Follicular Lymphoma (FL)

 

CD10+, CD19+, CD20+, BCL2+, BCL6+

CD5-, CD43-

t(14;18) IGH-BCL2 translocation

Pathology

 

Germinal centre B cell is the cell of origin (centrocyte old morphology term)

 

LN Biopsy

Can see the classic morphology even macroscopically.

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Immunophenotype

 

CD10+ (marker of GC when present in mature lymphomas)

CD 19+, CD20+, BCL2+, BCL6+

CD43-

 

Cytogenetics

 

t(14;18) - BCL2-IGH - Almost always present

MLL-2 gene mutated in 90% of FL.

 

t(14;18):

50% of healthy people have circulating t(14;18) cells, but at no increased risk of developing lymphoma. So t(14;18) is a pre-requisite of FL, but is not pathognomonic.

“FL in situ” – may occur in normal patient with circulating t(14;18) cells that happen to be passing through the germinal centre at time of biopsy. Again, no increased risk for developing lymphoma.

 

MLL-2 (Mixed-Lineage Leukaemia) gene:

Gene for histone acetyl. Most frequent mutation seen in FL. Combined with t(14;18) causes FL in mice.

 

Great many other B cell receptor pathway mutations have been identified.

 

Staging

 

PET?

  • FL is PET avid. Upstages many people. Good way to exclude patients from radiotherapy only.

  • Exact role unclear and practice varies but NICE recommends PET-CT prior to stage I/II disease where radiotherapy-only treatment is planned (PET will upstage 10-60% of patients)

BM Biopsy?

  • Not necessarily required – Will it change the management?

 

Prognosis

 

Current generalized OS is 20 years

Progression of Disease at 24 months (‘POD24’) is an important prognostic cut off, high risk group for those with a PFS shorter than 2 years after 1st line therapy.

 

FLIPI – calculate at time of diagnosis

  • Age >60

  • Raised LDH

  • Hb <120g/l

  • Stage III or IV

  • 5 or more nodal areas involved

 

Median PFS based on FLIPI score

  • 0-1      84 months

  • 2          70 months

  • 3-5      42 months

 

Treatment

 

When?

  • Bulk: >5cm? >7cm? >10cm? No single cut, patient-by-patient assessment

  • B Symptoms

  • Cytopenias

  • Organ compromise

  • ‘Growing’ e.g. interval change on repeat CT after 3-6 months

  • (BNLI and GELF both have published ‘criteria to not watch & wait’)

 

What?

  • The only good quality evidence demonstrating an increase in OS is for the addition of Rituximab to Chemotherapy.

  • Most other data refer to PFS, e.g. no change in OS with R-maintenance.

  • Therefore, in young patients the question is not which treatment is best, but rather which order is best

 

Stage 1 (or 2 in a single nodal group)

  • 50% cure rate with full surgical excision or radiotherapy (in UK)

  • Stage 2a treated with ISRT —> 10-yr disease-free survival 50% & only 1% relapse with the radiotherapy field, i.e. curative if truly localised disease.

Stage 2 in different nodal group

  • Unusual scenario, patient-by-patient assessment

 

1st Line in advanced disease

  • Rituximab-Chemo

  • Obinutuzumab-Chemo (Gallium trial)

  • (Not FCR – toxic, too high a TRM rate)

  • (R2 – Rituximab + Lenalidomide – used in USA)

 

Choice of 1st line chemo

  • CHOP – Previous standard of care. TRM 1% in Gallium trial. ?Waste of anthracycline upfront

  • Benda – Probably better PFS & better tolerated during treatment (fewer neutropenic infections than CHOP). But longer term severe infections in 6 months post treatment —> TRM 5% in Gallium (PCP pneumonia)

  • CVP – lower CR rate and shorter PFS

 

Choice of 1st line Anti-CD20

  • Rituximab – standard of care, plenty of historical data

  • Obinutuzumab – Gallium trial. Small but statistically significant increase in PFS (NNT = 25 to delay 2nd line treatment). No difference in OS. More toxic, especially in combo with bendamustine.

 

R-Maintenance post 1st line

  • Every two months for two years.

  • Based on PRIMA trial, which used R-CHOP à Not strictly approved for post R-Benda but we do in East of England.

  • Controversial – medicalizes patients for two years and increases risk of severe infection. Does not alter OS.

 

Autograft?

  • Recommended if relapse within 2 years of 1st line therapy, i.e. POD24

  • May provide 10-15 year remission

 

2nd Line if remission >2 years

  • One of the above that had not been used 1st line

 

3rd Line

  • Clinical trial is first preference.

    • E.g. UNITY – PI3Kdelta/WNT inhibitor / Anti-CD20 / Benda

  • GemCis / DHAP / Bendamustine

  • Not Idelasilib (PI3K delta/gamma inhibitor) – too toxic, CMV/PCP deaths.