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 age 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
Excision or core biopsy, or peripheral blood flow if leukaemic
Small to intermediate sized cells with irregular, cleaved nuclei
CD19+, CD20+, CD5+, FMC7+, Surface Ig+
CD10-, CD23-, CD200-
Ki67 proliferation index is a prognostic factor (>30% correlates w/ poor outcomes)
Immunohisto: Cyclin D1+, BCL2+, SOX11+, BCL6-
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.
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 for 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