Reviewed by C.H. Weaver M.D., Medical Editor 1/2020
Mantle cell lymphoma (MCL) is a lymphoproliferative disorder derived from a subset of naive pre-germinal center cells localized in primary follicles or in the mantle region of secondary follicles. Mantle cell lymphoma (MCL) accounts for between 2% and 10% of all non-Hodgkin lymphomas (NHL).(1) Mantle cell lymphoma involves the abnormal growth of immune cells known as B cells, and can affect lymph nodes, the spleen, blood, bone marrow, and other tissues.
Mantle cell lymphoma affects men more often than women and is most common in older adults; roughly half of people with MCL are over the age of 68 at the time of diagnosis and the majority are diagnoses with advanced disease.(1) The causes of the condition are unknown.
Mantle cell lymphoma is considered a fairly aggressive type of NHL, with the average survival of less than 3 years however the use of newer precision cancer medicines, stem cell transplant and immunotherapy continues to improve outcomes.
Signs & Symptoms of Mantle Cell Lymphoma
Symptoms that may be caused by MCL or other types of non-Hodgkin lymphoma include the following:(2)
- Swollen, painless lymph nodes in the neck, armpits, or groin
- Unexplained weight loss
- Soaking night sweats
- Coughing, trouble breathing, or chest pain
- Weakness and tiredness that don’t go away
- Pain, swelling, or a feeling of fullness in the abdomen
Mantle cell lymphoma is considered an aggressive form of non-Hodgkin lymphoma, though outcomes can vary considerably among patients. Median overall survival is roughly 5 to 7 years.(3)
Diagnosis and Staging of Mantle Cell Lymphoma
If lymphoma is suspected, patients will usually have a biopsy performed. A biopsy involves the removal and examination of a sample of affected tissue. It allows a doctor to determine the presence and type of lymphoma. A diagnostic workup may also involve a physical exam, blood tests, and imaging scans.
If the biopsy confirms a diagnosis of mantle cell lymphoma, patients often undergo additional tests and imaging scans to determine the extent (stage) of the disease. Stage ranges from I to IV, with higher stages indicating more extensive disease. A majority of patients with MCL have Stage III or Stage IV disease at the time of diagnosis.2 Additional tests that are often performed may include:
- Bone marrow aspirate/biopsy
- Immunophenotyping helps differentiate MCL from other small B-cell lymphomas.
- Body CT scanning is important for initial staging and for assessing response to treatment.
- Blood studies
- Beta2-microglobulin: An elevated level indicates a poor prognosis
Immunophenotyping: MCL cells are monoclonal B cells with the following characteristics:
- CD5+ and pan B-cell antigen positive (eg, CD19, CD20, CD22).
- Lack expression of CD10 and CD23.
- Overexpress cyclin D1
Another tool that may be used to assess patients is the Mantle Cell International Prognostic Index (MIPI). The MIPI uses four pieces of information—age, performance status (ability to perform activities of daily living), lactate dehydrogenase levels, and leukocyte count—to classify MCL patients as low risk, intermediate risk, or high risk. Overall survival tends to be worse in higher-risk patients.(4) Information about stage and MIPI result help guide treatment decisions.
Treatment of Advanced Mantle Cell Lymphoma
Most patients with MCL are diagnosed with an advanced stage of the disease. Some of these patients will have indolent (slow-growing) MCL that can be managed with close observation, but a majority of patients will require treatment.(1)
Although newer approaches to treatment have improved outcomes for people with MCL, most people will eventually experience a relapse. Given the limitations of standard treatments, people with MCL may wish to participate in a clinical trial. Clinical trials are studies that evaluate the effectiveness and safety of new cancer drugs or cancer treatment strategies.
Standard initial drug therapy for MCL typically involves a combination of chemotherapy drugs often combined with the precision cancer medicine Rituxan® (rituximab). Rituxan is a type of precision cancer medicine known as a monoclonal antibody that recognizes and targets a specific protein (CD20) found on the surface of B cells, including the cancerous B cells of MCL. The binding of Rituxan to the B cell prompts the immune system to destroy the cell and may also have direct anticancer effects on the cell.
There are several drug combinations used to treat MCL and some are more intensive than others. Because more intensive treatments tend to have more side effects, they are often reserved for younger patients or patients in good overall health.
Rituxan combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with cyclophosphamide, vincristine, and prednisone (R-CVP) are two of the more widely used initial treatment regimens for MCL however clinical trial results have demonstrated that Treanda (bendamustine) or Imbruvica (ibrutinib) combined with Rituxan (BR) are also effective treatment options compared to R-CHOP or R-CVP.
Follow-up results from a 5-year study showed that BR has better long-term disease control than R-CHOP or R-CVP in patients with MCL. Overall survival without cancer progression at 5 years from treatment was 65.5% for BR and 55.8% for R-CHOP/R-CVP. There were no significant differences observed in OS between the study arms.(5)
Medications used to Treat Mantle Cell Lymphoma
- Leukeran (chlorambucil)
- Cyclophosphamide, vincristine, and prednisone (CVP)
- Cyclophosphamide, doxorubicin vincristine, and prednisone (CHOP)
- Hyperfractionated cyclophosphamide, vincristine, (Adriamycin), and dexamethasone (hyper-CVAD)
- Treanda (bendamustine) (5)
- Velcade (bortezomib),cyclophosphamide, doxorubicin, and prednisone.(7)
- Revlimid (Lenalidomide)(9)
- Imbruvica (Ibrutinib)(6)
For patients who respond to initial treatment, additional treatment options include maintenance Rituxan (long-term Rituxan that is given to maintain the treatment response as long as possible) or high-dose chemotherapy followed by an autologous stem cell transplant. An autologous stem cell transplant uses the patient’s own blood stem cells—collected prior to treatment—to replace the stem cells that are destroyed during high-dose chemotherapy.
If the MCL does not respond to initial treatment or later returns, patients may be treated with a different drug combination than was used originally. An allogeneic stem cell transplant (a stem cell transplant using donor stem cells) may also be an option.
Treatment of Early-Stage MCL
Treatment of Stage I or Stage II MCL may involve radiation therapy, the types of drug therapies that are also used for advanced disease, or both radiation therapy and drug therapy. Because relatively few people are diagnosed with early-stage MCL, there is limited information available about which approach is most effective.
Maintenance Therapy for Mantle Cell Lymphoma
The randomized phase 3 European MCL Elderly trial initially published in 2012 enrolled a total of 560 patients with newly diagnosed MCL who were treated with with R-CHOP or Rituxan, fludarabine, and cyclophosphamide (R-FC). Of these patients, 316 individuals who responded to treatment underwent a second randomization to receive Rituxan or interferon-alfa maintenance therapy.
After a median follow-up of 7.6 years, the median duration of survival with R-CHOP was superior at 6.4 years Among patients who responded to R-CHOP, the average time to MCL progression and overall survival duration with maintenance Rituxan were 5.4 and 9.8 years, respectively, compared with 1.9 years and 7.1 years with interferon-alfa.
Among patients treated with R-CHOP, Rituxan maintenance was still ongoing 2 years after initiation in 58% of patients and 5 years after initiation in 32% of patients. Patients should discuss the role of Rituxan maintenance with their treating physician irrespective of initial therapy choice as it clear improves overall survival duration. (20)
Strategies to Improve Treatment & Research Updates
Researchers continue to develop and test new approaches to treatment of MCL including new drug development and combinations, stem cell transplant, CAR T cell therapy, and newer precision cancer medicines. Patients should discuss how clinical trials fit into the overall management of their MCL with their oncologist.
Calquence (acalabrutinib) is an inhibitor of Bruton tyrosine kinase. . The drug works by permanently binding BTK, which is part of a chain of proteins that relays growth signals from the surface of B cells to genes in the cell nucleus enabling cancer cells to survive and grow. Drugs that block BTK stop the flow of these growth signals and the B cells die. Unlike Imbruvica, the first BTK approved data reported from a clinical study suggests that Calquence may more selectively block the BTK pathway and avoid some known side effects. (4)
The approval of Calquence was based on the results from a single clinical trial that included 124 patients with mantle cell lymphoma who had received at least one prior treatment. Overall, 81 percent of patients had a complete or partial response (40 percent complete response, 41 percent partial response).
Common reported side effects of Calquence included headache; diarrhea; bruising; fatigue and muscle pain (myalgia); and reduced levels of red blood cells (anemia), platelets (thrombocytopenia) and neutrophils (neutropenia) in the blood. Additional cancers, known as second primary malignancies, have occurred in some patients taking Calquence, and women who are breastfeeding should not take Calquence because it may cause harm to a newborn baby.
Imbruvica is a targeted agent that works by inhibiting the enzyme needed by the cancer to multiply and spread. The drug’s approval was based on the results of a study that included 111 patients with MCL who were given Imbruvica daily until their disease progressed or side effects became intolerable. Results of the study indicated that nearly 66 percent of patients experienced an objective response—meaning their cancer shrank or disappeared after treatment.
Imbruvica + Rituxan
A total of 40 treatment-naïve patients with indolent clinical forms of MCL were enrolled in a trial evaluating Rituxan + Imbruvica. Patients were treated for 2 years and therapy was discontinued if they were negative for evidence of minimal residual disease (MRD) for at least 6 months.
Overall 75% of patients had a complete response to treatment and undetectable MRD was achieved after 12 cycles in 87% of these patients. (17) These results have been confirmed by another trial and provide the option of a "chemotherapy free" treatment approach for early and later stage patients. (19)
The most common side effects reported in participants receiving Imbruvica are low levels of platelets in the blood (thrombocytopenia), diarrhea, a decrease in infection-fighting white blood cells (neutropenia), anemia, fatigue, musculoskeletal pain, swelling (edema), upper respiratory infection, nausea, bruising, shortness of breath (dyspnea), constipation, rash, abdominal pain, vomiting, and decreased appetite. Other clinically significant side effects include bleeding, infections, kidney problems and the development of other types of cancers.
Velcade® approved for mantle cell lymphoma was based on the PINNACLE trial, which included patients with mantle cell lymphoma who had received at least one prior therapy. The following results were reported from this trial. Overall anticancer responses were achieved in 31% of patient and the median duration of response to therapy was 9.3 months. The most common side effects were lack or loss of bodily strength, changes in nerve sensation, constipation, diarrhea, nausea, and decreased appetite.
Stem Cell Transplant “mini” stem cell transplants appear highly effective in the treatment of recurrent mantle cell lymphoma. One type of therapeutic approach that is associated with higher rates of sustained remission (disappearance of detectable cancer) than conventional therapy is high-dose therapy and an allogeneic stem cell transplant.
High doses of therapy are used to kill more cancer cells than conventional doses; however, the high doses also tend to damage healthy cells, such as blood cells. Therefore, a patient’s own stem cells (immature blood cells) can be re-infused following therapy (autologous), or a donor’s stem cells can be infused following therapy (allogeneic). An advantage to an allogeneic stem cell transplant is the properties of the donor stem cells to recognize the patient cancer cells as foreign, and mount an attack against them (graft-versus-lymphoma effect). Unfortunately, the donor stem cells may also recognize the patients’ healthy cells as foreign and mount an attack on these cells, resulting in a potentially life-threatening condition called graft-versus-host disease.
Researchers from the MD Anderson Cancer Center conducted a clinical trial to evaluate non-myeloablative "mini" allogeneic stem cell transplants in the treatment of recurrent mantle-cell lymphoma. A complete disappearance of detectable cancer (complete remission) was achieved in 17 patients. At an average of over 26 months follow-up, progression-free survival was 82%. No patients had died up to 100 days following treatment, and treatment was generally well tolerated.(10-13)
A CAR T-Cell Option for Mantle Cell Lymphoma
Ninety-three percent of patients with relapsed/refractory MCL responded to treatment with KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, according to results from the ZUMA-2 trial presented at the 2019 ASH Annual Meeting. (18)
CAR therapies utilize T-cells (CART T), a patient’s own immune cells that are re-programmed to recognize and kill cancer cells throughout the body. The process involves the removal of some T cells from a patient, and through laboratory processes, these T cells are re-programmed to identify a patient’s cancer cells.
Once the T cells have been programmed to identify a patient’s cancer cells, they are replicated in the laboratory, and infused back into the patient. These re-programmed T cells circulate throughout the body, identifying the cancer cells and mounting an immune attack against them. Simultaneously, the T cells are replicating within the body, so that more of the immune cells can identify and attack the cancer cells.
The ZUMA-2 clinical trial treated 74 patients with relapsed/refractory MCL who had received up to five prior lines of therapy, including an anti-CD20 antibody, chemotherapy, and a BTK inhibitor with a single infusion of KTE-X19 at a target dose of 2×106 CAR T cells/kg.
Findings for the first 60 treated patients with a median follow-up of 12.3 months were reported at ASH.
- 93% overall response rate - 67% complete response
- One-year overall survival of 83%
- Cytokine release syndrome (CRS) in 91% a median of two days after KTE-X19 administration – all resolved.
Although longer-term follow-up is needed to confirm these early study findings CAR T cell therapy appears to be a promising new treatment option for individuals with relapsed or recurrent MCL.
Radioimmunotherapy (RIT) is a type of biological therapy that uses two separate strategies to target and kill cancer cells: radioactive isotopes and monoclonal antibodies. Monoclonal antibodies are proteins that can be produced in a laboratory and are able to identify specific antigens (proteins and/or carbohydrates) on the surface of certain cells such as cancer cells, and bind to them. This binding stimulates the immune system to attack the cells to which the monoclonal antibody is bound. When the monoclonal antibody binds to cancer cells, the attached radioactive isotope spontaneously emits radiation, destroying the cancer cells in its vicinity. RIT not only provides two separate treatment strategies, but also allows the delivery of greater amounts of radiation to the cancer cells while minimizing radiation exposure to normal cells.
Researchers from Germany reported the result of a small clinical trial to evaluate the efficacy of RIT in 12 patients with relapsed mantle cell lymphoma. Following therapy, 7 of 8 patients treated with high doses achieved a complete disappearance of cancer (remission) and one achieved a partial remission. At the time of trial publication 6 of the 8 patients who achieved a complete remission were still in complete remission and 7 of the 8 patients were alive 42 months from treatment.(14,15)
Epigenetic Therapy An epigenetic/immunotherapy regimen of cladribine, Rituxan® and vorinostat produced a 100 percent response rate and complete remissions in 86 percent of patients with newly diagnosed mantle cell lymphoma.16
The combination of cladribine (a purine analogue and hypomethylating agent with known epigenetic activity) and Rituxan (a targeted agent known as a monoclonal antibody) had been shown to be effective in mantle cell lymphoma. As a result of the synergistic effect of these two agents, researchers decided to add vorinostate, which is part of a class of drugs known ashistone deacetylase inhibitors.
The researchers conducted a phase II study that included 37 patients with newly diagnosed mantle cell lymphoma. The patients’ median age was 64 and 95 percent of patients had Stage IV disease. Patients received the three-drug combination every 28 days for up to six cycles. Responses were evaluated after two and six cycles. The results indicated a 100 percent overall response rate—meaning every patient experienced a response to the treatment. What’s more, 86 percent of patients experienced complete remission and 14 percent had a partial remission.
The majority of side effects were hematologic and reversible and included neutropenia, thrombocytopenia, fatigue, anorexia, and dehydration. There was one death during the study—a patient with relapsed, refractory mantle cell lymphoma with extensive pulmonary involvement, who died of pulmonary hemorrhage.
At a median follow up of 14.7 months four patients have relapsed and three have died. Of the relapsing patients, two had blastic MCL. No patient achieving a complete response has relapsed.
- Shah BD, Martin P, Sotomayor EM. Mantle cell lymphoma: a clinically heterogeneous disease in need of tailored approaches. Cancer Control. 2012;19:227-235.
- National Cancer Institute. What You Need to Know About™ Non-Hodgkin Lymphoma. 2008.
- Leukemia and Lymphoma Society. Mantle Cell Lymphoma Facts. July 2012.
- Vose JM. Mantle cell lymphoma: 2012 update on diagnosis, risk-stratification, and clinical management. American Journal of Hematology. 2012;87:605-609.
- J Clin Oncol. 2019 Feb 27. Epub ahead of print
- FDA approves Imbruvica for rare blood cancer. [FDA News Release]. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374761.htm
- Kahl B, Bernstein S, Fisher R. Multicenter Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma. Journal of Clinical Oncology. 2006;24:4867-4874.
- Millennium Pharmaceuticals. FDA Approves VELCADE® (Bortezomib) for Injection for Aggressive Form of Non-Hodgkin’s Lymphoma. Available at: http://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsmediaArticle&ID=940527&highlight=. Accessed December 2006.
- Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. Journal of Clinical Oncology. 2008;26:4952-4957.
- Thieblemont C, Antal D, Lacotte-Thierry L et al. Chemotherapy with rituximab followed by high-dose therapy and autologous stem cell transplantation in patients with mantle cell lymphoma. Cancer. 2005;104:1434-41.
- Khouri I, Lee M, Saliba R, et al. Nonablative allogeneic stem cell transplantation for advanced/recurrent mantle-cell lymphoma, Journal of Clinical Oncology. 2003;21:4407-4412.
- Pott C, Schrader C, Gesk S, et al. Quantitative Assessment of Molecular Remission after High-Dose Therapy with Autologous Stem Cell Transplantation Predicts Long-Term Remission in Mantle Cell Lymphoma. Blood. 2006; 107: 2271-2278.
- Smith MR, Li H, Gordon L et al. Phase II Study of Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Immunochemotherapy Followed by Yttrium-90–Ibritumomab Tiuxetan in Untreated Mantle-Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499. Journal of Clinical Oncology. 2012;30:3119-3126.
- Behr T, Gotthardt M, Schipper M, et al. High-dose myeloablative versus conventional low-dose radioimmunotherapy (RIT) of mantle cell lymphoma (MCL) with the chimeric anti-CD20 antibody C2B8. Proceedings from the 49th Annual Meeting of the Society of Nuclear Medicine. Los Angeles, CA. June, 2002.
- Hasanali Z, Sharma K, Spurgeon S, et al. Combined epigenetic and immunotherapy produces dramatic responses in 100% of newly diagnosed mantle cell lymphoma patients. Presented at the 2013 Annual Meeting of the American Association of Cancer Research in Washington DC, April 6-10, 2013. Abstract LB-140.
- Gine E, de Fatima De La Cruz M, Grande C, et al. Efficacy and Safety of Ibrutinib in Combination with Rituximab As Frontline Treatment for Indolent Clinical Forms of Mantle Cell Lymphoma (MCL): Preliminary Results of Geltamo IMCL-2015 Phase II Trial. Presented at: the 2019 ASH Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 752.
- Wang ML, Munoz J, Goy A, et al. KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients (Pts) With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results of the Phase 2 ZUMA-2 Study. Abstract #754. Presented at the 2019 ASH Annual Meeting, December 9, 2019; Orlando, FL.
- J Clin Oncol. 2019 Dec 5. Epub ahead of print