Chapter 63: Mantle Cell Lymphomas

Mantle cell lymphoma (MCL) cells display an immunophenotype similar to lymphocytes in the mantle zone of normal germinal follicles, surface immunoglobulin (sIg) M+, sIgD+, CD5+, CD20+, CD10–, CD43+. In contrast to chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), MCL cells typically do not express CD23.

MCL had been previously classified as an intermediate-grade lymphoma and called "intermediate lymphocytic lymphoma." It also had been termed centrocytic lymphoma and previously confused with other types of lymphoma or leukemia, such as SLL, CLL, or marginal zone lymphoma.

Insight into the pathophysiology of MCL was realized with discovery of the cytogenetic abnormality t(11;14) (q13;q32) in the tumor cells, a translocation resulting in the over expression of the cell cycle regulator cyclin D1.

However, it is almost certain that additional genetic events are involved in development of the fully transformed state as low numbers of cells carrying the t(11;14) translocation have been found in the blood of some healthy individuals without any evidence of disease.

The ATM (ataxia-telangiectasia mutant) gene is mutated in approximately 40 percent of patients. ATM inactivation facilitates genomic instability in lymphoma cells through impaired response to DNA damage.

Additional genetic anomalies that could contribute to the disease include losses in chromosomes 1p13-p31, 2q13, 6q23-27, 8p21, 9p21, 10p14-15, 11q22-23, 13q11-13, 13q14-34, 17p13, and 22q12; gains in chromosomes 3q25, 4p12-13, 7p21-22, 8q21, 9q22, 10p11-12, 12q13, and 18q11q23; and high copy-number amplifications of certain chromosomal regions.

The typical presentation is that of an older patient with lymphadenopathy in several sites (e.g., cervical, axillary, inguinal).

The patient may be asymptomatic but a significant proportion may have fever, night sweats, or weight loss.

The liver may be enlarged and the spleen is enlarged in 40 percent of patients at the time of diagnosis. In 25 percent of the cases, there is symptomatic gastrointestinal involvement.

A number of adverse prognostic features of MCL have been identified, including the expression of the Ki67 proliferation antigen in a high proportion of lymphoma cells, high serum level of β₂-microglobulin in the absence of renal dysfunction, high serum levels of lactic acid dehydrogenase (LDH), presence of blastoid cytology, advanced patient age, late Ann Arbor stage, extranodal presentation, constitutional symptoms, among others.

A prognostic model called the Mantle Cell International Prognostic Index (MIPI) has been introduced, which uses four independent prognostic factors: age, performance status, LDH, and leukocyte count.

There is no consensus on the risk of central nervous system (CNS) disease in patients with MCL or the need to give CNS prophylaxis. Studies have reported an incidence of CNS of 4 percent and a 5-year actuarial risk of 26 percent.

Approximately 50 percent of patients present with blood and marrow involvement, sometimes with an overt leukemic phase, but more often with subtle involvement as detection of the malignant lymphocyte immunophenotype by flow cytometry of blood or marrow cells.

Almost all cases of MCL show overexpression of cyclin D1 mRNA. The rare cases that are negative for cyclin D1 usually overexpress cyclin D2 or D3.

MCL cells stain strongly for the antiapoptotic molecule BCL-2 and are negative for the germinal center markers CD10 and BCL-6.

The immunophenotype of MCL has some similarities to that of CLL or SLL.

In contrast to CLL or SLL, MCL cells react strongly with FMC7, a weak anti-CD20 mAb, and typically do not express CD23.

All cases of MCL express cyclin D1, typically at levels that are much higher than that of other lymphomas.

MCL is currently considered incurable but long-term remissions occur depending on the Mantle Cell International Prognostic Index (Fig. 63–1).

Localized disease is rare. Because of the presence of advanced disease at presentation, most patients require systemic therapy.

MCL is responsive to doxorubicin-containing chemotherapy, but the complete remission rates are approximately 35 percent, the duration of response is 10 to12 months, and the median survival 3 to 4 years, all of which are lower when compared with other lymphoma subtypes.

Fludarabine has been tested in a small number of untreated MCL patients and has achieved an overall response rate of approximately 40 percent with a complete remission rate of approximately 30 percent. The median overall survival (OS) in this study was 2 years.

The anti-CD20 monoclonal antibody rituximab is the most important recent addition to the therapy of lymphomas, including MCL. Rituximab alone produces an approximate 40 percent response in patients with untreated MCL. However, the lymphoma cells of some patients can lose expression of CD20 after repeated therapy.

In patients with blood involvement, the first dose of rituximab should be infused slowly and with close monitoring during initial therapy because of the risk of tumor lysis syndrome or cytokine-release syndrome.

Several studies suggest that cytarabine adds significantly to the response, as demonstrated by the difference in response between patients treated with essentially similar chemotherapeutic regimens without cytarabine (e.g., cyclophosphosphamide/adriamycin/vincristine/prednisone (CHOP) vs. dexamethasone/ high-dose cytosine arabinoside/cisplatin (DHAP).

Based on all these findings, chemotherapy for MCL is characterized by increasingly intensive combinations of therapy, including CHOP-R (plus rituximab), EPOCH-R, R modified hyper CVAD, and several others, with and without autologous hematopoietic stem cell transplantation as consolidation.

The inherent resistance of MCL to conventional doses of chemotherapy is evident at relapse. Among the studied salvage therapies, the proteasome inhibitor bortezomib has shown a 31 percent response rate as single-agent therapy. Temsirolimus is a promising mTOR inhibitor that has also shown a 38 percent overall response rate in relapsed MCL. Lenalidomide has shown a 53 percent overall response rate with 13 percent complete remissions.

Based on the radiation sensitivity of MCL, radioimmunoconjugates of anti-CD20 antibodies have shown substantial response rates in patients given the agents as initial therapy and in those with relapsed disease. However, such therapy should be considered primarily for patients who do not have extensive marrow involvement (e.g., < 15%) to avoid excessive myelotoxicity.

A reduced intensity allograft can achieve progression free survival and event-free survival rates of 40 to 80 percent and overall survival rates of 55 to 86 percent after a median follow-up of 2 to 3 years, with 5 to 30 percent acute graft-versus-host disease and 0 to 24 percent treatment-related mortality. Some experts believe that hematopoietic stem cell transplantation offers the best option for long-term remission in this disease.