Diffuse large b cell lymphoma (BSH 2016)
MYC, BCL2, BCL6, TP53, MYD88, EZH2 mutations/translocations
Most common haematological malignancy
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)
‘Double Hit’Lymphoma (& MYC Re-arrangements)
In 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), but evidence supporting this has limitations. Age and fitness still more important.
The MYC translocation partner is also important. Translocation with an immunoglobulin gene partner (MYC/Ig) has a worse prognosis than MYC/Non-Ig.
These tests can all be performed by FISH in most labs, in contrast to molecular tests below.
Double hit vs double expressor.
Double expression refers to MYC & BCL protein expression on histopathology stains and does not correlate with double hit cytogenetics. Double expression seen in 1/3 of patients and should probably be ignored prognostically.
Molecular Subtyping of DLBCL
ABC vs GCB
Gene Expression Profiling (GEP) used to identify ABC (Activated B Cell) and GCB (Germinal Centre B cell) molecular subtypes of DLBC early 2000’s.
ABC DLBCL has been associated with a poor prognosis, though this may be partly explained by 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.
New molecular Subtypes (Staudt et al 2018 among others)
Exome sequencing has identified large numbers of genes involved in the pathogenesis of DLBCL. Six distinct groups or ‘clusters’ of mutations have been found to correlate to prognosis and behaviour of the disease resulting in the following categories.
These subtypes still broadly correlate with the ABC/GCB categorization but added further detail.
No consensus on terminology yet - e.g. other research groups have found similar results but categorized as clusters 1-6.
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
Performance Status >2
Ann Arbor Stage >3
>2 Extranodal sites of disease
Score 0-1, 3yr OS 91%
Score 4-5, 3yr OS 59%
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, but 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
Tisagenlecleucel - NICE recommended (via cancer drug fund) after 2 or more prior therapies (Mar 2019)
Assessing Treatment Response
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