t(11;14) --> overexpression of Cyclin D1--> deregulation of cell cycle at G1-S phase boundary
Immunohist: Cyclin D1+, BCL2+, SOX11+, BCL6-
Flow: CD19+, CD20+, CD5+, FMC7+, Surface Ig+, CD10-, CD23-, CD200-
- 3-10% of NHL
- Median aged 60-65 years old
- Male > Female
- Worst features of low and high grade lymphoma. Incurable by standard therapy
- Median survival 4-5 years in all comers (8-12 years in younger, fitter patients)
- CNS relapse occurs in 4-8% - usually leptomeningeal and within 2 years
- >90% present with Stage 3-4 disease
- Splenomegaly, bone marrow infiltration and leukaemic involvement are common
- 30-50% of patients have >2 extranodal sites involved – esp. GI and liver
- Variable clinical course – aggressive blastoid variant or indolent disease
Sample - Excision or core biopsy, or peripheral blood flow if leukaemic
Morphology - Small to intermediate sized cells with irregular, cleaved nuclei
Immunophenotype – see above
Histology – Ki67 proliferation index is a prognostic factor (>30% correlates w/ poor outcomes)
Genetics – t(11;14)(q13;q32), can be detected by FISH
- TP53 mutation predicts a very poor outcome
Aberrant phenotype – many variants including cyclin D1 neg, CD10 pos or CD5 neg
Cyclin D1 Negative MCL – genuine cases do occur, typically will be SOX11+
MCL in situ – syn. Mantle Cell Neoplasia – CD5+, Cyclin D1+ small lymphocytes in the mantle zone of follicles in morphologically reactive lymph nodes. Low risk of progression to clinical disease.
Differential Diagnosis of Cyclin D1+ haem malignancies:
- Hairy Cell Leukaemia
- Diffuse Large B Cell Lymphoma
- FBC, Film, Flow cytometry
- U&E, LFT, LDH
- HIV, Hep C/B (for Rituximab)
- Bone marrow biopsy – may be omitted if periph. blood involvement present. Trephine not required if particulate aspirate for flow.
- +/- CSF flow and morphology
- CT N-P +/- MRI brain if CNS involvement suspected.
- PET-CT not routinely recommended as not shown to upstage patients compared to CT
- Microscopic presence of MCL in GI tract found in 92% of cases
- However, rarely changes management
- Perform upper and lower endoscopy if GI bleeding or Stage 1a disease and curative radiotherapy is being considered.
Prognostic Score – MIPI (Mantle Cell IPI), sMIPI and MIPI-c all provide prognostic information but do not currently affect treatment decisions.
1st Line Management
Lack of definitive data
Enroll in clinical trial where possible
- May be treatable with localized involved field radiotherapy alone (60-80% CR w/ possible cure)
- Include endoscopy in staging investigations if considering RT alone
Stage III/IV, Indolent Disease
- Can W&W closely, defers treatment by median of 12 months
- Indications to treat include: Bulky LN, B symptoms, Symptomatic organomegaly, BM failure
Stage III/IV, Fit
- R-Maxi-CHOP/cytarabine (NORDIC Protocol) --> Autograft in 1st CR
- R-DHAP x4 (LyMa Trial) --> Autograft in 1st CR
- Autograft significantly prolongs PFS, not clear that it improves OS.
- R-maintenance post autograft 2-monthly fpr 3 years
- Proven benefit after R-CHOP / R-DHAP (4-year PFS 85% / OS 89% vs 64/80% w/out)
Stage III/IV, Older/less fit
- Consider using Cumulative Illness Rating Scale (CIRS) to aid assessment of elderly patients
- R-CHOP / R-Bendamustine / VR-CAP
- R-maintenance 2-monthly until progression (funding restricts to a maximum 2 years)
- Proven benefit post R-CHOP with prolonged PFS (and OS in some studies)
- No benefit demonstrated post R-Benda
- Conflicting data on the benefit of CNS prophylaxis. BSH guidelines conclude unable to make a recommendation, but suggest consider its use in young patients with blastoid morphology.
Assessing Treatment Response
Assess response with an end of treatment CT Neck-Pelvis
End of treatment PET-CT may have prognostic significance but does not affect management decisions and so not currently recommended.
Minimal residual disease (MRD) monitoring of t(11;14) by PCR may predict relapse but is not currently in routine use.
2nd line management
Excluding transplant, 1st relapse has median survival of 1-2 years
No standard second line treatment
Fit patients should be considered for RIC allograft in 2nd remission
- Approved by NICE for 2nd line in combination with rituximab (but not 3rd)
- Most active single agent in relapsed MCL – 68% response rate, 21% CR.
- Also shown efficacy in CNS relapse
- 2016 trial ibrutinib vs temsirolimus – ibrutinib showed better PFS, no OS advantage
- R-CHOP / R-Benda / R-BAC, whichever not used previously
- Trial: BTK Inhibitors
- Bortezomib, Temsirolimus & lenalidomide are all licensed for relapsed MCL
- Venetoclax looks active in phase 1 trial
- Autograft prolongs disease response but no significant OS benefit yet shown
- MRD monitoring post-autograft predicts relapse