Mantle Cell Lymphoma

Updated: Feb 11, 2018
  • Author: Muhammad Rashid Abbasi, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Practice Essentials

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 68 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 common 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, with a median time to treatment failure of less than 18 months. Primary MCL therapy may consist of the following:

  • Single alkylating agents (eg, chlorambucil)

  • Cyclophosphamide, doxorubicin (Hydrodaunorubicin), vincristine (Oncovin), and prednisone (CHOP)

  • Cyclophosphamide, vincristine, and prednisone (CVP)

  • Hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone (hyper-CVAD)

  • Bortezomib (Velcade), rituximab, cyclophosphamide, doxorubicin, and prednisone

  • CHOP plus rituximab (R-CHOP)

  • Hyper-CVAD with autologous stem cell transplantation (ASCT)

Considerations in regimen selection are as follows:

  • Therapy with single alkylating agents may be preferable for elderly patients or for those with serious comorbid medical problems who require therapy for lymphoma

  • First-line therapy is with hyper-CVAD, with or without rituximab; or with bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone

  • Hyper-CVAD with rituximab (R–hyper-CVAD) has shown very encouraging  results but is intensive and relatively toxic

The following regimens have been studied for relapsed or refractory MCL:

  • R–hyper-CVAD

  • Hyper-CVAD with or without rituximab followed by ASCT

  • Nucleoside analogues and combinations

  • Salvage chemotherapy combinations followed by ASCT

  • Bortezomib (Velcade)

  • Lenalidomide (Revlimid)

  • Ibrutinib (Imbruvica)

  • Radioimmunotherapy

  • Rituximab

  • Rituximab and thalidomide combination

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

  • Acalabrutinib (Calquence)

Salvage chemotherapy combinations include the following:

The role of 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.

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Overview

Mantle cell lymphoma (MCL) is recognized in the Revised European-American Lymphoma and World Health Organization classifications as a distinct clinicopathologic entity. [1, 2] 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). [3] 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.

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Pathophysiology

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.

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Epidemiology

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL). NHL represents approximately 4% of all cancer diagnoses and the American Cancer Society estimated that in 2018, 74,680 new cases would occur. [4]  MCL is 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.

Overall, whites are at higher risk of developing NHLs than blacks and Asian Americans . The male-to-female ratio is 3:1, and the age range at presentation is 35-85 years, with median age being 68 years.

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Etiology

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 (Ebstein-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.

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Clinical Presentation

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
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Differential Diagnosis

See the list below:

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Workup

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). [5]

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

Disease

CD5

CD20

CD23

CD10

CD103

FMC7

Cyclin D1

Sig*

MCL

+

++

+/–

+

+

B-CLL/SLL

+

+

+

+

PLL

–/+

++

+/–

+

++

MZL§

++

+/–

+

SLVL||

++

–/+

+/–

++

LPL

+

–/+

++

FL#

++

+

+/–

++

HCL**

+

+

+

–/+

++

* SIg = surface immunoglobulins

B-CLL/SLL = B-cell chronic lymphocytic leukemia/small lymphocytic leukemia

PLL = prolymphocytic leukemia

§ MZL = marginal zone leukemia

|| SLVL = splenic lymphoma with villous lymphocytes

LPL = lymphoplasmacytic lymphoma

# FL = Follicular lymphoma

** HCL = Hairy cell leukemia

Cytogenetics

Most cases of MCL are associated with a chromosome translocation between chromosome 11 and 14, t(11;14)(q13;q32). [6, 7]

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. [7] 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). [7] 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. [7] 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. [7]

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.

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Treatment

Approach considerations

Treatment of mantle cell lymphoma (MCL) remains a difficult problem because of the lack of reliably curative treatments and the paucity of prospective clinical trials. [6] Although 50-90% of these patients respond to combination chemotherapy, relatively few (30%) have a complete response. More aggressive chemotherapy regimens are currently under investigation and may yield higher complete response rates.

An inexorable pattern of progression is characteristic, with a median time to treatment failure of less than 18 months. Median survival usually ranges from 2-5 years, and only 5-10% of patients survive 10 years.

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 stem cell rescue. [8]

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 stem cell transplantation  in the management of MCL supported autologous SCT as the standard first-line consolidation therapy, and that complete or partial remission should be achieved before autologous SCT is performed. The EBMT/EMCL supported considering allogeneic SCT for patients who relapse after autologous SCT. [9]

Vaughn et al reported that allogeneic hematopoietic cell transplantation (HCT) provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses. In this study, patients underwent HCT 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. [10]

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

Regimens for primary MCL therapy

Primary MCL therapy may consist of the following:

  • Single akylating agents
  • CVP (cyclophosphamide, vincristine, prednisone)
  • CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone)
  • Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone) with or without rituximab
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
  • Lenalidomide plus rituximab [11]
  • Hyper-CVAD with autologous stem cell transplantation

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 (mean age, 75 y) with MCL. [12]

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 therapy for lymphoma.

CVP and CHOP 

A randomized prospective trial that compared CVP with CHOP showed no advantage of adding doxorubicin, with similar response and survival rates. In some retrospective analyses, doxorubicin-containing regimens were associated with a longer event-free survival.

CVP is administered every 21 days, in the following regimen:

  • Cyclophosphamide at 400 mg/m 2/d PO days 1-5 or 750-1000 mg/m 2 IV on day 1
  • Vincristine at 1.4 mg/m 2 IV on day 1, not to exceed 2 mg
  • Prednisone at 100 mg/m 2/d PO on days 1-5

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

  • 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). [13] 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% (Maxidex 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.

R-CHOP

Another regimen is CHOP plus rituximab (R-CHOP). In a phase 2 randomized trial of CHOP versus R-CHOP in patients with previously untreated MCL, the complete response rate was higher with R-CHOP (34% vs 7%). The time to treatment failure was also in favor of R-CHOP, but the time to progression showed no significant difference. This study was reported by the German Low-Grade Lymphoma Study Group at the 2004 American Society of Clinical Oncology meeting.

Bortezomib

In October 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%. [14]

Hyper-CVAD with autologous stem cell transplantation

Hyper-CVAD with or without rituximab followed by autologous stem cell transplantation (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. [15]

Regimens for relapsed or refractory MCL

The following regimens have been studied for relapsed or refractory MCL:

  • R-hyper-CVAD
  • Hyper-CVAD with or without rituximab followed by ASCT
  • Nucleoside analogues and combinations
  • Salvage chemotherapy combinations followed by ASCT
  • Bortezomib (Velcade)
  • Lenalidomide (Revlimid)
  • Ibrutinib (Imbruvica)
  • Radioimmunotherapy
  • Rituximab
  • Rituximab and thalidomide combination
  • Acalabrutinib (Calquence)
  • High-dose chemotherapy with autologous bone marrow or stem cell transplantation

R-hyper-CVAD

This therapy is currently being tested in patients with relapsed MCL in whom fludarabine or CHOP failed, but the results are not yet available. However, based on the frontline data, this is an acceptable option in patients with relapse. Future combinations of R-hyper-CVAD with other biologicals or new agents are potentially promising options.

Hyper-CVAD with or without rituximab followed by ASCT

Studies have shown that ASCT either as frontline consolidation or in the context of relapse provides high response rates and may improve disease-free survival. Unfortunately, this therapy is still typically associated with a continuous pattern of relapse.

Nucleoside analogues and combinations

Fludarabine as a single agent has demonstrated activity in MCL. It has been used, with or without rituximab, in the following combinations:

  • Fludarabine, mitoxantrone, and dexamethasone (FND)
  • Fludarabine and cyclophosphamide (FC) [16]
  • Fludarabine, cyclophosphamide, mitoxantrone (FCM)

A higher complete response rate and/or longer response duration has been suggested when fludarabine is used in combination with an alkylator (eg, FC), with an anthracycline (eg, FND or fludarabine plus idarubicin), or both (eg, FCM). Such combinations could be used in refractory or relapse settings, with comparable response rates and duration of response.

The addition of rituximab to all of these regimens is clearly beneficial. For example, with FCM in a series of 38 patients with relapsed MCL, the overall response rate was 65% with rituximab versus 33% without rituximab, and the complete response rate was 35% with rituximab versus 0% without rituximab. [17]

Other nucleoside analogs have activity in MCL. For example, cladribine was found to be superior in combination with mitoxantrone.

Salvage chemotherapy combinations followed by ASCT

Rituximab, ifosfamide, carboplatin, etoposide (R-ICE) or etoposide, methylprednisolone (Solu-Medrol), high-dose cytarabine (Ara-C), cisplatin (ESHAP) followed by ASCT has been used. 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.

Bortezomib

Goy et al and O'Connor established the therapeutic activity of bortezomib (Velcade) 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. [18, 19]

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 2, 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. [20]

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. [21]  

Lenalidomide

On June 5, 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. [22]

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’s 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. [23]

Acalabrutinib

Acalabrutinib (Calquence) is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. In October 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%. [24]

Radioimmunotherapy

Both iodine-131–based tositumomab (Bexxar) [25] and yttrium-90–based ibritumomab tiuxetan (Zevalin) [26] have shown activity as single agents for salvage therapy in persons with MCL. Studies have reported responses with radioimmunotherapy (RIT) in MCL, including some complete responses that lasted more than 1 year. Additional ongoing studies are exploring combinations of RIT with chemotherapy for untreated or relapsed MCL. Strategies including RIT as part of high-dose therapy have shown encouraging results.

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

Rituximab

The anti-CD20 monoclonal antibody rituximab, used as a single agent, has activity in MCL, yielding a response rate of 35%, a complete response rate of 10-15%, and a median duration of response of approximately 1 year in rituximab-naive patients. The potential role of rituximab as a maintenance therapy for patients with MCL 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. [27]

Rituximab and thalidomide

Promising results have been shown using rituximab (standard dose) and thalidomide (200 mg/d, with incremental dose increases to 400 mg on day 15) continued as maintenance therapy until progression or relapse. [28] In a small series, the response rate was 81% (complete response rate of 31%) and the median progression-free survival was 20.4 months (95% confidence interval, 17.3-23.6). The estimated 3-year survival rate was 75%. This approach would be an appealing alternative in elderly patients.

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

High-dose chemotherapy with autologous bone marrow or stem cell transplantation has not proved curative for MCL when used as second-line therapy. [29] Long-term survival data are currently unavailable in the setting of high-dose chemotherapy applied as consolidation therapy to patients in first complete remission. [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
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Prognosis

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. Median time to treatment failure is less than 18 months. The median survival time is approximately 3 years (range, 2-5 y); the 10-year survival rate is only 5-10%.

Developing reliable prognostic markers has been difficult in the absence of better-standardized therapy. Younger age and limited disease are favorable prognostic features.

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.

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Patient Education

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 the Blood and Lymphatic System Center, as well as Lymphoma.

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Guidelines Summary

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) [3]

  • Revised European-American Classification of Lymphoid Neoplasms (REAL) [2]

  • World Health Organization (WHO) classification [31]

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. [1] In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. [2]

The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008, 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. [31]

Although considered obsolete, the National Cancer Institute’s Working Formulation (IWF) classification is still used mainly for historical data comparisons. [3]

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. [31]

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 peripheral B-cell neoplasms are as follows:

  • B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma

  • B-cell prolymphocytic leukemia

  • Lymphoplasmacytic lymphoma/immunocytoma

  • Mantle cell lymphoma

  • Follicular lymphoma

  • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type

  • Nodal marginal zone B-cell lymphoma (± monocytoid B cells)

  • Splenic marginal zone lymphoma (± villous lymphocytes)

  • Hairy cell leukemia

  • Plasmacytoma/plasma cell myeloma

  • Diffuse large B-cell lymphoma (DLBCL)

  • Burkitt lymphoma

Diagnosis

Mantle cell lymphoma (MCL) is diagnosed in accordance with the World Health Organization 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 [8] :

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

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

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

  • Immunohistochemistry for SOX 11, which is expressed in approximately 90% of MCLs but is negative in all other B-cell lymphoid neoplasms except Burkitt lymphomas and lymphoblastic lymphomas

Risk stratification

The European Society for Medical Oncology (ESMO) recommends the 2008 MCL International Prognostic Index (MIPI) for risk stratification. [32]  The MIPI includes the following risk factors [33] :

  • 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 [33] :

  • 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, it is not used to guide treatment decisions. [8, 32]

Treatment

The NCCN and ESMO offer similar treatment recommendations, as follows [8, 32]

  • 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 by both NCCN and ESMO

  • 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 aggressive regimens [8] :

  • CALGB regimen (Treatment 1, 2, 2.5: rituximab + methotrexate with augmented CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]; Treatment 3: etoposide, cytarabine, rituximab; Treatment 4: carmustine, etoposide, cyclophosphamide/autologous stem cell rescue; Treatment 5: rituximab maintenance) (Treatment 2.5 is given if the pre-Treatment 3 bone marrow biopsy contains >15% MCL.)
  • HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) + rituximab
  • Nordic regimen (dose-intensified induction immunochemotherapy with rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP]) alternating with rituximab + high-dose cytarabine)
  • Alternating RCHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)/(rituximab, dexamethasone, cisplatin, cytarabine)
  • RDHAP 
  • Sequential RCHOP/RICE (rituximab, ifosfamide, carboplatin, etoposide)

Less aggressive induction regimens include the following:

  • Bendamustine + rituximab
  • VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone)
  • Cladribine + rituximab (category 2B)
  • CHOP + rituximab
  • Lenalidomide + rituximab
  • Modified rituximab-hyperCVAD in patients older than 65 

For consolidation therapy, the NCCN recommends the following as first-line:

  • In patients who are candidates for it, high-dose therapy with autologous stem cell rescue (HDT/ASCR), plus rituximab maintenance (category 1 for rituximab maintenance)
  • In patients who are not candidates for HDT/ASCR, rituximab maintenance (category 1 following RCHOP)

Second-line therapy regimens are as follows:

  • Bendamustine ± rituximab
  • Bendamustine, bortezomib, and rituximab (category 2B)
  • Bortezomib ± rituximab
  • Cladribine + rituximab
  • FC (fludarabine, cyclophosphamide) ± rituximab (category 3)
  • Ibrutinib
  • Ibrutinib, lenalidomide, rituximab (category 2B)
  • Lenalidomide ± rituximab
  • PCR (pentostatin, cyclophosphamide, rituximab) (category 3)
  • PEPC (prednisone, etoposide, procarbazine, cyclophosphamide) ± rituximab (category 3)
  • Venetoclax
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