Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is recognized in the Revised European-American Lymphoma and World Health Organization classifications as a distinct clinicopathologic entity. ^{[4, 5]} MCL was not recognized by previous lymphoma classification schemes; it was frequently categorized as diffuse small-cleaved cell lymphoma (by the International Working Formulation) or centrocytic lymphoma (by the Kiel classification). ^[6] In the International Lymphoma Classification Project, it accounted for 8% of all non-Hodgkin lymphomas (NHLs).

For more information, see Non-Hodgkin Lymphoma and Pediatric Non-Hodgkin Lymphoma.

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder derived from a subset of naive pregerminal center cells localized in primary follicles or in the mantle region of secondary follicles. Most cases of MCL are associated with chromosome translocation t(11;14)(q13;q32). This translocation involves the immunoglobulin heavy-chain gene on chromosome 14 and the BCL1 locus on chromosome 11.

The molecular consequence of translocation is overexpression of the protein cyclin D1 (coded by the PRAD1 gene located close to the breakpoint). Cyclin D1 plays a key role in cell cycle regulation and progression of cells from G1 phase to S phase by activation of cyclin-dependent kinases.

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL). The American Cancer Society estimates that in 2025 there will be 80,350 new NHL cases in the United States, representing approximately 4% of all cancer diagnoses. ^{[7, 8]}  MCL is a relatively uncommon form of NHL, comprising 3-10% of NHL, with an annual incidence of 0.5 to 1 cases per 100,000 population. The exact international prevalence of MCL is difficult to estimate because of the lack of uniform classification and procedures used for diagnosis.

Surveillance, Epidemiology, and End Results (SEER) data show that the incidence of MCL per 100,000 population increased from 0.711 in 2000-2006 to 0.800 in 2007-2013 (P <  0.001), due mostly to an increased incidence in patients age 65 years and older. Relative 5-year survival rates showed a modest but significant increase over that period, most notably in patients 50-64 years of age (from 61.3% to 67.4%) and in those with stage IV disease (from 48.0% to 55.1%). ^[9]

Overall, Whites are at higher risk of developing NHLs than Blacks, Hispanics, or Asian Americans. The male-to-female ratio is 1.46:1, and most cases are diagnosed in patients age 65-74 years, with median age at diagnosis being 68 years. ^[8]

No causative factor has been identified for mantle cell lymphoma (MCL) or for most other types of non-Hodgkin lymphoma (NHL). NHL has been associated with viral infection (Epstein-Barr virus, HIV, human T-lymphotropic virus type 1, human herpesvirus 6), environmental factors (pesticides, hair dyes), and primary and secondary immunodeficiency.

Nonrandom chromosomal and molecular rearrangements play a major role in the pathogenesis of many lymphomas. The association of t(11;14)(q13;q32) with MCL suggests a causative role; t(11;14) juxtaposes the CCDN1 gene with the immunoglobin heavy chain locus, leading to overexpression of cyclin D1. ^[1]

History

Findings on the history may include the following:

• Stage IV disease in 70% of patients
• B symptoms, which include fever, night sweats, and weight loss, in 40% of patients
• Generalized lymphadenopathy
• Abdominal distention from hepatosplenomegaly
• Fatigue from anemia or bulky disease
• Less common symptoms caused by extranodal involvement of gastrointtestinal (GI) tract, lungs, and central nervous system (CNS)

Physical examination

Physical examination findings include the following:

• Generalized lymphadenopathy in 90% of patients
• Splenomegaly in 60% (may be massive)
• Hepatomegaly in 30%
• Poor performance status in 20%
• Less commonly, palpable masses in skin, breast, and salivary glands

Complications

Complications from disease progression may include the following:

• Cytopenias (neutropenia, anemia, thrombocytopenia) secondary to bone marrow infiltration
• GI, pulmonary, or CNS complications secondary to extranodal involvement
• Leukocytosis (lymphocytosis) in the leukemic phase of disease

The differential diagnosis for MCL includes the following:

• Chronic Lymphocytic Leukemia
• Hairy Cell Leukemia
• Diffuse Large Cell Lymphoma
• Follicular Lymphoma
• Myeloproliferative Disease
• Follicular center cell lymphoma
• Lymphoplasmacytic lymphoma
• Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type
• Nonneoplastic hyperplasias (Castleman disease, mantle zone hyperplasia, reactive follicular hyperplasia)
• Small lymphocytic lymphoma

MCL is diagnosed in accordance with the WHO criteria for hematologic neoplasms and detection of cyclin D1 expression or the t(11;14) translocation along with mature B-cell proliferation. The National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of MCL ^[10] :

• Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, cyclin D1, CD21, CD23, Ki-67, TP53

• Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10

The following studies may be useful in select circumstances:

• Fluorescence in situ hybridization (FISH) or cytogenetics for detection of t(11;14), t(14;18), CLL panel.

• Cell surface marker analysis by flow cytometry: CD200

• TP53 sequencing in patients with typical MCL with an expected aggressive clinical course or if upfront transplantation is anticipated

• Immunohistochemistry: LEF1 is a diagnostic marker for chronic lymphocytic B-cell leukemia (CLL), so if present, it helps distinguish MCL from variant CLL; SOX11 or IGHV sequencing may be useful for determing clinically indolent MCL; may also help in diagnosis of MCL with CCND1 mutations, which promote resistance to ibrutinib

Risk stratification

The European Society for Medical Oncology (ESMO) recommends the 2008 MCL International Prognostic Index (MIPI) for risk stratification. ^[11]  The MIPI includes the following risk factors ^[12] :

• Age: 50-59 (1 point); 60-69 (2 points); ≥70 (3 points)

• Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (2 points)

• Lactate dehydrogenase level (ratio to upper limit of normal): 0.67-0.99 (1 point); 1.00-1.49 (2 points); ≥1.50 (3 points)

• White blood cell count (× 10⁹/L): 6700-9999 (1 point); 10,000-14,999 (2 points); ≥15,000 (3 points)

Based on the MIPI score, patients can be categorized as follows ^[12] :

• Low risk (0-3 points)

• Intermediate risk (4-5 points)

• High risk (≥6 points)

In addition, both the NCCN and ESMO recommend assaying Ki-67 proliferative antigen to evaluate cell proliferation. Low Ki-67 (<  30%) is associated with a more favorable prognosis; however, this finding alone is not used to guide treatment decisions. ^{[10, 11]}

The NCCN guidelines list the following as common presentations of indolent MCL (asymptomatic patients with indolent MCL may be candidates for active surveillance rather than therapy) ^[10] :

• Gastrointestinal  or blood/bone marrow involvement only
• Low tumor burden
• Ki-67 < 10%

Laboratory studies

Blood studies may yield the following results in MCL:

• Complete blood count: Anemia and cytopenias are secondary to bone marrow infiltration; lymphocytosis of more than 4000/µL occurs in 20-40% of cases
• Serum chemistry: Elevation of lactate dehydrogenase levels correlates with tumor burden
• Liver function tests: Abnormal findings result from liver involvement
• Beta2-microglobulin: An elevated level indicates a poor prognosis
• Gamma globulin: Hypogammaglobulinemia or monoclonal gammopathy are rare findings
• Coombs test: Rarely positive

Computed tomography

Body CT scanning is important for initial staging and for assessing the patient's response to treatment.

Immunocytochemistry

Tumor cells are monoclonal B cells that express surface immunoglobulin, immunoglobulin M, or immunoglobulin D. Cells are characteristically CD5⁺ and pan B-cell antigen positive (eg, CD19, CD20, CD22) but lack expression of CD10 and CD23. Cyclin D1 is overexpressed. Immunophenotyping helps differentiate MCL from other small B-cell lymphomas (see the Table, below). ^[13]

Table. Differential Diagnosis of Mantle Cell Lymphoma by Immunophenotyping (Open Table in a new window)

Cytogenetics

Most cases of MCL are associated with a chromosome translocation between chromosome 11 and 14, t(11;14)(q13;q32). ^{[3, 14]}

In a study of sox11, a transcription factor involved in embryonic neurogenesis and tissue remodeling, Chen et al concluded that nuclear expression of sox11 is highly associated with MCL, but it is independent of t(11;14)(q13;q32) in non–mantle cell B-cell neoplasms. ^[14] Chen et al assessed expression of sox11 and evaluated its association with t(11;14) and overexpression of cyclin D1 in 211 cases of B-cell neoplasms.

The investigators noted nuclear staining of sox11 in 95% (54/57) of MCLs (98% classical and 50% variant types). Of the 3 MCLs that were negative for the nuclear sox11 staining, 2 were positive for t(11;14). ^[14] The remaining 114 cases of B-cell lymphomas had variable cytoplasmic positive staining without nuclear positivity.

In addition, no nuclear staining of sox11 was found in 30 plasma cell myelomas, including 12 cases with t(11;14)(q13;q32), but intense nuclear staining of sox11 was present in 50% (5/10) of a subset of hairy cell leukemias, as well as an overexpression of cyclin D1. ^[14] Chen et al noted that the association with cyclin D1 overexpression in hairy cell leukemia may suggest sox11 involvement in cyclin D1 upregulation in hairy cell leukemia. ^[14]

Diagnostic procedures

Perform lymph node biopsy and aspiration together because aspiration alone is insufficient to establish a diagnosis. Use bone marrow aspirate/biopsy results for staging rather than diagnostic purposes.

Histologic findings

In the lymph node, MCL is characterized by expansion of the mantle zone that surrounds the lymph node germinal centers by small-to-medium atypical lymphocytes. These cells have irregular and indented nuclei, moderately coarse chromatin, and scant cytoplasm, resembling smaller cells of follicular lymphoma. However, mitoses are more numerous and large cells are infrequent.

A nodular appearance may be evident from expansion of the mantle zone in 30-50% of patients early in the disease. As disease progresses, the germinal centers become effaced, with obliteration of lymph node architecture.

A blastic variant of MCL, demonstrating numerous medium-to-large blastlike cells, has been reported and is associated with a more aggressive clinical course.

In bone marrow sections, neoplastic cells may infiltrate in a focal, often paratrabecular or diffuse pattern. Diagnosis of MCL should not be based on the examination of bone marrow alone; obtaining a lymph node biopsy is required.

Approach considerations

Standard first-line treatment for mantle cell lymphoma (MCL) consists of chemoimmunotherapy. ^[1] This may result in prolonged remission, but relapse is to be expected. ^[2] Options for relapsed/refractory disease include chemotherapy-free regimens with biologic targeted agents. Because of their efficacy in the relapsed/refractory setting, biologic agents are increasingly used for first-line treatment of MCL. Surgery is rarely indicated in MCL except for palliative procedures, such as relief of gastrointestinal obstruction.

Treatment choice in MCL is guided by risk stratification. ^[1] In select patients with indolent MCL—typically, those who are asymptomatic and have low tumor burden and proliferation—management can be with observation, with deferral of therapy until disease progression. ^[15] However, most patients ultimately require therapy. First-line treatment may result in prolonged remission, but relapse is to be expected. ^[2]

According to National Comprehensive Cancer Network (NCCN) guidelines, active surveillance may be considered in highly selected asymptomatic patients with stage II nonbulky and noncontiguous MCL. Active surveilance may also be considered in asymptomatic patients with indolent MCL that is bulky noncontiguous stage II or stage III-IV, but in most of those cases treatment is indicated, with selection based on TP53 mutation status. For stage I-II MCL that is nonbulky and noncontiguous, NCCN guidelines recommend a less-aggressive induction therapy regimen such as bendamustine plus rituximab (BR). ^[15] For stage I-II disease MCL that is nonbulky and contiguous, the NCCN guidelines recommend involved-site radiation therapy (ISRT) or a less-aggressive induction therapy regimen with or without ISRT. ^[10]

European Society for Medical Oncology (ESMO) guidelines advise that for limited nonbulky stages I-IIa MCL, shortened conventional chemotherapy induction followed by consolidation radiation therapy (RT) may be the most appropriate approach, as involved-field RT alone may not provide long-term remission. For patients with stage I-II disease who have a large tumor burden or adverse prognostic features, systemic therapy as indicated for advanced stages should be used, and consolidation RT may be considered. ^[11]

 For classical TP53 wild type, stage II bulky noncontiguous and stage III-IV, MCL, NCCN guidelines recommend aggressive therapy, in patients who are candidates for that. Patients with TP53 mutations have a poor prognosis when treated with conventional therapy, and the NCCN strongly recommends clinical trial enrollment in those cases. ^[10]

For advanced-stage disease in younger patients and selected elderly fit patients, the recommended aggressive approach is induction therapy  followed by consolidation therapy consisting of high-dose therapy with autologous hematopoietic stem cell transplantation (HSCT) rescue. Prophylaxis and monitoring for tumor lysis syndrome should be strongly considered during the induction therapy.

For induction therapy, the NCCN lists the following regimens as preferred when proceeding to transplantation is intended ^[10] :

• LyMA regimen – RDHA (rituximab, dexamethasone, cytarabine) plus platinum (carboplatin, cisplatin, or oxaliplatin) followed by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
• Nordic regimen – Dose-intensified R-CHOP (maxi-CHOP) alternating with rituximab plus high-dose cytarabine
• BR followed by rituximab and high-dose cytarabine
• TRIANGLE regimen – R-CHOP plus ibrutinib, alternating with RDHA ^[16]

Modified VR-CAP/R + ara-C (bortezomib [Velcade], rituximab, cyclophosphamide, doxorubicin, and prednisone, alternating with rituximab and high-dose cytarabine), has been used for transplant-eligible patients with MCL. A study in 37 patients reported a high rate of complete response (86%) and eligibility for autologous stem cell transplantation. ^[17]

Preferred regimens (ie, less aggressive) when there is no intention to proceed to transplantation are as follows: 

• BR
• VR-CAP
• R-CHOP
• Lenalidomide (continuous) + rituximab ^[18]
• Modified rituximab-hyperCVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone alternating with high-dose methotrexate and cytarabine) in patients older than 65 years

In January 2025, the US Food and Drug Administration approved the use of the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib with BR for previously untreated MCL in patients who are ineligible for autologous stem cell transplantation. Approval was based on results from the randomized controlled ECHO trial, conducted in 598 patients age 65 and older, in which median progression-free survival was 66.4 months in the acalabrutinib plus BR arm, versus 49.6 months in the placebo plus BR arm (hazard ratio 0.73, P =  0.016). ^[19]

For elderly patients who are not candidates for any of the above regimens, palliative chemotherapy should be considered, using milder chemo-immunotherapy regimens (eg, chlorambucil plus rituximab, BR).

For young patients (age ≤65 years), ESMO guidelines recommend induction therapy with dose-intensified immunochemotheapy (eg, R-CHOP, high-dose cytarabine) followed by ASCT with rituximab maintenance. For elderly patients, ESMO recommends conventional immunochemotherapy (eg, R-CHOP, VR-CAP, BR, R-BAC [rituximab, bendamustine, cytarabine ^[20] ) followed by rituximab maintenance. For compromised patients, options include R-chlorambucil, dose-reduced BR, R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), or possibly best supportive care. ^[11]

Regimens for relapsed or refractory MCL

Biologic agents have come to dominate the treatment of relapsed or refractory MCL. ^{[1, 2]} Commonly used biologic regimens include the following ^[10] :

• Covalent BTK inhibitors - acalabrutinib, ^[21] ibrutinib, zanubrutinib ^[22]
• Non-covalent BTK inhibitor - pirtobrutinib ^[23]
• Lenalidomide (relapsed or progressive disease after two prior therapies, one of which included bortezomib ^[24] ) plus rituximab
• Ibrutinib plus venetoclax
• Venetoclax with or without rituximab

Chemoimmunotherapeutic options, if not used in first-line therapy, include the following :

• Bendamustine plus rituximab
• R-BAC
• Bortezomib with or without rituximab
• Bortezomib, rituximab, high-dose cytarabine, and dexamethasone ^[25]
• GemOx (gemcitabine, oxaliplatin) plus rituximab
• RDHA

Salvage chemotherapy combinations followed by stem cell transplantation

Rituximab, ifosfamide, carboplatin, etoposide (R-ICE) or etoposide, methylprednisolone, high-dose cytarabine, cisplatin (ESHAP) followed by autologous HSCT(ASCT) has been used. ^[26] However, ASCT consolidation after salvage therapy remains controversial and may benefit only a subset of patients with relapsed MCL. On the other hand, data for nonmyeloablative allogeneic HSCT are very promising, with some long-term survivors, including patients in whom prior high-dose therapy had failed. ^[27]

CAR T-cell therapy

In 2020, the FDA granted accelerated approval to brexucabtagene autoleucel (Tecartus), a CD19-directed genetically modified autologous T-cell immunotherapy, for the treatment of relapsed or refractory MCL in adults. Approval was based on ZUMA-2, an open-label, multicenter, single-arm, phase II trial of patients with relapsed or refractory MCL who had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a BTK inhibitor. Of the 60 patients evaluable for efficacy, based on a minimum duration of follow-up for response of 6 months, the objective response rate was 87%, with a complete remission rate of 62%. ^{[28, 29]}

In May 2024, the FDA approved another CD19-directed CAR T-cell therapy, lisocabtagene maraleucel (Breyanzi), for adult patients with relapsed or refractory MCL based on results from an open-label, multicenter, multicohort, phase I (TRANSCEND NHL 001) trial. In 74 patients with MCL included in the primary analysis set, the objective response rate was 86.5% and the complete response rate was 74.3%. Patients had previously received 2 or more prior lines of therapy including a BTK inhibitor, alkylating agent, or CD20-targeted agent. ^[30]

Consultations

The following specialists may need to be consulted:

• Hematologist
• Oncologist
• Surgeon: for lymph node biopsy, palliative procedures, and placement of a venous access device (eg, Port-a-Cath, Infus-a-Port) for chemotherapy administration

Diet

Consultation with a dietitian may be necessary for patients with poor oral intake or marked weight loss. Special attention and support is required for patients receiving chemotherapy, such as appetite stimulants or diet supplements. Patients who are neutropenic require education about food hygiene.

Follow-up

Usually, treatment and follow-up care of patients with MCL is performed in an outpatient setting. Follow-up may include the following:

• Carefully monitor blood cell count prior to administering chemotherapy and 10-14 days after each treatment cycle.
• Evaluate disease by monitoring history, physical examination findings, and imaging study results
• Monitor adverse effects of chemotherapy by monitoring history, physical examination findings, and blood counts
• Provide symptomatic treatment for adverse effects such as nausea, vomiting, diarrhea, mucositis, and fatigue
• Provide psychosocial support

Admit patients for complications, disease progression, or adverse chemotherapy effects (eg, neutropenic fever or mucositis).

Complications of treatment

Complications from chemotherapy may include the following:

• Infection, neutropenia, anemia, and thrombocytopenia
• Fatigue
• Neuropathy
• Dehydration after diarrhea or vomiting
• Cardiac toxicity from doxorubicin

Mantle cell lymphoma (MCL) is associated with a poor prognosis. It exhibits a moderately aggressive course similar to that of other types of intermediate-grade non-Hodgkin lymphoma (NHL). Unlike intermediate-grade lymphomas, it is rarely curable with currently available standard treatment.

Despite response rates of 50-70% with many regimens, MCL typically progresses after chemotherapy. Overall 5-year relative survival is approximately 50%, ranging from approximately 75% in patients younger than 50 years to approximately 36% in those age 75 years and older. ^[9]

The blastoid variant, commonly associated with TP53 mutations, has been associated with a worse prognosis. Gene expression profile analysis identified MCL patient subsets with more than 5 years' difference in median survival, based on cyclin D1 and other proliferation signature genes.

Using genomic and transcriptomic profiling, Li et al identified four molecular subsets of MCL that correlated with prognosis. Mutational signatures and 5-year overall survival (OS) were as follows ^[31] :

• Mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling: 100% OS
• del(11q)/ATM mutations and upregulation of NF-κB and DNA repair pathways: 56.7% OS
• Mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets: 48.7% OS
• del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures: 14.2% OS

Clearly explain all available treatment options and provide detailed instruction about the adverse effects of chemotherapy. Consider enrollment of the patient into a clinical trial. Provide psychosocial counseling.

 

The following organizations have published guidelines with recommendations on the diagnosis and treatment of mantle cell lymphoma:

• National Comprehensive Cancer Network ^[10]
• European Society for Medical Oncology (ESMO) ^[11]

Key recommendations from those guidelines have been reviewed and integrated throughout the article.