Mantle Cell Lymphoma (MCL) (BSH 2018 & 2018)

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-

 

Intro

- 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

 

Clinical Presentation

- >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

 

DIAGNOSIS

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

- Myeloma

- Diffuse Large B Cell Lymphoma

 

INVESTIGATIONS

 

Laboratory

- 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

 

Imaging

- CT N-P +/- MRI brain if CNS involvement suspected.

- PET-CT not routinely recommended as not shown to upstage patients compared to CT

 

Endoscopy?

- 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.

 

MANAGEMENT

 

1st Line Management

 

Lack of definitive data

Enroll in clinical trial where possible

 

Stage I/IIa

- 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

 

CNS Prophylaxis?

- 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

 

Ibrutinib

- 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

 

Or

- 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

 

Transplant

- Autograft prolongs disease response but no significant OS benefit yet shown

- MRD monitoring post-autograft predicts relapse