Introduction

Unfortunately, mantle cell lymphoma is currently incurable and individuals are often given a prognosis of 2-9 years post-diagnosis. Recently developed treatments however have shown promise in achieving remission, although relapse is common.¹ 

Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that originates sporadically in the mantle zone of the lymph node. This cancer of the white blood cells is characterised by the dysregulation of signalling pathways within the body. Cells can divide uncontrollably to produce cancerous tissue within the lymphatic system.² Targeted therapy is a novel and rapidly-advancing approach aiming to reduce side effects that conventional treatments cause. Targeted therapy is an umbrella term that refers to drugs targeting specific cancer-causing molecules or processes in our body, and leaving healthy tissues unharmed.

Biological background

The lymphatic system spans the entirety of the body and is essential in supporting the immune system. Specifically, lymph vessels transport white blood cells (lymphocytes) throughout the body to fight infection. MCL is the production of abnormal B cells which are essential in antibody production. The accumulation of these abnormal cells disrupts the ability to fight infection by hindering the production of antibodies and allowing tumours to form.³ 

Cancer of the lymphatic system is aggressive in nature. Cells may invade surrounding tissues or other tissues of the lymph, spreading throughout the body. This is namely metastasis or terminal cancer. As such, early diagnosis and intervention are essential for a positive prognosis.³ 

Prevalence 

Annually, 1 in 200,000 people are diagnosed with MCL, making up 5% of all non-Hodgkin’s cases. These individuals tend to be males of an average age of 60 to 70 years old (assigned men at birth(AMAB) are 3 times more likely than women to develop MCL).⁴ 

Symptoms

Often, individuals with MCL do not experience symptoms until the latter stages of the disease. Symptoms are similar to most types of non-Hodgkin lymphoma, these may include:³

• Swellings in the neck, armpit, or groin (these are commonly painless)
• Abdominal pain
• Diarrhoea or vomiting 
• Night-time sweats or unexplainable fevers 
• Itching 
• Weight loss or loss of appetite 
• Anaemia (may cause excess bruising)

Factors influencing mantle cell lymphoma

The cause of Mantle Cell Lymphoma is largely unknown, however, it is thought to correlate with a genetic mutation that prevents the immune system from functioning correctly. It is currently undetermined why the mutation occurs and is likely a random event, although the incidence may be higher in a familial lineage.⁴ 

Treatment options

The course of treatment is decided through consultation with the therapy algorithm, which is governed by an individual's fitness profile, age, and disease stage.⁵

The leukaemic, non-nodal subtype make up roughly 10-15% of patients who, at their current disease state, are eligible for close monitoring without the need for immediate intervention. Of these individuals, 1 in 2 may not require treatment until 2 years post-diagnosis.⁶ 

Individuals experiencing an aggressive, symptomatic subtype of the disease however require the initiation of therapy on time in. Most patients present with a combination of intrusive disease features that quickly damage body function and hinder quality of life.⁶ 

Current treatment 

The standardised treatment for those who are physically fit (usually ≤65 years old), in an early I or II disease stage, is a combination of chemotherapy and a monoclonal antibody (Rituximab); given as an intravenous infusion.⁷ This is consolidated with a course of radiotherapy. For those individuals >65 years old with multiple additional comorbidities, a course involving rituximab maintenance is preferential. However, these regimes are commonly associated with several serious side effects including:⁸

• Fatigue 
• Nausea and vomiting 
• Hair loss 
• Headaches
• Itching, rashes or dry skin
• Swelling across the body (oedema)
• Allergic reactions 
• Increased susceptibility to bruising and bleeding 
• Increased risk of infection 

Additionally, these treatments are not curative. They are commonly successful in causing shrinkage of tumours (remission), but do not prevent a relapse meaning masses often return within the subsequent months or years. Treatment regimes that do not require chemotherapy are therefore under heavy investigation to achieve better patient outcomes and reduce side effects.^6,7 In these instances, clinical trials of targeted therapies are preferred.⁸ 

Targeted therapies

There are an increasing number of targeted therapies currently in clinical trials for treating mantle cell lymphoma, both as single agents and combinational therapies. These include:^6,7

• Bruton’s Tyrosine Kinase (BTK) inhibitors
  • Ibrutinib (Imbruvica^®)
  • Acalabrutinib (Calquence^®)
  • Zanubrutinib (Brukinsa^®)
• BCL-2 Inhibitors
  • Venetoclax (Venclexta^®)
• PI3K Inhibitors
  • Idelalisib (Zydelig^®)
  • Duvelisib (Copiktra^®)

BTK inhibitors

BTK inhibitors are the current front runners in targeted therapy for mantle cell lymphoma. Ibrutinib, acalabrutinib and zanubrutinib are targeted therapies given orally, that are particularly potent in the treatment of relapsed mantle cell lymphoma patients.⁹ They specifically target the B cell receptors, preventing abnormal cells from replicating uncontrollably. In doing so, the abnormal cells are destroyed and the immune system is mediated.¹⁰ 

BTK inhibitors are largely considered more effective and safer than immunochemotherapy in achieving prolonged remission.¹¹ There is an approximately 70% response rate to BTK inhibitors, with 20% of those achieving complete remission. However, there are still some associated side effects including:

• Atrial fibrillation (can be associated with flutters in the chest)
• Hypertension
• Rashes
• Diarrhoea 

These side effects occur in less than 25% of patients and are well monitored throughout the treatment regime.¹²

There are currently 48 clinical trials worldwide investigating BTK inhibitors for mantle cell lymphoma. They are analysed as single agents but also in combination with other medications to achieve a prolonged remissive state.¹³ Although effectiveness and safety analyses are promising, long-term effects of treatment require monitoring. 

BCL2 inhibitors

Venetoclax is the current BCL2 inhibitor on the market. It targets proteins that cause cellular death, destroying tumour cells and achieving molecular remission. These drugs are often used in combination with other target therapies to increase safety and effectiveness.¹⁴

PI3K inhibitors

These targeted therapies are often used in circumstances of relapsed mantle cell lymphoma. Idelalisib and Duvelisib show success in 1 in 2 patients. However, they are proven most effective when combined with BTK inhibitors. The combinational therapy shows better efficacy and reduces rates of side effects including:¹⁵

• Hyperglycemia (high blood sugar)
• Hypertension
• Fatigue
• Diarrhoea

Targeted therapies vs conventional therapies 

Conventional therapies include predominantly a combination of chemotherapy, immunotherapy and radiotherapy drugs, all of which elicit a variety of side effects. Side effects are largely attributable to the drugs being non-specific and therefore often ‘normal’ cells are affected and destroyed also. This significantly hinders the immune system. 

Targeted therapies reduce this burden upon the immune system by targeting the damaged cells only. They are also often given orally, as a tablet, which can increase patient compliance as it is less invasive than intravenous infusions or injections.¹⁶ 

Emerging therapies

There are several new emerging therapies currently in clinical trials for the treatment of mantle cell lymphoma. All use a targeted approach upon specific cells or proteins associated with tumour growth. Some examples are included below:¹⁷

• CAR-T cell therapy
• Immune checkpoint inhibitors
• Proteasome inhibitors
  • Bortezomib (Velcade^®)
  • Lenalidomide
• Monoclonal antibodies

Patient management 

As MCL is currently incurable, often treatment regimes reach a point where they are no longer effective. Patient management of symptoms and treatment side effects is therefore the last intervention deployed.

Monitoring and management of symptoms

The best way to control mantle cell lymphoma is to monitor and manage symptoms to alleviate the disease state. These strategies include:¹⁸

• Active monitoring: symptoms and overall health are assessed regularly
• Maintenance therapy: monoclonal antibody therapy is often used beyond remission to prevent relapse

Quality of life assurance

It is important to understand that living with MCL is often full of uncertainty. Therefore, alongside clinical treatment of the disease, it is important to consider the associated psychological effects. Below are some suggestions for dealing with mental health struggles:¹⁹

• Acknowledge and share your emotions: talking to others can help
• Manage stress: try to engage in activities that make you happy and ask for help when you need it
• Understand your condition: ask questions and read about your condition
• Make healthy choices: living a healthy lifestyle with increased chances of a better prognosis

Summary

Mantle cell lymphoma is a rare, debilitating type of blood cancer. It is important that upon diagnosis, the disease state is identified so that the best course of treatment can be established on a patient-to-patient basis. There is a range of therapies available for patients that achieve remission, however, the current first-line treatment is unable to provide a cure and therefore relapse is common.

To overcome such, several target therapies are within development, BTK inhibitors have been evidenced as the most effective therapies thus far. However, physical treatment cannot remain effective without the management of quality of life. It is incredibly important to acknowledge your mental health and lifestyle throughout this diagnosis as it is likely a stressful period with many unknowns.