Mantle Cell 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. MCL represents 2-10% of all non-Hodgkin lymphomas.

Clinical presentation

The male-to-female ratio in MCL is 3:1, and the age range at presentation is 35-85 years, with a median of 67 years. Findings on the history 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 commonly, symptoms caused by extranodal involvement of GI tract, lungs, and CNS

Physical examination findings include the following:

• Generalized lymphadenopathy in 75%
• Splenomegaly in 60% (may be massive)
• Hepatomegaly in 30%
• Poor performance status in 20%
• Less commonly, palpable masses in skin, breast, and salivary glands

Workup

Studies and procedures for diagnosing and staging MCL are as follows:

• Lymph node biopsy and aspiration; aspiration alone is insufficient to establish a diagnosis
• Use bone marrow aspirate/biopsy results for staging rather than diagnostic purposes
• 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 may yield the following results in MCL:

• CBC: 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

On immunophenotyping, tumor cells in MCL are monoclonal B cells with the following characteristics:

• Express surface immunoglobulin, immunoglobulin M, or immunoglobulin D
• Are characteristically CD5 ⁺ and pan B-cell antigen positive (eg, CD19, CD20, CD22)
• Lack expression of CD10 and CD23
• Overexpress cyclin D1

Management

Reliably curative treatments for MCL are lacking. An inexorable pattern of progression is characteristic. Treatment selection takes into account patient age, fitness, and whether autologous stem cell transplantation (ASCT) is planned.

Standard first-line treatment consists of chemoimmunotherapy. ^[1] This may result in prolonged remission, but relapse is to be expected. ^[2] Options for second-line therapy in patients with relapsed/refractory disease include chemotherapy-free regimens with biologic targeted agents such as covalent Bruton tyrosine kinase (BTK) inhibitors, lenalidomide,venetoclax, and chimeric antigen receptor (CAR) T-cell therapy. ^{[3, 1, 2]} Because of their efficacy in the relapsed/refractory setting, biologic agents are increasingly used for first-line treatment of MCL. ^[1] See Treatment, below.

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 2023 there will be 80,550 new NHL cases in the United States, representing approximately 4% of all cancer diagnoses. ^[7]  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%). ^[8]

Overall, Whites are at higher risk of developing NHLs than Blacks and 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 67 years. ^[9]

No causative factor has been identified for mantle cell lymphoma (MCL) or for most patients with non-Hodgkin lymphoma (NHL) of other types. 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 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

Laboratory studies

Blood studies may yield the following results in mantle cell lymphoma (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). ^[10]

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, 11]}

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. ^[11] 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). ^[11] 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. ^[11] 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. ^[11]

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

Although indolent mantle cell lymphoma (MCL) may be managed with observation in selected cases (eg, patients with noncontiguous, nonbulky stage II disease ^[12] ), most patients ultimately require therapy. Standard first-line treatment consists of chemoimmunotherapy. ^[1] This may result in prolonged remission, but relapse is to be expected. ^[2]

Options for second-line therapy in patients with relapsed/refractory disease include chemotherapy-free regimens with biologic targeted agents such as covalent Bruton tyrosine kinase (BTK) inhibitors, lenalidomide,venetoclax, and chimeric antigen receptor (CAR) T-cell therapy. ^{[3, 1, 2]} Because of their efficacy in the relapsed/refractory setting, biologic agents are increasingly used for first-line treatment of MCL. ^[1] Given the poor prognosis in MCL with TP53 mutation, clinical trial participation is strongly encouraged for these patients. ^{[12, 1]}

 Stage I or II localized MCL is an extremely rare presentation, and literature on its management is retrospective and anecdotal. For stage II (bulky) and stages III-IV MCL, National Comprehensive Cancer Network (NCCN) guidelines recommend induction therapy with any of several regimens; patients who show a complete or partial response should then be considered for high-dose therapy followed by autologous hematopoietic stem cell transplantation (HSCT) rescue. ^[12]

A consensus statement by the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation and the European MCL Network (EBMT/EMCL) on the role of HSCT in the management of MCL supports autologous HSCT (ASCT) as the standard first-line consolidation therapy, and recommends that complete or partial remission be achieved before ASCT is performed. The EBMT/EMCL supports considering allogeneic HSCT for patients who experience relapse after ASCT. ^[13]

Vaughn et al reported that allogeneic HSCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses. In this study, patients underwent HSCT after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab.The 5-year rates of overall survival (OS) and progression-free survival (PFS) in 70 patients were 55% and 46%, respectively. The 10-year rates of OS and PFS in 33 patients were 44% and 41%, respectively. ^[14]

Surgery is rarely indicated for therapeutic purposes in MCL. Exceptions include palliative procedures, such as relief of gastrointestinal obstruction.

Regimens for primary MCL therapy

In young, fit patients, commonly used induction chemotherapy regimens incorporate cytarabine and rituximab. These include the following:

• RDHA ( rituximab, dexamethasone, cytarabine) plus platinum (carboplatin, cisplatin, or oxaliplatin)
• R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone) alternating with R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin)
• Nordic regimen (defined previously)
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) plus rituximab
• Rituximab, bendamustine followed by rituximab, and high-dose cytarabine.
• Nordic regimen (dose-intensified R-CHOP)
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) plus rituximab
• Rituximab, bendamustine followed by rituximab, and high-dose cytarabine

Regimens commonly used in older patients include the following:

• Bendamustine plus rituximab (BR)
• R-CHOP
• VR-CAP (bortezomib [Velcade], rituximab, cyclophosphamide, doxorubicin, prednisone)
• R-BAC (rituximab, bendamustine, cytarabine)
• Lenalidomide plus rituximab (R ²) ^[15]
• BR plus ibrutinib

A study by Griffiths et al found that the addition of rituximab to a standard first-line chemotherapy regimen significantly improved survival in older patients with MCL. In 638 patients whose mean age at diagnosis was 75 years, median survival was 37 months for chemotherapy plus rituximab versus 27 months for chemotherapy alone (P< 0.001). ^[16]

A European MCL Network trial in 870 patients with MCL (median age 57 years) compared standard care (high-dose cytarabine-containing immunochemotherapy followed by ASCT and, in some cases, rituximab maintenance) with standard care plus ibrutinib and ibrutinib without ASCT. On follow-up for a median of 2.5 years, standard care was not superior to ibrutinib without ASCT, and standard care plus ibrutinib was superior to standard care alone, with respect to rates of failure-free survival. ^[17]

Single alkylating agents

This therapy (eg, chlorambucil, 0.1-0.2 mg/kg for 3-6 wk) may be preferable for elderly patients or for those with serious comorbid medical problems who require treatment for lymphoma.

Ibrutinib plus rituximab

In a multicenter single-arm, open-label, phase II study of ibrutinib plus rituximab in patients with previously untreated indolent MCL, 40 of 50 patients (80%) achieved a complete response after 12 cycles, and two patients achieved a partial response. In addition, 87% of patients had undetectable minimal residual disease (MRD) in peripheral blood. At 2 years, 24 of 35 evaluable patients (69%) were able to discontinue ibrutinib because of undetectable MRD. Criteria for study eligibility were absence of disease-related symptoms, nonblastoid variants, Ki-67 < 30%, and largest tumor diameter ≤ 3 cm. ^[18]

R-CHOP 

R-CHOP is administered every 21 days, in the following regimen:

• Rituximab 375 mg/m ² IV on day 1
• Cyclophosphamide at 750 mg/ ² IV on day 1
• Doxorubicin at 50 mg/ ² IV on day 1
• Vincristine at 1.4 mg/ ² IV on day 1, not to exceed 2 mg
• Prednisone at 100 mg/d PO on days 1-5

Hyper-CVAD (with or without rituximab)

Hyper-CVAD with or without rituximab is a first-line regimen. Single-institution data (ie, M.D. Anderson Cancer Center) using hyper-CVAD plus rituximab yielded encouraging results as front-line therapy, especially in patients younger than 65 years.

Frontline therapy with hyper-CVAD plus rituximab (R-hyper-CVAD) in patients with MCL shows a higher complete response rate and response duration than any other regimen (100% response rate with 89% complete response). ^[19] At 36 months, the failure-free survival rate was greater than 80% in patients younger than 65 years, versus less than 50% in patients older than 65 years. In addition to age (ie, >65 y), beta2-microglobulin was found to be a very strong prognostic factor, especially in patients older than 65 years. Although very encouraging, this regimen is intensive and relatively toxic; data must be confirmed in randomized trials.

The hyper-CVAD drug regimen is a total of 8 cycles: 4 cycles of course A and 4 cycles of course B. Each cycle is started upon hematologic recovery, usually every 3 weeks.

Course A is as follows:

• Rituximab at 375 mg/m ² on day 1 of each cycle
• Cyclophosphamide at 300 mg/m ² IV over 3 hours every 12 hours for 6 doses on days 1, 2, and 3 (mesna may be given as an uroprotectant at the same total dose as cyclophosphamide but given by continuous infusion starting with cyclophosphamide and ending 5 h after the last dose)
• Methotrexate at 12 mg IT on day 2
• Doxorubicin at 40 mg/m ² IV on day 4
• Vincristine at 2 mg IV on days 4 and 11
• Dexamethasone at 40 mg/d PO/IV on days 1-4 and 11-14
• Cytarabine at 70 mg IT on day 7

Course B is as follows:

• Rituximab at 375 mg/m ² on day 1 of each cycle
• Methotrexate at 1000 mg/m ² IV over 24 hours on day 1
• Leucovorin at 25 mg/m ² IV, 24 hours after the completion of the methotrexate infusion, every 6 hours for 6 doses
• Sodium bicarbonate at 600 mg PO (starting day before methotrexate) 3 times day for 4 days
• Cytarabine at 3 g/m ² IV over 2 hours every 12 hours for 4 doses on days 2 and 3

Premedication and supportive measures are recommended in combination with the R-hyper-CVAD regimen. With high-dose methotrexate, give hydration with sodium bicarbonate for 48 hours. Prophylactic use of dexamethasone 0.1% ophthalmic solution 1-2 drops every 4 hours while the patient is awake, for 7 days (during high-dose cytarabine administration) helps prevent conjunctivitis. Antibiotic prophylaxis may also be given. Additionally, doses should be modified according to the protocol being used.

Hyper-CVAD with or without rituximab followed by ASCT was tested at the M.D. Anderson Cancer Center as a frontline regimen. It did not appear superior to hyper-CVAD over time, especially after the addition of rituximab to hyper-CVAD. ^[20]

Bortezomib

In 2014 the US Food and Drug Administration (FDA) approved bortezomib for previously untreated patients with MCL. Bortezomib was already approved for patients with relapsed/refractory MCL.

Extension of the drug's indication was based on a phase III clinical trial of 487 previously untreated patients with MCL. The study compared the combination of bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone with the standard R-CHOP regimen. The bortezomib combination improved progression-free survival by 11 months. The complete response rate for patients receiving the bortezomib combination regimen was 44%, compared with R-CHOP at 34%. ^[21]

RBAC500

The RBAC500 regimen consists of rituximab at 375 mg/m² on day 1, bendamustine at 70 mg/m² on days 2 and 3, and cytarabine at 500 mg/m² on days 2 to 4 every 4 weeks, for up to six cycles. In a phase II study of RBAC500 as first-line therapy in elderly patients, 52 of 57 patients achieved a complete response. Toxicity developed in 23 patients but was manageable with appropriate supportive care and dose reduction. Maintenance therapy is not required. ^[22] NCCN guidelines recommend RBAC500 as an option for induction therapy when there is no intention to proceed to transplantation. ^[12]

Chemotherapy-free regimens

A single-arm phase II trial demonstrated high response rates and durable survival with ibrutinib plus rituximab (IR) in 50 previously untreated older patients (age ≥ 65 years) with MCL. However, 21 patients discontinued therapy because of toxicity; 11 patients developed atrial fibrillation, so the authors strongly recommend baseline evaluation for cardiovascular risks in further studies of this regimen. ^[23]

Preliminary studies are investigating a variety of chemotherapy-free triplet regimens, for both untreated and relapsed MCL. These regimens include ibrutinib/obinutuzumab/venetoclax, acalabrutinib/venetoclax/rituximab, ibrutinib/rituximab/venetoclax, and zanubrutinib/obinutuzumab/venetoclax. ^[1]

Maintenance therapy

In addition to its use as a part of induction therapy regimens, the anti-CD20 monoclonal antibody rituximab has established a role in maintenance therapy for patients with MCL. National Comprehensive Cancer is not yet well defined. The benefit of rituximab has been confirmed in combination with all chemotherapy regimens tested.

Borgerding et al reported responses to repeat treatment with rituximab in approximately two thirds of patients with MCL who had responded to initial treatment. However, lasting remissions in these cases were achieved only by high-dose chemotherapy with stem cell transplantation. ^[24]

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 ^[12] :

• Covalent BTK inhibitors - acalabrutinib (Calquence), ibrutinib (Imbruvica), zanubrutinib (Brukinsa)
• Non-covalent BTK inhibitor - pirtobrutinib (Jaypirca)
• Lenalidomide plus rituximab
• Ibrutinib plus venetoclax
• Venetoclax with or without rituximab

Chemoimmunotherapeutic options, if not used in first-line therapy, include the following ^[12] :

• Bendamustine plus rituximab
• RBAC500
• Bortezomib with or without rituximab
• GemOx (gemcitabine, oxaliplatin) plus rituximab
• RDHA

Salvage chemotherapy combinations followed by autologous stem cell transplantation

Rituximab, ifosfamide, carboplatin, etoposide (R-ICE) or etoposide, methylprednisolone (Solu-Medrol), high-dose cytarabine (Ara-C), cisplatin (ESHAP) followed by ASCT has been used. ^[25] 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 transplantation are very promising, with some long-term survivors, including patients in whom prior high-dose therapy had failed.

Modified VR-CAP/R+ara-C (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone, alternating with rituximab and high-dose cytarabine), has been used for transplant-eligible patients with MCL. Most patients had intermediate- or high-risk disease by both (mantle-cell lymphoma international prognostic index (MIPI)-B and MIPI-C category. Complete response to induction was achieved in 32 (86%) of 37 evaluable patients; 2 achieved partial response, and 3 had primary refractory disease. Stem cell collection was successful in 1 attempt in 30 of 32 patients. The median follow-up of survivors measured from start of treatment is 17.4 months. Five patients have progressed, and 4 have died (2 owing to lymphoma, 2 from toxicity). ^[26]

Bortezomib

Goy et al and O'Connor established the therapeutic activity of bortezomib in relapsed and refractory MCL, and their work has been extended and confirmed in multicenter trials in the US and Canada with single-agent bortezomib, bortezomib in combination with chemotherapy and/or rituximab, and as a component of front-line therapy for MCL and other lymphomas. ^{[27, 28]}

The FDA has approved bortezomib for MCL in patients who have received at least one previous therapy. This approval was based on findings from the PINNACLE trial, a prospective, phase II, multicenter, single arm, open-label study of 155 patients. Overall response rate was 31% with 8% complete response. Median duration of response was 9.3 months in responding patients and 15.4 in patients with CR. 41. ^[29]

The bortezomib regimen consists of 1.3 mg/m² IV push twice per week (days 1, 4, 8, 11) followed by a 10-day treatment-free period (21 day cycle) for 8 cycles. Patients with stable disease or partial responses could receive treatment for up to 1 y, not to exceed maximum 17 cycles.

Starting therapy with subcutaneous (SC) administration of bortezomib may be considered for patients who have or are at high risk for peripheral neuropathy. Moreau et al observed the incidence of grade 2 or greater peripheral neuropathy was 24% for SC compared with 41% for IV; grade 3 or higher occurred in 6% when administered SC vs 16% for IV administration. ^[30]  

Lenalidomide

In 2013, the FDA approved lenalidomide (Revlimid) for the treatment of MCL patients whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. The recommended dose and schedule for lenalidomide treatment is 25 mg PO once daily on days 1-21 of repeated 28-day cycles.

Approval was based on a single-arm, multicenter clinical trial involving 134 patients who had relapsed after, or were refractory to, bortezomib or a bortezomib-containing regimen. Overall response rate was 26%, and complete response (or complete response unconfirmed) was achieved by 9 patients. Partial response was achieved by 25 patients. Among these 34 patients, median duration of response was 16.6 months. ^[31]

The effectiveness of lenalidomide in combination with ibrutinib and venetoclax, especially in the management of p53-mutated cases, remains inconclusive. ^[32]

Ibrutinib

Ibrutinib (Imbruvica) was approved by the FDA in 2013 for treatment of MCL in patients who have received at least 1 prior therapy. It is a Bruton tyrosine kinase (BTK) inhibitor. BTK is a signaling molecule of the B-cell antigen receptor (bcr) and cytokine receptor pathways that results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. The recommended dose is 560 mg PO once daily.

Approval was based on the results of a multicenter, international, single-arm trial of 111 patients with previously treated MCL. The efficacy results demonstrated a 68% overall response rate; 21% of patients achieved a complete response and 47% of patients achieved a partial response. The median duration of response was 17.5 months. ^[33]

Ibrutinib and palbociclib 

A phase I trial of ibrutinib plus palbociclib in previously treated MCL found that maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg days 1-21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3-4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, respectively, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase II multicenter clinical trial to further characterize efficacy is ongoing. ^[34]

Acalabrutinib

Acalabrutinib (Calquence) is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. In 2017, the FDA granted an accelerated approval to acalabrutinib as a treatment for adult patients with MCL following at least 1 prior therapy. The approval was based on findings from the 124-patient ACE-LY-004 phase II trial, in which the investigator-assessed objective response rate (ORR) was 81% with acalabrutinib (95% confidence index [CI], 73%-87%). The complete response rate with acalabrutinib was 40% and the partial response rate was 41%. ^[35]

Zanubrutinib

In 2019, the FDA granted accelerated approval to another BTK inhibitor, zanubrutinib (Brukinsa), for MCL in patients who have received at least 1 prior therapy. Approval was based on results from two phase II, open-label, single-arm trials, which showed an overall response rate of 84% In one study, MCL patients (n=86) had a 59% complete response and a 24% partial response rate. In the other study, MCL patients (n=32) had a 22% complete and 62% partial response rate. ^[36] For both studies the primary endpoint was overall response rate, based on the 2014 Lugano classification and assessed by an independent review committee. 

Pirtobrutinib 

Pirtobrutinib (Jaypirca) is a non-covalent (reversible) BTK inhibitor. It gained accelerated approval from the FDA in January 2023 for adults with relapsed or refractory mantle cell lymphoma after at least 2 lines of systemic therapy, including a covalent BTK inhibitor (eg, ibrutinib, acalabrutinib, zanubrutinib). Approval was based on the phase I/II BRUIN trial that showed ORR of 50%, complete response rate of 13%, and partial response rate of 38% in patients treated with pirtobrutinib. ^[37] An open-label phase III study is under way to confirm these results. 

Radioimmunotherapy

Both iodine-131–based tositumomab (Bexxar) ^[38] and yttrium-90–based ibritumomab tiuxetan (Zevalin) ^[39] have shown activity as single agents for salvage therapy of MCL. Studies have reported responses with radioimmunotherapy (RIT) in MCL, including some complete responses that lasted more than 1 year. A phase II open-label study of RIT followed by chemotherapy with CHOP for untreated MCL reported a high response rate and a long duration of response. ^[40]

The use of RIT as part of a nonmyeloablative allotransplantation conditioning regimen is another promising strategy currently being tested in clinical trials.

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% (95% CI: 75, 94), with a complete remission rate of 62% (95% CI: 48, 74). ^{[41, 42]}

Lisocabtagene maraleucel, an anti-CD19 autologous CAR T-cell product with a 4-1BB costimulatory domain, has demonstrated efficacy in a phase I trial in patients with relapsed/refractory B-cell non-Hodgkin lymphoma, including patients with MCL. ^[1]

High-dose chemotherapy with autologous bone marrow or stem cell transplantation

High-dose chemotherapy with ASCT has not proved curative for MCL when used as second-line therapy. ^[43] Long-term survival data are currently unavailable in the setting of high-dose chemotherapy applied as consolidation therapy to patients in first complete remission. ^[44]

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 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. ^[8]

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 ^[45] :

• 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.

For patient education information, see Lymphoma.

Guidelines contributors:  Priyank P Patel, MD , Hematology/Oncology Fellow, Roswell Park Cancer Institute, University at Buffalo;  Francisco J Hernandez-Ilizaliturri, MD; Chief, Lymphoma and Myeloma Section; Professor of Medicine, Department of Medical Oncology; Director of The Lymphoma Translational Research Program; Associate Professor of Immunology, Roswell Park Cancer Institute 

Non-Hodgkin Lymphoma (NHL) Classification Schemas

The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:

• National Cancer Institute’s Working Formulation (IWF) ^[6]
• Revised European-American Classification of Lymphoid Neoplasms (REAL) ^[5]
• World Health Organization (WHO) classification ^[46]

The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J. ^[4] In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. ^[5]

The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008 and 2016, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin. ^[46]

Although considered obsolete, the National Cancer Institute’s Working Formulation (IWF) classification is still used mainly for historical data comparisons. ^[6]

World Health Organization Classification

The WHO modification of the REAL classification of NHL is based on morphology and cell lineage. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms. ^[46]

The WHO classification subtypes for NHL precursors are as follows:

• Precursor B–lymphoblastic leukemia/lymphoma
• Precursor T–lymphoblastic lymphoma/leukemia

The WHO classification subtypes for mature B-cell neoplasms are as follows:

• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma
• B-cell prolymphocytic leukemia
• Splenic marginal zone lymphoma 
• Hairy cell leukemia
• Splenic B-cell lymphoma/leukemia, unclassifiable; this includes splenic diffuse red pulp small B-cell lymphoma and hairy cell leukemia-variant
• Lymphoplasmacytic lymphoma/immunocytoma; this includes Waldenström macroglobulinemia
• Heavy chain diseases: Alpha, gamma, and mu heavy chain diseases
• Plasma cell myeloma
• Solitary plasmacytoma of bone
• Extraosseous plasmacytoma
• Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma
• Nodal marginal zone lymphoma (includes pediatric nodal marginal zone lymphoma)
• Follicular lymphoma (includes pediatric follicular lymphoma)
• Primary cutaneous follicle center lymphoma
• Mantle cell lymphoma (MCL)
• Diffuse large B-cell lymphoma (DLBCL), NOS: This includes T-cell/histiocyte rich large B-cell lymphoma; primary DLBCL of the CNS; primary cutaneous DLBCL, leg type 9; and Epstein-Barr virus (EBV)–positive DLBCL of the elderly
• DLBCL associated with chronic inflammation
• Lymphomatoid granulomatosis
• Primary mediastinal (thymic) large B-cell lymphoma
• Intravascular large B-cell lymphoma
• Anaplastic lymphoma kinase (ALK)–positive large B-cell lymphoma 
• Plasmablastic lymphoma
• Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
• Primary effusion lymphoma
• Burkitt lymphoma
• B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma
• B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma

Diagnosis

MCL is diagnosed in accordance with the WHO criteria for hematological 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 ^[12] :

• 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 may help distinguish MCL from variant CLL; SOX11 or IGHV sequencing may be useful for determing clinically indolent MCL; may also help in diagnosis of CCND1-MCL

Risk stratification

The European Society for Medical Oncology (ESMO) recommends the 2008 MCL International Prognostic Index (MIPI) for risk stratification. ^[47]  The MIPI includes the following risk factors ^[48] :

• 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 ^[48] :

• 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 is not used to guide treatment decisions. ^{[12, 47]}

Treatment

The NCCN and ESMO offer similar treatment recommendations, as follows ^{[12, 47]} :

• Chemotherapy followed by involved-site radiation therapy (ISRT), 30-36 Gy, is the preferred treatment option for limited stage I or II (non-bulky) disease, although this presentation is rare.

• For advanced-stage disease in younger patients and selected elderly fit patients, the recommended approach is aggressive induction therapy with a regimen such as hyperCVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone alternating with high-dose methotrexate and cytarabine) + rituximab, followed by consolidation therapy consisting of high-dose therapy with autologous stem cell rescue.

• Prophylaxis and monitoring for tumor lysis syndrome should be strongly considered during the induction therapy.

• In elderly fit patients, less-aggressive treatment regimens, such as R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by rituximab maintenance is recommended.

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

• For relapsed or refractory disease, recommendations include high-dose therapy with autologous stem cell rescue and second-line agents bendamustine, bortezomib, temsirolimus, ibrutinib or lenalidomide with rituximab. Allogeneic stem cell transplantation can be considered in selected patients as part of a second-line consolidation.

For induction therapy, the NCCN lists the following regimens as preferred when proceeding to transplantation is intended ^[12] :

• RDHA (rituximab, dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin)
• Alternating R-CHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)/(rituximab, dexamethasone, cisplatin, cytarabine) 
• Nordic regimen (dose-intensified induction immunochemotherapy with rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP]) alternating with rituximab + high-dose cytarabine)
• Rituximab and bendamustine  followed by rituximab and high-dose cytarabine

Preferred regimens when there is no intention to proceed to transplantation are as follows: 

• Bendamustine + rituximab
• VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone)
• R-CHOP
• Lenalidomide (continuous) + rituximab
• Modified rituximab-hyperCVAD in patients older than 65 

For consolidation therapy when transplantation is intended, the NCCN recommends high-dose therapy with autologous stem cell rescue (HDT/ASCR), plus rituximab maintenance.

For second-line and subsequent therapy, preferred regimens are as follows:

• Continuous BTK inhibitor - Acalabrutinib, zanubrutinib
• Lenalidomide + rituximab