A New Entity?
Cytogenetics and Pathology
Clinical Presentations and Treatment Results
Prognosis and Future Prospects
Mantle cell lymphoma (MCL) is a malignancy composed of cells that have normal counterparts found in the mantle zone of the lymph node, a thin area surrounding individual follicles. These cells have small to medium sized nuclei, which are often indented, or folded in the middle (cleaved), and have certain markers such as CD5, CD20, and FMC7 on their surface. They are occasionally confused with the cells of small lymphocytic lymphoma (SLL). Previously, because of microscopic similarities, these lymphomas were also considered to be related to the cells of chronic lymphocytic leukemia and the so-called “poorly differentiated” cells formed in biopsies of follicular lymphomas, disease that are considered slow-growing. Because of the microscopic resemblance to these other lymphomas, MCL was also considered to behave like an indolent lymphoma. Its behavior was not thoroughly investigated until the 1990s, after it became clear that an oncogene, the bcl-1, was a marker for this disease. Investigators now recognize that this malignancy is a discrete entity, apparently unrelated to small lymphocytic lymphoma or small cleaved cell lymphoma, and has a prognosis quite different from these two malignancies.
Bcl-1, also known as PRAD-1 and Cyclin-D1, is a normal gene located on chromosome 11 and is normally responsible for production of a protein, also known as cyclin-D1, which, along with other cyclins, promotes growth of normal and tumor cells. When this protein is normally produced by the bcl-1 gene, the protein makes normal lymphocytes grow and reproduce. However, in the case of MCL, the malignant cell has somehow developed abnormal exchange of DNA on chromosome 11 for DNA found on chromosome 14. This exchange of DNA or genetic material, is called a translocation, and when it occurs, it may be responsible for abnormal functioning of the cell by causing overproduction of cyclin-D1. In the case of MCL, the normal gene bcl-1, because it is abnormal in its overproduction of its protein, becomes known as an oncogene, because it is related to development of the cancer. Interestingly, other genes may also be translocated along with bcl-1: some of these are responsible for rendering chemotherapy agents less effective, and may be associated with development of resistance of lymphoma cells to drugs used to treat patients with these diseases.
Health
Under the microscope, MCL has four recognizable forms: in one type, known as mantle zone lymphoma, the malignant cells are limited to the zone surrounding normal follicular centers. This type may be slow growing in behavior and very responsive to standard chemotherapy. However, the other three types, including nodular and diffuse forms, in which the cells assume a “pseudofollicular” or diffuse pattern throughout the node, and the blastic variant, resembling a transformation similar to that seen in follicular lymphomas, carry poor prognoses in many cases with median survivals of three to four years.
Clinical Presentations and Treatment Results
MCL accounts for five to seven percent of adult non-Hodgkin’s lymphomas in the United States and Europe. It predominantly affects older males and initially appears to be an indolent disease, often with multiple enlarged (two to five centimeters) nodes, marrow involvement, usually with five to ten percent of the marrow space occupied by the disease, and involvement of the spleen. Gastrointestinal involvement is frequent, especially in the colon and stomach; however, it is usually only seen under the microscope, and rarely causes symptoms. In some patients, the disease initially appears to be aggressive, with bulky masses (seven to ten centimeters), extensive involvement of the bone marrow with cells spilling into the blood, like a leukemia, and resistance to standard drugs. Patients with the blastic type may even have signs of central nervous system involvement. However, most patients with MCL will have no or minimal symptoms in spite of having evidence of extensive disease. Initial serum levels of lactate dehydrogenase (LDH) and beta-2 microglobulin are elevated in 26 percent and 52 percent of patients, respectively, and are considered to be tests that measure the aggressiveness of these diseases. The Ki-67, a test performed on tissue biopsies, also measures rapidity of growth and is greater than 10 percent in more than 60 percent of the patients.
In a study conducted in Europe, investigators compared results of treatment of patients with MCL and those reported for intermediate grade and indolent lymphomas. Patients with MCL had a pattern of continual relapse after initial therapy, similar to that seen with indolent lymphomas and yet much faster than slow growing diseases perhaps more similar to that of aggressive lymphomas. In a study conducted by the Southwest Oncology Group, patients with the nodular form had a disease that seemed to be more slowly growing than that reported for the diffuse forms when treated with standard chemotherapy, including CHOP. Others have also reviewed the data on therapy using standard CHOP and COP chemotherapy from their own institutions, and have concluded that standard CHOP therapy does not cure most patients with this type of lymphoma. Recently, investigators have reported results using CHOP and the Rituxan® antibody as initial treatment for MCL. Unfortunately, in this setting, and with these patients, there was no definite improvement over results reported with CHOP alone.
Because of the success of purine analogs, including fludarabine (Fludara®), 2-CDA (Leustatin®), and Pentostatin (Nipent®) in therapy of indolent lymphomas, investigators have used these drugs to treat patients with mantle cell lymphomas. Results have been disappointing not only for patients in relapse, but also when the drugs were used as initial therapy. Investigators have also used standard chemotherapy regimens to induce a complete or partial response, and have then given further intensive chemotherapy and stem cell rescue (SCT), using the patient’s own stem cells. However, as is the case in management of many patients with follicular lymphomas, standard chemotherapy regimens do not often render the blood or bone marrow free of submicroscopic involvement by MCL. Therefore, it is not surprising that patients who undergo autologous SCT, using their own stem cells as rescue, often have recurrence of the disease, since malignant cells may be infused with the patient’s own stem cells following high-dose therapy. Investigators have tried to purge, or get rid of the stem cells of submicroscopic lymphoma involvement, but so far, this technique has been mostly ineffective for MCL. Another way of avoiding tumor contamination of stem cells is to use a matched donor’s marrow or blood stem cells, known as allogeneic transplant, usually from a brother or sister. However, this method of therapy is very risky in persons over 50 when high doses of chemotherapy are used in conjunction with the transplant, because of a high incidence of graft-versus-host-disease (GVHD).
In 1991, because of poor results obtained with CHOP in treatment of MCL, investigators at M.D. Anderson Cancer Center began treating relapsed patients with a regimen designed for patients with poor-risk leukemia known as Hyper-CVAD. This regimen incorporates high dose cyclophosphamide given every 12 hours for six doses as a “fractionated” method, and a continuous intravenous infusion of doxorubicin, plus vincristine and dexamethasone, alternated with high doses of cytosine arabinoside (Ara-C) and methotrexate (Mtx).
We have analyzed our findings of therapy for 28 patients in relapse with the disease. The median age was 60 years; 24 of the patients were less than 66 years of age, and 20 of these underwent SCT following treatment with Hyper-CVAD. Thirty percent of the patients who completed treatment remain free of disease, and 50 percent are alive at 3 years. Eight patients over the age of 66 did not receive SCT. Twenty percent of these patients are free of disease. Reasons for lower response rates in older patients in relapse may be due to decreased doses of Ara-C and Mtx, decreased immune function in older patients, or the lack of SCT in these patients.
So far, we have used Hyper-CVAD in 37 patients with previously untreated MCL who are 65 years or younger. The following table summarizes the response rates seen in this study and compares them with those we have observed in the past with CHOP.
| Treatment | Number of Patients | Complete Response | Partial Response | Failure-free Survival at 4 Years | Overall Survival at 4 Years |
| CHOP | 26 | 6 (23%) | 16 (61%) | 10% | 30% |
| Hyper-CVAD | 37 | 33 (89%) | 3 (8%) | 79% | 90% |
Because of the success observed with Hyper-CVAD, we are currently investigating the value of adding Rituxan to the Hyper-CVAD regimen. Patients who enter complete remission after two weeks of therapy are treated with Hyper-CVAD alone. Patients who are still in partial remission undergo SCT after six cycles.
Finally, we have recently reported results of therapy for 16 patients with MCL in relapse using “mini” allogeneic transplant, with stem cells from a sibling and “mini” doses of chemotherapy. The average age of these patients was 52 years and the range was 30 to 60. Eight of the 10 patients with lymphoma sensitive to chemotherapy remain free of disease, whereas only 2 of the six with disease considered resistant to chemotherapy remain free of disease. Although the number of patients in this study is small, there is a possibility that Hyper-CVAD followed by allogeneic SCT may be more appropriate therapy than autologous SCT for patients with MCL.
Prognosis and Future Prospects
With standard CHOP therapy, the median survival for patients with MCL is in the range of two to five years. Intensive therapies, including Hyper-CVAD and autologous transplant, may represent significant advances over CHOP in the management of this disease, but newer treatments for patients over 65, and newer drugs are needed before more patients with this disease can be cured. The use of non-myeloablative or “mini” allogeneic transplants is being explored as a way of addressing this problem. Incorporation of Rituxan® into this regimen and eliminating transplantation is also a new avenue for research and should be investigated further in larger numbers of patients. Finally, new therapies for B-cell indolent and aggressive lymphomas are also being studied in MCL, including vaccine therapies, and trials which study antisense bcl-2 in therapy of lymphomas should also include patients with MCL. For example, a specific vaccine trial is underway at the NCI, using a vaccine developed specifically for each patient. This trial and others using vaccines may result in protecting the patient from developing relapse, after entering remission following chemotherapy, but may also prove beneficial in therapy of relapsed disease. Antisense bcl-2, one of a group of small molecules which may work by suppressing expression of bcl-2, or protein which often prevents lymphoma cells from dying, is also in early trials; patients with MCL will benefit by all research directed at new avenues such as these, designed to help patients with all types of B-cell lymphomas.
For additional reading references, please contact LRFA at (310) 204-7040 or helpline@lymphoma.org.
Fredrick Hagemeister, MD, is an Internist, a Professor of Medicine and Chief of the Lymphoma Section, Lymphoma Section of the Department of Lymphoma/Myeloma, Division of Medicine of the M.D. Cancer Center.
Mantle Cell GlossaryNodular Mantle Cell Lymphoma
Diffuse MCL
Blastic MCL
Beta-2 Microglobulin
Lactate Dehydrogenase (LDH)
Graft-Versus-Host-Disease (GVHD)
Nodular mantle cell lymphoma: a type of MCL where the malignant cells are distributed within "nodules," which are spherical structures inside the lymph glands.
Diffuse MCL: a type of MCL in which the malignant cells are distributed in a diffuse fashion within the lymph gland. This type of MCL invades the lymph gland without arranging itself into nodules.
Blastic MCL: This refers to a type of MCL that contains immature-looking cells that resemble cells known as a blasts.
Beta-2 microglobulin: A portion of a molecule that is found on nearly all cells. Elevated levels can indicate the presence of certain diseases.
Lactate Dehydrogenase (LDH): An enzyme detected in the blood. In lymphoma, an increase in LDH levels sometimes correlates with the presence and/or increase of tumor cells.
Graft-versus-host-disease (GVHD): A serious complication of allogeneic stem cell transplantation that occurs when the donor’s immune cells attack the patient’s normal tissue.
