Mantle cell lymphoma

Mantle cell lymphoma

What every physician needs to know:

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin’s lymphoma, comprising approximately 7% of all cases. The median age of patients at diagnosis is 65 and males represent 75% of cases. The vast majority of patients present with stage IV disease, and the gastrointestinal tract, Waldeyer’s tonsillar ring, bone marrow, and spleen are commonly involved.

MCL is not curable with combination chemotherapy. The median overall survival is 6 to 7 years, which is significantly shorter compared to indolent subtypes of non-Hodgkin’s lymphoma, such as follicular lymphoma. Intensive chemotherapy with or without consolidation with autologous stem cell transplant prolongs progression free survival in younger patients, and allogeneic stem cell transplantation may result in long term disease control in highly selected patients.

Are you sure your patient has mantle cell lymphoma? What should you expect to find?

Patients with mantle cell lymphoma typically present with diffuse lymphadenopathy, splenomegaly and bone marrow infiltration. Atypical lymphocytes may be seen in the peripheral blood. Given that the gastrointestional tract is frequently involved by disease, patients may present at the time of screening colonoscopy with diffuse, small polyps (lymphomatoid polyposis) in the bowel. Patients may present with fevers, night sweats or weight loss.

An adequate tissue biopsy is critical for the diagnosis of mantle cell lymphoma. A fine needle aspirate may be highly suggestive of mantle cell lymphoma, but an excisional biopsy allows for the subtyping of mantle cell lymphoma. There are several morphologic subtypes of MCL, including the mantle zone, blastoid variant and the pleomorphic variants.

Typical MCL is comprised of small to medium sized lymphoid cells with irregular nuclei. The mantle zone variant is comprised of cells which resemble the normal cells occupying the lymph node mantle zone. The blastoid variant contains lager malignant cells, resembling lymphoblasts, and the pleomorphic variant is typified by small to intermediate cells with admixed large, atypical cells. MCL typically expresses CD20, CD5 and cyclin D1, and is negative for CD23. In rare cases, CD5 is negative. The majority of cases harbor the t(11;14) chromosomal translocation, which is not specific for MCL.

Beware of other conditions that can mimic mantle cell lymphoma:

MCL can mimic a number of other subtypes of non-Hodgkin’s lymphoma.

MCL can present with prominent splenomegaly with circulating atypical lymphocytes, mimicking the clinical presentation of chronic lymphocytic leukemia. In these cases, the malignant cells may harbor chromosomal abnormalities seen in chronic lymphocytic leukemia (CLL), such as deletion 13q and deletion 17p, in addition to the typical t(11;14) found in MCL. CLL has dim CD20 expression and is CD23 positive, compared to MCL, which is CD20 bright and CD23 negative. Like MCL, marginal zone lymphoma can present with involvement of the gastrointestinal tract or with splenomegaly and circulating disease.

Morphologically, both entities can present with small lymphoid cells. Marginal zone lymphoma is cyclin D1 negative and typically lacks CD5 expression. Morphologically, MCL can also have nodular appearance, resembling follicular lymphoma (FL). The immunophenotypes of the two diseases are distinct. The majority of FL cases express CD10 but are negative CD5 and cyclin D1. The blastoid variant of MCL has a high proliferation index, and the lymphoid cells may mimic the appearance of lymphoblasts seen in lymphoblastic lymphoma.

Which individuals are most at risk for developing mantle cell lymphoma:

There are no clear predisposing factors for mantle cell lymphoma. The disease affects significantly more men than women. As with other subtypes of non-Hodgkin lymphoma, there may be an increased risk in patients who have a positive family history of lymphoma.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Patients with mantle cell lymphoma should have a complete blood count with differential, and an evaluation of renal and liver function.

Lactate dehydrogenase (LDH) and beta-2 microglobulin are important in determining the prognosis of MCL.

For patients with a high burden of disease or blastoid variant MCL, a uric acid should be measured to determine the risk of tumor lysis syndrome.

Hepatitis B serologies should be obtained in all patients who will receive therapy with rituximab, given the risk of viral reactivation associated with chemoimmunotherapy.

A bone marrow biopsy should be performed as part of the staging evaluation.

Routine sampling of cerebral spinal fluid is not typically indicated in the absence of clinical signs or symptoms, though patients with the blastoid variant are at higher risk of involvement of the central nervous system.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of mantle cell lymphoma?

Computed tomography (CT) scans of chest, abdomen and pelvis should be obtained as part of the staging evaluation. A neck CT may be helpful under certain circumstances, though lymphadenopathy involving the neck and involvement of Waldeyer’s tonsillar ring may be appreciated on examination in many cases. Positron emission tomography is also a useful imaging modality in this disease. MCL is nearly uniformly fluorodeoxyglucose (FDG) avid and may highlight areas of disease, including the gastrointestinal tract, which may not be evident on CT scans. Evaluation of the gastrointestional tract (GI) with upper and lower endoscopies may be useful to fully stage patients.

If you decide the patient has mantle cell lymphoma, what therapies should you initiate immediately?

Patients with MCL do not typically require urgent therapy for bulky or symptomatic disease. Rarely, patients with involvement of the GI tract may present with intussusception or bowel obstruction. In addition, patients may occasionally present with splenic rupture requiring emergent surgery. The blastoid variant is more likely to present with rapidly progressive disease. Steroids may temporize symptoms until more definitive therapy can be initiated.

More definitive therapies?

Because MCL is a rare disease, there are few randomized studies to guide initial therapy and clinical trial participation is encouraged. A subset of patients, typically those with low volume, asymptomatic disease who often present with disease circulating in the peripheral blood and splenomegaly, those with a low Ki-67 fraction or with mantle zone histology on pathologic review, may have a more indolent course. These patients may be candidates for observation, as demonstrated by a study from Cornell, which examined the role of observation in selected patients and showed no adverse impact on overall survival.

CHOP (Cytoxan, doxorubicin, vincristine and prednisone) in combination with the anti-CD20 antibody, rituximab, has a very high response rate in MCL. Fewer than half of patients, however, achieve a complete remission and the time to treatment failure is disappointing, at less than 2 years. For younger patients without significant co-morbidities, more aggressive approaches are typically advocated.

Rituximab plus hyper-CVAD (hyperfractionated Cytoxan, vincristine, adriamycin and dexamethasone alternating with methotrexate and high dose cytarabine) is highly active in MCL and a large single institutional study demonstrated overall response rate and complete remission rates of approximately 100% and 87% respectively. The 3 year failure free and overall survival rates were 64% and 82%. For patients 65 years of age or younger, the 3 year failure free survival was 73%. The combination, however, is highly myelosuppressive, and infectious complications are common. When the regimen was administered in the cooperative group setting by the Southwest Oncology Group, approximately half of patients received all planned therapy and median progression free and overall survival were 4.8 and 6.8 years respectively.

An alternative approach to the initial therapy of MCL employs consolidation of patients in first remission, using high dose chemotherapy with autologous stem cell rescue. A randomized study from Germany assigned patients with advanced stage MCL to interferon-alpha versus autologous stem cell transplant (ASCT) following initial chemotherapy (CHOP or CHOP-like with or without rituximab). The median progression free survival was significantly longer in the ASCT group at 29, versus 17 months without a difference in overall survival. A subsequent study evaluated dose-intensified RCHOP (CHOP plus rituximab) alternating with rituximab and cytarabine followed by ASCT in responding patients. The 4 year event free and overall survival were 63% and 81% respectively.

A recent preliminary study from France randomized patients to RCHOP versus RCHOP alternating with RDHAP (Rituxan, dexamethasone, cytarabine, cisplatin) followed by ASCT. Both progression free survival and overall survival were superior in the latter arm.

For older patients with co-morbidities or those who are not candidates for ASCT, RCHOP alone does not result in durable control of disease. Bendamustine plus rituximab is a highly active regimen and the preliminary results comparing this regimen to RCHOP, revealed a benefit in progression free survival in the bendamustine arm. A randomized study from Europe compared RCHOP to FCR (fludarabine, Cytoxan, rituximab) with a second randomization to interferon versus rituximab maintenance. RCHOP was superior to FCR, and was significantly better tolerated than FCR. In addition, there was a benefit in terms of progression free survival in those patients receiving rituximab maintenance.

For patients with recurrent disease: ibrutinib, an oral inhibitor of BTK (Bruton’s tyrosine kinase) was recently approved in relapsed/refractory mantle cell lymphoma with overall and complete response rates of 68% and 21% respectively with median PFS of approximately 14 months. Bortezomib, lenalidomide, and temsirolimus are active drugs with more than 30 to 50% of patients responding to single agent therapy. Bendamustine is a highly active agent in this setting and may be combined with rituximab. In addition, second line chemotherapy regimens typically used in aggressive lymphomas, such as: RICE (rituximab, ifosfamide, carboplatin, etoposide), RDAP (rituximab, dexamethasone, cytarabine, Cisplatin), Rgem-ox (rituximab, gemcitabine, oxaliplatin) are also active regimens. For younger patients with chemotherapy sensitive disease, reduced intensity allogeneic stem cell transplant may offer the possibility of long term disease control. Graft-versus host disease and infectious complications, however, may cause significant short and long term morbidity and mortality.

What other therapies are helpful for reducing complications?

Patients with significant tumor burden, as evidenced by bulky disease, an elevated LDH and/or high uric acid level, should receive allopurinol for tumor lysis prophylaxis. Rasburicase should be administered in the rare event that a patient develops frank tumor lysis. In patients over 65 receiving aggressive chemoimmunotherapy regimens, white blood cell growth factors (Neupogen or pegfilgrastim) should be employed to reduce the rates of febrile neutropenia.

In addition, patients receiving bendamustine are at increased risk for varicella zoster reactivation and patients receiving fludarabine are at risk for both Pneumocystis jiroveci pneumonia and zoster and these patients should receive appropriate prophylaxis.

What should you tell the patient and the family about prognosis?

Mantle cell lymphoma is not curable with conventional chemoimmunotherapy. Overall, the median survival is approximately 6 to 7 years. For younger patients, aggressive chemotherapy with or without consolidation with high dose chemotherapy and stem cell rescue prolongs progression free survival, compared to standard therapy with a median of more than 5 years. For patients with chemotherapy responsive disease, allogeneic stem cell transplant, typically employing reduced intensity conditioning regimens, may offer long term control of disease with 3 year progression free survival rates in the 30 to 50% range. The toxicity of this approach, however, is significant with non-relapse mortality at 1 year of greater than 10% and up to 50% of patients will develop chronic graft-versus host disease.

The Mantle Cell Lymphoma International Prognostic Index is a strong predictor of outcome and has been validated in multiple studies. In the simplified version, patients receive points based on age, ECOG (Eastern Cooperative Oncology Group) performance status, LDH, and white blood cell count. Patients are then divided into low, intermediate, and high risk groups with median survivals of “not reached”, “51 months”, and “29 months” respectively.

The Ki-67 fraction is also a strong predictor of outcome with patients in the less than 10% range having the most favorable outcome. Patients with Ki-67 fractions between 10 and 30%, have an intermediate prognosis and those at greater than 30%, have the most unfavorable outcomes. In addition, the blastoid variant of MCL, which typically has a high Ki-67 fraction has a clinically aggressive course and is also associated with a higher risk of relapse in the central nervous system (CNS).

What if scenarios.

What if a patient relapses following high dose chemotherapy and autologous stem cell rescue?

There are a number of active chemotherapy agents for patients with relapsed disease, including ibrutinib, bortezomib, lenalidomide, and bendamustine, as well as combination regimens used in aggressive lymphomas. For younger patients without significant co-morbidities, patients whose disease responds to chemotherapy may be candidates for reduced intensity allogeneic stem cell transplantation.

What if a patient develops disease involving the central nervous system?

Patients should receive high dose methotrexate or cytarabine based regimens which achieve adequate CNS penetration with or without intrathecal chemotherapy for leptomeningeal involvement. If a patient has a favorable response to therapy, stem cell transplantation should be considered.

Pathophysiology

The majority of cases of MCL are thought to arise from pre-germinal center B-cells, that demonstrate rearranged heavy and light chain genes, typically without somatic hypermutation. A subset of cases, however, may be derived from B-cells which are antigen experienced as evidenced by somatic hypermutation.

The vast majority of cases of MCL harbor a translocation t(11;14)(q13;q32), juxtaposing the cyclin D1 (BCL-1, CCND1 or PRAD1) locus and the immunoglobulin heavy chain gene locus on chromosome 14, leading to over expression of cyclin D1, which regulates the G1 phase of the cell cycle. Standard cyotogentics identify the t(11;14) translocation in approximately half of cases, but the vast majority of cases will be positive by fluorescence in situ hybridization.

A very small subset of cases express cyclin D2, as opposed to cyclin D1, but overexpression of SOX11 is seen in both groups. Additional genetic events that inactivate the normal pathways of response to DNA are common. The PI3K/AKT/mTOR and nuclear factor kappa-light-chain-enhancer of activated B cell (Nf-kappa B) pathways also appear to be important in the pathogenesis of MCL.

The majority of cases of the blastoid variant harbor additional cytogenetic abnormalities, with frequent mutations involving p53. In addition, abnormalities in genes involved in the cell cycle, such as p16, p17 and p27, are common. Copy number changes have also been frequently identified in mantle cell lymphoma, particularly gains in 3q and 6p and losses of 13q.

What other clinical manifestations may help me to diagnose mantle cell lymphoma?

Mantle cell lymphoma frequently involves the gastrointestional tract. Patients undergoing routine colonoscopy are rarely found to have diffuse small polyps, which on pathologic examination demonstrate involvement by MCL. Patients with involvement of Waldeyer’s tonsillar ring have a particularly high risk of gastrointestinal (GI) involvement.

Typically, patients with MCL present with asymptomatic, diffuse lymphadenopathy, and splenomegaly, but may also develop fevers, night sweats, or weight loss, particularly in patients with a high disease burden or with blastoid variant. Involvement of the CNS is very rare at presentation with MCL but is more common in patients with the blastoid variant.

Occasionally, patients will present in with a significant lymphocytosis with or without splenomegaly and lymphadenopathy mimicking the presentation of CLL. The immunophenotype (CD20 bright with absent CD23) and flourescence in situ hybridization (FISH) cytogenetics demonstrating a t(11;14) are critical for establishing the diagnosis of MCL, though chromosomal abnormalities typical of CLL, such as deletions in13q and 17p may be identified in these cases.

What other additional laboratory studies may be ordered?

N/A

What’s the Evidence?

Hoster, E, Dreyling, M, Klapper, W. “A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma”. Blood. vol. 111. 2008. pp. 558(This analysis of outcome of 455 patients identified a new prognostic index predictive of survival in patients with advanced stage mantle cell lymphoma.)

Determann, O, Hoster, E, Ott, G. “Ki-67 predicts outcome in advanced-staged mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group”. Blood.. vol. 111. 2008. pp. 2385-7. (In this paper, the Ki-67 fraction was identified as an independent predictor of survival in MCL.)

Herrmann, A, Hoster, E, Zwingers, T. “Improvement of overall survival in advanced stage Mantle Cell Lymphoma”. J Clin Oncol.. vol. 27. 2009. pp. 511(This paper demonstrated a significant improvement in the overall of patients with mantle cell lymphoma treated in the 1970 ’s and 80’s compared to patients treated in the mid-90’s to 2004.)

Howard, OM, Gribben, JG, Neuberg, DS. “Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival”. J Clin Oncol.. vol. 20. 2002. pp. 1288-1294. (This is a phase two study of patients mantle cell lymphoma treated with RCHOP chemotherapy. Despite high overall and molecular completes response rates, the median progression free survival was poor at 16.6 months.)

Romaguera, JE, Fayad, L, Rodriguez, MA. “High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine”. J Clin Oncol.. vol. 23. 2005. pp. 7013-7023. (This is a phase two study of RHyper-CVAD in MCL and demonstrates a 64% 3 year failure free survival.)

Damon, LE, Johnson, JL, Niedzwiecki, D. “Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909”. J Clin Oncol.. vol. 27. 2009. pp. 6101-8. (In this phase two study of aggressive chemoimmunotherapy followed by autologous stem cell transplant in MCL a cooperative group setting, the 5 year progression free survival was 56%.)

Dreyling, M, Lenz, G, Hoster, E. “Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network”. Blood. vol. 105. 2005. pp. 2677-2684. (This randomized study demonstrated a prolongation of progression free survival in patients who received autologous stem cell transplantation compared to interferon.)

Geisler, CH, Kolstad, A, Laurell, A. “Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group”. Blood. vol. 112. 2008. pp. 2687-93. (This phase two study showed a 4 year event free survival of 63% in MCL patients treated with aggressive chemoimmunotherapy followed by autologous stem cell transplant MCL.)

Martin, P, Chadburn, A, Christos, P. “Outcome of deferred initial therapy in mantle-cell lymphoma”. J Clin Oncol.. vol. 27. 2009. pp. 1209-13. (This study demonstrates that in selected patients with MCL, deferred initial therapy is a reasonable therapeutic option.)

Perez-Galan, P, Dreyling, M, Wiestner, A.. “Mantle cell lymphoma: biology, pathogenesis and the molecular basis of treatment in the genomic era”. Blood. vol. 117. 2011. pp. 26-38. (This paper is a comprehensive review of the biology of mantle cell lymphoma and examines rationale targeted approaches to therapy.)

Wang, ML, Rule, S, Martin, P, Goy, A. “Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma”. N Engl J Med.. vol. 369. 2013 Aug 8. pp. 507-16. (This pivotal phase 2 study demonstrates remarkable activity in relapsed, refractory MCL with an overall response rate of 68%.)

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