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, more frequently, MCL assumes a more virulent character, akin to that of an aggressive NHL variant.
There is great variability in the initial treatment of MCL used in clinical practice. While some advocate intensive chemotherapy with autologous transplantation, others prefer combination chemotherapy regimens used for aggressive NHL subtypes. (See "Initial treatment of mantle cell lymphoma".)
Despite all efforts to the contrary, therapy for MCL is not curative and virtually all patients will have refractory or recurrent disease. Treatment of recurrent MCL is difficult, due to the rapid development of chemotherapy resistance. There are multiple chemotherapy regimens that may be tried and clinical practice varies greatly by center. Given the limited efficacy of these agents and paucity of data comparing these various treatment options, participation in a clinical trial is encouraged whenever possible.
The treatment of relapsed or refractory mantle cell lymphoma will be discussed here. The initial treatment of mantle cell lymphoma and the clinical and pathologic features of this disorder are discussed separately. (See "Initial treatment of mantle cell lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma".)
GOALS OF CARE AND APPROACH — With the possible exception of hematopoietic cell transplantation (HCT), available therapies for relapsed or refractory MCL are not curative, and the goal of treatment is to prolong progression-free survival and palliate symptoms. Most patients with relapsed disease are offered treatment with a salvage regimen. If chemosensitivity is shown, young patients without significant comorbid disease may benefit from high dose therapy with autologous stem cell support or allogeneic HCT. (See 'Hematopoietic cell transplantation' below.)
CHEMOTHERAPY
Choice of regimen — A number of treatment regimens have been evaluated in patients with recurrent or refractory MCL, with variable success. Some of these agents are undergoing further investigation for use in combination therapies. We encourage patients to participate in clinical trials whenever available. (See 'Clinical trials' below.)
Most patients with MCL experience serial relapse and may be treated with many available agents at some point during their disease course. A preferred order for their use has not been established. A choice is primarily made based on the patient's prior treatment, patient comorbidities and performance status, the regimens' expected toxicities, and the clinician's experience with the regimens. Most of these regimens have not been compared directly in randomized trials.
Potential salvage regimens include:
●Ibrutinib – Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor that is relatively well tolerated. Responses are seen in approximately two-thirds of patients with the majority lasting more than one year. Ibrutinib may be preferred for patients wishing to avoid an infusional regimen and for older or more frail patients who are unlikely to tolerate R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or BR (bendamustine plus rituximab). (See 'Ibrutinib' below.)
●Acalabrutinib – Acalabrutinib is a second generation BTK inhibitor with activity and toxicity that are comparable to ibrutinib.
●Lenalidomide – Lenalidomide is an oral medication that has single agent activity with objective responses in approximately two-thirds of patients with relapsed and refractory MCL. Neutropenia, thrombocytopenia, neuropathy, thrombosis, and teratogenicity are the major toxicities. (See 'Lenalidomide' below.)
●R-CHOP or BR – The sequential use of standard chemoimmunotherapy regimens can offer long survival in a select group of patients with MCL [1]. As an example, BR (bendamustine plus rituximab) results in response rates >75 percent in patients with relapse following initial treatment with R-CHOP. However, given the increased use of BR in the initial management of MCL, the number of patients that are candidates for this approach is small. The response rate to R-CHOP following BR is not well established. In the previously untreated population, R-CHOP is more toxic than BR but results in similar response rates [2]. Rituximab as a single agent has limited activity but is relatively well tolerated; we would use single-agent rituximab only for the small group of patients who got significant benefit from initial therapy with single-agent rituximab and whose comorbidities might limit use of other agents. (See "Initial treatment of mantle cell lymphoma", section on 'Conventional chemoimmunotherapy' and 'Single-agent rituximab' below.)
●Aggressive combination chemotherapy – R-ICE (rituximab, ifosfamide, carboplatin, etoposide) or R-DHAP (rituximab, dexamethasone, high dose cytarabine, and cisplatin) may be a reasonable option for some patients, particularly as a bridge to hematopoietic cell transplantation (HCT).
●Other agents – Bortezomib has a relatively good toxicity profile but lower response rates in uncontrolled prospective trials, so we usually reserve it for patients with multiply relapsed MCL. Temsirolimus has shown modest response rates and is used in Europe. The use of purine analog based therapies is limited due to the high toxicity in this population.
Young patients without significant comorbid diseases whose disease responds to subsequent therapy may benefit from nonmyeloablative allogeneic HCT, ideally administered as part of a clinical trial. (See 'Hematopoietic cell transplantation' below.)
Ibrutinib — Single-agent treatment with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib results in an at least partial response in approximately two-thirds of patients and a median progression-free survival (PFS) of ≥15 months. Ibrutinib has demonstrated improved efficacy and better tolerability when compared with temsirolimus, but it has not been directly compared with other agents in this setting. A small case report also demonstrated responses in three patients with central nervous system involvement, suggesting that ibrutinib might cross the blood brain barrier [3].
Ibrutinib has been evaluated in several prospective trials:
●In a phase III, open-label, multicenter trial, 280 patients (median age 68 years) with relapsed or refractory MCL were randomly assigned to receive ibrutinib or temsirolimus [4,5]. Patients progressing on temsirolimus were allowed to receive subsequent therapy with ibrutinib. At a median follow-up of 39 months, ibrutinib resulted in:
•Higher rates of overall response (OR; 77 versus 47 percent), complete response (CR; 23 versus 3 percent), and duration of response (DOR; 23 versus 6 months).
•Superior median PFS (15.6 versus 6.2 months; hazard ratio [HR] 0.45, 95% CI 0.35-0.60).
•A trend toward longer overall survival (OS; 30.3 versus 23.5 months; HR 0.74, 95% CI 0.54-1.02); 39 percent of patients progressing on temsirolimus received ibrutinib as subsequent therapy.
•Lower incidence of severe (grade 3/4) toxicity (75 versus 87 percent); the most common toxicities with ibrutinib were diarrhea, fatigue, and cough.
•Improved quality of life measured by two patient-reported outcome instruments (FACT-Lym and EQ-5D-5L) [6].
On a preplanned subgroup analysis, there did not appear to be a benefit among the patients with blastoid variant MCL; however, this subgroup accounted for a small percentage of the total patient group (12 percent).
●A phase II trial evaluated ibrutinib in 111 patients with relapsed or refractory MCL who had received a median of three prior therapies (range: one to five) [7,8]. Patients received a median of eight months of treatment; 46 and 22 percent remained on therapy at one and two years, respectively. The OR rate was 67 percent (23 percent complete) with an estimated median DOR of 17.5 months. After a median follow-up of 27 months, the estimated PFS and OS rates at 24 months were 31 (95% CI 22-40 percent) and 47 percent (95% CI 37-57 percent), respectively. The most common toxicities were mild to moderate diarrhea (54 percent), fatigue (50 percent), nausea (33 percent), and dyspnea (32 percent). The most common severe (grade 3/4) toxicities were neutropenia (17 percent), thrombocytopenia (13 percent), and anemia (11 percent). There were three cases of febrile neutropenia.
●A phase II trial evaluated ibrutinib plus rituximab in 50 adults (median age 67 years) with relapsed/refractory MCL and a median of three prior therapies [9]. The OR rate was 88 percent (44 percent complete) with a median time to response of 1.8 months. At a median follow-up of 17 months, the median PFS was not reached for the population as a whole. Among the 12 patients with Ki-67 ≥50 percent, the median PFS and OS were 5.9 and 13.6 months, respectively. The majority of patients reported mild to moderate fatigue, diarrhea, myalgia, nausea, oral mucositis, dyspnea, and peripheral sensory neuropathy. Severe (grade 3/4) toxicities were uncommon.
●A phase II study of ibrutinib plus venetoclax (BCL2 inhibitor) that included 23 patients with relapsed or refractory MCL reported 42 percent CR at 16 weeks by positron emission tomography (PET) [10]. Half of the patients had mutations of TP53 and 75 percent had a high-risk prognostic score. Clearance of minimal residual disease was reported in 67 and 38 percent by flow cytometry and polymerase chain reaction (PCR), respectively. Toxicity included tumor lysis syndrome (8 percent), diarrhea (83 percent), fatigue (75 percent), and nausea/vomiting (71 percent).
Ibrutinib is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with MCL who have received at least one prior therapy [11,12]. The recommended dose and schedule is ibrutinib 560 mg (four 140 mg capsules) taken orally once daily. Ibrutinib should not be administered with strong CYP3A inhibitors or inducers (table 1). Reduced doses are necessary if a moderate CYP3A inhibitor must be used. Ibrutinib should not be used in patients with baseline hepatic impairment. Dose modifications for toxicity are available in the package insert.
Serious and potentially fatal renal toxicity has occurred in patients treated with ibrutinib. In one report of 111 patients receiving ibrutinib for MCL, acute renal failure developed in three (2.7 percent) [7]. Creatinine levels should be periodically monitored during therapy, and patients should be encouraged to maintain hydration.
Studies evaluating the prognosis of patients who progress on ibrutinib have had mixed results. In a multicenter retrospective analysis of 114 patients with MCL who progressed while receiving ibrutinib, the median OS following ibrutinib discontinuation was 2.9 months (95% CI 1.6-4.9) [13]. In the 73 patients known to have received subsequent therapy, the median OS was 5.8 months (95% CI 3.7-10.4). In contrast, better results with subsequent treatment were seen in patients progressing on ibrutinib in the phase III trial described above [14]. Further studies are needed to better define the prognosis of this population.
Acalabrutinib — Acalabrutinib is a second generation BTK inhibitor with more selective activity and less toxicity than ibrutinib, but there is less experience with this agent.
A multicenter study of 124 patients with relapsed MCL (median age 68) reported that acalabrutinib 100 mg twice daily achieved OR in 81 percent (40 percent CR), with two-month median time to response [15]. The most common adverse reactions were grade 1-2 headache (38 percent), diarrhea (31 percent), fatigue (27 percent), and myalgia (21 percent); the most common grade ≥3 adverse events were neutropenia (10 percent), anemia (9 percent), and pneumonia (5 percent); one patient had grade 3 gastrointestinal hemorrhage; and treatment was discontinued for adverse events in 6 percent. An abstract reported that median DOR was 26 months, median PFS 20 months, and OS was 72 percent at 24 months [16].
From a database of more than 600 patients treated with acalabrutinib, severe (grade 3/4) toxicities included hemorrhage (2 percent), cytopenias (neutropenia, anemia, thrombocytopenia in 23, 11, and 8 percent, respectively), infection (18 percent), and atrial fibrillation/flutter (1 percent) [17].
The FDA granted accelerated approval of acalabrutinib for treatment of adults who have received at least one prior therapy for MCL [17]. The recommended dose is 100 mg orally approximately every 12 hours. Dose adjustments for co-administration with CYP3A inhibitors and inducers (table 1) are described in the package insert. The oral capsule, but not the oral tablet, is affected by co-administration with acid-reducing medications (eg, proton pump inhibitors); refer to product labeling for specific recommendations.
Zanubrutinib — Zanubrutinib is a selective, irreversible, second-generation BTK inhibitor.
A multicenter phase 2 study (NCT03206970) of zanubrutinib (160 mg twice daily by mouth) in 86 patients with previously treated MCL reported 84 percent ORR (59 percent CR); median duration of response was 19.5 months [18]. A similar ORR was reported in another study of zanubrutinib that included 32 patients with previously treated MCL.
The most common adverse events (≥20 percent) include cytopenias, rash, bruising, diarrhea, and cough.
Zanubrutinib is approved by the FDA under accelerated approval for treatment of adults with MCL who have received at least one prior treatment [18].
Lenalidomide — Several phase II trials have reported on the efficacy of lenalidomide in relapsed non-Hodgkin lymphoma (NHL), including MCL [19-29]. Approximately one-third of patients will respond to therapy. A response is typically seen within the first two months and the median DOR is 9 to 17 months. The most common severe (grade 3/4) toxicities are neutropenia and thrombocytopenia.
Examples of trials that have examined lenalidomide in relapsed or refractory MCL include:
●An international phase II trial of single-agent lenalidomide (25 mg once daily for 21 days every 28 days) in 134 patients with relapsed or refractory MCL who had received prior therapy with bortezomib demonstrated an OR rate of 28 percent (7 percent CR) [27]. After a median follow-up of 9.9 months, the median time to response was 2.2 months and median DOR was 16.6 months (95% CI 7.7-26.7 months). The estimated median OS was 19 months (95% CI 12-24 months). The most common severe (grade 3/4) toxicities included neutropenia (43 percent), thrombocytopenia (28 percent), anemia (11 percent), pneumonia (8 percent), fatigue (7 percent), and diarrhea (6 percent). Dose reductions were required in 38 percent and the average daily dose was 20 mg.
●In another international phase II trial (SPRINT), 254 patients with relapsed MCL who were not candidates for intensive therapy were randomly assigned in a 2:1 ratio to receive lenalidomide at the same dose and schedule described above versus a single agent of the investigator's choice [28]. Patients on this control arm received rituximab (32 percent), gemcitabine (24 percent), fludarabine (21 percent), chlorambucil (13 percent), or cytarabine (10 percent), and were allowed to receive lenalidomide at the time of progression. After a median follow-up of 15.9 months, lenalidomide improved PFS over that seen with investigator's choice (median 8.7 versus 5.2 months; HR 0.61, 95% CI 0.44-0.85). Toxicities were similar to those reported in the trial above.
Lenalidomide is approved by the FDA for the treatment of patients with MCL whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib [30]. Lenalidomide has black box warnings regarding embryo-fetal toxicity, hematologic toxicity, and venous thromboembolism. In the United States, the use of lenalidomide is subject to the RevAssist program (www.REVLIMID.com) developed in an attempt to minimize the potential for pregnancy among patients taking this medication and associated birth defects.
Bortezomib — Prospective phase II trials of bortezomib in patients with relapsed or refractory MCL demonstrated OR rates from 29 to 50 percent and CR rates from 4 to 8 percent [31-37]. The median DOR is approximately 10 months. Adverse events are similar to those previously reported for bortezomib in patients with multiple myeloma and most commonly include anorexia, nausea and vomiting, peripheral neuropathy, cutaneous reactions, neutropenia, and thrombocytopenia. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)
Response rates may be higher when bortezomib is combined with other regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). In one randomized trial, the addition of bortezomib resulted in a higher OR rate (83 versus 48 percent), CR rate (35 versus 22 percent), and longer median OS (36 versus 12 months) [38]. There was a higher incidence of severe (grade 3/4) neutropenia (30 versus 20 percent), febrile neutropenia (20 versus 13 percent), and infections in non-neutropenic patients (39 versus 17 percent) in those receiving bortezomib.
Based partly on these studies, the FDA granted approval to bortezomib for the treatment of patients with MCL who have received at least one prior therapy [39].
Caution should be used when combining bortezomib with rituximab in patients with recurrent MCL, as several studies have demonstrated high rates of toxicity:
●A phase I/II trial of bortezomib plus rituximab in 42 patients with recurrent/refractory MCL, follicular lymphoma, or Waldenström macroglobulinemia demonstrated responses in 11 of 19 patients with MCL [40]. Toxicity was significant with 16 of 42 patients requiring discontinuation of treatment due to side effects.
●In another study, 25 patients with relapsed follicular lymphoma or MCL (14 patients) were treated with bortezomib plus rituximab [41]. The OR rate was 29 percent in patients with MCL, but toxicity was significant with 52 percent developing grade 3 neurologic toxicity.
●In another phase II study, 16 patients with relapsed or refractory MCL who were treated with bortezomib plus rituximab and pulsed dexamethasone demonstrated a response rate of 81 percent (44 percent complete) with a median OS of 39 months [42]. Severe (grade 3/4) toxicities included thrombocytopenia (38 percent), fatigue (19 percent), and peripheral neuropathy (13 percent).
Single-agent rituximab — Prospective phase II trials have investigated the use of single-agent rituximab in patients with MCL [43-45]. OR rates were approximately 28 percent and did not differ between patients with newly diagnosed or recurrent disease. Median DOR was 14 months. Common side effects include infusional reactions and infections, neither of which is typically severe. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)
One of these prospective trials included 28 patients with previously treated MCL [43]. The OR rate seen in this subgroup was 37 percent with 14 percent CRs. At a median follow-up from treatment of 1.3 years, the projected median DOR was 1.2 years.
Bendamustine plus rituximab — Prospective trials evaluating the combination of bendamustine plus rituximab (BR) in relapsed or refractory MCL have reported OR rates of 75 to 92 percent [46-49]. The most common severe side effects include infection, myelosuppression, and fatigue.
●In a multicenter, open-label, phase 3 trial, 230 patients with relapsed or refractory indolent lymphoma or MCL were randomly assigned to receive BR versus fludarabine plus rituximab [49]. In a per-protocol analysis, patients who received BR had higher response rates and superior PFS and OS. A subset analysis confirmed the superior PFS rate among the 47 patients with MCL (median 18 versus 5 months).
●A prospective, phase II trial evaluated BR in 45 patients with relapsed/refractory non-blastoid MCL and a median of two prior therapies [48]. The OR rate was 82 percent (40 percent CR) with a median DOR of 1.6 years. The estimated OS at three years was 55 percent. The most common non-hematologic toxicities were nausea (69 percent), fatigue (56 percent), anorexia (42 percent), constipation (38 percent), diarrhea (36 percent), vomiting (36 percent), and weight loss (31 percent).
●A multicenter phase II trial including 18 patients with MCL treated with bendamustine, mitoxantrone, and rituximab for four cycles reported an OR rate of 78 percent with 33 percent CRs [50]. The median PFS time and two-year survival rate were 21 months and 60 percent, respectively.
●A multicenter phase II trial investigated the use of bendamustine, bortezomib, and rituximab in 30 patients with relapsed or refractory indolent NHL, seven of whom had MCL [51]. The OR rate was 83 percent (71 percent among those with MCL). Common toxicities included nausea (50 percent), neuropathy (47 percent), fatigue (47 percent), constipation (40 percent), and fever (40 percent). One patient died of sepsis. At a median follow-up of 24 months, the PFS rate at two years was 47 percent.
Purine analog therapy — The purine analogs fludarabine and cladribine have limited utility in relapsed/refractory MCL, when used either as single agents or as components of combination chemotherapy regimens. Myelosuppression is the most common toxicity associated with both agents.
The following examples illustrate what is known about their efficacy in this setting:
●Fludarabine – In two prospective phase II trials that included 6 and 13 patients, respectively, with relapsed/refractory MCL, single-agent fludarabine resulted in partial responses in fewer than half and no CRs [52,53].
●Cladribine – A non-randomized, single-arm trial of single-agent cladribine included 25 patients with recurrent MCL, who had an OR rate of 46 percent, including 21 percent CRs [54].
●Combination therapy – Fludarabine and cladribine have activity against relapsed or refractory MCL and other B cell lymphomas when combined with rituximab or other chemotherapy agents [55,56]. Dose-limiting hematopoietic side effects may occur in up to one-half of patients.
In a randomized trial of 48 patients with relapsed or refractory MCL, the addition of rituximab to fludarabine, cyclophosphamide, and mitoxantrone (FCM) increased the OR rate (58 versus 46 percent) and CR rate (29 versus 0 percent) [57]. The most common severe (grade 3/4) side effects were neutropenia (40 percent), lymphopenia (51 percent), and thrombocytopenia (12 percent).
Temsirolimus — Temsirolimus is active as a single agent and in combination with standard chemotherapy or rituximab in patients with relapsed or refractory MCL.
A randomized trial demonstrated reduced PFS and worse tolerability when compared with ibrutinib, as described above [4,5] (see 'Ibrutinib' above). Another phase III trial evaluated two doses of single-agent temsirolimus (175 mg weekly for three weeks followed by either 75 mg or 25 mg weekly) versus investigator's choice of therapy (mostly gemcitabine or fludarabine) in 162 patients with heavily pretreated relapsed or refractory MCL [58]. Compared with investigator's choice of therapy, both temsirolimus regimens were associated with higher rates of OR and PFS, but also with substantial cytopenias and asthenia.
Temsirolimus is approved by the European Medicines Agency (EMA) for the treatment of relapsed or refractory MCL.
CAR-T therapy — Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy achieves durable remissions in a majority of patients with relapsed or refractory MCL but is associated with serious and potentially life-threatening toxicity.
Brexucabtagene autoleucel (formerly called KTE-X19) is a CAR-T cell therapy directed against CD19. In a multicenter study of relapsed or refractory MCL, treatment of 60 patients with a single dose of KTE-X19 (2 x 106 CAR-T cells/kg) achieved OR in 93 percent (95% CI 84-98 percent) and CR in 67 percent (95% CI 53-78 percent) [59]. At 12 months, estimated rates of PFS and OS were 61 and 83 percent, respectively. The median age of patients was 65 years (range, 38 to 79 years) and all patients had previously been treated with a BTK inhibitor, anthracycline- or bendamustine-based chemotherapy, and an anti-CD20 monoclonal antibody. The study enrolled 74 patients and KTE-X19 was successfully manufactured in 96 percent, with a median of 16 days from leukapheresis to delivery; several patients died or developed exclusionary complications before CAR-T administration. Serious (grade ≥3) adverse events occurred in all patients, including cytopenias (94 percent) and infections (32 percent, including two fatal events). Grade ≥3 cytokine release syndrome occurred in 15 percent and neurologic events in 31 percent, respectively; none of these events was fatal.
Brexucabtagene autoleucel is approved by the FDA for treatment of multiply relapsed MCL [60]. The FDA label includes warnings about cytokine release syndrome (CRS), neurologic toxicities, and severe, potentially fatal opportunistic infections, including disseminated fungal infections (eg, candida, aspergillus) and viral reactivation (eg, human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]). Management of CRS and neurologic complications are discussed separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)
Other regimens — A number of other regimens have been evaluated in phase I or II prospective studies. As examples:
●A prospective, phase II study of rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with rituximab plus methotrexate and cytarabine in 29 patients with relapsed or refractory MCL reported an OR rate of 93 percent (45 percent CR) [61]. Grade 3/4 toxicities included neutropenia (74 percent) and thrombocytopenia (63 percent). Eleven percent of patients had neutropenic fever. At a median follow-up of 40 months, the median failure-free survival time was 11 months.
●A trial of thalidomide plus rituximab in 16 patients with recurrent MCL demonstrated OR rates of 81 percent with five CRs [62]. Median PFS was 20 months. Grade 3/4 toxicities included thromboembolic events and neutropenia.
●A phase II study of the radioimmunoconjugate ibritumomab tiuxetan (a murine anti-CD20 monoclonal antibody conjugated to Yttrium-90) in 34 patients with relapsed or refractory MCL who had received a median of three prior treatments reported an OR rate of 31 percent and a median OS of 21 months [63]. This response rate is lower than that seen with the use of this agent in relapsed indolent lymphoma. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Radioimmunotherapy'.)
●A prospective trial of rituximab, thalidomide, prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) in 22 older adults (median age 68 years) with relapsed MCL reported an OR rate of 73 percent (32 percent complete) [64]. The median PFS was 10 months. The most common severe (grade 3/4) toxicities included neutropenia (64 percent), infection (23 percent), thrombocytopenia (18 percent), and anemia (5 percent).
●A phase II trial of the humanized anti-CD20 monoclonal antibody obinutuzumab in 40 patients with relapsed or refractory MCL or diffuse large B cell lymphoma reported an OR rate of 30 percent (13 percent CR) [65]. Infusion reactions were seen in 75 percent and were severe in 8 percent (three patients). The median DOR was 9.8 months.
●A phase I dose-escalation trial evaluating the PI3K-delta inhibitor idelalisib in 40 patients with heavily pretreated (median four prior therapies) relapsed or refractory MCL noted an OR rate of 40 percent [66]. Median PFS was 3.7 months and the PFS at one year was 22 percent. Common adverse events included diarrhea, nausea, pyrexia, fatigue, and rash. Idelalisib is associated with an increase in opportunistic infections and the manufacturer recommends prophylaxis for Pneumocystis jirovecii pneumonia (PCP) and monitoring for cytomegalovirus. (See "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors' and "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Idelalisib'.)
●A phase I, multicenter, open-label study evaluated polatuzumab vedotin, an investigational anti-CD79B antibody conjugated to monomethyl auristatin E, with or without rituximab in 95 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or NHL [67]. Partial responses were seen in all four patients with MCL who received single-agent polatuzumab vedotin and in two of three who received combination therapy.
●In a phase I trial of venetoclax, at least a partial response was seen in 21 of 28 (75 percent) patients with relapsed MCL; six were complete [68]. Estimated median PFS was 14 months. Complete responses were more durable than partial responses.
HEMATOPOIETIC CELL TRANSPLANTATION — Studies using high dose chemotherapy followed by hematopoietic cell transplantation (HCT) have had variable results in patients with relapsed MCL [69]. Autologous HCT is not curative and not commonly employed in this setting. There are very limited data on the use of myeloablative allogeneic HCT in this patient population and this approach is likely too toxic. In contrast, studies evaluating nonmyeloablative allogeneic HCT demonstrate promise.
Eligibility for HCT is primarily determined based on the type of HCT, the patient's age, their performance status, and/or the presence of comorbid conditions. This is discussed in more detail separately. (See "Determining eligibility for autologous hematopoietic cell transplantation" and "Determining eligibility for allogeneic hematopoietic cell transplantation".)
Autologous HCT — Many clinicians offer conventional chemotherapy followed by high dose chemotherapy and autologous HCT (peripheral blood progenitor cell rescue) as part of the initial treatment of patients with MCL. Studies have also evaluated its use in the setting of relapsed and resistant disease [70-75]. Although autologous HCT does not appear to be curative, some patients may experience a prolonged remission. Median event-free survival after autologous HCT is approximately three years. (See "Initial treatment of mantle cell lymphoma", section on 'Autologous transplantation'.)
This was best illustrated in an analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) registry that identified patients who had undergone autologous HCT in first partial or complete remission after one (134 patients) or two (115 patients) lines of chemotherapy, and compared their outcomes with those of 132 patients with chemotherapy-sensitive disease who had undergone autologous HCT at a later time in their disease course [75]. Estimated rates of five-year survival were similar for those who attained a complete remission after one or two lines of chemotherapy (75 versus 70 percent), but were inferior for those who had only a partial response (38 percent). When compared with HCT at a later time, HCT in first partial or complete remission was associated with superior five-year survival (61 versus 44 percent).
These results suggest that autologous HCT in first complete remission is effective regardless of whether it requires one or two lines of chemotherapy to attain the remission. Outcomes are inferior for those who are unable to attain a complete remission and for those who undergo autologous HCT at the time of relapse.
Nonmyeloablative HCT — Initial results of nonmyeloablative allogeneic HCT for relapsed or refractory MCL are promising, but longer follow-up is necessary before this becomes a standard approach [76-80].
●In one study, 18 subjects with advanced recurrent MCL, 16 of whom had chemosensitive disease, were treated with nonmyeloablative allogeneic HCT [76]. Complete remission was obtained in 17 of the 18 patients with a day 100 mortality of zero. At a median follow-up of 26 months, estimated three-year event-free survival was 82 percent.
●A prospective, multicentered, phase II trial of reduced-intensity conditioning followed by allogeneic HCT included 14 patients with relapsed or refractory MCL [81]. At a median follow-up of 33 months, three-year overall survival for patients with MCL was 45 percent. The rate of transplant-related mortality was 13 percent among all patients in the trial. Overall three-year cumulative incidence of graft-versus-host disease (GVHD) was 49 percent.
●A retrospective analysis of consecutive patients undergoing nonmyeloablative allogeneic HCT for lymphoma at a single institution included 15 patients with MCL [82]. Approximately one-third had received a prior autologous HCT. At a median follow-up of 26 months, estimated one-year and three-year overall survival rates for patients with MCL were 60 and 40 percent, respectively. Progression-free survival at the same time points was 30 and 40 percent, respectively. Acute GVHD occurred in 20 percent.
●An analysis of the CIBMTR registry identified patients with chemotherapy-sensitive MCL who had undergone reduced-intensity conditioning allogeneic HCT in first partial or complete remission after no more than two prior lines of chemotherapy (50 patients) or at a later time point in their disease course (88 patients) [75]. Reduced-intensity conditioning allogeneic HCT was associated with a non-relapse mortality rate of 17 to 25 percent. When compared with HCT at a later time, HCT in first partial or complete remission was associated with superior five-year survival (62 versus 31 percent) and lower rates of relapse/progression at five years (15 versus 38 percent). However, similar survival rates were seen when autologous HCT was employed.
RADIATION THERAPY — Although MCL cells are extremely radiosensitive in vitro [83], use of radiation therapy (RT) in MCL, even in patients with localized disease, is not curative [84]. However, RT may be helpful on occasion for local disease control in patients with chemotherapy-refractory disease [85,86].
CLINICAL TRIALS — Often there is no better therapy 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).
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. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. 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 subtype of non-Hodgkin lymphoma (NHL) with a variable course. These patients are best treated by physicians with specific expertise in this area.
●A number of chemotherapy regimens have been evaluated in patients with recurrent or refractory MCL, with variable success. Some of these agents are undergoing further investigation for use in combination therapies. All patients should be encouraged to participate in clinical trials whenever available. (See 'Chemotherapy' above.)
●For those young patients without significant comorbid diseases who do not have access to clinical trials or who choose not to participate in a clinical trial, we offer treatment with one of the salvage regimens described above. If chemotherapy sensitivity is shown, high dose therapy with autologous stem cell support may be considered, but is not curative. The role of allogeneic hematopoietic cell transplantation is uncertain. (See 'Hematopoietic cell transplantation' above.)
●The salvage regimen used for a particular patient depends on patient comorbidities, side effect profiles, prior therapies, and the clinical situation of the patient in question.
