, rituximab is designed to target the protein CD20, which is present on B-cells. Rituximab then flags this cell to the immune system, which then kills the cell.⁸ It may be used in patients who are unable to undergo radiotherapy or their disease is not suitable. It is often well tolerated and may be used by itself or in combination with other drugs or radiotherapy.⁶ 

Chemoimmunotherapy 

Patients with MZL often have long periods of remission and require no treatment; however, they frequently undergo relapse, which may happen multiple times during their lives. If the disease has progressed with the above treatments or is disseminated, then often the next step is chemoimmunotherapy. This may involve various combinations of chemotherapy drugs with drugs that enhance the immune system. These may include: 

• Rituximab-bendamustine
• Rituximab-chlorambucil
• Rituximab-fludarabine
• Rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP)

Chemoimmunotherapy can also be used in the refractory/relapse setting, depending on which previous lines of treatment the patient has already received and the type of disease they have.⁹ 

Autologous stem cell transplantation

Stem cell transplants are not commonly used for the treatment of MZL. They are usually only considered if relapse occurs quickly after treatment with chemoimmunotherapy for nodal MZL. Stem cell transplants allow very high doses of chemotherapy to be given prior to ‘rescuing’ with stem cells. Due to the intensity of the treatment, the patient needs to be well enough to tolerate the transplant.⁵ 

Ibrutinib

The most recent novel agents are being considered for use in the treatment of MZL. Due to the rarity of some types of MZL, clinical trials are slow to recruit enough patients; therefore, the significance of some novel drugs is difficult to determine. Ibrutinib is a first-in-class Bruton Tyrosine Kinase Inhibitor (BTK), which interferes with the cell signalling responsible for cell growth. This prevents cell division and stops the cancerous B cells from multiplying.¹⁰ Ibrutinib may be used in the salvage setting when relapse has occurred and the disease is refractory to other treatments; however, it is also being studied for use as a first-line setting.^9,11 

Lenalidomide

Lenalidomide is both a targeted therapy and immunotherapy with a complex mechanism of action. It works to prevent the cancer from generating new blood vessels, inhibits growth, and enhances the immune system.¹² It may be used as a monotherapy or in combination with Rituximab, often in the relapse/refractory setting.⁹ 

PI3K inhibitors

There are now a variety of drugs that inhibit the phosphatidyl-inositol 3-kinase (PI3K) pathway.⁹ This pathway is responsible for cell survival; therefore by blocking parts of this pathway can result in cell death. These drugs may be used in haematological malignancies as the PI3K pathway is often overactivated, providing a target for treatment. Further studies are needed to determine their role within MZL treatment due to possible concerns over the safety profile.¹³

Clinical trials 

Clinical trials are often ongoing for the treatment of many different types of cancers. Patients may be eligible for certain trials depending on the type and stage of disease and what treatments they have previously received. There are lots of drugs currently being studied in clinical trials for different types of lymphomas, some of which may be trialled in MZL. These include:

• B-cell receptor pathway inhibitors 
• Proteasome inhibitors 
• BCL-2 inhibitors
• Immunomodulating drugs
• Antibody treatments 
• CAR-T cell therapy

These all work in different ways with the aim of killing the cancerous cells while preserving normal healthy cells. The efficacy of treatment and side effects are both closely monitored during clinical trials to determine if the drug is beneficial and if the drug works better than the current standard of care.⁵ 

Supportive treatment

Treatment can vary in intensity and, therefore, severity of side effects. It is important to look after your general health whilst undergoing treatment and after treatment to help reduce side effects and the impact on life after treatment. The most common side effects include tiredness, fatigue, fertility issues, and immunosuppression. These can last for varying lengths of time and may develop at the time of treatment or years afterwards. Eating healthily and doing regular exercise can help maintain a healthy lifestyle and improve some side effects.¹⁴ 

Summary

MZL is a relatively rare, heterogeneous lymphoma, making specific treatment protocols a challenge to determine due to the difficulty in performing specific clinical trials. They are usually indolent in nature, with long periods of remission requiring no treatment, only monitoring. Relapse is very common; however, treatment is usually successful and may consist of a variety of different modalities ranging from simple medications to more intensive stem cell transplants. The development of new novel drugs is quickly changing the treatment landscape for many haematological malignancies, and MZL treatment is also changing. Further studies and trials are needed to determine the best sequence of treatments.