eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoma, Mantle Cell

Muhammad Rashid Abbasi, MD, 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
Joseph A Sparano, MD, Professor of Medicine, Albert Einstein College of Medicine/Cancer Center; Program Director, Director of Breast Medical Oncology, Department of Internal Medicine, Division of Oncology, Montefiore Medical Center

Updated: May 14, 2007

Introduction

Background

Mantle cell lymphoma (MCL) is recognized in the Revised European-American Lymphoma and World Health Organization classifications as a distinct clinicopathologic entity. 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). In the International Lymphoma Classification Project, it accounted for 8% of all non-Hodgkin lymphomas (NHLs).

Pathophysiology

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.

Frequency

United States

NHL represents approximately 4% of all cancer diagnoses and is the seventh most common cancer. MCL represents 2-10% of all NHLs. In 1999, more than 55,000 new cases of NHL were diagnosed. The incidence of NHL of all types has increased by approximately 40% over the last 20 years, although the cause for this increase is unknown.

International

NHLs are 5 times more common than Hodgkin disease, representing approximately 4% of all cancers diagnosed internationally. The exact international prevalence of MCL is difficult to estimate because of the lack of uniform classification and procedures used for diagnosis.

Mortality/Morbidity

MCL is associated with a poor prognosis. Although MCL represents only 6% of NHLs, it remains incurable with current chemotherapeutic approaches. Despite response rates of 50-70% with many regimens, the disease typically progresses after chemotherapy. 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.
• 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.

Race

Overall, whites are at higher risk for developing NHLs than blacks and Asian Americans.

Sex

The male-to-female ratio is 4:1.

Age

The age range at presentation is 35-85 years. Median age is 60 years.

Clinical

History

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

Physical

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

Causes

• No causative factor has been identified for MCL or for most patients with 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.

Differential Diagnoses

Chronic Lymphocytic Leukemia
Hairy Cell Leukemia
Lymphoma, Diffuse Large Cell
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Myeloproliferative Disease

Other Problems to Be Considered

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

Workup

Laboratory Studies

• CBC count
  • Anemia and cytopenias are secondary to bone marrow infiltration.
  • Lymphocytosis of more than 4000/µL occurs in 20-40% of cases.
• Chemistry
  • Patients have elevated lactate dehydrogenase levels, which correlate with tumor burden.
  • Patients have abnormal liver function test results from liver involvement.
• Beta2-microglobulin: The level may be elevated, which indicates a poor prognosis.
• Rare findings: These include hypogammaglobulinemia, monoclonal gammopathy, and a positive Coombs test result.

Imaging Studies

• Body CT scan: This study is important for initial staging and for assessing the patient's response to treatment.

Other Tests

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 Table).^1,2

Differential Diagnosis of MCL by Immunophenotyping

*Surface immunoglobulins.
^† B-cell chronic lymphocytic leukemia/small lymphocytic leukemia.
^‡ Prolymphocytic leukemia.
^§ Marginal zone leukemia.
^|| Splenic lymphoma with villous lymphocytes.
^¶ Lymphoplasmacytic lymphoma.
^# Follicular lymphoma.
**Hairy cell leukemia.

Cytogenetics

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

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

Lymph node

Tumor 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.

Bone marrow

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

Medical Care

• MCL remains a difficult problem because of the lack of reliably curative treatments and the paucity of prospective clinical trials.⁴
• 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.

Surgical Care

• Surgery, such as lymph node biopsy, is indicated for diagnosis.
• Albeit rarely, surgery may be indicated for therapeutic purposes, such as GI obstruction.

Consultations

• 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.

Medication

Regimens for primary MCL therapy

• 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 regimens: Combination chemotherapy (ie, cyclophosphamide, vincristine, prednisone [CVP]; cyclophosphamide, hydroxydaunomycin, Oncovin [vincristine], prednisone [CHOP]) was studied in a randomized prospective trial. The comparison of CVP and 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. The dosages for CVP and CHOP chemotherapy regimens are as follows:
  • CVP (administered every 21 d)
    • 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 (administered every 21 d)
    • 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) regimen
  • First-line therapy is with hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (hyper-CVAD) with or without rituximab. 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 persons with MCL shows a higher complete response rate and response duration than any other regimen (100% response rate with 89% complete response). 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 hematological 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 mg/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% (Pred Forte 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 also prophylaxis may be given. Additionally, doses should be modified according to the protocol with which the patient is being treated.
• R-CHOP regimen: Another regimen is CHOP plus rituximab (R-CHOP). A phase 2 randomized trial of CHOP versus R-CHOP in patients with previously untreated MCL was reported by the German Low-Grade Lymphoma Study Group at the 2004 American Society of Clinical Oncology meeting. The complete response rate was higher with R-CHOP (34% vs 7%; P = .00024). The time to treatment failure was also in favor of R-CHOP, but the time to progression showed no significant difference.
• 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.⁵

Regimens for relapsed or refractory MCL

• 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, although this therapy is still typically associated with a continuous pattern of relapse.
• Nucleoside analogues and combinations
  • With the use of fludarabine, mitoxantrone, and dexamethasone (FND); fludarabine and cyclophosphamide (FC); and fludarabine, cyclophosphamide, mitoxantrone (FCM), all with or without rituximab, evidence has shown that fludarabine as a single agent has activity in MCL. A higher complete response rate and/or longer response duration has been suggested when 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.⁶
  • Other nucleoside analogs have activity in MCL, such as 2-chlorodeoxyadenosine, which was also found to be superior in combination with mitoxantrone.
• Salvage chemotherapy combinations (eg, R-ICE, ESHAP) followed by ASCT: Rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) or etoposide, methylprednisolone (Solu-Medrol), high-dose cytosine arabinoside, and cisplatin (ESHAP) followed by ASCT has been used; however 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, with some long-term survivors, including patients in whom prior high-dose therapy had failed.
• Bortezomib (Velcade)
  • Recent trials from the Memorial Sloan-Kettering Cancer Center, National Cancer Institute of Canada, and M.D. Anderson Cancer Center have shown promising results with bortezomib for MCL. Goy and O'Connor have established the therapeutic activity of bortezomib in relapsed and refractory MCL, and their work is now being 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.⁷
  • FDA has recently (12/06) approved Velcade for MCL in patients who have recieved at least one prior 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% CR. Median duration of response was 9.3 months in responding patients and 15.4 in patients with CR.
    • Velcade Regimen: Velcade 1.3 mg/m² IV push twice per week (days 1, 4, 8, 11) followed by 10-day treatment free period (21 day cycle) for 8 cycles. Patients with stable disease or partial responses could receive up to 1 y; not to exceed maximum 17 cycles.
• Radioimmunotherapy
  • Both iodine I 131–based tositumomab (Bexxar) and yttrium 90–based ibritumomab tiuxetan (Zevalin) have shown activity as single agents for salvage therapy in persons with MCL.⁸ 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.
• Monoclonal antibodies: 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.
• Rituximab and thalidomide combination: 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. In this 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 been proven curative for MCL when used as second-line therapy. Long-term survival data are currently unavailable in the setting of high-dose chemotherapy applied as consolidation therapy to patients in first complete remission
  • New agents and combinations in trials:
    • Chemotherapy + Rituximab followed by RIT: this option is currently being tested as part of frontline therapy.
    • mTOR inhibitors 14, CDK inhibitors or small molecule inhibitors of Bcl-2 family members.⁹ However these compounds are still being tested as part of clinical trials. Preclinical data suggest that several of these new biological agents can be combined with rituximab showing additive or synergistic effect.
    • Combination of bortezomib and rituximab, which was tested in indolent NHL (follicular and marginal zone) 15 and is currently being tested in MCL as well.
    • Promising results have also been shown using rituximab (standard dose) and thalidomide 16 with an ORR of 81% (CR rate 31%) and median progression-free survival (PFS) was 20.4 months (95% CI, 17.3 to 23.6) in the relapse setting.
    • Lenalidomide - rituximab also being tested.
  • For selected patients, allogeneic hematopoietic stem cell transplantation from HLA-matched donors is a potential therapeutic option that remains investigational.

Alkylating agents

Impair cell function by forming covalent bonds with DNA, RNA, and proteins. Alkylating agents are not cell cycle phase–specific and are used for both hematologic and nonhematologic malignancies.

Chlorambucil (Leukeran)

Used mainly for CLL, Hodgkin disease, indolent NHL, and Waldenström macroglobulinemia. Reliably absorbed in GI tract and administered PO.

Dosing

Adult

0.1-0.2 mg/kg PO, 4-10 mg/d, for 3-6 wk

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity (and cross-hypersensitivity); history of prior resistance

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Slowly progressive lymphopenia and some neutropenia; do not administer before fourth wk of radiation or chemotherapy

Cyclophosphamide (Cytoxan)

Used mainly in combination regimens for hematologic and nonhematologic malignancies. Part of CHOP and CVP regimens for lymphoma treatment.

Dosing

Adult

750-1000 mg/m² IV on day 1 in CHOP and CVP regimens

Pediatric

Not established

Interactions

Barbiturates may increase cyclophosphamide conversion to its toxic metabolites; chloramphenicol half-life is increased; succinylcholine metabolism is blocked; increases leukopenia with thiazide diuretics; anticoagulants effect increased; digoxin level decreased; doxorubicin-induced cardiotoxicity increased

Contraindications

Documented hypersensitivity; severely depressed bone marrow function; nursing mothers; serious infection

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Depressed bone marrow function, known hypersensitivity, and recent radiation therapy

Anthracycline antibiotics

Bind to nucleic acid by intercalation with base pairs of DNA double helix, interfering with DNA synthesis. Causes inhibition of DNA topoisomerases I and II.

Doxorubicin (Adriamycin)

Important part of multiple chemotherapeutic regimens for lymphomas, including CHOP.

Dosing

Adult

50 mg/m² IV on day 1 of CHOP regimen

Pediatric

Not established

Interactions

Increases incidence of cyclophosphamide-induced hemorrhagic cystitis; increases hepatotoxicity with 6-mercaptopurine; cyclosporin may induce coma and/or seizures; phenobarbital increases elimination; phenytoin levels may be decreased

Contraindications

Marked myelosuppression; previous treatment with complete cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Not an antimicrobial agent; red discoloration of urine; discontinue nursing during treatment; check and monitor cardiac function (LVEF) prior to therapy; rate of CHF exceeds 5% if cumulative dose >500-550 mg/m²

Vinca alkaloids

Inhibit microtubule assembly, causing arrest of cell division at metaphase stage of mitosis. Cell cycle phase–specific at M and S phases.

Vincristine (Oncovin)

Used in hematologic and nonhematologic malignancies. Part of CVP and CHOP regimens for lymphoma.

Dosing

Adult

1.4 mg/m² IV; not to exceed 2 mg

Pediatric

Not established

Interactions

May decrease blood levels of phenytoin; may increase methotrexate cellular uptake

Contraindications

Documented hypersensitivity; IT administration can result in death; preexisting neurotoxicity or neuromuscular disease

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

No IT use; impaired liver function; concomitant neurotoxic drugs; patient receiving radiation to fields that include liver

Corticosteroids

Glucocorticoids cause profound and varied metabolic effects. In addition, modify immune responses to diverse stimuli.

Prednisone (Deltasone)

Used in combination chemotherapy regimens, especially for hematologic malignancies. Part of CVP and CHOP regimens for lymphoma treatment.

Dosing

Adult

100 mg/m² PO days 1-5 in CHOP and CVP regimens

Pediatric

Not established

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; systemic fungal infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with dyspepsia, peptic ulcer disease, advanced diabetes, or known psychiatric history

Interferons

Mechanism by which exerts antitumor or antiviral activity not clearly understood. However, direct antiproliferative action against tumor cells, inhibition of virus replication, and modulation of host immune responses are believed to possibly play important roles.

Interferon alfa-2b (Intron A)

Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Dosing

Adult

5 million IU SC 3 times/wk for as long as 18 mo in conjunction with or following an anthracycline-containing chemotherapy regimen

Pediatric

Not established

Interactions

Potential risk of renal failure when administered concurrently with interleukin 2; theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Rarely, acute hypersensitivity reaction occurs; can exacerbate psoriasis; variation exists in dosage, route, and adverse effects with different brands; caution against performing tasks that would require complete mental alertness (eg, operating machinery, driving a motor vehicle); not known whether drug is excreted in human milk; caution in patients with prior psychiatric history

Monoclonal antibodies

Rituximab is a genetically engineered chimeric (murine and human) monoclonal antibody directed against the CD20 antigen found on surface of normal cells and in high copy number on malignant B lymphocytes.

Rituximab (Rituxan)

Increasingly being used in CD20-positive low-grade lymphomas refractory to conventional therapy.

Dosing

Adult

375 mg/m² as a slow IV infusion; repeat dose once qwk for 4 wk

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Infusion-related hypersensitivity reaction during first infusion may rarely be fatal, usually occurs within 30-120 min of starting infusion, and resolves by slowing infusion rate and providing supportive measures; patients with leucocytosis from circulating lymphoma cells, bulky sites of lymphoma, or pulmonary involvement are at increased risk for pulmonary reaction

Proteasome inhibitor

Disrupts cell cycle and pathways supporting cell growth.

Bortezomib (Velcade)

First drug approved of anticancer agents known as proteasome inhibitors. The proteasome pathway is an enzyme complex existing in all cells. This complex degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts pathways supporting cell growth, thus decreases cancer cell survival.

Dosing

Adult

1.3 mg/m² IV bolus 2 times/wk for 2 wk (ie, days 1, 4, 8, and 11); rest for 10 d (ie, days 12-21), then repeat cycle

Pediatric

Not established

Interactions

Substrate of CYP450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4; may inhibit CYP450 2C19, therefore caution with coadministration of isoenzyme 2C19 substrates (eg, barbiturates, phenytoin, valproic acid, imipramine, lansoprazole, warfarin)

Contraindications

Documented hypersensitivity to bortezomib, boron, or mannitol

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse effects include nausea, fatigue, diarrhea, constipation, headache, decreased appetite, thrombocytopenia, anemia, fever, vomiting, or peripheral neuropathy (modify dose if neuropathy occurs); may cause hypotension; caution with hepatic impairment; at least 72 h should elapse between each dose

Follow-up

Further Inpatient Care

• Admit patients for complications or disease progression.
• Admit patients for adverse chemotherapy effects, such as neutropenic fever or mucositis.

Further Outpatient Care

• Usually, treatment and follow-up care of patients with MCL is performed in an outpatient setting.
• 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 CBC counts.
• Provide symptomatic treatment for adverse effects such as nausea, vomiting, diarrhea, mucositis, and fatigue.
• Provide psychosocial support.

Complications

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

Prognosis

• MCL exhibits a moderately aggressive course similar to that of intermediate-grade NHL. Unlike intermediate-grade lymphomas, it is rarely curable with currently available standard treatment.
• Median overall survival is 2-5 years. Younger age and limited disease are favorable prognostic features. Complete responses are rare with standard chemotherapy. Median time to treatment failure is less than 18 months.

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 excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Lymphoma.

Miscellaneous

Medicolegal Pitfalls

• Failure to ensure that the patient understands this disease and the available treatment options prior to starting a treatment modality, such as chemotherapy
• Failure to discuss all risks (including, but not limited to, death) and benefits, answer questions, or obtain informed consent prior to initiating chemotherapy
• Failure to prevent medication errors (a common source of lawsuits)
• Failure to pay special attention while writing and administering chemotherapy, with chemotherapy checks at the pharmacy and nursing levels prior to administration

References

1. Gao J, Peterson L, Nelson B, Goolsby C, Chen YH. Immunophenotypic variations in mantle cell lymphoma. Am J Clin Pathol. Nov 2009;132(5):699-706. [Medline].

2. Bogner C, Dechow T, Ringshausen I, Wagner M, Oelsner M, Lutzny G, et al. Immunotoxin BL22 induces apoptosis in mantle cell lymphoma (MCL) cells dependent on Bcl-2 expression. Br J Haematol. Oct 11 2009;[Medline].

3. Chen YH, Gao J, Fan G, Peterson LC. Nuclear expression of sox11 is highly associated with mantle cell lymphoma but is independent of t(11;14)(q13;q32) in non-mantle cell B-cell neoplasms. Mod Pathol. Oct 2 2009;[Medline].

4. Weigert O, Unterhalt M, Hiddemann W, Dreyling M. Mantle cell lymphoma: state-of-the-art management and future perspective. Leuk Lymphoma. Oct 28 2009;[Medline].

5. Kasamon YL, Jones RJ, Brodsky RA, Fuchs EJ, Matsui W, Luznik L, et al. Immunologic recovery following autologous stem-cell transplantation with pre- and posttransplantation rituximab for low-grade or mantle cell lymphoma. Ann Oncol. Oct 30 2009;[Medline].

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Keywords

mantle cell lymphoma, MCL, lymphocytic lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma, ILL, diffuse poorly differentiated lymphocytic lymphoma, PDL, centrocytic lymphoma, diffuse small-cleaved cell lymphoma, DSCCL, mental zone lymphoma

Contributor Information and Disclosures

Author

Muhammad Rashid Abbasi, MD, 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
Muhammad Rashid Abbasi, MD is a member of the following medical societies: American College of Physicians, American Medical Association, and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Joseph A Sparano, MD, Professor of Medicine, Albert Einstein College of Medicine/Cancer Center; Program Director, Director of Breast Medical Oncology, Department of Internal Medicine, Division of Oncology, Montefiore Medical Center
Joseph A Sparano, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Michael Paul Kosty, MD, Associate Director, Associate Professor, Department of Internal Medicine, Divisions of Supportive Care Services and Hematology and Oncology, Ida M and Cecil H Green Cancer Center, Scripps Clinic
Michael Paul Kosty, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Wendy Hu, MD, Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center
Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Clinical guidelines

Rituximab in lymphoma and chronic lymphocytic leukemia: a clinical practice guideline.
Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]. 2005 Feb 17 (revised 2005 Dec 22). 46 pages. NGC:005095

Ibritumomab tiuxetan in lymphoma: a clinical practice guideline.
Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]. 2006 Jul 17. 42 pages. NGC:005224

Clinical trials

Safety and Efficacy of RAD001 in Patients With Mantle Cell Lymphoma Who Are Refractory or Intolerant to Velcade® Therapy.

Rituximab, Lenalidomide, and Bortezomib in Mantle Cell Lymphoma

Zevalin-BEAM/BEAC With Autologous Stem Cell Support as Consolidation in First Line Treatment of Mantle Cell Lymphoma

Related eMedicine topics

Lymphoma, Diffuse Mixed

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Cutaneous B-Cell Lymphoma

Malignant Lymphoma

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