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Mantle cell lymphoma: Initial management

Mantle cell lymphoma: Initial management
Literature review current through: Jan 2024.
This topic last updated: Mar 31, 2023.

INTRODUCTION — Mantle cell lymphoma (MCL) is B cell non-Hodgkin lymphoma (NHL) with features of both indolent and aggressive NHLs that has a heterogeneous natural history. MCL is usually composed of small- to medium-sized lymphoid cells that express BCL2, CD5, and nuclear cyclin D1. Nearly all cases have the t(11;14) chromosomal translocation, which involves rearrangement of an immunoglobulin heavy chain and CCND1 (the gene that encodes cyclin D1), resulting in overexpression of cyclin D1.

Most cases of MCL (ie, "classic" or "aggressive" MCL) present with multiple sites of lymph node involvement, with or without extranodal involvement, and have an aggressive natural history. However, one-fifth of patients manifest a more indolent course that may not require immediate treatment. Conversely, patients with certain adverse clinical or pathologic features respond poorly to conventional therapy. Rare patients manifest limited-stage (stage I) MCL. Patients with indolent MCL, adverse features, or stage I MCL often require distinctive management.

Initial treatment of MCL is discussed in this topic.

Related topics include:

(See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)

(See "Treatment of relapsed or refractory mantle cell lymphoma".)

PRETREATMENT EVALUATION — Pretreatment evaluation of a patient with mantle cell lymphoma (MCL) includes disease staging and assessment of comorbid conditions that can affect treatment, including suitability for autologous transplantation.

Clinical and laboratory — History and physical examination, laboratory and clinical testing, and imaging are used to determine disease stage. MCL is staged according to Lugano criteria (table 1) [1].

We perform the following pretreatment studies in patients with MCL:

Clinical – History and physical examination should evaluate the patient for constitutional "B" symptoms (ie, fevers, sweats, unintentional weight loss). Special attention should be given to gastrointestinal symptoms, enlargement of liver and spleen, and possible involvement of Waldeyer's ring.

Laboratory studies – Screening laboratory studies should include:

Hematology – Complete blood count (CBC) and differential count.

Chemistries – Electrolytes, glucose, kidney function, liver function tests, lactate dehydrogenase (LDH), and uric acid.

Infections – HIV and Hepatitis B testing (including hepatitis B surface antigen and core antibody). For patients with a history of hepatitis B, e antigen and viral load should be measured and consultation with a gastroenterologist or hepatologist is helpful.

Imaging – Positron emission tomography (PET)/computed tomography (CT) or contrast-enhanced CT of chest, abdomen, and pelvis. PET activity is judged according to the five-point PET scale (Deauville score) (table 2).

Clinical testing – The following tests are performed in selected patients:

Cardiac – Echocardiogram or radionuclide ventriculogram (RVG or MUGA) should be performed if treatment with an anthracycline is expected.

Gastroenterology – We generally obtain upper endoscopy and colonoscopy only for patients with gastrointestinal (GI) symptoms.

Some experts perform these studies to exclude subclinical GI involvement for patients who appear to have stage I disease based on clinical evaluation and imaging.

Bone marrow examination – Bone marrow examination should be performed to evaluate unexplained cytopenias and to confirm stage I disease; it is not required for staging other patients with MCL.

We perform bone marrow examination for patients who appear to have stage I disease based on clinical evaluation and imaging. Bone marrow examination is generally not required if MCL cells are seen on the blood smear or if there is obvious marrow involvement on PET; note that PET is not sensitive for marrow involvement by MCL.

Neurologic – Patients with unexplained neurologic findings should undergo central nervous system (CNS) imaging and lumbar puncture (LP), including cytology and flow cytometry of cerebrospinal fluid.

If an LP is planned and there are concerns about seeding the CNS with circulating MCL cells, the diagnostic procedure can be combined with administration of intrathecal chemotherapy, or the LP can be deferred until the white blood cell count has declined after beginning systemic therapy.

Some experts perform an LP for all patients who have the blastoid variant of MCL, regardless of neurologic abnormalities, because of an increased risk of CNS involvement [2].

Fertility counseling – Patients of childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

General approaches to the diagnostic work-up and staging of non-Hodgkin lymphoma are presented separately (table 1). (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

MCL subtypes — There are two major subtypes of MCL that are distinguished by clinical presentation and pathologic features [3,4]:

Classic (aggressive) MCL – Most cases of MCL have an aggressive course, whether it manifests as nodal disease, extranodal involvement (eg, GI tract or marrow), or both.

The malignant cells of classic MCL have unmutated IGHV genes, overexpress SOX11, and often have other mutations and epigenetic modifications.

Indolent MCL – Approximately 20 percent of cases of MCL have an indolent course with a more favorable prognosis [5]. The malignant cells generally have mutated IGHV, a low proliferative fraction (eg, Ki-67 <10 percent), and do not express SOX11 [6]. Common presentations of indolent MCL include:

Leukemic, non-nodal MCL – Leukemic, non-nodal MCL typically presents with lymphocytosis and splenomegaly that resembles chronic lymphocytic leukemia, but it may become aggressive if mutations of TP53 or other key genes are acquired.

GI tract-only involvement – For patients with MCL that involves the GI tract-only (especially when it is limited to microscopic disease), the natural history is generally indolent.

Indolent nodal MCL – A subset of patients with nodal MCL have indolent disease. Such cases usually manifest low disease burden, normal serum lactate dehydrogenase (LDH), and low Ki-67 index.

Management of indolent MCL is discussed below. (See 'Indolent MCL' below.)

Disease stage — We distinguish management of MCL according to disease stage, as follows:

Advanced-stage MCL – Nearly all patients with MCL present with advanced-stage disease (stages II to IV MCL and any case with >10 cm disease ["bulky" disease]).

Limited-stage (ie, stage I) MCL – True stage I MCL (ie, non-bulky disease involving only a single lymph node region) is extremely rare.

Nearly all cases of suspected stage I MCL are found to have other sites of subclinical involvement, such as disease of the GI tract or marrow involvement. We generally perform endoscopy/colonoscopy and bone marrow examination in patients who appear to have stage I disease based on clinical evaluation and imaging. (See 'Clinical and laboratory' above.)

Management of limited-stage MCL is discussed below. (See 'Stage I MCL' below.)

Fitness — We assess functional (performance) status and determine if the patient is a candidate for intensive therapies, including autologous transplantation.

Performance status – We assess functional status according to ECOG or Karnofsky score (table 3).  

Transplant eligibility – Autologous hematopoietic cell transplantation (HCT) is a standard approach for consolidation therapy with MCL. Soon after diagnosing MCL, we refer fit individuals ≤65 years to transplant specialists to evaluate eligibility for autologous HCT, which requires adequate performance status and good kidney, liver, heart, and lung function, as discussed separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

Prognostic factors — We evaluate patients using a clinical prognostic index and assess pathologic features of the tumor cells prior to treatment.

Prognostic index – The Mantle Cell Lymphoma International Prognostic Index (MIPI) (calculator 1) (table 4) can be used to stratify patients with MCL into low-, intermediate-, and high-risk groups [7].

Modified versions incorporate Ki-67 index (MIPI-B) or miR-18b (MIPI-B-miR) into the MIPI model; these modified indices were effective for estimating prognosis in trials with long-term follow-up [8-10]. MIPI was more accurate than the International Prognostic Index (IPI) for predicting survival outcomes in an analysis of 158 patients receiving intensive induction chemoimmunotherapy and autologous HCT [11].

MIPI is discussed in greater detail separately. (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis", section on 'Prognostic features'.)

Pathologic features – We consider pathologic features of the tumor cells when planning management.

Adverse – The following features are associated with especially poor outcomes in patients with advanced-stage MCL and may influence management (see 'MCL with adverse features' below):

-Mutated TP53

-Blastoid phenotype

-Complex karyotype – ≥3 chromosomal abnormalities, in addition to t(11;14)

Favorable – Up to one-fifth of cases of MCL are SOX11-negative; many such cases manifest as leukemic, non-nodal MCL (eg, blood, marrow, and/or spleen) or GI tract-only disease, while sparing lymph nodes. (See 'Indolent MCL' below.)

OVERVIEW OF MANAGEMENT — Most patients with MCL present with symptomatic disease that requires treatment, but selected patients may benefit from initial observation. (See 'Indolent MCL' below.)

For patients with MCL who receive systemic therapy, we recommend treatment that includes rituximab plus chemotherapy, rather than chemotherapy alone, based on improved survival and little toxicity.   

A meta-analysis of seven studies (which included 1943 patients with MCL or indolent lymphomas) reported that, compared with chemotherapy alone, treatment that included rituximab was associated with superior OS, response rates, and disease control [12,13]. Mortality benefits were seen in the subset of patients with MCL (HR 0.60, 95% CI 0.37-0.98). Observational data also support a survival benefit with the addition of rituximab to chemotherapy (median survival 37 months versus 27 months) [14].

Management of MCL is guided by the clinical presentation and pathologic features of the disease.

The natural history of MCL is heterogeneous; while most patients have classic (aggressive) MCL, a minority of patients have indolent MCL, which may be observed rather than treated at diagnosis.

Classic (aggressive) MCL – Most patients present with advanced-stage nodal MCL (stages II-IV and all cases with disease >10cm), with or without extranodal involvement of the gastrointestinal (GI) tract, bone marrow, blood, or other sites.

Management of classic MCL is stratified according to age and fitness. (See 'Fit, younger patients' below and 'Older or less-fit patients' below.)

Treatment comprises (algorithm 1):

Induction therapy – Induction chemoimmunotherapy seeks to relieve symptoms and reduce disease burden in anticipation of post-induction management.

Post-induction therapy – Induction therapy, alone, is rarely sufficient to achieve long-term disease control of MCL. Post-induction therapy for nodal MCL is used to sustain symptom relief and prolong survival.

Post-induction therapy is guided by medical fitness and comprises:

-Consolidation therapy – For younger (eg, ≤60 or ≤65 years), medically-fit patients, autologous hematopoietic cell transplantation (HCT) is considered a standard approach for consolidation therapy. Routine use of autologous HCT may evolve with changes in induction therapy, as discussed below. (See 'Fit, younger patients' below.)  

-Maintenance therapy – Maintenance therapy refers to prolonged, lower intensity treatment following autologous HCT or after completing induction chemoimmunotherapy. (See 'Post-transplant maintenance therapy' below and 'Maintenance therapy' below.)

Nodal MCL with mutated TP53, the blastoid variant, or central nervous system involvement is often poorly controlled using standard treatments. We strongly encourage such patients to participate in a clinical trial, when available. Management of MCL with adverse features is discussed below. (See 'MCL with adverse features' below.)

Indolent MCL – Approximately one-fifth of patients with MCL have a more indolent natural history.

Many indolent cases manifest as leukemic, non-nodal MCL (which typically presents asymptomatically with splenomegaly and/or blood and marrow involvement) or GI tract-only disease. However, some cases of nodal MCL, especially those with low tumor burden nodal involvement, normal serum lactate dehydrogenase (LDH), and low Ki-67 index may have an indolent course. Management of indolent forms of MCL is discussed below. (See 'Indolent MCL' below.)

Limited-stage MCL – Presentation with asymptomatic stage I MCL (ie, non-bulky disease involving a single lymph node region) is extremely rare. In nearly all cases, thorough evaluation reveals subclinical involvement of the GI tract or other sites. Management of stage I MCL is discussed below. (See 'Stage I MCL' below.)

MCL occasionally presents with intestinal obstruction or intussusception caused by extensive intestinal polyposis. Surgery may be of value for patients who present with bowel obstruction or uncontrollable bleeding from intestinal polyposis. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)

Management of MCL is evolving as newer agents and regimens are incorporated into standard care. Our approach is consistent with various national and international guidelines and expert panels, including the National Comprehensive Cancer Network, American Society of Transplantation and Cellular Therapy, Center for International Blood and Marrow Transplant Research, European Society for Blood and Marrow Transplantation, European Society for Medical Oncology, and European Hematology Association [15-18].

FIT, YOUNGER PATIENTS — We judge fitness and age in this setting according to suitability for intensive therapies, including autologous hematopoietic cell transplantation (HCT).

Eligibility for autologous HCT varies among institutions, but generally requires age ≤60 or ≤65 years and adequate heart, lung, liver, and kidney function, as described separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

Induction therapy for fit, younger patients — For medically-fit, younger patients with classic MCL, we suggest induction therapy using rituximab plus bendamustine (R-B) or one of the high-dose cytarabine (HiDAc)-containing intensive regimens listed below (algorithm 1), rather than R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, dexamethasone, alternating with high-dose methotrexate and cytarabine). This suggestion is based on the favorable balance of toxicity and long-term survival using the preferred induction regimens for patients who will proceed to autologous HCT as consolidation therapy.

Note that selected patients with indolent MCL can be initially observed, rather than immediately initiating therapy. Most such cases manifest as leukemic, non-nodal MCL or gastrointestinal tract (GI)-only MCL, but some patients with nodal MCL also have an indolent natural history (especially those with low nodal tumor burden, low serum lactate dehydrogenase [LDH], and low Ki-67 index). Management of indolent MCL is discussed below. (See 'Indolent MCL' below.)

Patients who have nodal MCL with mutated TP53, blastoid morphology, or central nervous system involvement often experience inferior outcomes using standard treatments [19]. We strongly encourage such patients to participate in a clinical trial. (See 'MCL with adverse features' below.)

We consider the following induction regimens acceptable for fit, younger patients with MCL:

Rituximab plus bendamustine (R-B) (see 'Rituximab-bendamustine (R-B)' below)

More intensive HiDAc-containing regimens (see 'Intensive induction regimens' below)  

R-B/R-HiDAC – R-B followed by rituximab plus HiDAc (see 'R-B/R-HiDAc' below)

R-DHAPRituximab, dexamethasone, HiDAc, plus cisplatin, carboplatin, or oxaliplatin (see 'R-DHAP' below)

R-CHOP/R-DHAPRituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), alternating with R-DHAP (which can include cisplatin, carboplatin, or oxaliplatin) (see 'R-CHOP/R-DHAP' below)

Nordic regimenRituximab plus maxi-CHOP (dose-intensified CHOP), alternating with R-HiDAc (see 'Nordic regimen' below)

There is disagreement about the contribution of the induction regimen to long-term outcomes in patients who subsequently undergo autologous HCT. Some experts favor induction using R-B because of its balance of efficacy and modest toxicity. Other experts favor more intensive, HiDAc-containing regimens; such regimens are more toxic than R-B, but there is uncertainty about whether transplanted patients experience similar or modestly improved long-term outcomes compared with those who received R-B induction [20,21].

Management of MCL is evolving and we await results of ongoing randomized clinical trials for treatment of MCL, including studies that incorporate a Bruton tyrosine kinase inhibitor (BTKi) into induction therapy. As an example, in the TRIANGLE trial, patients were randomly assigned to one of three arms: R-CHOP/R-DHAP followed by autologous HCT; R-CHOP/R-DHAP plus ibrutinib followed by autologous HCT; and R-CHOP/R-DHAP plus ibrutinib without transplantation. This trial also incorporates ibrutinib into post-induction management and will evaluate the role of autologous HCT as consolidation therapy. Before endorsing such an approach, we await publication of this and other ongoing trials of front-line therapy for MCL.

We do not favor induction therapy using either R-CHOP alone or R-HyperCVAD. Randomized trials demonstrated that R-CHOP was less effective than either R-B or R-CHOP/R-DHAP, while R-HyperCVAD is associated with excessive toxicity and impaired stem cell collection, as described below.

No randomized trials have directly compared the various preferred induction regimens described above, but long-term outcomes after autologous HCT are similar and are presented below. (See 'Rituximab-bendamustine (R-B)' below and 'Intensive induction regimens' below.)

The following studies support our treatment preferences:

R-B is less toxic than R-HyperCVAD – SWOG S1106 is the only trial of MCL that randomly assigned patients to induction therapy using R-B versus a more intensive regimen; the trial was closed early because R-HyperCVAD was associated with excessive toxicity and inadequate mobilization of stem cells for transplantation [22]. R-HyperCVAD caused more grade ≥3 anemia, neutropenia, and thrombocytopenia and nearly one-third of patients failed to mobilize even 1.5 x 106 stem cells. Among patients on the R-HyperCVAD arm, 7 of 17 did not complete the planned course of induction therapy, compared with 8 of 35 on the R-B arm. Longer-term follow-up of the 52 evaluable patients (of 160 planned enrollees) reported no significant differences in two-year OS or PFS between trial arms [23].

A population-based study reported that long-term outcomes were similar between patients <65 years who underwent autologous HCT after induction with R-CHOP versus R-HyperCVAD; however, R-HyperCVAD was associated with more adverse events, including unplanned hospital admissions for febrile neutropenia [20].  

Outcomes with R-B are superior to R-CHOP or R-CVP – R-B achieved superior progression-free survival (PFS) with less toxicity when it was directly compared with R-CHOP or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) in the randomized StiL [24] and BRIGHT [25,26] trials of patients with MCL and indolent lymphomas. Details of the StiL and BRIGHT trials are presented below. (See 'Rituximab-bendamustine (R-B)' below.)

Role of high-dose cytarabine (HiDAc) – The importance of HiDAc was demonstrated in the MCL-Younger trial, in which 497 patients ≤65 years who were to undergo autologous HCT were first randomly assigned to six cycles of R-CHOP versus three cycles each of R-CHOP alternating with R-DHAP (which includes HiDAc) [27]. When adjusted for MIPI (Mantle cell lymphoma International Prognostic Index [MIPI]) prognostic score and with >10 year follow-up, R-CHOP/R-DHAP achieved superior overall survival (OS; median not reached versus 11.3 years; hazard ratio [HR] 0.74 [95% CI 0.56-0.98]) and longer median time to treatment failure (TTF; 8.4 versus 3.9 years) [28]. There was a trend to more secondary hematologic malignancies in the R-CHOP/R-DHAP arm (4.5 versus 1.4 percent at 10 years).

Response assessment — After completing induction therapy, we assess treatment response using positron emission tomography (PET), scored according to the five-point PET scale (Deauville score) (table 2) and Lugano criteria [1].

Treatment response is judged as follows:

Complete response (CR) – PET score 0 to 3 (with or without a residual mass) and no evidence of bone marrow involvement

Partial response (PR) – PET score 4 or 5 (with reduced uptake compared with baseline), no new progressive lesions, and bone marrow activity less than baseline

No response – PET score 4 or 5 (unchanged from baseline), no new lesions, and bone marrow activity unchanged from baseline

Progressive disease – PET score 4 or 5 (increased compared with baseline), new sites of disease, and new or recurrent bone marrow activity

Outside of a clinical study, we do not routinely assess measurable residual disease (MRD) after completion of induction therapy for MCL. We await results of an ongoing phase 3 clinical trial (E4151; NCT03267433) that uses MRD to guide post-induction management of MCL.

Post-induction management — Subsequent management of MCL for transplant-eligible patients is guided by the response to induction therapy (algorithm 1). (See 'Response assessment' above.)

Complete response (CR) – For patients who achieve CR, we proceed to consolidation therapy, as described below. (See 'Consolidation therapy' below.)

Less than CR – For patients who do not achieve CR to induction therapy, we treat for relapsed or refractory (r/r) MCL, as described separately. (See "Treatment of relapsed or refractory mantle cell lymphoma".)

Consolidation therapy — For fit, younger patients who achieve CR after induction therapy, we suggest consolidation using autologous hematopoietic cell transplantation (HCT), rather than proceeding directly to maintenance therapy or observation alone (algorithm 1). This suggestion is based on superior survival and acceptable toxicity with autologous HCT. (See 'Autologous transplantation' below.)

Autologous transplantation versus maintenance therapy – The European MCL Network trial randomly assigned patients ≤65 years with advanced stage MCL to autologous HCT versus maintenance therapy using interferon alfa (IFNa) [29]. With 14-year median follow-up, transplantation achieved superior overall survival (OS; 7.5 versus 4.8 years; hazard ratio [HR] 0.66 [95% CI 0.46-0.95]) and superior progression-free survival (PFS; 3.3 versus 1.5 years; HR 0.50 [95% CI 0.36-0.69]) [30]. Patients in this trial were randomly assigned to induction therapy with CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) versus R-CHOP (rituximab added to CHOP). Importantly, only patients who initially received CHOP had superior OS (HR 0.52 [95% CI 0.33–0.82]) and PFS (HR 0.40 [95% CI 0.26–0.61]) with autologous HCT compared with IFNa; there were no significant differences in OS or PFS between autologous HCT and maintenance IFNa therapy for patients who initially received R-CHOP.

Autologous transplantation versus no transplantation – Analysis of the Swedish and Danish lymphoma registries reported that 273 of 1389 patients diagnosed with MCL from 2000 to 2011 underwent autologous HCT [31]. Compared with patients who received systemic therapy without transplantation, survival was superior for patients who underwent autologous HCT (HR 0.55 [95% CI 0.37-0.83]).

It is uncertain if autologous HCT can cure MCL. In one study, with median follow-up of 6.5 years (some patients were followed for 10 years), median event-free survival (EFS) was 7.4 years, but relapses occurred as long as 9 years after transplantation [10]. In another study, among 1029 patients <65 years who were followed for a median of 6.3 years (and up to 17 years), compared with patients who were not transplanted, autologous HCT transplantation was associated with superior OS and PFS, but there was no plateau on either curve, indicating continued late relapses [32].

Post-transplant maintenance therapy — Following autologous HCT for MCL, we suggest post-transplantation maintenance therapy using rituximab (algorithm 1), rather than lenalidomide maintenance or observation alone, based on superior survival and acceptable toxicity in randomized trials.

Many experts obtain a repeat PET scan at day 100 after transplantation; for patients who remain in CR, we proceed to maintenance therapy, while patients who have disease progression are treated for relapsed/refractory MCL. Some experts proceed directly to maintenance therapy without a repeat PET. Management of relapsed/refractory MCL is discussed separately. (See "Treatment of relapsed or refractory mantle cell lymphoma".)

Rituximab maintenance therapy is given at 375 mg/m2 every two months for three years [33]. Rituximab is associated with the risk of infusion reactions and immunosuppression, and there is a risk of hepatitis B reactivation in patients who are positive for HbsAg or anti-HBc. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab' and "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab' and "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Type of immunosuppressive therapy'.)

Trials that evaluated maintenance therapy following autologous HCT include:

Rituximab maintenance versus observation – The following phase 3 trials demonstrated a survival advantage with rituximab maintenance versus observation after transplantation for MCL:

LYSA – The phase 3 Lymphoma Study Association (LYSA) trial of 240 patients who underwent autologous HCT for MCL reported that three years of post-transplant rituximab maintenance therapy achieved superior survival, compared with observation alone [33]. Patients received induction therapy with four cycles of R-DHAP (rituximab, dexamethasone, high dose cytarabine, plus a platinum compound), followed by autologous HCT; they were then randomly assigned to three years of maintenance rituximab versus observation. With median follow-up >4 years since transplantation, rituximab achieved superior four-year OS (89 percent [95% CI 81-94] versus 80 percent [95% CI 72-88]; hazard ratio [HR] 0.50 [95% CI 0.26-0.99]) and superior four-year PFS (83 percent [95% CI 73-88] versus 64 percent [95% CI 55-73]; HR 0.40 [95% CI 0.23-0.68]). There was no significant difference in grade ≥3 adverse effects (AEs) between the trial arms.

Nordic – For patients treated with the Nordic MCL induction regimen who underwent autologous HCT, post-transplant rituximab maintenance was superior to observation [34]. Among 112 transplanted patients, compared with observation, rituximab maintenance was associated with superior five-year PFS (73 versus 68 percent; HR 0.36 [95% CI 0.20-0.84]), but five-year OS was 78 percent in both arms.

Lenalidomide maintenance versus observation – In a randomized trial that compared lenalidomide maintenance versus observation after autologous HCT, lenalidomide achieved superior PFS, but it is generally not used because it caused excessive toxicity [35]. Notably, only one-half of patients completed their assigned lenalidomide maintenance therapy, mostly due to excessive adverse events. There was no statistically significant difference in three-year OS (93 versus 86 percent), but three-year PFS was superior with lenalidomide (80 percent versus 64 percent; HR 0.51 [95% CI 0.3-.087]). Lenalidomide was associated with more grade ≥3 neutropenia (59 versus 11 percent), nonhematologic AEs (31 versus 8 percent, mostly infections), and secondary malignancies (5 percent versus 3 percent; none were fatal).

Monitoring for disease relapse after completion of maintenance therapy is described below. (See 'Monitoring' below.)

OLDER OR LESS-FIT PATIENTS — For patients who are not eligible for autologous transplantation because of age (eg, ≥65 years), comorbid conditions, or limited fitness, we treat with lower-intensity chemoimmunotherapy and maintenance therapy to control symptoms, reduce the burden of disease, and prolong survival.

Induction for older or less-fit patients — There is no consensus regimen in this setting; our preferred options include:

Rituximab plus bendamustine (R-B) (see 'Rituximab-bendamustine (R-B)' below)

VR-CAPBortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone (see 'VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone)' below)

Rituximab plus lenalidomide (see 'Rituximab plus lenalidomide' below)

No studies have directly compared outcomes with these regimens and the preferred treatment approach varies among clinicians. Administration and outcomes with these regimens are presented below. (See 'Rituximab-bendamustine (R-B)' below and 'Lower-intensity regimens' below.)

Treatment that includes a Bruton tyrosine kinase inhibitor (BTKi) is also an option in this setting, but these agents are not currently approved for initial therapy of MCL.

Maintenance therapy — Post-induction management is guided by the response to induction therapy, as described above (see 'Response assessment' above):

Complete response (CR) or partial response (PR) – For older/less-fit patients with a CR or PR after induction therapy, we suggest rituximab maintenance therapy, rather than maintenance therapy using interferon (IFN) alfa, based on superior survival and little toxicity in a randomized trial and in other studies.

Rituximab maintenance therapy is given at 375 mg/m2 every two months for three years [33]. Rituximab is associated with the risk of infusion reactions and immunosuppression, and there is a risk of hepatitis B reactivation in patients who are positive for HBsAg or anti-HBc. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab' and "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab' and "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Type of immunosuppressive therapy'.)

Studies of rituximab maintenance therapy for older or less fit patients after induction therapy include:

MCL-Elderly – The phase 3 MCL-Elderly trial reported that maintenance rituximab achieved superior survival compared with maintenance IFNa in patients who were not eligible for transplantation [36]. In this trial, 274 patients >60 years were first randomly assigned to induction therapy with fludarabine, cyclophosphamide, and rituximab (R-FC) versus R-CHOP; patients who achieved CR or PR after induction therapy were again randomly assigned to maintenance therapy using rituximab versus IFNa. Compared with IFNa, rituximab reduced the risk of progression or death (HR 0.55 [95% CI 0.36-0.87]), with a trend toward improved four-year OS (87 versus 63 percent); rituximab was associated with grade ≥3 leukopenia and infections in <5 percent of patients. More than one-half of patients continued rituximab maintenance for ≥2 years and one-third continued it for ≥5 years. With longer follow-up (median eight years), rituximab maintenance achieved significantly superior OS (9.8 versus 6.4 years, respectively) and PFS (5.2 versus 2.0 years); the benefits of rituximab maintenance were even greater for patients who received R-CHOP rather than R-FC induction therapy [37].

Flatiron database – Maintenance rituximab was associated with improved outcomes compared with observation alone, according to retrospective analysis of 4216 patients treated in community settings in the Flatiron electronic record-derived database [38]. Compared with observation, maintenance rituximab was associated with superior OS (HR 1.51 [95% CI 1.19-1.92]) and longer time to next treatment (HR 1.96 [95% CI 1.61-2.38]). The superior efficacy of maintenance rituximab was validated in an independent cohort of 1168 patients treated in academic medical centers; among these patients, rates of OS were 92 versus 73 percent for rituximab maintenance versus observation, respectively, and rates of PFS were 74 versus 49 percent, respectively.

Some experts do not offer rituximab maintenance to patients who received induction therapy with R-B, based on preliminary results from the StiL NHL-7 MAINTAIN trial, reported only as an abstract (in 1996) [39]. After nearly five years of follow-up of 168 patients who received R-B induction therapy, two years of rituximab maintenance did not achieve a survival advantage, compared with observation alone. We await publication of these results before concluding that rituximab maintenance does not improve outcomes in patients treated with R-B.

We also await results from ongoing phase 3 trials of maintenance therapy in this setting, including ECOG-ACRIN E1411 (NCT01415752) and MCL-R2 Elderly (NCT01865110).

Stable or progressive disease – For older or less-fit patients who have stable disease or progressive disease after induction therapy, we treat for refractory MCL, as described separately. (See "Treatment of relapsed or refractory mantle cell lymphoma".)

SPECIAL POPULATIONS — Management of patients with the following presentations differs from that of advanced-stage nodal MCL.

Indolent MCL — For asymptomatic patients with indolent MCL, we suggest initial observation rather than immediate treatment, based on favorable outcomes in retrospective studies, the opportunity to delay or avoid treatment-related adverse effects (AEs), and absence of evidence that delayed initiation of treatment affects disease response.

Most often, indolent MCL manifests as leukemic, non-nodal MCL or gastrointestinal tract (GI)-only MCL, but selected cases of nodal MCL may also have an indolent natural history (eg, low nodal tumor burden, low serum lactate dehydrogenase [LDH], and low Ki-67 index).

Studies of observation in selected asymptomatic patients with MCL include:

In a single center study, initial observation was used for 22 percent (90 of 404) of patients with MCL [40]. Among the patients who underwent initial observation, 91 percent had advanced-stage disease, including bone marrow involvement in 72 percent, leukemic involvement (ie, absolute lymphocyte count >5 x 109/L) in 26 percent, and 20 percent with ≥2 sites of extranodal involvement. Expectant monitoring continued for ≥6 months in 93 percent of the observed patients, while 71 percent ultimately received therapy (after a median of 23 months). Pathologic features did not predict the duration of observation; Ki-67 was ≥30 percent in one-quarter of the patients who were observed, while 3 of 25 observed patients had mutated TP53; none of the observed patients had the blastoid variant of MCL. Among the 30 patients who were observed for ≥2 years, 17 had a low tumor burden without leukemic involvement; 9 had leukemic disease with minimal nodal disease, with or without splenomegaly; and 4 had GI tract-only disease. Compared with treated patients, the observed patients had superior overall survival (OS; 11.4 years versus 9.4 years), but there was no difference when comparing time from start of treatment to death, suggesting that the longer survival of observed patients was not related to greater treatment sensitivity.

In another single institution study, one-third of 97 patients were monitored for ≥3 months before beginning systemic therapy [41]. Among patients who underwent initial observation, median time to initial treatment was 12 months (range 4 to 128 months). 

In a population-based study, 17 percent of patients were managed with observation alone for ≥3 months [42]. Among the observation-only patients, 80 percent were monitored expectantly for ≥1 year and 13 percent were observed for >5 years; median time to first treatment was 35 months (range 5-79 months). More than two-thirds of observed patients had nodal presentations. Median OS was longer in the observation group compared with the early treatment group (72 versus 53 months), but multivariable analysis reported that treatment was not associated with improved OS.

Initial observation (ie, treatment deferred >90 days from diagnosis) was used for 6 percent of 8029 patients in the US National Cancer Database; median time to initial treatment was 121 days (range, 91 to 1153 days) [43]. Patients who deferred therapy were more likely to have stage I or II disease or extranodal involvement, and they were less likely to have B symptoms. Another population-based study reported initial observation in 2.4 percent of 1389 patients with MCL [31].

Some asymptomatic patients may choose early treatment rather than observation. If so, treatment is similar to that for older or less-fit patients, as described above. (See 'Older or less-fit patients' above.)

Stage I MCL — Stage I MCL is extremely rare; most cases of suspected stage I MCL have subclinical disease at other sites, as discussed above. (See 'Disease stage' above.)

We generally use radiation therapy for patients with documented stage I MCL to relieve symptoms and control disease at that site.

In a retrospective study of 26 patients with limited-stage MCL, those treated with RT (with or without chemotherapy) had improved five-year progression-free survival (PFS; 73 percent versus 13 percent) and a trend towards improved overall survival (OS) compared with patients who did not receive RT [44]. Six of 17 patients treated with RT were alive without disease progression at >5 years.

MCL with adverse features — Patients with MCL with mutated TP53, central nervous system involvement, or blastoid morphology generally have poor outcomes with conventional treatment, including autologous hematopoietic cell transplantation (HCT) [19]. We strongly encourage such patients to participate in a clinical trial; information and instructions for referring a patient in the US to an appropriate research center can be obtained from https://www.clinicaltrials.gov/.

Outside of a clinical trial, treatment of MCL with adverse features should focus on symptom relief, reducing disease burden, and prolonging survival, while limiting excessive treatment-related adverse effects. We generally avoid autologous hematopoietic cell transplantation (HCT) in this setting because there is no evidence that it improves long-term outcomes for these patients.

Our approach for treatment of MCL with adverse features follows:

Induction therapy – We generally treat using R-B or another lower-intensity induction chemoimmunotherapy regimen:

Rituximab-bendamustine (R-B) – (See 'Rituximab-bendamustine (R-B)' below.)

Other lower-intensity regimens – (See 'Lower-intensity regimens' below.)

There are few studies of treatment outcomes in this higher-risk population of patients. Studies that included patients of all ages or used heterogeneous treatment regimens in this setting reported inferior outcomes in patients with mutated TP53 or complex karyotype [45-51].

Avoidance of autologous HCT – Among 183 patients ≤65 years with MCL in the Nordic MCL2 and MCL3 trials who were treated with intensive induction therapy followed by autologous HCT, TP53 mutations were independently associated with inferior outcomes; mutated TP53 was found in 11 percent of patients in these trials [19]. With median follow-up of 9.2 years, compared with no TP53 mutation, patients with mutated TP53 had 1.8-year median OS (versus median not reached), 0.9-year median PFS (versus median 10.2 years), and 1.0-year median time to relapse (versus 12.3 years). Mutated TP53 was independently associated with inferior OS (HR 6.2 [95% CI 2.6-14.9]), PFS (HR 6.8 [95% CI 3.4-13.8]), and cumulative incidence of relapse (HR 6.9 [95% 3.3-14.5]) in multivariate analysis. Blastoid variant and Ki-67 index ≥30 percent were associated with inferior outcomes, but they were not independently associated with decreased survival.

Maintenance therapy – For patients who achieve CR, we treat with maintenance rituximab, as described above. (See 'Maintenance therapy' above.)

Allogeneic HCT has been associated with long term disease control in patients who have MCL with adverse features, but this benefit must be weighed against the short-term and long-term adverse effects of allogeneic transplantation. It should be noted that the following studies preceded use of chimeric antigen receptor (CAR)-T cell therapy for management of relapsed or refractory MCL. (See "Treatment of relapsed or refractory mantle cell lymphoma".)

Among 42 patients (median age 61 years; range 34 to 74 years) who underwent non-myeloablative or reduced intensity conditioning allogeneic HCT for MCL in a single-institution study, two-year OS was 78 percent (95% CI 60-88 percent), two-year PFS was 61 percent (95% CI 43-75 percent), relapse rate was 19 percent, and non-relapse mortality was 20 percent [52]. There was no difference in OS or relapse rate when comparing post-allogeneic HCT outcomes among patients who had mutated TP53 versus those without mutant TP53. This observation has been interpreted by some to indicate that allogeneic HCT can overcome the negative prognostic impact of mutated TP53 (in contrast with outcomes after autologous HCT) [19]. These results are comparable with other published reports on allogenic HCT in MCL patients [53,54].

MONITORING — Following completion of therapy, we restage patients with positron emission tomography (PET) and monitor for relapse and treatment-related complications.

The frequency and nature of follow-up visits is influenced by preferences of the patient and physician. No prospective studies have compared various follow-up protocols.

Relapses of MCL can continue long after completion of therapy, including after autologous transplantation; as described above, there is no clear plateau for survival or relapse after transplantation. (See 'Consolidation therapy' above.)

Our approach to monitoring patients with MCL follows:

Clinical – History, physical examination, and laboratory studies are scheduled every two or three months in the first year, every three to six months in the second year, and then every 6 to 12 months for at least five years. Subsequent follow-up is yearly, or as clinically indicated

Imaging – We limit the number of imaging studies, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)

We generally perform imaging as clinically indicated (ie, for new or progressive symptoms or other evidence of progression). Some experts instead favor routine surveillance. Because most relapses occur in the first two to four years after treatment, an example of surveillance imaging might be contrast-enhanced computed tomography (CT) of chest, abdomen, and pelvis no more than every six months for the first two years, and then no more than annually for two additional years.

Relapse can be suggested by clinical evaluation or imaging, but it must be confirmed by biopsy. Management of relapsed MCL is discussed separately. (See "Treatment of relapsed or refractory mantle cell lymphoma".)

CHEMOIMMUNOTHERAPY REGIMENS — The choice of initial chemoimmunotherapy is guided by clinical presentation and medical fitness, as described above. (See 'Overview of management' above.)

Rituximab-bendamustine (R-B) — Rituximab-bendamustine (R-B) is one of the preferred induction regimens for patients with nodal MCL (See 'Induction therapy for fit, younger patients' above and 'Induction for older or less-fit patients' above.)

Administration – Up to six cycles of:

Bendamustine – 90 mg/m² intravenously over 30–60 minutes on days 1 and 2 of a four-week cycle

Rituximab – 375 mg/m² intravenously on day 1 of each cycle

Outcomes – In the randomized StiL and BRIGHT trials, R-B achieved improved progression-free survival (PFS) and less toxicity, when directly compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) [24,25]. R-B was less toxic and had similar efficacy when compared with R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, dexamethasone, alternating with high-dose methotrexate and cytarabine) in another phase 3 trial (SWOG S1106) [22,23].

StiL – The randomized StiL (Study Group Indolent Lymphomas) trial compared R-B versus R-CHOP as first-line therapy in patients with advanced MCL, follicular, and indolent B cell lymphomas; MCL accounted for 18 percent of 514 patients [24]. Among patients with MCL, median progression-free survival (PFS) was higher with R-B than R-CHOP (35 months versus 22 months). R-B was also associated with fewer serious AEs (19 versus 29 percent) and less grade ≥3 neutropenia (29 versus 69 percent), peripheral neuropathy (all grades; 7 versus 29 percent), and infectious complications (all grades; 37 versus 50 percent). Fatal sepsis occurred in one patient treated with R-B and five patients in the R-CHOP arm and the incidence of second cancers was similar (8 versus 9 percent, respectively). Notably, data from more than one-half of patients in the trial were censored before the minimum period of follow-up.

BRIGHT – The phase 3 BRIGHT trial, which included 447 patients with MCL and indolent lymphomas, reported that R-B achieved superior PFS and response rates compared with R-CHOP or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), but there was no difference in OS [25,26]. Patients were randomly assigned to R-B versus pre-selected R-CHOP or R-CVP. Among the 64 patients with MCL, R-B achieved superior overall response rate (ORR; 94 versus 85 percent) and complete responses (CR; 50 versus 27 percent) [26]. With longer follow-up, R-B achieved superior five-year PFS (66 versus 56 percent; hazard ratio [HR] 0.61 [95% CI 0.45-0.85]) [25]. R-CHOP/R-CVP was associated with more grade ≥3 neutropenia (54 versus 38 percent, respectively), but similar rates of grade ≥3 infections (6 versus 9 percent, respectively). There were more secondary malignancies (mostly skin cancers) with R-B compared with R-CHOP/R-CVP (five patients versus three patients).

SWOG S1106 – This trial, which randomly assigned patients to induction therapy using R-B versus R-HyperCVAD was closed early because R-HyperCVAD caused excessive toxicity and inadequate mobilization of stem cells for transplantation [22]. Rates of two-year OS and PFS were similar between trial arms among the 52 evaluable patients (of 160 planned enrollees) who completed therapy [23].

Intensive induction regimens — There is no consensus intensive regimen for MCL. Each of the preferred, high-dose cytarabine (HiDAc)-containing intensive regimens is associated with high rates of response, but substantial toxicity in younger, fit patients with MCL. No randomized trials have directly compared these regimens and the preferred treatment varies among institutions and clinicians.

We consider any of the following intensive regimens acceptable for induction therapy of nodal MCL, as discussed above (see 'Fit, younger patients' above):

R-B/R-HiDAc – Rituximab-bendamustine (R-B) followed by rituximab plus HiDAc

R-DHAPRituximab, dexamethasone, HiDAc, plus cisplatin, carboplatin, or oxaliplatin

R-CHOP/R-DHAPRituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), alternating with R-DHAP (six cycles total)

Nordic regimenRituximab plus maxi-CHOP (dose-intensified CHOP), alternating with R-HiDAc

We do not favor induction therapy using R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, dexamethasone, alternating with high-dose methotrexate and cytarabine). This judgement is based on a randomized trial of R-B versus R-HyperCVAD that was terminated early because HyperCVAD caused excessive toxicity and impaired stem cell collection [22]. Furthermore, in patients with MCL who subsequently underwent autologous HCT, R-HyperCVAD induction was associated similar survival but excess toxicity when compared with compared with induction using R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in a population-based study [20]. (See 'Fit, younger patients' above.)

R-B/R-HiDAc — The R-B/R-HiDAc regimen comprises three cycles of R-B and three cycles of R-HiDAc.

Among 87 evaluable patients with MCL who were treated with R-B/R-HiDAc, followed by autologous hematopoietic cell transplantation (HCT), three-year OS and PFS were 92 and 83 percent, respectively [55]. Among enrolled patients, 92 percent completed induction therapy and 84 percent proceeded to autologous HCT. Induction therapy with R-B/R-HiDAc was associated with 97 percent ORR (90 percent CR). Grade ≥3 adverse events (AEs) included 85 percent thrombocytopenia, 83 percent neutropenia, and 15 percent febrile neutropenia; there were no treatment-related deaths during induction therapy. All 23 patients who were evaluated for measurable residual disease (MRD) were MRD-negative after transplantation; MRD subsequently became positive in only one patient (who later relapsed clinically).

In a study of 21 patients (42 to 69 years old) who underwent autologous HCT after R-B/R-HiDAc, after median follow-up of 13 months, median OS was not reached and PFS was 96 percent [56]. Among 15 patients who were evaluable for measurable residual disease (MRD), 93 percent were MRD-negative.

R-DHAP — This regimen comprises rituximab, dexamethasone, HiDAc, plus a platinum-based agent (ie, cisplatin, carboplatin, or oxaliplatin).

Retrospective analysis of the LyMA trial, which treated with four cycles of R-DHAP induction therapy, reported that compared with cisplatin and carboplatin, outcomes were superior when oxaliplatin was used as platinum-based agent [57]. Among 298 enrolled patients, investigators were allowed to choose the platinum compound to be used in R-DHAP induction therapy; patients subsequently underwent autologous HCT. According to an intention-to-treat analysis, there was a trend toward superior four-year OS with carboplatin (92 percent in 38 patients), compared with 76 percent for patients treated with either cisplatin (184 patients) and carboplatin (76 patients); oxaliplatin was also associated with a trend toward superior four-year PFS (87 versus 65 percent for cisplatin/carboplatin) and improved CR. Oxaliplatin and carboplatin were better tolerated than cisplatin.

R-CHOP/R-DHAP — This regimen comprises alternating courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 5) and R-DHAP (six cycles total).

A phase 3 trial of 497 patients ≤65 years compared R-CHOP/R-DHAP versus six cycles of R-CHOP; each induction regimen was followed by autologous HCT [27,28]. With six-year median follow-up, survival was similar (76 percent five-year OS with R-CHOP/R-DHAP versus 69 percent with R-CHOP), but the alternating regimen achieved superior median time to treatment failure (TTF; not reached versus 9 years) and longer remission duration (84 months versus 49 months).

A phase 2 study of 60 patients treated with R-CHOP/R-DHAP followed by autologous HCT reported 75 percent five-year OS and 83 month median EFS; there were no treatment-related deaths [58].

Nordic regimen — This regimen comprises six cycles total of R-maxi-CHOP (which includes cyclophosphamide 1200 mg/m2 and doxorubicin 75 mg/m2) alternating with R-HiDAc [59].

Among 160 patients treated with the Nordic MCL2 regimen, followed by autologous HCT, after follow-up >11 years, median OS and PFS were 12.7 years and 8.5 years, respectively [60]. Survival curves did not reach a plateau, even after a decade of follow-up.

Lower-intensity regimens — We consider the following lower-intensity induction regimens suitable for patients with MCL who are not transplant-eligible. (See 'Induction for older or less-fit patients' above.)

VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) — In the VR-CAP regimen, bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 of each cycle) replaces vincristine in R-CHOP (table 5).

In the phase 3 LYM-3002 trial of 487 patients with MCL who were not eligible for transplantation, VR-CAP achieved superior survival compared with R-CHOP [61,62]. VR-CAP achieved longer median OS (91 months versus 56 months; HR 0.66 [95% CI 0.51-0.85]) and median PFS (25 versus 14 months; HR 0.63 [95% CI 0.50-0.79]), but more grade ≥3 AEs (93 versus 84 percent). Long-term follow-up reported one case of lung cancer and one case of gastric cancer in the VR-CAP group. A higher incidence of herpes zoster reactivation (5 versus 1 percent) with VR-CAP led to a protocol amendment to mandate antiviral prophylaxis.

Rituximab plus lenalidomide — This regimen comprises:

Rituximab – 375 mg/m2 once weekly for the first 4 weeks

Lenalidomide – 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles

In a study of 38 patients, rituximab-lenalidomide was associated with 87 percent ORR (including 61 percent CR) [63]. With median follow-up >5 years, three-year OS and PFS were 90 and 80 percent, respectively, and estimated five year OS and PFS were 77 and 64 percent [46].

Addition of a third agent to rituximab-lenalidomide caused substantial toxicity. Addition of bendamustine in 51 patients was associated with 42 percent grade ≥3 infections and second cancers in 16 percent [64]. Addition of bortezomib as a third agent was associated with 70 percent two-year PFS, but 51 percent of patients experienced grade ≥3 neutropenia [65].

AUTOLOGOUS TRANSPLANTATION — Autologous hematopoietic cell transplantation (HCT) is standard care for young, medically-fit patients who achieve a complete response (CR) after induction therapy for MCL. (See 'Consolidation therapy' above.)

The induction regimen for MCL does not clearly affect long-term outcomes after transplantation. As examples, similar post-HCT survival was reported when patients received induction therapy using R-B, R-B/R-HiDAc, and R-CHOP/R-HiDAc [10,23,55]. Long-term outcomes after autologous HCT are better when patients achieve a complete response (CR) to induction therapy [66]. Compared with autologous HCT, allogeneic HCT using reduced intensity conditioning in first remission offered no survival advantage in a population-based study [67].

Maintenance therapy with rituximab after autologous HCT is discussed above. (See 'Post-transplant maintenance therapy' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of mantle cell lymphoma".)

SUMMARY AND RECOMMENDATIONS

Description – Mantle cell lymphoma (MCL) is a B cell non-Hodgkin lymphoma (NHL) with features of both indolent and more aggressive NHL that has a heterogeneous natural history. MCL can involve lymph nodes and/or extranodal disease.

Overview of management – Most patients present with symptomatic advanced-stage (stages II-IV) classic MCL that requires treatment, but selected patients with indolent MCL may benefit from initial observation. Treatment of classic MCL generally includes induction therapy followed by consolidation and/or maintenance therapy.

For patients with MCL who receive systemic therapy, we recommend treatment that includes rituximab plus chemotherapy, rather than chemotherapy alone (Grade 1B). (See 'Overview of management' above.) 

Management may differ for patients with indolent MCL, MCL with adverse pathologic features, and rare patients with stage I disease MCL. (See 'Special populations' above.)

Younger, fit patients – Medically-fit patients ≤60 or ≤65 years who are suitable for autologous hematopoietic cell transplantation (HCT) (See 'Fitness' above.)

Induction therapy – For younger, fit patients with classic MCL, we suggest induction therapy using rituximab plus bendamustine (R-B) or a more intensive regimen that includes high-dose cytarabine (HiDAc) (algorithm 1), rather than R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, dexamethasone, alternating with high-dose methotrexate and cytarabine) (Grade 2C). (See 'Induction therapy for fit, younger patients' above.)

Consolidation – For younger, fit patients with a complete response (CR) to induction therapy, we suggest autologous HCT (algorithm 1), rather than observation or maintenance therapy alone (Grade 2C). (See 'Consolidation therapy' above.)

Autologous HCT is discussed above. (See 'Autologous transplantation' above.)

For patients who did not achieve CR, we treat for relapsed/refractory (r/r) MCL. (See "Treatment of relapsed or refractory mantle cell lymphoma".)

Maintenance – After autologous HCT, we suggest three years of rituximab maintenance therapy (algorithm 1), rather than lenalidomide maintenance or observation alone (Grade 2C). (See 'Post-transplant maintenance therapy' above.)

Older or less-fit patients – Patients who are not suitable for autologous HCT (See 'Older or less-fit patients' above.)

Induction therapy – Preferred regimens for older, less-fit patients include are described above. (See 'Induction for older or less-fit patients' above.)

Maintenance therapy – For older, less-fit patients with CR or partial response (PR), we suggest three years of maintenance therapy with rituximab, rather than interferon alfa maintenance therapy or observation alone (Grade 2C).

For patients without CR/PR, we treat for r/r MCL. (See "Treatment of relapsed or refractory mantle cell lymphoma".)

Indolent MCL – For asymptomatic patients with indolent MCL, we suggest initial observation rather than immediate treatment (Grade 2C). (See 'Indolent MCL' above.)

Most cases of indolent MCL manifest as leukemic, non-nodal MCL or gastrointestinal tract-only disease, but selected cases of nodal MCL may also have an indolent natural history.

Chemoimmunotherapy – Treatment of MCL varies according to age, fitness, institutional approach, and patient preference (see 'Overview of management' above):

Regimens – Chemoimmunotherapy regimens for MCL include:

-Rituximab-bendamustine (See 'Rituximab-bendamustine (R-B)' above.)

-Intensive regimens – (See 'Intensive induction regimens' above.)

-Lower-intensity regimens – (See 'Lower-intensity regimens' above.)

Monitoring – Monitoring for relapse and treatment-related complications is discussed above. (See 'Monitoring' above.)

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Topic 4719 Version 59.0

References

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