INTRODUCTION — Mantle cell lymphoma (MCL), one of the B cell non-Hodgkin lymphomas (NHL), has a variable course. A minority of patients with this disorder may survive untreated for many years. However, in more patients, MCL assumes a more virulent character, akin to that of an aggressive NHL variant.
The initial treatment of MCL will be discussed here. Clinical and pathologic features, diagnosis, and differential diagnosis of this disorder are discussed separately, as is the treatment of relapsed or refractory MCL. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma" and "Treatment of relapsed or refractory mantle cell lymphoma".)
ONCOLOGIC EMERGENCIES — Oncologic emergencies and treatment-related hematologic toxicities are common in the aggressive NHLs. Clinicians must always be alert to their potential presence and be prepared to deal with them urgently and effectively. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Oncologic emergencies'.)
Emergencies that are more common in patients with MCL include hyperleukocytosis and intestinal obstruction or intussusception:
●Involvement of the gastrointestinal tract is common in MCL, occasionally presenting with multiple intestinal polyposis and intestinal obstruction or intussusception. (See "Etiologies, clinical manifestations, and diagnosis of mechanical small bowel obstruction in adults" and "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)
●Uncommonly, patients with MCL may have marked lymphocytosis mimicking prolymphocytic leukemia. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)
INDICATIONS FOR TREATMENT — While most patients with MCL who do not begin therapy will die of their disease within a few years, a small proportion, increasingly better defined, may remain stable for years. These occasional patients with low tumor burden (table 1), low-risk (table 2) disease may have an indolent course, managed by observation, splenectomy, or treatment with alkylating agents analogous to the treatment of patients with small lymphocytic lymphoma or chronic lymphocytic leukemia [1-4]. (See "Initial treatment of stage I follicular lymphoma" and "Overview of the treatment of chronic lymphocytic leukemia".)
While we know that a small proportion of these patients will progress slowly, it is very difficult to identify these patients at the time of diagnosis. As an example, a retrospective analysis of 97 patients with asymptomatic MCL treated at a single institution found that approximately one-third of patients were observed for more than three months before initiating therapy [5]. Treatment was postponed for more than one year in 14 patients and more than five years in three patients. This suggests that some patients with MCL may have an indolent course; however, on multivariate analysis, clinical characteristics including age, stage, World Health Organization performance status, extranodal status, and lactate dehydrogenase (LDH) level were not able to predict which patients would progress slowly. Clinicians differ in their management of patients expected to have a more indolent course. While some advocate watch and wait, others feel this is the group that might benefit from aggressive therapies. (See 'Overview' below.)
Pathologic features may provide some insight into which patients will be more likely to progress. Expression of Ki-67 (a measure of proliferative activity), SOX11 (a transcription factor), and TP53 (a tumor suppressor) may have prognostic value in MCL [6-12]. As examples:
●Ki-67: A correlative study evaluated the prognostic value of Ki-67 in 508 patients treated on prospective trials [8]. A Ki-67 index <30 percent was associated with longer progression-free survival (PFS) and overall survival (OS), independent of the Mantle Cell Lymphoma International Prognostic Index (MIPI) score. Five-year OS for those with a Ki-67 <10 percent, 10 to 30 percent, and >30 percent were estimated to be 73, 75, and 41 percent, respectively.
●SOX11: Overexpression of SOX11 has been associated with a more aggressive clinical course. Up to 20 percent of MCL develops from antigen-experienced SOX11-negative B cells. This variant typically involves the peripheral blood, bone marrow, and/or often spleen (while sparing lymph nodes), and this "leukemic" variant is often clinically indolent. (See "Pathobiology of mantle cell lymphoma".)
●TP53: High levels of TP53 expression predicted inferior OS and shorter time to treatment failure (TTF) in multivariate analysis of 365 patients treated on prospective studies [12]. Compared with tumors with low TP53 expression and adjusting for MIPI score and Ki-67 index, hazard ratios for OS and TTF were 2.1 and 2.0, respectively, in patients with high TP53 expression.
These research observations have not yet been validated in routine clinical practice.
In our clinical experience, those with more indolent tumors comprise a small percentage of patients with MCL and typically present with lymphocytosis, a few enlarged lymph nodes, splenomegaly, SOX11 negativity, and a Ki-67 index <30 percent [6,13].
Despite this, the long-term outlook for most patients with MCL is unfavorable with median OS times with treatment of 8 to 10 years. There is no evidence that currently available treatment programs are curative [14]. However, patients with advanced or symptomatic disease are treated with combination chemotherapy to decrease tumor bulk and alleviate symptoms. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma", section on 'Prognosis'.)
PRETREATMENT EVALUATION — The pretreatment evaluation both determines the bulk of disease and provides information about the individual's comorbidities that are likely to have an impact on treatment options. In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with MCL:
●Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase (LDH), hepatitis B, human immunodeficiency virus (HIV), and uric acid. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Unilateral bone marrow biopsy is recommended for patients with cytopenias of unknown cause in addition to visual inspection of the blood smear and consideration of flow cytometry of the peripheral blood. Bone marrow biopsy may be omitted in patients with normal peripheral blood counts (ie, no cytopenias) and for those not undergoing active therapy.
●We perform a lumbar puncture on patients with the MCL blastic variant or those with central nervous system symptoms. When performed, cerebrospinal fluid should be sent for both cytology and flow cytometry.
●Integrated whole body positron emission tomography with computed tomography (PET/CT) is the preferred pretreatment imaging study. MCL is considered a typically fluorodeoxyglucose (FDG)-avid tumor such that involved areas should show activity on PET scan. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging'.)
●Upper endoscopy and colonoscopy are performed for patients with gastrointestinal symptoms or findings on physical examination suggestive of gastrointestinal involvement. We limit endoscopy in asymptomatic patients to those clinical situations in which identification of involvement would change management (eg, stage I/II disease). (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Gastric lymphoma'.)
●Whether all patients require a baseline study of cardiac ejection fraction (eg, echocardiogram or MUGA) prior to receiving an anthracycline is controversial, and clinical practice is variable. A baseline evaluation may not be necessary for those under the age of 65 years who lack cardiac risk factors. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)
●Men and women 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".)
INITIAL TREATMENT
Overview — As described above, most patients require treatment of MCL at the time of diagnosis. While occasional patients with low stage, low-risk disease may have an indolent course that can be observed initially, combination chemotherapy plus immunotherapy (ie, chemoimmunotherapy) remains the main treatment modality. Surgery is usually not employed, but may be of value in patients with MCL involving the gastrointestinal tract presenting with bowel obstruction or uncontrollable bleeding, usually from extensive colonic polyposis. Likewise, radiation therapy is usually reserved for palliation. Allogeneic hematopoietic cell transplantation (HCT) may be considered for patients with relapsed or refractory disease, ideally in the context of a clinical trial. (See "Treatment of relapsed or refractory mantle cell lymphoma", section on 'Radiation therapy' and "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)
There is a diversity of clinical practice and ambiguity surrounding the preferred treatment approach for patients with MCL. Whenever possible, young, otherwise healthy patients with advanced, symptomatic MCL should be referred to a center offering a clinical trial.
Outside of a clinical trial, treatment options include:
●Conventional chemoimmunotherapy (eg, BR, R-CHOP) alone or followed by maintenance rituximab – This approach is appropriate for patients who are not candidates for autologous HCT. Although it is not curative, a majority of patients will attain a complete remission (CR). Maintenance rituximab appears to prolong progression-free survival (PFS) and overall survival (OS) in patients treated with R-CHOP, but a benefit has not been demonstrated for maintenance therapy for patients treated with BR. (See 'Conventional chemoimmunotherapy' below and 'Maintenance therapy' below.)
●Conventional chemoimmunotherapy followed by autologous HCT and maintenance rituximab – This is our preferred treatment for patients who are eligible for HCT. The addition of HCT improves PFS and may improve OS. Non-randomized studies suggest that this approach is as effective and less toxic than more intensive chemoimmunotherapy (R-Hyper-CVAD). The benefit of HCT appears to be greatest among those in first CR after no more than two chemotherapy regimens [15]. The incorporation of high dose cytarabine (eg, R-CHOP plus R-DHAP) prior to HCT improves PFS, but not OS. (See 'Autologous transplantation' below.)
●Intensive chemoimmunotherapy (eg, R-Hyper-CVAD/cytarabine/MTX) alone – Non-randomized, single-center trials suggest improved survival in young adults (<60 years of age) treated with R-Hyper-CVAD/cytarabine/MTX when compared with those treated with conventional chemotherapy alone. However, studies in cooperative group settings have not confirmed these benefits and have demonstrated significant toxicity with this regimen. Importantly, the toxicity excludes its use in older adults (ie, >65 years of age) and limits its use in individuals between the ages of 60 and 65 years. (See 'Hyper-CVAD/cytarabine/MTX' below.)
●Conventional chemoimmunotherapy plus involved-site radiation therapy (ISRT) – Patients with stage I/II disease may achieve prolonged PFS and local control following abbreviated chemoimmunotherapy (eg, three cycles) plus ISRT. In a registry analysis, the administration of radiation therapy to 43 patients (3.6 percent of total patients with all stages) with stage I/II disease resulted in an estimated OS at three years of 93 percent [16].
●ISRT alone – ISRT alone is an acceptable option for selected patients with low bulk (<10 cm) stage I/II disease. A multicenter retrospective study of 179 patients with early stage disease reported that, compared to patients who received chemotherapy or chemotherapy plus RT, OS of 24 patients who received RT alone was similar, but there was a trend toward lower freedom from relapse due of relapse at distant sites [17].
Few well-controlled studies have compared the various treatment approaches. While some prospective, non-randomized trials have suggested longer median OS rates with a more aggressive treatment approach (either R-Hyper-CVAD/cytarabine/MTX or HCT), these are also associated with a higher incidence of treatment-related toxicities. The uncertainty surrounding the benefits of more aggressive therapy was highlighted by a single-institution retrospective analysis of 111 patients with newly diagnosed MCL, 70 percent of whom were treated with conventional chemotherapy (R-CHOP-like or CHOP-like regimens) without HCT [18]. Median OS was seven years. The three- and five-year OS rates of 86 and 66 percent respectively, were similar to those seen in prospective studies of R-Hyper-CVAD/cytarabine/MTX.
The evidence supporting these various approaches is described in the following sections. In addition, we offer guidance on the selection of therapy for different patient populations based on our interpretation of the literature and experience. (See 'Our treatment approach' below.)
Role for rituximab — The monoclonal CD20 antibody rituximab is known to be beneficial in the initial treatment of several types of non-Hodgkin lymphoma (NHL), including MCL. Initial comparisons with historical controls suggested that rituximab may play a role in the treatment of MCL, while prospective randomized trials have had mixed results [16,19-27].
A 2007 meta-analysis of the use of rituximab plus chemotherapy for patients with indolent NHL or MCL found that patients treated with rituximab plus chemotherapy had superior OS, response, and disease control than patients treated with chemotherapy alone [14,28]. However, only three small studies were available for MCL in this study. A subsequent retrospective analysis of the Surveillance Epidemiology and End Result (SEER) and Medicare databases of 638 older adults with MCL who received initial chemotherapy with (64 percent) or without rituximab reported that the addition of rituximab was associated with superior median survival (37 versus 27 months) [29]. On multivariate analysis, the addition of rituximab was associated with lower rates of both all-cause (hazard ratio [HR] 0.58; 95% CI 0.41-0.82) and cancer-specific mortality (HR 0.56, 95% CI 0.37-0.84) at two years.
For patients with MCL, we recommend the addition of rituximab to combination chemotherapy rather than chemotherapy alone. This is primarily due to the low risk of toxicity related to the addition of rituximab and a possible but uncertain benefit in OS. Rituximab can be incorporated into either conventional chemotherapy regimens or aggressive treatment programs.
The role of rituximab in maintenance therapy of MCL is discussed below. (See 'Maintenance therapy' below.)
Induction chemoimmunotherapy — Induction chemoimmunotherapy used for patients with MCL can be conceptually divided into two groups based on intensity:
●Conventional chemoimmunotherapy – Conventional chemotherapy includes regimens such as R-CHOP, R-CHOP/R-DHAP, VcR-CAP, and the off-label use of bendamustine plus rituximab (BR) [30]. We use conventional chemoimmunotherapy for induction in most patients with MCL. Patients who attain an at least partial response (PR) following conventional chemoimmunotherapy are considered for consolidation with autologous HCT. However, a CIMBTR database analysis suggests that the best outcome is in first CR after no more than two regimens. Those who are not candidates for HCT may be candidates for maintenance rituximab; however, the efficacy of maintenance rituximab may differ depending on the induction regimen used. (See 'Conventional chemoimmunotherapy' below and "Determining eligibility for autologous hematopoietic cell transplantation".)
●R-Hyper-CVAD/cytarabine/MTX – R-Hyper-CVAD/cytarabine/MTX (RH) employs rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high dose methotrexate and cytarabine. RH is used by some clinicians for the treatment of younger (<60 years of age) patients without comorbidities, especially those with disease that displays characteristics that suggest a low likelihood of response to conventional chemoimmunotherapy (eg, blastic variant of MCL, high IPI score, high MIPI score).
A multicenter trial that randomly assigned 52 patients with MCL to four cycles of RH versus six cycles of BR reported comparable rates of response and survival, but greater toxicity with RH [31]. The study closed early because of excess toxicity and inadequate stem cell mobilization in the RH arm; 9 of 17 patients treated with RH and 23 of 35 patients treated with BR underwent autologous HCT. After five years of follow-up, PFS and OS for patients treated with RH were 62 and 74 percent, respectively, and 66 and 80 percent for BR [32]. Autologous HCT and maintenance rituximab have not demonstrated a benefit in patients initially treated with R-Hyper-CVAD/cytarabine/MTX. (See 'Hyper-CVAD/cytarabine/MTX' below.)
Conventional chemoimmunotherapy — Conventional chemoimmunotherapy is our preferred initial treatment for most patients with MCL. With conventional chemoimmunotherapy alone, the overall response rate is approximately 80 percent; the median OS in historical studies using this approach ranges from three to four years with less than 15 percent of patients alive at five years [23,33,34]. Median survival times with this approach have improved over time in part due to the incorporation of consolidation and/or maintenance therapy and the development of novel therapies for the treatment of relapsed disease [35]. A choice among various conventional regimens depends on patient characteristics and physician comfort. In general, we prefer the off-label use of bendamustine plus rituximab (BR) based on its acceptable toxicity profile and good response rates. R-CHOP/R-DHAP, R-CHOP, or VcR-CAP are acceptable alternatives. R-CHOP/R-DHAP is more toxic and reserved for patients who are candidates for autologous HCT. The use of fludarabine-based regimens (eg, FCR) is limited due to high toxicity in this population.
Two randomized studies comparing BR with R-CHOP reported that BR was less toxic and produced superior PFS and similar survival rates [36-38]. BR has not been compared with R-CHOP/R-DHAP, or VcR-CAP.
●BR (bendamustine, rituximab) – A randomized trial (StiL trial) comparing bendamustine (90 mg/m2 days 1 and 2) plus rituximab (375 mg/m2 day 1) every 28 days for six cycles versus standard R-CHOP for six cycles in 514 patients with advanced follicular or other indolent lymphoma, and MCL (18 percent), suggested that BR resulted in superior median PFS (69.5 versus 31.2 months, HR 0.58, 95% CI 0.44-0.74) for all histologic subtypes except marginal zone lymphoma with less toxicity, including lower rates of grade 3 and 4 neutropenia (29 versus 69 percent) and leukocytopenia (37 versus 72 percent), fewer infectious episodes (37 versus 50 percent), less paresthesia (7 versus 29 percent), less stomatitis (6 versus 19 percent), and no alopecia [36]. There was no difference in OS at a median follow-up of 45 months. The number of second malignancies was similar between the two treatment arms (20 versus 23 cases). The long-term toxicity profile and impact on future treatments, including hematopoietic stem cell collection, are unknown.
In the international phase III BRIGHT trial, 447 previously untreated patients with MCL (74 patients), advanced follicular lymphoma, or other indolent lymphoma were randomly assigned to six cycles of BR (according to the dose and schedule described above) or to either R-CHOP or R-CVP (as determined by the investigator prior to randomization) [37]. For patients with MCL, after a minimum follow-up of five years (median 65 months), BR achieved superior PFS (HR 0.40; 95% CI 0.21-0.75), EFS (HR 0.35; 95% CI 0.16-0.60), duration of response (HR 0.47; 95% CI 0.24-0.91), and CR (50 versus 27 percent) [39]. BR did not achieve superior OS, but this may reflect subsequent lines of therapy, which included BR for patients in the R-CHOP/R-CVP group. BR was associated with more drug hypersensitivity and vomiting, but use of prophylactic antiemetics was not specified in the protocol and was more common among patients assigned to R-CHOP; BR was associated with lower rates of peripheral neuropathy/paresthesia and alopecia. There was a higher rate of second malignancies with BR, but the greatest difference between treatment groups was in squamous and basal cell skin cancers.
●VcR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) – In a randomized trial of VcR-CAP versus R-CHOP in 482 transplant-ineligible patients with previously untreated MCL, VcR-CAP resulted in superior median PFS (25 versus 14 months; HR 0.63, 95% CI 0.50-0.79) [40,41]. Rates of overall response and CR were 92 and 53 percent, respectively. VcR-CAP was associated with higher rate of severe (grade 3/4) neutropenia (85 versus 67 percent), thrombocytopenia (57 versus 6 percent), and peripheral neuropathy (8 versus 4 percent), and a higher incidence of herpes zoster reactivation (4.6 versus 0.8 percent), which resulted in a protocol amendment to mandate antiviral prophylaxis. Bortezomib (1.3 mg/m2) is administered on day 1, 4, 8, and 11 of each 21-day cycle. At least 72 hours should elapse between bortezomib doses. The dosing and schedule of the other drugs is as given in R-CHOP. Six cycles are planned. An additional two cycles (for a total of eight cycles) are given to patients with a response first documented at cycle 6. The greater toxicity with this regimen limits its use in older patients not eligible for transplant.
●R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (table 3) – The most common severe (grade 3/4) side effect is granulocytopenia (60 percent) [23,42]. Other common side effects are generally mild to moderate alopecia, nausea, vomiting, and infusion-related reactions. Reported overall response and CR rates are approximately 85 and 35 percent, respectively. The estimated rates of two- and four-year survival are 75 and 60 percent, respectively. Median survival in retrospective studies has been as long as seven years [18]. In small phase II trials, the addition of bortezomib to R-CHOP resulted in overall response and CR rates of approximately 80 and 65 percent, respectively [43,44]. Rates of PFS and OS at two years were 44 and 86 percent, respectively.
●R-CHOP plus R-DHAP (rituximab, dexamethasone, high dose cytarabine, and cisplatin) – Alternating cycles of R-CHOP or R-DHAP are given every 21 days for a total of six cycles. A randomized trial in 497 younger adults (median age 55 years) with previously untreated MCL compared six cycles of this regimen versus six cycles of R-CHOP, both followed by myeloablative therapy and rescue with autologous HCT [45]. After a median follow-up of six years, R-CHOP/R-DHAP resulted in longer time to treatment failure (median 9.1 versus 3.9 years; five-year failure-free rate 65 versus 40 percent). The difference in OS did not reach statistical significance (HR 0.78; 95% CI 0.57-1.07); however, the precision of the estimate was limited since the lower limit of the confidence interval included a 43 percent improvement in survival, which if true would be clinically meaningful. R-CHOP/R-DHAP was associated with higher rates of hematologic toxicity, febrile neutropenia, and renal toxicity, although treatment-related mortality was similar in both groups (3.4 percent). We do not routinely use R-CHOP/R-DHAP due to toxicity concerns and lack of a proven survival benefit.
Other less widely studied conventional chemotherapy regimens that have been used for the treatment of MCL include the NORDIC regimen [46,47], the CALGB regimen [48], sequential R-CHOP/R-ICE [49], R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) [18,33,50], and bendamustine plus rituximab and cytarabine [51].
Anthracycline-based regimens, such as R-CHOP, are frequently used, but the additional benefit gained by including an anthracycline is not entirely clear. Interest in using anthracycline-based regimens was initially driven by a retrospective analysis of 65 patients with MCL, which noted a survival advantage with anthracycline-containing regimens [52]. Subsequent randomized trials have had mixed results with two demonstrating no survival advantage when CHOP was compared with the non-anthracycline-containing regimens CVP and MCP (mitoxantrone, chlorambucil, prednisone) [33,34], and another demonstrating a survival advantage of R-CHOP over the combination of FCR (fludarabine, cyclophosphamide, and rituximab) [42]. The latter compared R-CHOP with FCR in 560 older adults (>60 years) with newly diagnosed MCL [42]. R-CHOP resulted in similar CR rates (34 versus 40 percent), but lower hematologic toxicity and higher rates of OS at four years (62 versus 47 percent). These studies suggest that R-CHOP is an acceptable regimen for the treatment of newly diagnosed MCL. In contrast, FCR appears to be more toxic and less efficacious than R-CHOP. This, in combination with other studies that have suggested that FCR may impair subsequent peripheral blood stem cell collection, supports our preference of R-CHOP over FCR in this setting [53].
For most patients, we suggest conventional chemoimmunotherapy, such as BR, R-CHOP/DHAP, VcR-CAP, or R-CHOP, rather than FCR or more intensive chemoimmunotherapy (eg, R-Hyper-CVAD/cytarabine/MTX). This preference places a low value on the potential, but unproven, benefit of more aggressive chemoimmunotherapy regimens (eg, R-Hyper-CVAD/cytarabine/MTX) and a high value on the known, more tolerable, side effect profiles of conventional chemoimmunotherapy.
Hyper-CVAD/cytarabine/MTX — Intensive chemotherapy programs, such as those used in other highly aggressive NHL variants (eg, Burkitt lymphoma, lymphoblastic lymphoma), with or without subsequent HCT, have been employed in an attempt to obtain better long-term disease control. However, at present there is no evidence that currently available aggressive treatment programs are curative [54,55].
Perhaps the most commonly used aggressive induction therapy regimen is R-Hyper-CVAD/cytarabine/MTX, which employs rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high dose methotrexate and cytarabine and/or HCT [22,56-58].
An initial single institution prospective trial evaluated six cycles of R-Hyper-CVAD/cytarabine/MTX in 97 evaluable patients with previously untreated MCL [21]. The rate of CR plus unconfirmed CR was 87 percent. None of the patients went on to receive HCT. At a median follow-up of 40 months, three-year failure-free survival and OS rates were 64 and 82 percent, respectively, without a plateau in the curves. Twenty-nine percent of patients were not able to complete the planned number of treatment cycles due to toxicity. There were eight deaths including four cases (three fatal) of treatment-related acute myeloid leukemia/myelodysplastic syndrome (AML/MDS), which developed while the patients were in CR.
A subsequent report of this trial with a median follow-up of eight years observed that the median OS had still not been reached, while the median time to failure was 4.6 years [59]. On subset analysis, patients 65 years of age or younger had significantly higher rates of OS at eight years (68 versus 33 percent) when compared with older patients. Since the prior publication, an additional patient developed MDS thereby increasing the rate of AML/MDS to 5 percent. No additional late toxicities were observed.
Attempts to replicate this regimen in a cooperative group setting have highlighted the difficulty of administration due to toxicity. Importantly, the toxicity excludes its use in older adults (ie, >65 years of age) and limits its use in individuals between the ages of 60 and 65 years. Individuals age 60 to 65 years require dose modifications of cytarabine, which may limit efficacy [21].
●In a multicenter prospective European trial, initial treatment with R-Hyper-CVAD/cytarabine/MTX in 60 patients with MCL was associated with 83 percent overall response rates (including 72 percent CR) [60]. However, 63 percent of patients were unable to complete the planned treatment course, mostly due to toxicity. Half of the patients experienced grade ≥3 toxicity, the majority of which were hematologic and infectious. After a median follow-up of 46 months, OS and failure-free survival at two years were 86 and 61 percent, respectively.
●A SWOG prospective phase 2 study of R-Hyper-CVAD/cytarabine/MTX in 49 patients reported a median PFS and OS of 4.8 and 6.8 years, respectively [61]. In this setting, 19 patients (39 percent) were unable to complete the planned treatment regimen secondary to toxicity.
While the results from the single institution, uncontrolled trials are promising, R-Hyper-CVAD/cytarabine/MTX has many associated toxicities and has not been directly compared with conventional chemotherapy. In addition, as the cooperative group studies suggest, like with many other regimens, excellent patient outcomes in a single institution do not necessarily translate to excellent outcomes in practice at other institutions.
Clinical trials are evaluating modified versions of R-Hyper-CVAD/cytarabine/MTX that incorporate other agents (eg, bortezomib) in an attempt to reduce toxicity and improve response rates [62,63]. As an example, a phase II trial evaluated the use of rituximab and bortezomib plus a modified hyper-CVAD induction therapy followed by either two years of maintenance rituximab or autologous HCT in 75 adults (median age 62 years) with previously untreated MCL. The overall response and CR rates were 95 and 68 percent, respectively. After a median follow-up of 4.5 years, the estimated rates of PFS and OS at three years were 72 and 88 percent, respectively. There were no treatment-related deaths. The most common severe (grade 3/4) toxicities were neutropenia (84 percent), thrombocytopenia (67 percent), and anemia (33 percent). There were no cases of severe peripheral neuropathy.
Our treatment approach — Whenever possible, young, otherwise healthy patients with advanced, symptomatic MCL should be referred to a center offering a clinical trial. Outside of a clinical trial, a choice between treatment options depends on patient characteristics (eg, age or comorbidities), patient preferences, side effect profiles, and the physician's comfort with the various regimens. The International Prognostic Index (IPI) (table 2) or the Mantle Cell Lymphoma International Prognostic Index (MIPI) score (calculator 1) (table 4) may help to assimilate some of this information. The following are guidelines based on our practice, which tends to favor the less aggressive treatment approaches; however, more aggressive treatment approaches used by other expert clinicians would also be acceptable. Eligibility for autologous HCT varies across countries and institutions. Details regarding HCT eligibility are presented separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)
●The occasional patient with clinically indolent, low-risk disease may have an indolent course that can be observed initially. (See 'Indications for treatment' above.)
●Young patients (eg, <60 years of age) with a good performance status (eg, ECOG <2) (table 5) are candidates for treatment with either Hyper-CVAD alone or conventional chemoimmunotherapy followed by autologous HCT and subsequent maintenance rituximab. For such patients, we offer induction with conventional chemoimmunotherapy rather than Hyper-CVAD. In general, we prefer BR based on its acceptable toxicity profile, high response rates, and our experience with this regimen. While R-CHOP/R-DHAP, VcR-CAP, and R-CHOP are acceptable alternatives, they are associated with greater toxicity and have not demonstrated a survival benefit. (See 'Conventional chemoimmunotherapy' above.)
●For older adults with a good performance status, we offer induction with conventional chemotherapy. In general, we prefer BR based on its good tolerability, high response rates, and our experience with this regimen. We do not consider Hyper-CVAD to be an acceptable option for this population, largely due to toxicity that severely limits the ability to administer this regimen to patients in this age group [60,64,65]. Induction therapy with BR is followed by autologous HCT or observation, depending on HCT eligibility. Rituximab maintenance does not appear to offer further benefit after induction with BR, but may be considered after R-CHOP induction. (See 'Maintenance therapy' below.)
This general approach places a high value on the potential improvement in PFS and OS with more intensive therapy (ie, Hyper-CVAD or HCT) while trying to avoid the high rates of toxicity associated with Hyper-CVAD in the cooperative group setting.
RESPONSE EVALUATION — One month following the completion of planned therapy (or sooner if the outcome is unfavorable), the response to treatment should be documented by history, physical examination, laboratory studies (complete blood count, lactate dehydrogenase, and biochemical profile), and computed tomography (CT) scan. Studies evaluating positron emission tomography (PET) in the response evaluation of patients with MCL have had mixed results [66-68].
We do not perform endoscopy as part of our treatment response evaluation. In contrast, the National Comprehensive Cancer Network (NCCN) recommends that both upper endoscopy and colonoscopy be performed to assess response to treatment [69]. However, this approach has not been evaluated prospectively.
Using information gathered from the history, physical, and CT scan, disease response is determined (table 6).
Treatment options for patients who achieve a partial remission include second-line chemotherapy regimens, high dose therapy with autologous HCT, allogeneic transplantation, or enrollment in a clinical trial of investigational agents. These are discussed in more detail separately. (See "Treatment of relapsed or refractory mantle cell lymphoma".)
CONSOLIDATION — Consolidation therapy refers to the administration of a finite amount of additional treatment following an initial partial response (PR) or complete response (CR) to induction chemotherapy in an attempt to deepen the response and prolong remission. Autologous hematopoietic cell transplantation (HCT) is a form of consolidation therapy that is commonly employed in MCL. Autologous HCT appears to improve outcomes following initial therapy with conventional chemoimmunotherapy (eg, R-CHOP, R-CVP, BR). In contrast, autologous HCT has not demonstrated a benefit in patients initially treated with more intensive chemoimmunotherapy, such as R-Hyper-CVAD/cytarabine/methotrexate [65]. In addition, reduced intensity conditioning followed by allogeneic HCT offers no survival advantage in first remission [15].
A retrospective analysis of 167 younger adults (<65 years of age) with newly diagnosed MCL treated at NCCN centers with one of the following approaches: R-Hyper-CVAD/cytarabine/MTX alone (50 percent), R-Hyper-CVAD/cytarabine/MTX followed by HCT (13 percent), R-CHOP followed by HCT (20 percent), or R-CHOP alone (17 percent) [65]. When compared with R-CHOP alone, treatment that incorporated R-Hyper-CVAD/cytarabine/MTX or HCT resulted in superior progression-free survival (PFS) and overall survival (OS). The addition of HCT after induction with R-Hyper-CVAD/cytarabine/MTX did not appear to improve outcomes.
Long-term follow-up of a phase 3 trial reported superior survival after myeloablative conditioning autologous HCT compared with maintenance therapy with IFN alfa until progression; the trial was initiated in the pre-rituximab era (39 percent were treated with rituximab-containing induction therapy) [70]. Among 269 enrolled patients and after median follow-up of 14 years, those who were randomly assigned to transplantation had superior OS (7.5 versus 4.8 years; adjusted hazard ratio [aHR] 0.66 [95% CI 0.46-0.95]) and superior PFS (3.3 versus 1.5 years; aHR 0.50 [95% CI 0.36-0.69]) compared with maintenance therapy; aHR included adjustment for the mantle cell lymphoma international prognostic index (MIPI) score.
Autologous transplantation — For medically-fit patients, we suggest consolidation with autologous HCT after induction therapy, rather than chemoimmunotherapy alone. (See 'Overview' above.)
Following autologous HCT, we offer maintenance therapy with rituximab. (See 'Maintenance therapy' below.)
Autologous HCT is not curative in patients with advanced MCL and has not shown improved OS when compared with combination chemotherapy alone [45,71,72]. Five-year OS rates with this approach have ranged from 50 to 75 percent [35,46-48,71-79]. Outcomes are better for those who attain a CR prior to autologous HCT than those with positive PET scan or detectable measurable residual disease (MRD; also referred to as minimal residual disease) [80]. We usually incorporate high dose cytarabine into the induction regimen to deepen the response prior to autologous HCT (eg, bendamustine rituximab followed by rituximab cytarabine [81]).
A prospective trial of 122 patients <65 years of age with advanced stage MCL randomly assigned patients to treatment with autologous HCT or maintenance therapy with interferon alfa after achievement of CR or PR following CHOP-like induction therapy [73]. At a median follow-up of 25 to 34 months, median PFS was significantly longer in the patients receiving HCT (39 versus 17 months), although there was no significant difference in OS at two years (86 versus 82 percent).
The following is a survey of other retrospective and prospective studies that have evaluated this approach:
●A single-center phase 2 trial evaluated three cycles of bendamustine rituximab (BR) and three cycles of rituximab plus cytarabine followed by autologous HCT in 23 transplant-eligible patients with MCL [81]. One patient died of progressive disease and one declined HCT in CR. CR was achieved in 75 percent prior to HCT and 96 percent at the end of study. Of the 15 patients evaluable for MRD after HCT, 93 percent achieved MRD negativity. After a median follow-up of 13 months, PFS and OS were both 96 percent.
●A single-center retrospective analysis of 118 consecutive patients with MCL who received autologous HCT for MCL reported rates of OS and PFS at five-years of 57 and 48 percent, respectively [82]. The Mantle Cell Lymphoma International Prognostic Index (MIPI) at the time of diagnosis was the strongest predictor of survival after HCT (hazard ratio [HR] 3.5; 95% CI 2.1-6.0). In comparison, increased intensity of the induction regimen prior to HCT was not associated with improved survival after HCT. (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma", section on 'Prognosis'.)
●In an analysis of the Swedish and Danish lymphoma registries, 273 of 1389 patients diagnosed with MCL between 2000 and 2001 underwent HCT. Among patients receiving systemic therapy, a survival advantage was seen for the subset of patients who were candidates for and proceeded with autologous HCT (HR 0.55; 95% CI 0.37-0.83) [16].
●An analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) registry identified patients who had undergone autologous HCT (249 patients) or reduced intensity conditioning (RIC) allogeneic HCT (50 patients) in first PR or CR after no more than two prior lines of chemotherapy [15]. When compared with 132 patients who underwent autologous HCT at a later point in the disease course, autologous HCT in first PR or CR was associated with superior five-year survival (61 versus 44 percent). When compared with autologous HCT, RIC allogeneic HCT was associated with greater nonrelapse mortality at one year (25 versus 3 percent), a lower cumulative incidence of relapse/progression at five years (15 versus 32 percent), and similar rates of OS at five years (62 versus 61 percent).
●A prospective phase II nonrandomized trial included 160 consecutive, previously untreated patients with MCL less than 66 years old treated with dose-intensified R-CHOP alternating with rituximab plus high dose cytarabine followed by high dose chemotherapy and autologous HCT in responders [46]. Rates of overall response and CR were 96 and 54 percent, respectively. In an intention-to-treat analysis with a median observation of 3.9 years, the four-year rates of event-free survival (EFS) and OS were 63 and 81 percent, respectively. In a subsequent report of the same trial with a median observation of 6.5 years, the estimated 10-year EFS and OS rates were 43 and 58 percent, respectively [47].
●A single-arm phase II study evaluated autologous HCT for 87 patients with newly diagnosed MCL up to 66 years of age [78]. Patients who had an at least partial initial response to three courses of R-CHOP chemotherapy were eligible to proceed with the HCT protocol that included consolidation with high dose cytarabine followed by stem cell mobilization with rituximab, conditioning with BEAM, and infusion of autologous stem cells. The overall response and CR rates were 70 and 64 percent, respectively. OS rates at four years were 66 and 79 percent for the group as a whole and those patients who had an at least PR to R-CHOP, respectively.
●In a post hoc analysis of a prospective trial, achievement of PET negativity prior to autologous HCT was associated with superior EFS (HR 6.00; 95% CI 2.37-15.19), PFS (HR 6.82; 95% CI 2.63-17.70), and OS (HR 13.79; 95% CI 4.07-46.8) [80]. Achievement of MRD negativity was also associated with improved clinical outcomes.
New induction regimens, including combinations of monoclonal antibodies and chemotherapy, followed by autologous or allogeneic HCT in first remission, may have an impact on the outcome of these patients [73,77,83-86]. More extended follow-up of patients treated with these approaches, including the use of allogeneic HCT, will be required.
MAINTENANCE THERAPY
After autologous transplantation — For patients with MCL who undergo autologous hematopoietic cell transplantation (HCT), we recommend rituximab maintenance therapy, rather than observation alone; maintenance rituximab was associated with little toxicity and superior overall survival (OS) compared with observation alone in a phase 3 trial [87].
After HCT for MCL, we suggest maintenance therapy with rituximab, rather than lenalidomide; this suggestion is based on improved OS and little toxicity with maintenance rituximab versus no demonstrated improvement in OS and significant toxicity with lenalidomide, when comparing two different phase 3 trials [87,88].
●Rituximab achieved superior OS compared with observation – A phase 3 Lymphoma Study Association (LYSA) trial that included 240 patients who had undergone autologous HCT for MCL reported that three years of maintenance therapy with rituximab achieved superior OS and progression-free survival (PFS) compared with observation alone [87]. Patients were treated with four cycles of induction therapy (R-DHAP; rituximab, dexamethasone, high dose cytarabine, cisplatin) followed by autologous HCT and then randomly assigned to three years of maintenance rituximab (375 mg/m2 every two months) versus observation. With median follow-up >4 years since transplantation, rituximab maintenance was associated with superior OS (89 [95% CI 81-94] versus 80 percent [95% CI 72-88 percent], respectively) and improved PFS (83 [95% CI 73-88] versus 64 percent [95% CI 55-73 percent]). There was no significant difference between trial arms in grade ≥3 adverse effects (AE).
●No OS advantage with lenalidomide maintenance – A multicenter, open-label, phase 3 trial reported that lenalidomide maintenance was associated with improved PFS, but no difference in OS compared with observation; lenalidomide was associated with substantially more grade ≥3 hematologic and non-hematologic AEs [88]. Patients were treated with three cycles of R-CHOP (rituximab, doxorubicin, vincristine, cyclophosphamide) followed by autologous HCT; those with complete response (CR) or partial response (PR) were randomly assigned (1:1) to observation versus oral lenalidomide (15 mg per day for patients with platelets >100×10⁹/L or 10 mg per day for platelets 60 to 100×10⁹/L) on days 1 to 21 every 28 days for 24 months; only one-half of patients completed their assigned lenalidomide maintenance therapy, mostly due to AEs. With median follow-up >3 years after transplantation, there was no difference in three-year OS (93 versus 86 percent; hazard ratio [HR] 0.92; 95% CI 0.40 to 2.08), but three-year PFS was superior with lenalidomide compared with observation (80 percent versus 64 percent; HR 0.51; 95% CI 0. 30 to 0.87). 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 fatal).
After response to R-CHOP — For patients who achieve at least a partial response (PR) to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and do not plan to undergo autologous HCT, we suggest maintenance rituximab until disease progression rather than observation or maintenance interferon (IFN) alfa. This suggestion is based on superior survival and little toxicity with rituximab versus IFN alfa in a phase 3 trial; rituximab has not been directly compared with observation alone in this setting.
An international trial randomly assigned 274 patients (>60 years old who achieved at least a PR to induction therapy and were not eligible for HCT) to maintenance therapy with rituximab versus IFN alfa [42]. Compared with IFN alfa, rituximab improved OS at four years (87 versus 63 percent, respectively) and the risk of progression or death (HR 0.55; 95% CI 0.36 to 0.87).
We do not routinely administer rituximab maintenance therapy for patients who were treated with bendamustine-rituximab (BR) or other induction regimens, because there is no current evidence that it is associated with superior survival in this setting. The StiL NHL7-2008 MAINTAIN study, reported in abstract form, did not show a difference in PFS or OS after median follow-up of nearly five years among 168 patients with newly diagnosed MCL who were randomly assigned to two years of maintenance rituximab versus observation after induction therapy with BR [89].
Rituximab maintenance is generally administered at a dose of 375 mg/m2 every two months until progression. Rituximab therapy 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'.)
SURVEILLANCE FOR RELAPSE — Following the completion of therapy, restaging, and documentation of CR, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends on the comfort of both the patient and physician. There have been no prospective, randomized trials comparing various schedules of follow-up. When planning the post-treatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)
Our approach to patient surveillance is to schedule patient visits every two months during the first year, every three months during the second year, and every six months starting two years after CR. At these visits we perform a history and physical examination, complete blood count, chemistries, and lactate dehydrogenase. We typically perform CT scans every six months for the first three years of follow-up. This is principally because the majority of relapses occur in the first two to four years after treatment.
Relapsed disease can be suggested by changes on imaging studies but can only be confirmed by biopsy. As such, a biopsy should always be obtained to document relapsed disease before proceeding to salvage therapy. (See "Treatment of relapsed or refractory mantle cell lymphoma".)
CLINICAL TRIALS — Often there is no better treatment strategy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).
Many agents are under active investigation, including combinations of agents already used in MCL, agents approved for other diseases, and novel agents. As an example, the combination of lenalidomide plus rituximab achieved overall and complete response rates of 92 and 64 percent, respectively in a small multicenter study [90]. With more than five years follow-up in 36 evaluable patients, three-year progression-free survival and overall survival were 80 and 90 percent, respectively, and toxicity was manageable [91]. However, data from confirmatory studies and evaluation of long-term toxicity are needed before this combination is incorporated into standard management.
Studies are also evaluating the role of measurable residual disease (MRD; also referred to as minimal residual disease) assessment in the management of patients with MCL.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
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 — Mantle cell lymphoma (MCL) is an uncommon type of B cell non-Hodgkin lymphoma with a variable outcome. Combination chemotherapy plus immunotherapy (ie, chemoimmunotherapy) remains the main treatment modality with or without high dose therapy and autologous hematopoietic cell transplantation (HCT). Surgery is usually not of benefit, but may be of value in patients presenting with bowel obstruction. Likewise, radiation therapy is usually reserved for palliation. (See 'Indications for treatment' above and 'Overview' above.)
●There is a small subset of patients with MCL that will have a more indolent course and may not require treatment initially; however, the majority of patients will require treatment at the time of diagnosis. (See 'Indications for treatment' above.)
●In addition to a history and physical, the pretreatment evaluation includes, at minimum, laboratory studies (complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase [LDH], hepatitis B, HIV, and uric acid), PET/CT, and bone marrow biopsy. Other studies are symptom or treatment specific. (See 'Pretreatment evaluation' above.)
●There is a diversity of clinical practice and ambiguity surrounding the preferred treatment approach for patients with MCL. Whenever possible, young, otherwise healthy patients with advanced, symptomatic MCL should be referred to a center offering a clinical trial. Outside of a clinical trial, a choice between treatment options depends on patient characteristics such as age or comorbidities, patient preferences, side effect profiles, and the physician's comfort with the various regimens. The following are guidelines based on our practice, which tends to favor the less aggressive treatment approaches; however, more aggressive treatment approaches used by other expert clinicians would also be acceptable.
●Disease response is determined using information gathered from a history, physical examination, and CT scan obtained one month after completion of induction therapy (table 6). (See 'Response evaluation' above.)
●For all patients with MCL, we recommend the addition of rituximab to combination chemotherapy (ie, chemoimmunotherapy) rather than chemotherapy alone (Grade 1B). (See 'Role for rituximab' above.)
●For most patients, we suggest induction with conventional chemoimmunotherapy (eg, BR, R-CHOP, VcR-CAP) rather than more intensive chemoimmunotherapy (eg, R-Hyper-CVAD/cytarabine/MTX) (Grade 2C). (See 'Induction chemoimmunotherapy' above.)
In general, we prefer BR (bendamustine rituximab) based on its acceptable toxicity profile, outcomes, and our experience with this regimen. Acceptable alternatives include VcR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone), R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab), and R-CHOP alternating with R-DHAP (rituximab, dexamethasone, high dose cytarabine, and cisplatin). However, these alternative regimens are associated with greater toxicity and have not demonstrated a survival benefit over BR.
Some experts treat younger (eg, <60 to 65 years old), healthy patients with Hyper-CVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high dose methotrexate and cytarabine, because they find the greater toxicity acceptable in the face of high response rates.
●For patients with newly diagnosed MCL, young and fit, who have had at least a partial response (PR) to induction with conventional chemoimmunotherapy, we suggest consolidation with autologous HCT rather than observation or maintenance therapy alone (Grade 2C). In contrast, we do not offer autologous HCT to patients who choose more intensive induction chemoimmunotherapy, such as R-Hyper-CVAD. (See 'Consolidation' above.)
●We recommend maintenance therapy with rituximab rather than observation alone in the following settings (Grade 1B), based on superior overall survival (OS) and progression-free survival (PFS) with little additional toxicity (see 'Maintenance therapy' above):
•Following autologous HCT, we treat with maintenance rituximab for a total of three years.
•For patients who achieve at least a PR to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) induction therapy and do not plan to undergo autologous HCT, we suggest maintenance rituximab until disease progression.
We do not routinely administer rituximab maintenance therapy for patients who were treated with BR or other induction regimens. However, maintenance rituximab following BR is an acceptable option, because data are emerging regarding potential benefits, even though a survival advantage has not been demonstrated.
●Surveillance for relapse is scheduled according to the comfort levels of both the patient and physician. Patients are followed with serial history, physical examination, laboratory evaluation (complete blood count, chemistries, and LDH), and imaging studies. Relapsed disease can be suggested by changes on imaging studies but can only be confirmed by biopsy. (See 'Surveillance for relapse' above.)
