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Treatment of relapsed or refractory mantle cell lymphoma

Treatment of relapsed or refractory mantle cell lymphoma
Literature review current through: Jan 2024.
This topic last updated: Aug 31, 2023.

INTRODUCTION — Mantle cell lymphoma (MCL) is a B cell non-Hodgkin lymphoma that can have a variable course. Although some patients may survive untreated for years, most patients experience a more aggressive course. MCL is often responsive to initial therapy, but some patients do not achieve a complete response (CR) with initial treatment (primary refractory disease), and others experience one or more relapses after achieving CR.

Conventional chemoimmunotherapy has limited, transient benefit for relapsed or refractory (r/r) MCL due to rapid development of chemotherapy resistance. Management of r/r MCL has improved with the availability of Bruton tyrosine kinase inhibitors (BTKis) and chimeric antigen receptor (CAR)-T cell therapy, which offer greater efficacy with acceptable toxicity. Nevertheless, therapy for MCL is generally not curative, and most patients will experience multiple relapses. Enrollment in a clinical trial is encouraged.

Treatment of r/r MCL is discussed here.

Initial treatment of MCL and clinical and pathologic features are discussed separately. (See "Mantle cell lymphoma: Initial management" and "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)

DEFINITIONS — Relapsed or refractory (r/r) MCL refers to disease that was not cured by initial treatment.

Relapsed MCL – Recurrence of MCL after achieving a complete response (CR). The interval from completion of therapy to recurrence (ie, the duration of CR) has prognostic impact.

Refractory MCL – Failure to achieve a CR with initial induction therapy is called primary refractory MCL or primary induction failure. Patients with refractory MCL generally have less favorable outcomes than patients with relapsed disease.

Prognosis generally declines with each subsequent relapse. The goals of care for r/r MCL are influenced by the number of prior relapses, previous treatments, age, fitness, and patient preference. Prognostic factors for r/r MCL are discussed below. (See 'Prognosis' below.)

EVALUATION

Clinical and laboratory

Clinical – The presence of B symptoms and lymph node, organ involvement, or other extranodal disease should be documented by history and physical examination. (See "Mantle cell lymphoma: Initial management".)

Laboratory

Hematology – Complete blood count (CBC) with leukocyte differential count

Chemistries – Serum electrolytes, glucose, blood urea nitrogen (BUN) and creatinine, calcium, uric acid, and liver function tests, including lactate dehydrogenase (LDH)

Infectious – Human immunodeficiency virus (HIV) and hepatitis B virus testing

Pregnancy testing – If appropriate

Clinical testing

Cardiac – Electrocardiogram (ECG), echocardiogram, and/or radionuclide ventriculogram (RVG), as clinically indicated.

Other – Endoscopy/colonoscopy, contrast-enhanced computed tomography (CT), or other clinical testing should be performed, if clinically indicated, to evaluate potential extranodal involvement.

Diagnosis — Pathologic confirmation is generally required to diagnose relapsed or refractory (r/r) MCL, but the need for a biopsy may vary with the clinical setting:

Relapsed MCL – A biopsy is required to confirm the diagnosis and to exclude other conditions for a suspected first relapse of MCL.

A repeat biopsy may not be needed to confirm subsequent relapses if the diagnosis is supported by clinical and imaging data.

Refractory MCL – A repeat biopsy is preferred to confirm the diagnosis of primary refractory MCL and to exclude a reactive, post-treatment inflammatory response. However, a biopsy may not be required if positron emission tomography (PET)/CT revealed a clear progression of the size and metabolic activity of a disease site.

If a biopsy is not performed in this setting, the morphology, immunophenotype, and cytogenetic/molecular features of the initial biopsy specimen should be reviewed to ensure that MCL was correctly diagnosed.

Pathologic and genetic features for a diagnosis of MCL are described separately. (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis", section on 'Diagnosis'.)

Restaging — Restaging is based on clinical evaluation, laboratory studies, and PET/CT, according to the Lugano criteria (table 1).

Imaging – PET/CT is scored using the five-point (Deauville) scale (table 2).

Bone marrow examination – Bone marrow aspirate and biopsy are generally not required for restaging r/r MCL because PET is a good predictor for marrow involvement.

If bone marrow examination is performed, it should be analyzed by microscopy, cytogenetics (using fluorescence in situ hybridization [FISH] or Giemsa-stained chromosome analysis), and molecular studies, as described separately. (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis", section on 'Pathology'.)

Fitness — We assess and classify fitness according to functional status and comorbid conditions. Age, per se, is not a measure of fitness.

Functional status – A fitness assessment should include performance status (table 3).

Comorbid conditions – Risk for bleeding, thromboembolism, cardiac conditions, liver disease, and other comorbid conditions may affect a patient's suitability for various agents used to treat r/r MCL, as described in the sections that follow.

Fitness should be reassessed at the time of each relapse, as it may change with subsequent relapses and/or prior treatments.

FIRST RELAPSE OR PRIMARY REFRACTORY DISEASE — The choice of salvage therapy for first relapse or primary refractory MCL is guided by whether the patient was previously treated with a Bruton tyrosine kinase inhibitor (BTKi).

Treatment for frail patients is discussed below. (See 'Frail patients' below.)

No prior Bruton tyrosine kinase inhibitor — For first relapse of MCL or primary refractory MCL in a BTKi-naïve patient, we suggest salvage therapy using either acalabrutinib or zanubrutinib rather than ibrutinib or other treatments. This suggestion is based on the more favorable balance of outcomes and toxicity with acalabrutinib or zanubrutinib compared with other treatments.

When the second-generation BTKis, acalabrutinib and zanubrutinib, are not available, treatment with ibrutinib is acceptable.

Administration – BTKis should be avoided in patients with a high risk for bleeding (eg, patients receiving anticoagulants or with severe thrombocytopenia) or cardiovascular disorders (eg, dysrhythmias, uncontrolled hypertension).

We generally administer BTKis as single agents rather than combined with rituximab or other drugs.

Selection of salvage therapy for patients who are not candidates for BTKi treatment is discussed below. (See 'Second relapse' below.)

All BTKis may interact with CYP3A inhibitors or inducers (table 4) and may require dose modification, as described in the package inserts.

AcalabrutinibAcalabrutinib is taken 100 mg twice daily by mouth.

The oral capsule, but not the oral tablet, is affected by coadministration with acid-reducing medications (eg, proton pump inhibitors), as described in the product label.

IbrutinibIbrutinib is taken 560 mg (four 140 mg capsules) by mouth once daily.

Ibrutinib should not be used in patients with baseline hepatic impairment. Dose modifications for toxicity are described in the package insert.

ZanubrutinibZanubrutinib is taken 320 mg once daily by mouth (or 160 mg twice daily by mouth), swallowed whole with water and with or without food. Patients should be advised to not open, break, or chew capsules.

We repeat positron emission tomography (PET) after two to four treatment cycles to assess the initial response to therapy and proceed according to the findings (table 5):

Complete response or partial response – Treatment continues until there is disease progression or drug intolerance.

Stable disease or progressive disease – Treat as per second relapse. (See 'Second relapse' below.)

Abrupt BTKi discontinuation has been associated with rapid disease progression [1]. If chimeric antigen receptor (CAR)-T cell therapy is being considered for disease progression while using a BTKi, it is important to either continue the BTKi or switch to another therapy prior to leukapheresis for harvesting T cells.

Acalabrutinib and zanubrutinib are approved by the US Food and Drug Administration (FDA) for treatment of relapsed or refractory (r/r) MCL after ≥1 prior therapy; neither agent is approved by the European Medicines Agency (EMA) for r/r MCL.

Ibrutinib is approved by the EMA for r/r MCL. Ibrutinib was FDA approved for treatment of r/r MCL after ≥1 prior treatment, but the manufacturer requested withdrawal of approval for that indication (based on results from a phase 3 trial in patients with previously untreated MCL [2]).

Toxicity – The most common, serious adverse effects (AEs) associated with BTKi therapy are bleeding, arrhythmias, opportunistic infections, and second primary malignancies; other toxicities include cytopenias, headache, upper respiratory tract infection, and diarrhea. Treatment interruption, dose reduction, or discontinuation may be required to manage toxicity.

Ibrutinib was associated with more AEs than zanubrutinib in a randomized trial for Waldenström macroglobulinemia [3]. For patients treated with ibrutinib, serum creatinine should be monitored, and patients should be encouraged to maintain hydration, as ibrutinib has been associated with serious and potentially fatal renal toxicity; acute renal failure developed in 3 percent of 111 patients treated with ibrutinib for MCL [4].

OutcomesAcalabrutinib, ibrutinib, and zanubrutinib are all effective for r/r MCL, but they have not been directly compared in randomized studies in this setting.

In a real-world study, BTKis were used in more than one-half of 933 patients with r/r MCL; bortezomib, lenalidomide, and venetoclax were other agents that were used [5].

Studies of individual BTKis for r/r MCL include:

Acalabrutinib – In a study of 124 patients with r/r MCL, acalabrutinib was associated with a 72 percent 24-month overall survival (OS), 49 percent 24-month progression-free survival (PFS), and 81 percent overall response rate (ORR; including a 40 percent complete response [CR]) [6,7]. Grade ≥3 AEs included infections (15 percent), anemia (10 percent), and neutropenia (10 percent).

Zanubrutinib – In a study of 86 patients with r/r MCL, zanubrutinib was associated with a 76 percent 12-month PFS and 22-month median PFS [8]. The most common grade ≥3 AEs were neutropenia (20 percent) and lung infection/pneumonia (9 percent). Major bleeding was reported in three patients, and there were no reports of atrial fibrillation.

In an earlier study that included 37 patients with r/r MCL (among 48 enrolled patients), the 12-month OS was 87 percent, 12-month PFS was 83 percent, and ORR was 84 percent (including a 25 percent CR) [9].

IbrutinibIbrutinib is effective as monotherapy and when combined with other agents for treating r/r MCL.

-Monotherapy – Pooled analysis of three studies (370 patients with r/r MCL) reported that ibrutinib for first relapse of MCL was associated with a 68 percent two-year OS, 57 percent two-year PFS, and 66 percent ORR (including a 20 percent CR) [10].

-A real-world analysis of 211 patients treated with ibrutinib for first relapse of MCL was associated with a 24-month median OS, 18-month median PFS, and 69 percent ORR (including 27 percent CR); the inferior survival outcomes compared with the pooled analysis (above) may be related to older age and worse performance status [11].

-Ibrutinib monotherapy was associated with a 47 percent 24-month OS, 31 percent 24-month PFS, and 67 percent ORR (including a 23 percent CR) in a multicenter study of 111 patients with r/r MCL (who had a median of three prior therapies) [4,12].

In a phase 3 trial (RAY) of 280 patients with r/r MCL, compared with temsirolimus, ibrutinib achieved superior PFS and a trend toward a better OS, but there were more grade ≥3 bleeding events (9 versus 5 percent) and more atrial fibrillation (5 versus 1 percent) [13,14]. Ibrutinib was associated with better survival than bendamustine-based treatment for patients who had an initial treatment response <24 months, but outcomes did not differ between treatments for patients whose first remission was ≥24 months in a retrospective study [15].

-Combination therapyIbrutinib has been combined with rituximab or venetoclax for treatment of r/r MCL.

A phase 2 study reported that ibrutinib plus rituximab was associated with an 88 percent ORR (including a 44 percent CR) in 50 adults with r/r MCL who had a median of three prior therapies [16]. In a study that included 50 patients with r/r MCL (a median of three prior therapies), ibrutinib plus rituximab was associated with a 43-month median PFS and 58 percent CR [17].

Treatment with ibrutinib plus venetoclax in 23 patients with r/r MCL reported a 42 percent CR by PET at 16 weeks [18]. One-half of the patients had mutations of TP53 and 75 percent had a high-risk prognostic score. Grade ≥3 AEs included diarrhea (71 percent), neutropenia (33 percent), thrombocytopenia (17 percent), and anemia (12 percent).

Prior Bruton tyrosine kinase inhibitor treatment — Management for patients who previously received a BTKi is guided by the following clinical features:

Remote Bruton tyrosine kinase inhibitor therapy – If BTKi use was remote (eg, relapse >1 year since exposure), we suggest salvage therapy with a BTKi, as discussed above. (See 'No prior Bruton tyrosine kinase inhibitor' above.)

Other patients – For primary refractory MCL or relapse ≤1 year since last exposure, we suggest lenalidomide based on its efficacy and modest toxicity.

Lenalidomide is approved by the EMA for treatment of r/r MCL, and it is approved by the FDA for treatment of adults with r/r MCL after two prior therapies, one of which included bortezomib. Lenalidomide has boxed warnings regarding embryo-fetal toxicity, hematologic toxicity, and venous thromboembolism. In the United States, lenalidomide is subject to the RevAssist program to minimize the potential for pregnancy and associated disability since birth.

We consider CAR-T cell therapy (see 'Medically fit' below), pirtobrutinib (see 'Less fit' below), and venetoclax (see 'Venetoclax' below) acceptable in this setting, but they lack regulatory approval for first relapse or primary refractory disease.

Lenalidomide administrationLenalidomide is given 25 mg by mouth on days 1 to 21 of 28-day cycles.

We repeat PET after two to four cycles and continue treatment for patients with CR or partial response (PR) (table 5). For patients with less than PR, we treat as per second relapse. (See 'Second relapse' below.)

Treatment should continue until disease progression or drug intolerance, which generally occurs within one year.

If rituximab is added to lenalidomide, it is given by infusion at 375 mg/m2 on day 1 of each treatment cycle for six months.

Antithrombotic prophylaxis should be given according to the patient's underlying risk of venous and arterial thromboembolism. Our approach to prophylaxis for patients receiving lenalidomide for r/r MCL is like that applied to patients with multiple myeloma, as discussed separately. (See "Multiple myeloma: Prevention of venous thromboembolism".)

ToxicityLenalidomide is associated with an increased risk for arterial and venous thromboembolism, cytopenias, and embryo-fetal toxicity.

Rituximab may also be associated with infusion reactions, reactivation of hepatitis B, and rare cases of progressive multifocal leukoencephalopathy. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Incorporation of rituximab'.)

OutcomesLenalidomide, with or without rituximab, is effective and well tolerated for the treatment of r/r MCL.

-MonotherapyLenalidomide achieved better outcomes than the investigator's choice of therapy in the randomized MCL-002/SPRINT trial of 254 patients with r/r MCL who were ineligible for intensive chemotherapy or hematopoietic cell transplantation [19]. Lenalidomide achieved a superior PFS (nine versus five months; hazard ratio [HR] 0.61 [95% CI 0.44-0.84]) among 254 patients who were randomly assigned (2:1) to either lenalidomide or the investigator's choice of monotherapy (rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine). The most common grade ≥3 AEs were neutropenia (73 percent with lenalidomide versus 34 percent) and thrombocytopenia (18 versus 28 percent).

Lenalidomide was associated with a 19-month median OS, 4-month median PFS, 28 percent ORR (including an 8 percent CR), and 17-month duration of response (DOR) in an earlier study (MCL-001; EMERGE) of 134 patients with r/r MCL who were previously treated with bortezomib [20]. Other studies reported similar outcomes with lenalidomide for r/r MCL [21,22].

-Lenalidomide plus rituximab

Lenalidomide plus rituximab was associated with a 24-month median OS, 11-month median PFS, and 57 percent ORR (including a 36 percent CR) with a 19-month median DOR in a study of 52 patients with r/r MCL [23]. Grade ≥3 AEs included neutropenia (66 percent) and thrombocytopenia (23 percent). Lenalidomide, rituximab, plus ibrutinib in 50 patients with r/r MCL reported a 76 percent ORR (including a 56 percent CR) [24].

MONITORING — We monitor the patient clinically for disease progression during and after salvage therapy.

We generally schedule follow-up visits every three to six months for five years and then yearly, or as clinically indicated.

Clinical/laboratory evaluation – Visits include clinical evaluation and screening laboratory studies, including complete blood count (CBC) with leukocyte differential count and serum chemistries, including lactate dehydrogenase (LDH).

Imaging – Imaging should be performed as clinically indicated, but to lessen radiation exposure, we do not perform routine (ie, scheduled) positron emission tomography (PET) and/or CT.

If there is clinical evidence of relapse, we restage with PET/CT and begin management for second relapse. (See 'Second relapse' below.)

SECOND RELAPSE — Most patients who are treated for primary refractory MCL or first relapse of MCL will again relapse within one to two years. Diagnosis of second relapse is discussed above. (See 'Diagnosis' above.)

Management of second relapse of MCL is guided by medical fitness.

Medically fit — For fit patients with second relapse of MCL and fit patients who did not achieve a complete response (CR) with initial salvage therapy, we suggest chimeric antigen receptor (CAR)-T cell therapy using brexucabtagene autoleucel rather than other treatments.

Brexucabtagene autoleucel (formerly KTE-X19) is a CD19-directed CAR-T cell therapy that received accelerated approval by the US Food and Drug Administration (FDA) for treatment of relapsed or refractory (r/r) MCL.

Administration – A single dose of 2 x 106 CAR-positive viable T cells/kg body weight (maximum 2 x 108 cells) is administered in a health care facility that is certified for its use.

Toxicity – Brexucabtagene is associated with potentially fatal cytokine release syndrome (CRS); neurologic events; and opportunistic infections, including disseminated fungal infections (eg, Candida, Aspergillus) and viral reactivation (eg, human herpes virus-6 [HHV-6] encephalitis and John Cunningham [JC] virus-associated progressive multifocal leukoencephalopathy).

Diagnosis and management of CRS and neurologic events are discussed separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

Outcomes – Brexucabtagene was associated with an 83 percent estimated 12-month overall survival (OS), 61 percent 12-month progression-free survival (PFS), and 93 percent overall response rate (ORR; including a 67 percent CR) among 60 patients with r/r MCL (a median of 65 years) in a multicenter study [25]. All patients had been previously treated with acalabrutinib and/or ibrutinib, 81 percent had received ≥3 prior lines of treatment, one-third had blastoid or pleomorphic histology, and one-sixth of evaluable patients had TP53 mutation. The CAR-T cell product was successfully manufactured in 96 percent of patients, with a median of 16 days from leukapheresis to delivery. Grade ≥3 adverse effects (AEs) occurred in all patients, including cytopenias (94 percent) and infections (32 percent, including two fatal events). Grade ≥3 CRS occurred in 15 percent of patients (which required tocilizumab in 59 percent and glucocorticoids in 22 percent) and neurologic events in 31 percent; none of these events was fatal.

We monitor the patient for relapse after completing CAR-T cell therapy, as described above. (See 'Monitoring' above.)

Brexucabtagene autoleucel is approved by the FDA as third-line therapy for patients with r/r MCL after prior treatment with chemoimmunotherapy and a Bruton tyrosine kinase inhibitor (BTKi).

Lisocabtagene maraleucel (another CD19-directed CAR-T cell product) has similar activity. Treatment of 269 patients with various r/r B cell lymphomas with adverse features (but not including any patients with r/r MCL) was associated with a 73 percent ORR (including 53 percent CR) and AEs (2 percent grade ≥3 CRS; 20 percent grade ≥3 neurologic events) to brexucabtagene autoleucel [26]. Lisocabtagene maraleucel is not approved in this setting.  

Less fit — For patients with second relapse of MCL who are not medically fit for CAR-T cell therapy, we suggest pirtobrutinib rather than other treatments.

Most patients with second relapse of MCL were previously treated with a BTKi, either with initial treatment or for first relapse/primary refractory disease. Pirtobrutinib noncovalently binds BTK distant from the C481 residue, which is the binding site for other BTKis and the most common site for mutations associated with BTKi resistance [27].

Pirtobrutinib is approved by the FDA for treatment of r/r MCL after ≥2 lines of systemic therapy, including a BTKi.

Where pirtobrutinib is not available and for patients with a contraindication to BTKi treatment, alternative salvage therapy is discussed below. (See 'Subsequent relapses' below.)

AdministrationPirtobrutinib 200 mg is taken once daily by mouth and swallowed whole with water (with or without food). Strong CYP3A inhibitors (table 4) should be avoided. If treatment with a strong or moderate CYP3A inducer is unavoidable, the dose of pirtobrutinib should be increased.

We repeat positron emission tomography (PET) after two to four treatment cycles to assess the initial response to therapy (table 5). Further management is guided by the PET findings:

Complete response or partial response – Treatment continues until disease progression or drug intolerance.

Stable disease or progressive disease – Treat as per third or later relapse. (See 'Subsequent relapses' below.)

Toxicity – As with other BTKis, pirtobrutinib is associated with cytopenias, infections, hemorrhage, and atrial fibrillation/flutter.

Outcomes

For 120 patients with r/r MCL who were previously treated with a BTKi (among 323 patients with various r/r B cell malignancies), pirtobrutinib was associated with a 50 percent ORR (including a 13 percent CR) with an eight-month duration of response (DOR) [28]. The most common grade ≥3 AE was neutropenia (in 10 percent); other AEs included fatigue, diarrhea, and bruising.

A phase 1 to 2 study of pirtobrutinib (BRUIN) that included 90 patients with r/r MCL (who received a median three prior lines of therapy) reported a 58 percent ORR (including a 20 percent CR) and a 22-month median DOR [29]. Grade ≥3 AEs included hemorrhage (4 percent) and atrial fibrillation/flutter (1 percent).

SUBSEQUENT RELAPSES — Patients who experience a third or later relapse of MCL generally have a grim prognosis. Successive treatment with various agents is often the most effective method for symptom management, disease control, and prolongation of survival. Potential treatment options are described below. (See 'Salvage therapy for third or later relapse' below.)

Some patients choose palliation of symptoms rather than treatments to control the disease in this setting; management options are described below. (See 'Frail patients' below.)

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment that has been proven to achieve a durable response and potential cure in this setting. For medically fit patients with relapsed or refractory (r/r) MCL that responds adequately to salvage therapy, consolidation with allogeneic HCT is discussed below. (See 'Consolidation with allogeneic hematopoietic cell transplantation' below.)

Salvage therapy for third or later relapse — Selection of salvage therapy for third or later relapse is guided by previous therapy, fitness, comorbidities, and patient preferences.

There is no consensus in this setting. Our approach is informed by prior treatments, as follows:

No prior treatment with pirtobrutinib or lenalidomide – If not previously given, we favor treatment with pirtobrutinib or lenalidomide.

Pirtobrutinib Pirtobrutinib is contraindicated in patients with bleeding disorders and cardiac dysrhythmias, as discussed above. (See 'Less fit' above.)

Pirtobrutinib was associated with a 52 percent overall response rate (ORR; including a 13 percent complete response [CR]) with an eight-month duration of response (DOR) in 52 patients with r/r MCL who were previously treated with a Bruton tyrosine kinase inhibitor (BTKi) [28].

Lenalidomide Lenalidomide is associated with increased risk for arterial and venous thromboembolism, and antithrombotic prophylaxis should be given, as described above. (See 'Prior Bruton tyrosine kinase inhibitor treatment' above.)

In the MCL-004 study, lenalidomide was associated with a 29 percent ORR and 20-week DOR among 58 patients who were previously treated with ibrutinib; 13 received lenalidomide monotherapy, 11 were treated with lenalidomide plus rituximab, and 34 received lenalidomide plus other agents [30].

Prior treatment with pirtobrutinib and lenalidomide – Treatment options include:

Venetoclax – There are limited data regarding venetoclax therapy in patients with r/r MCL. Administration, toxicity, and outcomes with venetoclax-based therapy are presented below. (See 'Venetoclax' below.)

Venetoclax is not approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) for treatment of r/r MCL.

Bortezomib Bortezomib has limited activity for r/r MCL. Administration, toxicity, and outcomes with bortezomib are presented below. (See 'Bortezomib' below.)

Bortezomib is approved by the FDA for treatment of r/r MCL.

Other approaches – Various treatments, including temsirolimus, bendamustine, combination chemotherapy, and radiation therapy have been used for multiply relapsed MCL and may be beneficial for selected patients, as described below. (See 'Other systemic therapy' below.)

Outcomes for patients with r/r MCL who were previously treated with a BTKi are generally disappointing. Among 73 patients with r/r MCL who progressed after ibrutinib therapy, treatment using various single agents (eg, rituximab, lenalidomide, cytarabine, bendamustine, bortezomib) was associated with a six-month median overall survival (OS), two-month median progression-free survival (PFS), and 26 percent ORR (including a 7 percent CR) [31]. For 31 patients treated with various immunochemotherapy regimens after ibrutinib treatment, the median OS was eight months, and the ORR was 32 percent (including a 19 percent CR) with a six-month median DOR [32]. Another study of patients who progressed after ibrutinib reported 20 to 48 percent ORR (including 0 to 19 percent CR) [33].

Response assessment — We repeat positron emission tomography (PET) after two to four treatment cycles, assess response according to Lugano criteria (table 5), and proceed according to the findings:

Complete response or partial response

Fit, younger (eg, ≤70 years) patients – For selected fit patients with CR or partial response (PR) after salvage therapy for third or later relapse, we consider transplantation as consolidation therapy. (See 'Consolidation with allogeneic hematopoietic cell transplantation' below.)

Others – Continue treatment until disease progression or drug intolerance, then switch to an alternate approach. (See 'Salvage therapy for third or later relapse' above.)

Stable disease or progressive disease – Switch to an alternative salvage therapy or palliative management.

Consolidation with allogeneic hematopoietic cell transplantation — Consolidation therapy using allogeneic HCT can be considered for transplant-eligible patients with a robust response to salvage therapy for multiply relapsed MCL.

Salvage therapy prior to allogeneic HCT is described above. (See 'Subsequent relapses' above.)

Allogeneic HCT is the only treatment that has been proven to achieve a durable response and potential cure for patients with multiply relapsed MCL, but it is associated with substantial toxicity and possible transplantation-associated mortality. The decision to pursue allogeneic HCT should be made after discussion with the patient, with due consideration of the potential benefits and toxicity.

We generally restrict allogeneic HCT for patients with r/r MCL who meet the following criteria:

Third or later relapse – We consider allogeneic HCT only for patients who relapsed after receiving chimeric antigen receptor (CAR)-T cell therapy. (See 'Medically fit' above.)

Age and fitness – Most institutions restrict allogeneic HCT to medically fit patients ≤70 years without major comorbid conditions. Some experts apply less stringent age and/or fitness criteria, given the grim prognosis in this setting.

Details of eligibility for allogeneic HCT are discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Response to salvage therapy – Many experts reserve allogeneic HCT for patients who achieve CR to salvage therapy; some experts proceed to allogeneic HCT for patients with PR to salvage therapy.

Most experts favor nonmyeloablative (NMA) or reduced-intensity conditioning (RIC) rather than myeloablative conditioning (MAC) to reduce adverse effects (AEs) in this heavily pretreated population. Autologous HCT is not curative for r/r MCL, and it is not commonly employed in this setting.

Outcomes – Allogeneic HCT can provide robust and durable responses for patients with r/r MCL, but it is associated with substantial toxicity and possible transplantation-associated mortality. Outcomes with allogeneic HCT following CAR-T cell therapy are not yet available. It is difficult to draw conclusions about outcomes with HCT for r/r MCL because most studies are small and included heterogeneous patient populations (eg, transplantation after first, second, third, or later relapse), various conditioning regimens, and different graft sources.

Among 35 patients with r/r MCL who underwent RIC allogeneic HCT, the six-year OS was 53 percent, six-year PFS was 46 percent, and rates of treatment-related mortality (TRM) at 3 and 12 months were 0 and 9 percent, respectively [34]. Nearly two-thirds of patients were transplanted after achieving CR (including one-third who were in second CR). In a study of 33 patients who received RIC allogeneic HCT, outcomes after two years included 65 percent OS, 60 percent disease-free survival, 9 percent relapses, and 24 percent TRM [35]. None of the 13 patients who were transplanted in CR relapsed after a two-year observation. In another study, three-year OS and PFS were 86 and 82 percent, respectively, among 18 patients who received RIC allogeneic HCT for r/r MCL; 89 percent of patients had chemosensitive disease [36]. Other small studies of allogeneic HCT that included patients with r/r MCL have reported similar outcomes [37-40].

Toxicity is substantial, even with NMA conditioning regimens. Analysis of data from a transplant registry reported 17 to 25 percent nonrelapse mortality (NRM) among 133 patients who underwent RIC allogeneic HCT for r/r MCL [41].

Disease status at transplantation was the only predictor of outcomes in a retrospective analysis of 70 patients; two-year OS was 53 percent for 35 patients transplanted in CR, compared with 20 percent in PR, and 15 percent with stable or progressive disease [42]. Response duration >12 months after autologous HCT was associated with better outcomes with allogeneic HCT than earlier relapse or primary refractory disease [43]. Allogeneic HCT had similar activity in patients with r/r MCL with or without TP53 abnormalities in a study of 42 patients [44].

FRAIL PATIENTS — For frail patients with relapsed or refractory MCL, the focus of management is symptom control.

The choice of management is influenced by the extent of symptoms, site(s) of relapse, and patient preference. Palliative management (eg, radiation therapy) and supportive care can provide temporary relief of symptoms but generally do not prolong survival.

TREATMENTS

Bruton tyrosine kinase inhibitors

Acalabrutinib, ibrutinib, zanubrutinib – Administration, toxicity, outcomes, and approval by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for acalabrutinib, ibrutinib, and zanubrutinib are discussed above. (See 'No prior Bruton tyrosine kinase inhibitor' above.)

Pirtobrutinib – Administration, toxicity, outcomes, and approval by the FDA for pirtobrutinib are discussed above. (See 'Less fit' above.)

Lenalidomide — Administration, toxicity, outcomes, and approval by the FDA and the EMA for lenalidomide are discussed above. (See 'Prior Bruton tyrosine kinase inhibitor treatment' above.)

Other systemic therapy — There are limited roles for other agents in patients with relapsed or refractory (r/r) MCL.

Venetoclax — Venetoclax is an orally administered B cell leukemia/lymphoma 2 (BCL2) inhibitor with modest activity in r/r MCL, but there are limited outcomes data in patients who received venetoclax after prior treatment with a Bruton tyrosine kinase inhibitor (BTKi).

AdministrationVenetoclax is taken by mouth at doses up to 400 mg daily. Because of the risk of tumor lysis syndrome (TLS), we generally initiate treatment at 20 mg daily for one week and gradually escalate to the target dose of 400 mg daily over five weeks. However, more rapid dose escalation with inpatient monitoring may be considered for patients with highly proliferative disease [45]. 

Patients should be instructed to not chew, crush, or break tablets.

Venetoclax is not approved by the FDA or the EMA for r/r MCL.

Toxicity – Adverse effects (AEs) include hematologic and gastrointestinal toxicity, increased risk for infections, and possible TLS.

OutcomesVenetoclax has been used as monotherapy and in combination with other agents for r/r MCL.

A retrospective study of 81 patients with r/r MCL reported that venetoclax monotherapy or venetoclax plus either a BTKi or a monoclonal antibody was associated with a 42 percent overall response rate (ORR), but the median progression-free survival (PFS) was only four months; 91 percent of patients had received prior BTKi treatment [46].

A series of 24 patients with r/r MCL (two-thirds of whom had progressed on a BTKi) reported that venetoclax salvage was associated with a 14-month overall survival (OS), eight-month PFS, and 50 percent ORR (including 21 percent CR); one-half of the patients received venetoclax monotherapy, while others received venetoclax in combination with chemotherapy, BTKi, or obinutuzumab [47].

Treatment with venetoclax, ibrutinib, and obinutuzumab in 15 patients (including r/r MCL and treatment-naïve MCL) reported 100 percent one-year OS, 93 percent one-year PFS, and 86 percent ORR (including undetectable measurable residual disease [MRD] in two-thirds of patients) [48]. Grade ≥3 neutropenia was reported in 20 percent of patients.

Treatment of 20 patients with venetoclax after prior BTKi treatment reported a nine-month median OS, three-month median PFS, and 53 percent ORR (including an 18 percent complete response [CR]) with an eight-month median duration of response (DOR) [49]. There were three cases of grade 3 pneumonia, one case of grade 4 sepsis, and no cases of TLS.

A phase 1 study reported a 75 percent ORR (including a 21 percent CR) among 28 patients with MCL who had not received prior BTKi treatment [50].

Bortezomib — Bortezomib is a proteasome inhibitor that is approved by the FDA for treatment of MCL.

AdministrationBortezomib is given 1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle, either as a 3 to 5 second bolus intravenous injection or by subcutaneous injection.

A lower starting dose should be given for patients with moderate or severe hepatic impairment.

Details of administration, monitoring, and management of toxicity are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)

ToxicityBortezomib is associated with increased risk for infections (including reactivation of herpes zoster), neuropathy, cardiovascular events, and rare episodes of thrombotic microangiopathy, reversible posterior leukoencephalopathy syndrome, and progressive multifocal leukoencephalopathy.

High rates of toxicity, including peripheral neuropathy, were reported when bortezomib is combined with rituximab [51-53].

Outcomes

In a phase 2 study (PINNACLE) of 152 patients, bortezomib was associated with a 33 percent ORR (including an 8 percent CR) and nine-month median DOR; the median time to progression was six months [54]. With longer follow-up, the median OS was 24 months; in patients with responding disease the median OS was 35 months [55].

In a phase 3 trial for patients with r/r MCL, compared with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), bortezomib plus CHOP achieved a higher ORR (83 versus 48 percent), CR (35 versus 22 percent), and a longer median OS (36 versus 12 months) [56]. There was a higher incidence of grade ≥3 neutropenia (30 versus 20 percent), febrile neutropenia (20 versus 13 percent), and infections (39 versus 17 percent) in patients receiving bortezomib.

Other studies have also reported outcomes with bortezomib alone or combined with other agents, including rituximab, lenalidomide, and/or dexamethasone [51,52,57-64].

Temsirolimus — Temsirolimus is active for r/r MCL, but it was inferior to ibrutinib in a phase 3 trial, as described above. (See 'No prior Bruton tyrosine kinase inhibitor' above.)

Temsirolimus 175 mg weekly for three weeks followed by either 75 or 25 mg weekly achieved superior PFS and ORR compared with the investigator's choice of therapy but was associated with substantial cytopenias and asthenia in a phase 3 trial [65]. Temsirolimus was associated with inferior PFS, a trend toward inferior OS, and worse toxicity when compared with ibrutinib in another randomized trial, as described above [13,14]. (See 'No prior Bruton tyrosine kinase inhibitor' above.)

Temsirolimus is approved by the EMA for the treatment of r/r MCL.

Bendamustine — Bendamustine plus rituximab is efficacious and well tolerated in patients who were not previously treated with bendamustine.

Administration – Administration and toxicity of bendamustine are described separately. (See "Mantle cell lymphoma: Initial management", section on 'Rituximab-bendamustine (R-B)'.)

Outcomes – Following are studies with bendamustine-based therapy for r/r MCL.

Bendamustine plus rituximab was superior to fludarabine plus rituximab in a phase 3 trial of 219 patients with r/r MCL or indolent lymphomas [66]. With a median follow-up of eight years, bendamustine plus rituximab achieved superior OS (110 versus 49 months; hazard ratio [HR] 0.64 [95% CI 0.45-0.91]), median PFS (34 versus 12 months; HR 0.54 [95% CI 0.38-0.72]), ORR (82 versus 51 percent), and CR (40 versus 17 percent). Subset analysis confirmed superior median PFS among the 47 patients with MCL (18 versus 5 months; HR 0.45 [95% CI 0.22-0.76]).

Treatment with rituximab, bendamustine, and cytarabine in patients with prior BTKi treatment reported an 83 percent ORR and 10-month median PFS, but more than one-half of patients required dose reductions due to toxicity [67].

Treatment using bendamustine in 45 patients (with a median of two prior therapies) reported 55 percent three-year OS, 82 percent ORR (including a 40 percent CR) with a median DOR of 1.6 years [68]. The ORR was 82 percent (including a 40 percent CR) with a median DOR of 1.6 years.

A phase 2 study that included 18 patients with MCL reported that bendamustine, mitoxantrone, and rituximab were associated with a 78 percent ORR (including a 33 percent CR) [69]. The two-year OS was 60 percent and median PFS was 21 months.

Other management — Intensive chemotherapy has a limited role for management of r/r MCL, while monoclonal antibodies and radiation therapy can provide symptom relief in selected circumstances.

Intensive chemotherapy – More intensive chemoimmunotherapy can achieve a response in patients with r/r MCL, but relapses are common, and toxicity can be substantial in heavily pretreated patients. As a result, we generally restrict such treatments to patients who require a bridge to control disease prior to allogeneic hematopoietic cell transplantation.

Examples of regimens that have been used include R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone) [70] or gemcitabine, rituximab, plus a platin (eg, cisplatin [R-GDP] or oxaliplatin [R-GemOx]) [71,72].

Rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with rituximab plus methotrexate and cytarabine in 29 patients with r/r MCL reported an 11-month median failure-free survival and 93 percent ORR (including a 45 percent CR) [73]. Grade ≥3 AEs included neutropenia (74 percent), thrombocytopenia (63 percent), and febrile neutropenia (11 percent).

Monoclonal antibodies – CD20-directed monoclonal antibodies have modest activity as single agents for r/r MCL.

Rituximab – A prospective study of rituximab monotherapy in 28 patients with r/r MCL reported 37 percent ORR, 14 percent CR, and 1.2-year median DOR [74].

Obinutuzumab – A phase 2 study of the humanized anti-CD20 monoclonal antibody, obinutuzumab, in 40 patients with r/r MCL or diffuse large B cell lymphoma reported 30 percent ORR (including 13 percent CR), with a 10-month median DOR; infusion reactions were seen in 75 percent and were severe in 8 percent [75].

Radiation therapy – Radiation therapy can control local disease in patients with chemotherapy-refractory disease [76-78].

For older or less-fit patients with limited relapse (ie, stage I), radiation therapy alone can provide effective, temporary symptom relief.

CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY — Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy can achieve a robust response of relapsed or refractory (r/r) MCL in most patients, but it is associated with severe and potentially life-threatening toxicity.

Administration, toxicity, outcomes, and approval of CAR-T cell therapy for r/r MCL are presented above. (See 'Medically fit' above.)

ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION — Allogeneic hematopoietic cell transplantation is generally restricted to fit patients ≤70 years who seek consolidation after a robust response to fourth-line therapy (ie, treatment for third or later relapse), as described above. (See 'Consolidation with allogeneic hematopoietic cell transplantation' above.)  

PROGNOSIS — Outcomes for patients with relapsed or refractory (r/r) MCL are associated with clinical characteristics (eg, duration of initial response, number of prior relapses) and certain pathologic features.

These prognostic factors apply for patients treated with Bruton tyrosine kinase inhibitors (BTKi) and chemoimmunotherapy, but it is uncertain at present if they apply to patients treated with immunotherapy, such as chimeric antigen receptor (CAR)-T cell therapy.

Clinical features

Duration of complete response – Early relapse (ie, <24 months after initial treatment) was associated with inferior overall survival (OS) in retrospective studies of patients with r/r MCL [79,80].

Number of prior relapses – Disease progression after ≥2 lines of therapy is associated with a shortened time to subsequent relapse [43,79,81].

MCL International Prognostic Index score – The MCL International Prognostic Index (MIPI) is a validated risk score based upon clinical variables at diagnosis, including age, performance status, lactate dehydrogenase (LDH), and white blood cell (WBC) count [82-85], that provides prognostic information for patients with r/r MCL, including patients treated with a BTKi [10,81,86].

Pathologic features

Morphology – The blastoid and pleomorphic histologic variants of MCL are associated with high-risk disease [10,87], while patients with transformed MCL are at highest risk for poor outcomes [88].

Proliferative rate – Ki67 immunostaining has been identified as a high-risk prognostic factor in r/r MCL [8,16].

Mutation statusTP53 mutations, which are often associated with a high proliferative rate, were associated with inferior outcomes in multiple studies [5,8,89-93]. Mutations in NOTCH1, NOTCH2, and KMT2D and mutations or copy number loss of CDKN2A have also been associated with adverse prognosis [89,90,94].

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).

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

SUMMARY AND RECOMMENDATIONS

Description – Mantle cell lymphoma (MCL) that relapses after prior complete response (CR) or does not achieve CR with initial therapy (primary refractory disease) carries an adverse prognosis.

Evaluation and diagnosis – Clinical and laboratory evaluation, staging, fitness, and prognostic features are determined before treatment for relapsed or refractory (r/r) MCL. (See 'Evaluation' above.)

Most cases of primary refractory MCL and first relapse require pathologic confirmation, but a biopsy may not be required for subsequent relapses, as discussed above. (See 'Diagnosis' above.)

First relapse or primary refractory MCL – Management is stratified according to prior treatment with a Bruton tyrosine kinase inhibitor (BTKi):

No prior Bruton tyrosine kinase inhibitor – For first relapse of MCL or primary refractory disease in a BTKi-naïve patient, we suggest acalabrutinib or zanubrutinib rather than other treatments (Grade 2C). (See 'No prior Bruton tyrosine kinase inhibitor' above.)

Ibrutinib is acceptable when the other BTKis are not available.

Prior Bruton tyrosine kinase inhibitor or contraindication to Bruton tyrosine kinase inhibitor – Guided by the interval since the last BTKi treatment (see 'Prior Bruton tyrosine kinase inhibitor treatment' above):

-For patients in whom prior BTKi was remote (>1 year since exposure), we suggest salvage therapy with a BTKi (Grade 2C). (See 'No prior Bruton tyrosine kinase inhibitor' above.)

-For primary refractory MCL or relapse ≤1 year since exposure, we suggest lenalidomide (Grade 2C). (See 'Second relapse' above.)

Other acceptable options include chimeric antigen receptor (CAR)-T cell therapy, pirtobrutinib, or venetoclax, but these lack regulatory approval for first relapse or primary refractory disease.

Monitoring – The patient should be clinically monitored for disease progression/relapse during and after salvage therapy. (See 'Monitoring' above.)

Second relapse – For patients with second relapse of MCL, management is stratified by medical fitness:

Medically fit – For second relapse and for patients who did not achieve CR with salvage therapy, we suggest CAR-T cell therapy using brexucabtagene autoleucel rather than other treatments (Grade 2C). (See 'Medically fit' above.)

Less fit – For patients who are not eligible for CAR-T cell therapy, we suggest pirtobrutinib rather than other treatments (Grade 2C). (See 'Less fit' above.)

Subsequent relapses – There is no consensus for subsequent relapses. (See 'Subsequent relapses' above.)

Salvage therapy – Successive treatment with different agents is often most effective for symptom management, disease control, and prolongation of survival. (See 'Salvage therapy for third or later relapse' above.)

Consolidation therapy – Allogeneic hematopoietic cell transplantation (HCT) can be considered for consolidation therapy in selected transplant-eligible patients with a robust response to salvage therapy for multiply relapsed MCL. (See 'Consolidation with allogeneic hematopoietic cell transplantation' above.)

Frail patients – Guided by symptoms, sites of relapse, and patient preference. (See 'Frail patients' above.)

Treatments – Management and outcomes are discussed:

Bruton tyrosine kinase inhibitors.

-Acalabrutinib, ibrutinib, zanubrutinib (see 'No prior Bruton tyrosine kinase inhibitor' above).

-Pirtobrutinib (see 'Subsequent relapses' above).

Lenalidomide (see 'Prior Bruton tyrosine kinase inhibitor treatment' above).

Venetoclax (see 'Venetoclax' above).

Bortezomib (see 'Bortezomib' above).

Temsirolimus (see 'Temsirolimus' above).

Bendamustine (see 'Bendamustine' above).

Other approaches – More intensive combination chemotherapy, single-agent monoclonal antibodies, and radiation therapy have limited roles for management of r/r MCL. (See 'Other management' above.)

Chimeric antigen receptor T cell therapy – Administration, toxicity, and outcomes with CAR-T cell therapy are discussed above. (See 'Medically fit' above.)

Allogeneic hematopoietic cell transplantation – Roles for allogeneic HCT are discussed above. (See 'Allogeneic hematopoietic cell transplantation' above.)

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Topic 4735 Version 61.0

References

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