Mantle Cell Lymphoma (MCL) is a rare subtype of B-cell Non-Hodgkin’s lymphoma, meaning it starts in the B cell lymphocytes in the blood. These are white blood cells, very important in the production of antibodies that allow our bodies to combat infection. MCL is rare, affecting around 1 in 200,000 people, and also disproportionately seen in men over women, with the ratio being around 3 to 1. The median survival rate of MCL, meaning the time that passes between diagnosis and death, is generally around 5 years.1
MCL is caused by an error in the genetic replication process of the cells. This mutation, called a gene translocation, causes increased and uncontrolled division of B cells, which then take on other cancer properties and can spread around the body.1,2 While MCL is a genrally anunfavourable diagnosis, there are viable treatment options that can improve survival chances, especially if the cancer is detected at an early stage.
In this article, we will review some of the most common and effective treatment methodologies, discussing their various benefits and drawbacks. These range from conventional chemotherapy approaches, to targeted therapies, immunotherapies, and stem cell transplants, which show promise in managing and treating MCL.
Chemotherapy
Chemotherapy is the most traditional way to treat cancer, and has always been a vital component of managing MCL. Via combinations of different drugs, rapidly dividing cells are targeted and destroyed. As we saw earlier, one of the main defining characteristics of MCL (and all cancer cells) is uncontrolled division3, and so this method can effectively kill cancer cells. However, all cells in the body divide very often, just at a lower rate than cancer cells. This difference is often not apparent in common chemotherapy drugs, and so they end up attacking many different areas of the body, not just the cancer. Serious side effects can occur as a result of chemotherapy regimens4,5, in some cases invalidating the treatment altogether.
The most commonly used chemotherapy regimen to treat MCL is R-CHOP, which combines 5 drugs, often alternated with high doses of cytarabine (Ara-C).6
R-CHOP protocol:
- Rituximab: An antibody that helps the immune system destroy cancerous cells7
- Cyclophosphamide: An alkylating agent that causes cell death and immunosuppression8
- Doxorubicin: Inhibits replication of DNA9
- Vincristine: Stops cell division10
- Prednisone: Promotes lymphoid (B-cell) cell death11
High-dose cytarabine (Ara-C) is often alternated with R-CHOP, and has been seen to be both safe and effective in patients of all ages. However, younger patients seem to respond the best. While R-CHOP has been seen to be effective in treating MCL, it incurs significant general toxicity and relapse rates remain high, which is why other avenues of treatment need to be explored.12
Targeted therapies
BTK inhibitors: BTKs are a type of protein central to the division, survival, and proliferation of B-cells. The inhibition of BTKs reduces the division of malignant B-cells and removes cancerous B-cells from the tissues. Ibrutinib was one of the first BTK inhibitors available, but was associated with various harmful side effects. Zanubrutinib has been recently approved by the FDA, and it is more potent, more selective, and tolerated better than its predecessors.13
BCL-2 inhibitors: The BCL-2 protein acts to prevent cell death. Using compounds such as Venetoclax, BCL-2 can be inhibited and thus promote the destruction of B-cells.14 This type of treatment has been seen to be effective in conjunction with chemotherapy.
PI3K inhibitors: Inhibiting the PI3Kδ protein has been shown to be effective in combination with chemotherapies in treating MCL. This type of treatment is especially helpful for those patients intolerant to BTK inhibitors, as it provides an alternate strategy.15
Targeted therapies are, as their name suggests, more specific than classical chemotherapy drugs, and more efficiently target the B-cells in MCL. This means it avoids many of the harmful side effects that come with chemotherapy. However, resistance to targeted therapies is common, as cancers mutate to avoid them. This means they often need to be used in conjunction with each other as well as chemotherapy to achieve the optimal effect.16
Immunotherapies
This type of treatment uses a patient’s own immune system, empowering it via various methods to be able to find and destroy the cancer cells. This is an improvement of classic treatments, as it greatly reduces toxicity and the inherent risk of the treatment is low.
Monoclonal antibodies: Rituximab is a monoclonal antibody, and is a classical immunotherapy tool that has been used to treat MCL for a long time. It is a key component of the R-CHOP regimen. It binds to a protein known as CD20, which is located on the B-cells. This allows the immune system to locate the malignant B-cells much faster, selectively eliminating them.7
CAR T-cell therapy: In this treatment, the patient's blood is extracted. From this blood, the T cells are extracted. These types of cells are the ones responsible in the immune system for recognising and destroying potentially dangerous cells. They are engineered to have chimeric antigen receptors (CAR), using a virus vector which enables them to detect cancer cells faster and more effectively. The patient is then given chemotherapy before introducing the new and improved T-cells into their bloodstream.17
While CAR T-cell therapy is effective, it requires specialised medical centres and is very expensive, costing around 280,000 pounds per treatment in the UK18. Because of this, it cannot be used to treat MCL on a large scale, and more research needs to be done into ways of making this therapy more accessible to the general public.
Stem cell transplants
Stem cell (SC) transplantation is an option to replenish the blood with working immune cells after the first remission following chemotherapy, but medical centres that distribute the treatment often base eligibility on age and fitness, which is why the majority of stem cell transplants are done on younger, healthier patients. SC transplantation provides a chance for long-term remission.
There are two types of stem cell transplants that can be done in an MCL patient, and they differ in the origin of the stem cells that are transplanted. The first uses a patient’s own stem cells, known as autologous stem cell therapy (ASCT). Stem cells are extracted and re-infused after high-dose chemotherapy.20
Stem cells are essentially blank cells, and when infused into the blood, different chemical signals can influence what kind of cell they will specialise into19, in this case, subtypes of white blood cells. This treatment replenishes the body with immune cells, helping to eradicate any remaining cancer cells and encourage long-term remission.
The second type of stem cell transplant uses cells originating from outside the patient’s body, most commonly from donors. It is called an allogeneic stem cell transplant (allo-SCT), and is considered generally for high-risk patients. However, our immune system is designed to recognise and destroy anything external to our bodies, so allo-SCT incurs the risk of graft-versus-host disease (GvHD), where our own body attacks itself in an attempt to rid itself of invaders. As a result of this, allo-SCT carries a high risk of toxicity and transplant-associated mortality, so patients and donors need to be carefully chosen to reduce the risks.20
Summary
Mantle cell lymphoma is a rare disease, and largely incurable with current treatments. With a median survival of 5 years, it is a grim diagnosis to receive. Nonetheless, therapies have been developed to manage and combat it, including classic chemotherapies, targeted therapies, immunotherapies, and stem cell transplants which have shown varying degrees of effectiveness and are often used in combination with each other to achieve the most positive effect. R-CHOP is the most common chemotherapy regimen that is given to MCL patients.
As with ther chemotherapies, it targets mechanisms of cell division, which are vital to cancer survival and spread. However, with such a broad spectrum of targets, it also affects healthy cells, and causes a variety of very serious side effects.
Targeted therapies, such as BTK inhibitors and BCL-2 inhibitors target more specifically the pathologies of MCL, being the B-cells. This reduces the side effects seen in chemotherapy, but the long-term efficacy of these treatments is compromised by the regular appearance of mutations in the cancer that work around these therapies and develop resistance. Due to this, they usually need to be used in combination with chemotherapies and each other to ensure their effect.
Immunotherapies cut down further on side effects, as they use the body’s own immune system to selectively destroy the cancer. This can be done by tagging the cancer cells with monoclonal antibodies such as rituximab, allowing T-cells in the immune system to recognise them and remove them. Novel therapies such as CAR T-cell therapy have been shown to be effective, but are very expensive and inaccessible to the vast majority of the population.
Stem cell transplants are also used in select patients to avoid remission and remove any possible cancer cells that could have persisted after chemotherapy. Due to the inherent risk of the treatment, it is most commonly delivered to younger and healthier patients, as they have the highest chance of the treatment yielding a positive result. The patient’s own cells can be used in an autologous transplant, or a donor’s in an allogeneic transplant. The latter carries the most risk, as Graft v Host Disease can occur, which can be fatal. Therefore, it is almost exclusively performed in high-risk patients.
While MCL remains a difficult condition to treat, strides have been made in the development of more effective techniques that target cancer cells more effectively and cut down on harmful side effects. However, these are inaccessible to many people, and the main focus of research should be on ways to make these types of treatments commonplace, giving MCL patients hope for a disease-free future.
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