CD10 Lymphomas (BSH 2013/2016, ESMO 2015)
Normal B cell biology
BCL2 is a transcription factor promoting proliferation. It is upregulated within the germinal centre
BCL6 is an apoptotic protein, helping cells to die naturally. It is downregulated within the germinal centre.
C-MYC, located on chromosome 8, is a ‘global’ transcription factor with roles in proliferation and cellular growth. Under normal conditions it is able to induce apoptosis.
Most lymphomas are IgM B cells and go through a number of molecular steps to maintain IgM expression, it appears to linked to malignant cell survival.
Hence why IgM MGUS behaves as lymphoplasmacytic lymphoma, where other MGUS moves to myeloma.
Germinal Centre (CD10+) Lymphomas include:
- Burkitts (forced MYC expression with B cell receptor signaling)
MYC, BCL2, BCL6, TP53, MYD88, EZH2 mutations/translocations
30-60% of all non-Hodgkin lymphomas
WHO 2016 Classification:
GCB-Type (EZH2, BCL2, TP53, BCL6)
ABC-type (MYD88, TP53, BCL6)
Burkitt Lymphoma (MYC translocations 8;14, 2;8, 8;22)
High Grade Lymphoma with MYC and BCL2 and/or BCL6 re-arrangements
(Also: LBCL with IFR4 rearrangement, Burkitt-like lymphoma with 11q aberration, High Grade B Cell Lymphoma (HGBL), NOS)
60-70% cure rate in all-comers. Approaching 90% in young, fit patients.
Most relapses occur within 3 years.
Patients who are event-free at 2 years, have an identical OS to the general population
Gene Expression Profiling (GEP) used to identify ABC (Activated B Cell) and GCB (Germinal Centre B cell) molecular subtypes of DLBC around 15 years ago. ABC DLBCL has been associated with a poor prognosis, though this may be due to being found more commonly in elderly patients.
GCB typing by histopathology is not the same as by gene expression and the clinical significance of the former unclear. It may be over-interpretation of the histology.
- WHO 2016 = HG Lymphoma with MYC & BCL2 &/or BCL6 rearrangement
- MYC translocation + one other (BCL2 translocation, BCL6 translocation, TP53 mutation)
- MYC+TP53 appears to have a particularly poor prognosis
- But careful interpretation of prognostic significance of double hit lymphoma is required. Increasing tendency to treat as high risk with alternative regimes (R-CODOX/M-IVAC, R-DA-EPOCH), when actually it is based on small, biased case series – E.g. only the patients doing poorly were getting genotyped and they happened to be double hit, but we don’t know about the rest. Age and fitness still more important.
N.B. beware methodologies of studies. E.g. in US the data supporting R-DA-EPOCH over R-CHOP comes from national studies, which required patients to be fit enough in the first place to travel interstate for appointments.
Double hit vs double expressor.
- Double expression refers to MYC & BCL expression on histopathology stains and does not correlate with double hit cytogenetics. Double expression seen in 1/3 of patients and should be ignored prognostically.
Performance Status >2
Ann Arbor Stage >3
>2 Extranodal sites of disease
Score 0-1, 3yr OS 91%
Score 4-5, 3yr OS 59%
CNS Prophylaxis (BSH 2013)
4% of DLBCL patients treat with R-CHOP will relapse in the CNS
- IT Methotrexate 12-15mg x4 during chemotherapy
- +/- High dose Methotrexate 3-5g/m2 with folinic acid rescue at end of chemotherapy
Evidence is conflicting by BSH guidelines recommend:
CNS-directed therapy should be offered to patients with high grade lymphoma and:
- Either a raised LDH + more than one extra-nodal site of disease (not inc. spleen)
- Or anatomical sites that include testicular, breast or epidural
PET-CT Lugano Classification of visual Deauville criteria:
1 – No uptake
2 – Uptake £ mediastinum
3 – Uptake > mediastinum but £liver
4 – Moderately increased uptake compared with liver
5- Markedly increased uptake compared with liver and/or new lesions
Deauville 1-3 = Complete metabolic response
Deauville 4-5 = Partial response, no response or progressive disease
Burkitt Lymphoma/Leukaemia (BL) (How I treat 2014)
Ki67 >99%, CD10+/-, CD19+, CD20+, CD22+, CD38++, CD81++, CD43+, CD79a+, Ig+, BCL6+
TdT-, CD5-, BCL2-, CD23-
t(8;14) MYC-IGH, t(2;22) MYC-LambdaLC, t(2;8) MYC-KappaLC
Aggressive B-cell non-Hodgkin lymphoma, uniformly associated with MYC translocations.
Doubling time of 25 hours – probably fastest growing of any cancer
- Endemic (African)
- Immunodeficiency-associated (HIV)
Endemic (African) BL
Uniformly EBV positive
3-6 cases per 100,000 children per year in equatorial Africa
Incidence is increasing in line with increasing HIV and malaria
Classically presents with jaw or facial bone tumours
2-3 cases per million per year in Europe
30% of paediatric lymphomas, 1% of adult NHL
Men > Women (4:1)
Occurs independently of CD4 count and so incidence has not fallen with introduction of HARRT.
- Complete effacement of normal tissue architecture
- Medium sized, highly monomorphic cells with round nuclei, prominent nucleoli and basophilic cytoplasm with prominent cytoplasmic lipid vacuoles.
- Interspersed between these cells are benign histiocytes that have become enlarged and irregular due to ingestion of cellular debris à Starry sky appearance
- t(8;14) present in >80% of cases. Brings MYC under the control of IGH enhancer elements à increased MYC expression. Further 15% of cases have other MYC rearrangements.
- Additional mutations – CCND3, TP53, CDKN2A, TCF-3 (E2A), ID3
- EBV mechanism is poorly understood. BL cells express a latent viral protein, EBNA1, which is not known to be directly oncogenic.
Clinical trials – 75-90% OS
Real world data – 56% 5-yr OS
- Tumour lysis syndrome
- Renal impairment
- Blood product support
- Neutropenic sepsis
o 2 cycles each of CODOX-M and IVAC, alternating
o Includes high dose cytarabine and high dose MTX
o ALL regimens
- Autograft in first remission?
o PFS appears to be the same as for aggressive chemotherapy alone
CD10+, CD19+, CD20+, BCL2+, BCL6+
t(14;18) IGH-BCL2 translocation
Germinal centre B cell is the cell of origin (centrocyte old morphology term)
Can see the classic morphology even macroscopically.
CD10+ (marker of GC when present in mature lymphomas)
CD 19+, CD20+, BCL2+, BCL6+
t(14;18) - BCL2-IGH - Almost always present
MLL-2 gene mutated in 90% of FL.
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.
- FL is PET avid. Upstages many people. Good way to exclude patients from radiotherapy only. Exact role unclear and practice varies
- Not necessarily required – Will it change the management?
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
- Bulk: >5cm? >7cm? >10cm? No single cut, patient-by-patient assessment
- B Symptoms
- 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’)
- 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 2 in different nodal group
- Unusual scenario, patient-by-patient assessment
1st Line in advanced disease
- 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 à 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.
- 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
- Clinical trial is first preference.
o E.g. UNITY – PI3Kdelta/WNT inhibitor / Anti-CD20 / Benda
- GemCis / DHAP / Bendamustine
- Not Idelasilib (PI3K delta/gamma inhibitor) – too toxic, CMV/PCP deaths.