Epidemiology
Non-Hodgkin’s lymphomas (NHLs) are a very heterogeneous group of cancers that develop in the lymph nodes present throughout the body. There are over 25 subtypes of NHL, and mantle cell lymphoma accounts for 6 to 8% of these cases. In older staging systems, mantle cell lymphoma was classified as indolent because it was (and still is) generally incurable with chemotherapy. It also occurs more often in elderly patients, which is more characteristic of indolent NHL. However, the average survival is significantly shorter than with other types of indolent lymphomas, only two to three years. Currently, most oncologists view mantle cell lymphoma as an aggressive type and treat it accordingly. Approximately 4600 patients are diagnosed with mantle cell lymphoma in the United States each year.
Risk Factors
The exact cause of mantle cell lymphoma is most often unknown. As with most cancers, a family history increases a patient’s risk to some extent. In addition, suppression of the immune system may lead to the development of mantle cell lymphoma. This includes immune suppression associated with organ transplant (from the drugs taken to prevent organ rejection) and with HIV/AIDS infection. Occupational exposures, notably pesticides, also increase the risk of mantle cell lymphoma. In fact, the Midwest, where farming is prevalent, has the highest incidence of NHL in the United States. Finally, infection with viruses, such as hepatitis C and the Epstein-Barr virus, may increase the risk of developing mantle cell lymphoma.
Signs and Symptoms
Enlarged (swollen) lymph nodes are the most common presenting sign in patients with mantle cell lymphoma. The swollen lymph nodes are usually hard, fixed in place, and painless to the touch. In addition, some patients also have non-specific symptoms, such as fevers, drenching night sweats, and unexplained weight loss greater than 10% of body weight. These are termed "B" symptoms and indicate the presence of more advanced disease. Patients with mantle cell lymphoma tend to have bone marrow and spleen involvement more often than patients with other types of aggressive NHL. In addition, the gastrointestinal tract (most notably the colon) may be involved.
Diagnosis and Staging
The most important diagnostic procedure in patients suspected of having lymphoma is the lymph node biopsy. Many cancers can be diagnosed by inserting a small needle into the tumor mass and withdrawing cells for examination under a microscope. This is called a “fine needle aspiration” or FNA. For lymphoma diagnosis, however, the preferred technique is removal of the entire affected lymph node for examination by a pathologist. It is of the utmost importance that these biopsies are examined by a pathologist who is experienced in diagnosing lymphomas. Knowing the subtype of NHL is crucial for determining long-term prognosis and treatment options.
Once the diagnosis of mantle cell lymphoma is established, patients should undergo tests to determine the extent of disease. This should include CT scans of the chest, abdomen, and pelvis, a bone marrow biopsy, a complete blood count, serum chemistries (including lactate dehydrogenase (LDH) and uric acid), and an HIV test. Because the colon is frequently involved in mantle cell lymphoma, a colonoscopy is recommended as routine work-up as well. Hepatitis B testing is also recommended due to reports of hepatitis reactivation during chemotherapy. Finally, a baseline echocardiogram or MUGA scan to evaluate heart function should be done prior to chemotherapy, as some drugs can damage the heart.
All of the above testing leads physicians to establish a "stage" of mantle cell lymphoma for each patient. Stages for mantle cell lymphoma include the following:
- Stage I: One involved lymph node group
- Stage II: Two or more involved lymph node groups on the same side of the diaphragm
- Stage III: Multiple lymph node groups involved on both sides of the diaphragm
- Stage IV: Disseminated involvement of extra-nodal sites, such as the liver or bone marrow
An "A" or "B" is added to the stage number to indicate the presence or absence of the "B" symptoms previously described. For example, a person with mantle cell lymphoma with bone marrow involvement, as well as recurrent night sweats and weight loss, would be considered to have "Stage IVB" disease.
Prognostic Factors
Mantle cell lymphoma itself is considered a poor prognosis in patients with aggressive types of NHL, with an average survival of only two to three years. In addition, stage at the time of diagnosis is a crucial prognostic factor in patients with mantle cell lymphoma: A higher stage indicates more advanced lymphoma, and therefore has a worse prognosis. Unfortunately, 70% of patients with mantle cell lymphoma present with stage IV disease. Other poor prognostic factors include presence of "B" symptoms, concurrent HIV/AIDS infection, age greater than 60 years, high LDH level time of diagnosis (indicative of more advanced disease), and poor performance status (inability to care for oneself).
First-Line Treatment of Mantle Cell Lymphoma
As discussed, mantle cell lymphoma responds significantly less well to standard chemotherapy than other types of aggressive NHL. There is no standard first-line therapy, and all patients with this diagnosis should consider participation in a clinical trial.
Few patients present with localized mantle cell lymphoma, therefore clinical studies of treatments are limited to case series. Most guidelines recommend radiation to the sites of lymphoma, with or without combination chemotherapy such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Occasionally, patients may present with aymptomatic, advanced mantle cell lymphoma. Because advanced mantle cell lymphoma is not curable, these patients may be observed carefully until the disease progresses and/or symptoms occur.
Most patients with mantle cell lymphoma present with symptomatic advanced disease (stages III and IV). Treatment should consist of combination chemotherapy plus rituxumab. Rituximab is a monoclonal antibody drug that specifically kills B-cell lymphomas. It is synergistic with chemotherapy, meaning that the two types of medications work better together. All of the regimens used to treat other types of aggressive NHL, such as R-CHOP, have been used to treat mantle cell lymphoma as well. It should be noted that although up to 70% of patients will have a response to these regimens, none are curative in patients with advanced disease.
The regimen R-HyperCVAD has shown higher response rates (up to 80%) and the potential for prolonged survival compared to other regimens. This treatment includes the drugs rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating in cycles with high-dose methotrexate and cytarabine. R-Hyper-CVAD should be used very cautiously in patients over the age of 65 years due to toxicity risks. The addition of "R" or rituximab, in the regimens used to treat mantle cell lymphoma does significant increase the percentage of patients responding to treatment, but it is unclear if this drug actually improves overall survival.
The incurability of mantle cell lymphoma with standard doses of chemotherapy has lead many clinicians to consider hematopoietic stem cell transplant (also called bone marrow transplant) as part of first-line therapy in good performance status patients. The most common type of bone marrow transplant is an autologous transplant, in which the patient’s own blood stem cells are harvested, then re-infused following very-high-dose chemotherapy. Most studies to date have primarily included patients younger than 65 years. In these patients, bone marrow transplant produces durable remissions, with more than 80% of patients living at least three years.
Treatment of Recurrent/Refractory Mantle Cell Lymphoma
Regardless of the initial treatment given, almost all patients with mantle cell lymphoma have recurrent disease. The average time to recurrence of 18 months. Many salvage chemotherapy regimens have been studied for recurrent mantle cell lymphoma. None has proven superior to another, and patients are not cured with these standard-dose regimens. Participation in a clinical trial is always a good choice for patients with relapsed mantle cell lymphoma.
Most salvage regimens include the agent fludarabine:
- FC: fludarabine, cyclophosphamide
- FMR: fludarabine, mitoxantrone, rituximab
- FCMR: fludarabine, cyclophosphamide, mitoxantrone, rituximab
Other agents that have activity in recurrent mantle cell lymphoma include chemotherapy drugs such as cladribine and bendamustine, bortezomib (an agent which disrupts cellular homeostasis and has activity in indolent NHL as well), and anti-angiogenesis drugs such as thalidomide and lenalidomide, which inhibit blood vessel formation by the lymphoma cells.
Bone marrow transplant is also a treatment option for patients with a good performance status who have recurrent or refractory mantle cell lymphoma. This treatment strategy can improve the time patients are without active lymphoma, but bone marrow transplant is not a curative procedure in relapsed mantle cell lymphoma. If the patient has previously undergone an autologous bone marrow transplant as part of first-line therapy, then an allogeneic bone marrow transplant (blood stem cells from another person, usually a sibling) may be offered. Bone marrow transplant, especially the allogeneic type, is associated with a high degree of toxicity and should only be performed at cancer centers with staff experienced and skilled in this procedure.
Supportive Care Issues
Tumor lysis syndrome leading to kidney failure and heart arrhythmias is a risk in mantle cell lymphoma patients with advanced disease. These patients can be identified by a high LDH level, high uric acid level, and/or bulky disease (greater than 10 cm). Patients at high risk for tumor lysis syndrome usually receive their cycle or two of chemotherapy in the hospital.
Infections due to bone marrow involvement with lymphoma and/or chemotherapy immune suppression are common in mantle cell lymphoma patients. Prophylaxis with antibiotics may be appropriate in some, and patients should always contact their oncologist if they develop a fever.
Although they are important drugs for the treatment of mantle cell lymphoma, doxorubicin and mitoxantrone have the potential to cause congestive heart failure. Patients at highest risk are those receiving cumulative doses of doxorubicin greater than 450 mg/m2 or of mitoxantrone greater than 160 mg/m2, age greater than 70 years, and those with a history of heart disease. All patients receiving doxorubicin and/or mitoxantrone should have their heart function monitored regularly, and if there is evidence of heart failure, therapy should be stopped. Once damage to the heart occurs, it is generally not reversible.
