Mantle Cell Lymphoma

Lead: Irina Amitai/Rena Buckstein

Terms of use:

These guidelines are a statement of consensus of the OCC Hematology site group regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. Use of this site and any information on it is at your own risk.

Diagnosis and pathologic classification:

Mantle cell lymphoma (MCL) comprises about 3% to 10% of adult-onset NHL in western countries, and its incidence is rising. Median age at initial presentation is 68y. It is defined by the translocation (11;14)(q13;q32) resulting in constitutive overexpression of cyclin D1.

The morphology can range from small, more irregular lymphocytes (mimicking the centrocytes or small cleaved cells of follicular lymphoma) to lymphoblast-like cells (in the blastoid variant), and occasionally to mixtures of small and large cells or markedly atypical large cells (in the pleomorphic variant).

Most patients with MCL present with advanced stage disease at diagnosis (70%). 25% present with extranodal disease.

Note: Cyclin D1‐negative MCL is a rare but well recognized entity, with genuine cyclin D1‐negative cases of MCL lacking the IGH/CCND1 rearrangement, but cytomorphology, immunophenotype (other than cyclin D1 negativity) and a clinical course identical to cases of classical MCL. The lymphoma is characterized by a rearrangement of CCND2 in 55% of cases (Salaverria et al, 2013). Some cases involve CCND3. SOX11 is expressed within the nucleus of almost all cyclin D1‐negative cases enabling this entity to be reliably identified.

Recently, MCL has been categorized into two major subgroups (each evolving from a different cellular origin), included in the WHO 2016 update of lymphoid malignancies:
- Nodal MCL – the common variant, usually with an aggressive disease course. These patients exhibit unmutated IGHV gene rearrangement, SOX-11 overexpression, a higher degree of genomic instability (ATM, CDKN2A, chromatin modifier mutations are common).
- Leukemic non-nodal MCL – seen in 10% to 20% MCL patients. It commonly presents with lymphocytosis and splenomegaly. Generally associated with indolent disease course and superior outcome. They have a clinical picture similar to CLL, and may exhibit aberrant immunophenotype (CD200 expression, loss of CD5). However, they may acquire secondary abnormalities (e.g. TP53 mutations) that lead to a very aggressive course.
Baseline testing:
- Full history and physical including performance status/frailty index and documentation of B symptoms.
- CBC, Albumin, LDH, LFTs (Bilirubin, ALT, ALP), creatinine
- β2 microglobulin
- serum immunoglobulin levels
- Hepatitis B (including core antibody) & C screening and HIV serology
- CT head, neck, chest abdomen & pelvis
- Bone marrow aspiration/biopsy at initial diagnosis (The majority of MCL cases co‐express CD20, CD5, BCL2, cyclin D1 and SOX11 and are usually negative for CD10, BCL6 and CD23, but an aberrant immunophenotype, such as CD5 negativity or expression of CD10, BCL6 or CD23, occurs in 5–18% of cases). BM may be omitted in the presence of peripheral blood involvement.
- TB skin test
- Pathology review if not reported at Sunnybrook or UHN (mandatory to obtain the Ki-67% of MCL cells from the involved non-marrow tissue biopsies for prognostic purposes)
- TP53 sequencing (when intensive chemotherapy and auto-SCT planned since they may not benefit)
- IHC for SOX-11 and IGHV sequencing (SOX11 should be added in all cases of CD5‐positive/cyclin D1‐negative B‐cell lymphoma).
- Lumbar puncture (LP) with cytospin and immunophenotyping in blastoid/pleomorphic variant and those withCNS symptoms. Consider also in cases with high Ki-67%.
- Additional tests – based on clinical presentation.
- Colonoscopy and other endoscopy should be performed for clinical indications, or if radiotherapy for stage IA disease is considered (essential to confirm stage I-II disease, where endoscopy is performed, biopsies of any suspicious lesions, and also macroscopically normal areas, should be taken for histological examination).
- Assessment of heart function (MUGA/echo) (depending on clinical presentation and planned anthracycline-based protocol)
- Discuss sperm banking/fertility preservation
- PET: MCL is an FDG-avid lymphoma with high sensitivity of PET imaging for detecting disease involvement, but data on the role of PET in its management is scarce and controversial. PET scan may be considered in selected patients where it may alter treatment (i.e. in the <5% cases that seem to be very early stage, to rule out more advanced disease).

Staging and prognostic factors:

Patients should be staged according to the Ann Arbor staging system:

Stage

Single lymph node region (1) or single localized extranodal site (1E).
Two or more lymph node regions, same side of the diaphragm (2) or local extranodal involvement in two or more regions, same side of the diaphragm (2E).
Lymph node regions on both sides of the diaphragm (3) which may be accompanied by local extranodal extension (3E).
Diffuse involvement of one or more extranodal organs or sites (by convention, involvement of the bone marrow, liver, pleura, and cerebrospinal fluid are always considered Stage IV even if the disease is isolated to that organ).

Bulky tumour is defined as a single mass of tumour tissue 10 cm or larger in largest diameter.

A	No symptoms.
B	Fever (temperature >38.0ºC), drenching night sweats, unexplained loss of >10% of body weight within the preceding 6 months.
E	Involvement of a single extranodal site that is contiguous or proximal to the known nodal site.
S	Splenic involvement.

Several conventional prognostic factors are well established in patients with MCL who are treated with chemo-immunotherapies.
These include the MIPI risk score and simplified MIPI score (performance status, age, LDH levels > upper limit of normal, and white blood cell count), which divides the patients into low-, intermediate-, and high-risk categories.

Simplified MIPI score:

Points	Age (years)	ECOG	LDH (ULN)	WBC (10⁹/1)
0	<50	0-1	<0.67	<6.700
1	50-59	–	<0.67-0.99	6700-9.999
2	60-69	2-4	1.00-1.49	10,000-14,999
3	>70	–	>1.50	>15,000

For each prognostic factor, 0–3 points are given and the points are summed up to a maximum of 11. 0–3 points = low risk (med OS not reached)
4–5 points = intermediate risk (med OS 51mo)
6–11 points = high risk (med OS 29mo)

Biologic MIPI or c-MIPI: adding the Ki-67% (obtained from lymphoma-rich areas on non-bone-marrow involved tissue biopsies) to the simplified MIPI risk score is more discriminatory, providing a better prognostic value (low and intermediate MIPI scores are not well separated). Generally, a Ki-67% >30% is considered to be the high-risk category. C-MIPI defines 4 risk groups with 5-year OS ranging from 17% to 85%.

All patients should have their simplified or combined MCL international prognostic index (sMIPI or MIPI‐c, respectively) score recorded at baseline (MIPI score has not been prospectively studied to drive therapeutic decisions, and its relevance to novel therapies is unknown.

Hoster E, Dreyling, M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced mantle cell lymphoma. Blood. 2008;111:558–565.

MIPI risk score (QxMD)

Other poor prognostic factors include:

Blastoid and pleomorphic cytomorphology (aggressive clinical course, refractoriness to treatment and short survival)
Elevated absolute monocytic count (AMC)
Elevated Beta2 microglobulin (≥3.5)
SOX-11 expression and IGHV unmutated status: Clinically, low SOX11 expression correlates with a more indolent and non-nodal leukemic phase presentation, whereas increased SOX11 expression portends a more aggressive phenotype with nodal and extra-nodal sites of involvement. in a subset of patients with leukemic non-nodal presentation, negative SOX-11 with mutated IGHV identify a subset of patients with a favorable prognosis.
TP53- mutation (occur in approximately 10% of newly diagnosed cases)
complex karyotype, defined as having three or more chromosomal abnormalities in addition to t(11;14).
9p21 deletion (CDKN2A)

Treatment:

MCL is a rare disease and most of the available information is based on small phase II trials with historical controls.MCL is responsive to a variety of conventional chemotherapy regimens, but the remissions achieved are relatively short (median duration of remission in most previous trials was 1.5–3 years and the median OS was 3–6 years with standard chemotherapy). However, there is a wide variation in outcome.

Asymptomatic low MIPI MCL patients:

A watch-and-wait strategy is appropriate for a subset of patients (the so-called “smoldering MCL”: asymptomatic with good performance status, no B symptoms, normal LDH levels, non-bulky disease, low Ki-67%, and nonaggressive cytomorphology).

Patients with conﬁrmed early-stage MCL (stage 1A or 2A):

involved ﬁeld radiotherapy is recommended

Recommendations for Young (Age ≤ 70y) fit patients
- R-CHOP/R-DHAP (six alternating cycles of R-CHOP or R-DHAP every 3 weeks (stem-cell collection after the third cycle of R-DHAP)
- auto-SCT in CR1 (shown to prolong PFS and OS in retrospective studies and 1 RCT in the R era)
- Rituximab maintenance post auto-SCT (significantly prolongs PFS and OS)
Recommendation for age > 70 or those unfit for ASCT (any age)
- Bendamustine-Rituximab (BR) x 6 cycles (every 28 days) (higher PFS and TTNT compared with R-CHOP)
- Other possible regimens in selected cases(Note funding may not be available for all agents):
  - R-CHOP x 6 cycles or R-CVP x6 cycles
  - RBAC500 x 6 cycles (rituximab 375 mg/m² on day 1, bendamustine 70 mg/m² on days 2 and 3, and cytarabine 500 mg/m² on days 2–4; in phase II, 57 pts, 2-year PFS of 81%)
  - Lenalidomide-R (in phase 2, 38 pts, achieved 3-year PFS 80%, and 3-year OS 90%)
  - Bortezomib + R-CHP (“VR-CAP”) (OS benefit compared with R-CHOP in RCT 487 pts: med OS 90.7 vs 55.7mo)
- Rituximab maintenance x 2 years
Supportive/Ancillary treatment:
- Allopurinol 300 mg daily x 7 days starting D-1 for cycle 1 only
- Response assessment: According to Lugano criteria.
- G-CSF given for primary prophylaxis per NCCN guidelines.
- Febrile neutropenia should be managed following Febrile neutropenia guideline.
Transfusion Considerations:
The following patients require irradiated red blood cells and platelets and notification to the Blood Bank:
- Autologous stem cell transplant recipient starting 7 days before stem cell harvest and for 1 year after transplant.
- Prior or current treatment with a purine analog (fludarabine, cladribine, clofarabine, nelarabine, pentostatin), anti-thymocyte globulin (ATG), alemtuzumab or bendamustine for 1 year after last dose.
- Allogeneic stem-cell transplant recipient starting at time of conditioning regimen.
- See Sunnynet's Special Blood internal page.
Follow-up:
- Follow-up visits every 3 months for first 2 years, every 3-6 mo x 3 years, then annually or as clinically indicated.
- At each visit: history and physical exam, CBC, LDH, Cr.
  Surveillance imaging will be driven by clinical picture and age, receipt of ASCT – not more than once q6mo in first 2 years and then not more than 1/year.
- Counselling on physical and psychosocial issues, smoking cessation, age-appropriate cancer screening, immunizations
Second line:

Despite high response rates and improvement in PFS with current frontline approaches, patients will inevitably relapse.

The presence of MRD defined by individualized RT-PCR primers to detect clonal IgH rearrangements in the bone marrow or peripheral blood is associated with an increased risk of relapse post stem cell transplant (142 vs 35 months) However, there is currently no wide-scale approach for measuring MRD in large numbers of patients, and these methods will require validation across more institutions.

In general, if 1^st line (chemoimmunotherapy) achieved extended response ³24 months), then repeated chemoimmunotherapy (same or different regimen) may be considered. If the previous PFS was short, novel agents are preferred.
- BTK-inhibitor (Ibrutinib 560mg QD or acalabrutinib 100mg BID)
  - Patients receiving ibrutinib at first relapse had an ORR ~ 68%, median PFS of 33.6 months, with 1.5 OS 58%, and a median DOR of 34.4 months)
  - Acalabrutininb with lower rates of atrial fibrillation
  - All BTK inhibitors are considered equal in terms of efficacy
- Other options to be considered in selected cases (note funding may not be available for all agents):
  - Ibrutininb + venetoclax
  - Other FDA approved single agents include: bortezomib, lenalidomide, and temsirolimus (compared to IBR, all show lower responses and response durations, providing limited utility as single agents)
A summary of potential regimens with their response rates in this scenario is available in Table 2.

Beyond second line:
- Venetoclax (single agent)
- Ibrutininb + venetoclax
- R-LEN; BR/RBAC; RCHOP; GemOx-R; various bortezomib combinations
- PEPC (prednisone, etoposide, procarbazine, cyclophosphamide) +/- rituximab
- Allo-SCT (as 2nd line consolidation in younger patients who have relapsed post ASCT) may provide cure in some patients but with a high TRM.
- Blinatumomab CD19/CD3 BiTE
- CAR-T (67% CR rate in heavily pretreated patients (all previously exposed to IBR) 1y PFS 61%, n=68) - awaiting FDA approval.
Useful resources

Patient regimen information:

Key references:

Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130(17):1903–10.
Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL younger): a randomised, open-label, phase 3 trial of the European mantle cell lymphoma network. Lancet. 2016; 388(10044):565-575.
Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377(13):1250-1260.
Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab vs CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381 (9873):1203-1210.
Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123(19):2944-2952.
Flinn IW, van der Jagt R, Kahl B, et al. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with Bendamustine plus rituximab vs R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019; JCO1800605.
Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) vs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018;19(11):1449-1458.
LeCase AS, Vandergrift, JL, Rodriguez MA, et al. Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: An analysis form the NCCN NHL Database. Blood. 2012;119:2093–2099.
Ruan J, Martin P, Christos P, Cerchietti L, Tam W, Shah B, Schuster SJ, Rodriguez A, Hyman D, Calvo-Vidal MN, Smith SM, Svoboda J, Furman RR, Coleman M, Leonard JP. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018 Nov 8;132(19):2016-2025.
Hoster E, Kluin-Nelemans H, Hermine O, et al. Rituximab maintenance after first-line immunochemotherapy in mantle cell lymphoma: long-term follow-up of the randomized European MCL Elderly. Blood. 2017;130:153
Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017;4(1):e15-e23.Gerson JN, Barta SK, Villa D, et al. Consolidation with autologous hematopoietic cell transplant in first remission improves overall survival in younger patients with mantle cell lymphoma in the rituximab era [abstract]. Blood. 2017;130(suppl 1). Abstract 341.
Kolstad A, Pedersen LB, Eskelund CW, et al. : Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years. Biol Blood Marrow Transplant. 2017;23(3):428–35.
Rule S, Jurczak W, Jerkeman M, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Thieblemont C, Zhou W, Henninger T, Goldberg J, Vermeulen J, Dreyling M. Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia. 2018 Aug;32(8):1799-1803.
O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018 Apr 26;131(17):1910-1919. doi: 10.1182/blood-2017-10-810044. Epub 2018 Feb 2. PMID: 29437592; PMCID: PMC5921964.
Wang M, Rule S, Zinzani PL, et al. : Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659–67.
Tam CS, Anderson MA, Pott C, Agarwal R, Handunnetti S, Hicks RJ, Burbury K, Turner G, Di Iulio J, Bressel M, Westerman D, Lade S, Dreyling M Dawson SJ, Dawson MA, Seymour JF, Roberts AW. Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N Engl J Med. 2018 Mar 29;378(13):1211-1223.
Krüger WH, Hirt C, Basara N, et al. : Allogeneic stem cell transplantation for mantle cell lymphoma--final report from the prospective trials of the East German Study Group Haematology/Oncology (OSHO).Ann Hematol. 2014;93(9):1587–97.
Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020;382(14):1331-1342.

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Mantle Cell Lymphoma

Terms of use:

Diagnosis and pathologic classification:

Baseline testing:

Staging and prognostic factors:

Treatment:

Useful resources

Key references: