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
View Table | See Table |
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.
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 supports autologous SCT as the standard first-line consolidation therapy, and recommends that complete or partial remission be achieved before autologous SCT is performed. The EBMT/EMCL supports considering allogeneic SCT for patients who experience 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 treatment 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/m2/d PO days 1-5 or 750-1000 mg/m2 IV on day 1
Vincristine at 1.4 mg/m2 IV on day 1, not to exceed 2 mg
Prednisone at 100 mg/m2/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/m2 on day 1 of each cycle
Cyclophosphamide at 300 mg/m2 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/m2 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/m2 on day 1 of each cycle
Methotrexate at 1000 mg/m2 IV over 24 hours on day 1
Leucovorin at 25 mg/m2 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/m2 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.
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).[18]
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.[19, 20]
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.[21]
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.[22]
Lenalidomide
In June 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.[23]
The effectiveness of lenalidomide in combination with ibrutinib and venetoclax, especially in the management of p53-mutated cases, remains inconclusive.[24]
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.[25]
Ibrutinib and palbociclib
A phase I trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma 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.[26]
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%.[27]
Zanubrutinib
In November 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.[28] For both studies the primary endpoint was overall response rate, based on the 2014 Lugano classification and assessed by an independent review committee.
Radioimmunotherapy
Both iodine-131–based tositumomab (Bexxar)[29] and yttrium-90–based ibritumomab tiuxetan (Zevalin)[30] 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. 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.[31]
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.[32] 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.[33] Long-term survival data are currently unavailable in the setting of high-dose chemotherapy applied as consolidation therapy to patients in first complete remission.[34]
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
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[35]
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 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.[35]
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.[35]
The WHO classification subtypes for NHL precursors are as follows:
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[8] :
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.[36] The MIPI includes the following risk factors[37] :
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[37] :
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.[8, 36]
Treatment
The NCCN and ESMO offer similar treatment recommendations, as follows[8, 36] :
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 aggressive regimens[8] :
RDHA ((rituximab, dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin)
Alternating RCHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)/(rituximab, dexamethasone, cisplatin, cytarabine)
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)
Bendamustine + rituximab (category 2B)
Less aggressive induction regimens include the following:
Bendamustine + rituximab
VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone)
RBAC (rituximab, bendamustine, cytarabine) (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 following short response duration of prior chemoimmunotherapy:
Acalabrutinib
Ibrutinib ± rituximab
Lenalidomide ± rituximab
Venetoclax
Ibrutinib, lenalidomide, rituximab (category 2B)
Venetoclax ± ibrutinib (category 2B)
Second-line therapy regimens following extended response duration of prior chemoimmunotherapy:
Bendamustine ± rituximab
Bortezomib ± rituximab
Small molecule inhibitors
Bendamustine, bortezomib, and rituximab (category 2B)
PEPC (prednisone, etoposide, procarbazine, cyclophosphamide) ± rituximab (category 2B)
CHOP + rituximab (if not previously given) (category 2B)
VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) (category 2B)
Author
Muhammad Rashid Abbasi, MD, Former Assistant Professor of Medicine, Albert Einstein College of Medicine; Consulting Staff, Department of Internal Medicine, Division of Hematology/Oncology, Jacobi Medical Center, Morristown Memorial Hospital, and St Clare's Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Joseph A Sparano, MD, Professor, Department of Medicine (Oncology), Professor, Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine; Associate Chairman for Clinical Research, Department of Oncology, Montefiore Medical Center; Associate Director for Clinical Research, Albert Einstein Cancer Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Disclosure: Nothing to disclose.