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large b cell lymphomas (bsh 2024)

CD10+, CD20+

CD5 –

MYC, BCL2, BCL6, TP53, MYD88, EZH2 mutations/translocations

Intro

Most common haematological malignancy

30-60% of all non-Hodgkin lymphomas

WHO-HAEM5 Classification

DLBCL, NOS (within this, GCB vs Non-GCB / ABC)

DLBCL/HGBL with MYC and BCL2 rearrangement (“Double Hit”)

Burkitt Lymphoma (wihtin this, EBV+ vs EBV-)

HGBL, NOS - aggressive mature B-cell lymhpomas not fitting other groups.

LBCL of immune-privileged sites - new umbrella for primary CNS/occular/testicular lymphomas

Immune deficiency/dysregulation-associated lymphomas - new umbrella for lymphomas associated with HIV, primary immunodeficiencies, post-transplantation, iatrogenic immunodeficiencies. The nomenclature is a three step combo of histology + viral association + type of immune deficiency. e.g. PTLD

Primary mediastinal large B-cell lymphoma (PMBCL)

Mediastinal grey zone lymphoma - overlap between PMBL and Classical Hodgkin

Fluid-overload associated LBL - elderly, no underlying immunocompromise, presenting exclusively with involvement of body cavities (e.g. pleura). Usually with PMH of fluid overloading conditions (HF, ESRF etc). Favoruable prognosis.

T-cell/histiocyte-rich LBL

ALK+ LBL

LBL with IRF4 rearrangement

Lymphomatoid granulomatosis

EBV+ DLBCL

DLBCL asscoaited with chronic inflammation

Plasmablastic lymphoma

Primary cutaneous DLBLC, leg type

Intravascular LBL

KSHV/HHV8-asscoiated B-cell lymphoid proliferations and lymphomas

HGBL with 11q aberration - aggressive Burkitt-like lymphoma without the MYC rearrangement

Pathology

‘Double Hit’ Lymphoma (& MYC Re-arrangements)

• In WHO-HAEM5 = HG Lymphoma with MYC & BCL2 rearrangement

• But other MYC partners can be important, e.g. 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 (see bottom of page!). 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

GCB vs ABC/Non-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/Non-GCB 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.

diagnosis/work-up

Baseline Investigations / Work-up

History & Examination - to include assessment of ECOG performance status

Bloods - to include LDH, Urate, Hep B, Hep C, HIV

ECG +/- Echocardiogram

Biopsy - surgical excision or core biopsy (not FNA)

Imaging - PET-CT preferred. PET-CT better than BM biopsy for detecting marrow involvement.

Bone marrow biopsy - only for select cases, e.g. suspected co-existing diagnosis such as MDS

CNS - MRI brain + CSF when CNS involvement suspected (or screen high risk pts, see below)

Fertility - consider need for reproductive counselling +/- fertility preservation procedures

Tumour Lysis - Assess risk and plan prophylaxis

Direct patient to additional source of support/information

Prognosis

General points

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

IPI Score

Calculate IPI for all patients at diagnosis (NCCN-IPI also available)

• Age >60

• Raised LDH

• Performance Status >2

• Ann Arbor Stage >3

• >2 Extranodal sites of disease

Score:

• Score 0-1, 3yr OS 91%

• Score 4-5, 3yr OS 59%

Other important prognostic factors

‘Bulk disease’ (>7.5cm)

‘Double Hit’ (MYC + BCL2 co-translocation. See details above)

Cell of Origin (Germinal Centre (GC) vs less favourable Activated B Cell (ABC))

Gene Expression Profiling (GEP) not currently routine practice in UK (see details above)

first line treatment

Diagnosis and treatment should be discussed by multi-disciplinary team (MDT)

Offer trials where available

Supportive Care

Consider patient’s holistic needs and involve the wide hospital teams as needed.

Osteoporotic Fractures

• Up to 11% incidence of fracture at 18 months for patients >70 with high grade lymphoma

• Assess baseline risk with FRAX score —> consider Vitamin D and Bisphosphonates

Infection

• GCSF for all patients receiving curative-intent treatment

• Consider aciclovir, fluconazole, co-trimoxazole as local policies

Tumour lysis

• Assess TLS risk. See TLS page.

stage I and II disease

Intro

1/3 patients present with early stage disease

Consider bulk as >7.5cm (although it is a spectrum)

A very mixed group of patients, requires individualised treatment discussions

Age 18-60 AND age-adjusted IPI zero AND Non-bulk disease

• R-CHOP x4 with two additional rituximab. No need for RT. (based on FLYER 2019)

Age 61-80 AND age-adjusted IPI zero AND Non-bulk disease

• Interim PET-guided treatment

• PET2 complete response = further 2x R-CHOP

• PET2 non-completed response = further 4x R-CHOP plus 30Gy RT

• (Based on LYSA LNH 09-1B & S1001 2021)

IPI Score 0-1

• 3-4x R-CHOP followed by 30Gy RT

• or 6x R-CHOP without RT if risk/benefit advantage to this

IPI Score 2+

• 6x R-CHOP or 6x R-CHP-Pola

• +/- 30Gy RT depending on baseline factors

Additional radiotherapy candidates

• Consider for R-mini-CHOP, Extra-nodal disease, Bulky disease

Primary Extra-Nodal (EN) Disease

Intro

Area of uncertainty

EN sites associated with inferior outcomes treated as for advanced stage disease

Other EN sites poorly represented in trials

Testicular

• 6x R-CHOP + CNS prophylaxis + Contralateral testicular radiotherapy

Breast

• 6x R-CHOP + CNS prophylaxis + Consolidation radiotherapy

Gastric

• 6x R-CHOP +/- H.pylori eradication

Intravascular

• MRI brain + CSF as baseline to look for CNS involvement

• 6x R-CHOP + CNS prophylaxis

Leg-type cutaneous

• 6x R-CHOP + Consolidation radiotherapy

Bone

• 6x R-CHOP + Consolidation radiotherapy

Early Stage primary EN disease in sites not listed above

• Follow the early stage recommendations above

• Consider R-CHP-Pola for patients with IPI 2-5 and PS 0-2

• Consider CNS prophylaxis as per BSH 2020 below

advanced stage disease

IPI Score 1

• 6x R-CHOP

IPI Score 2-5

• 6x R-CHOP

• or 6x R-CHP-Pola provided PS 0-2 and fit for full-dose chemotherapy

IPI Score 3+ in <50yo with good PS and high CNS risk

• Consider dose-intensive regimens, e.g. R-CODOX-M/R-IVAC

‘Double Hit’ patients

• No consensus

• 6x R-CHOP or 6x R-CHP-Pola or 6x R-DA-EPOCH (see below)

Consolidation Radiotherapy

• No consensus. Patient-by-patient basis

• Start 6-8 weeks after completion of chemotherapy

CNS Prophylaxis?

• See below

Polatuzumab Vedotin

• Pola-R-CHP approved by NICE Jan 2023 for first line use. Pola can cause neuropathy —> omission of vincristine. May be more effective for Non-GC phenotypes. May complicate management of relapse.

• Polatuzumab Vedotin is an antibody-drug conjugate (Anti-CD79b). Phase Ib/II trial in 2020 compared R-Pola-Benda vs R-Benda, found CR/PFS/OS benefit in relapsed setting.

• POLLARIX Trial 2022 - Phase 3, R-CHOP vs Pola-R-CHP for previously untreated, primary DLBCL. >850 patients. 2-yr PFS 76% vs 70%. No difference in 2-yr OS. Heterogenous outcomes in subgroups but study not powered to interrogate this further. Higher rate of febrile neutropenia and diarrhoea vs R-CHOP.

• NEJM 2023 - Review of phase 1,2 and 3 data on Pola. Highly suggestive of significant benefit in non-GC phenotype patients. Mechanism for this not yet fully described.

R-DA-EPOCH

• Alliance 2019 - R-Da-EPOCH vs R-CHOP. No difference in OS or PFS. Sub analysis of high risk patients awaited (as of 2023)

• Leukaemia 2019 - Retrospec. 114 pts. DEL or DHL. R-CHOP vs R-da-EPOCH. After statistically filtering, suggestion of benefit for R-da-EPOCH in younger patients (<65). Proposed due to ability to dose escalate.

• Lancet Haematology 2018 - Phase 2 prospect. 53 pts with MYC-rearrangement. Only 24 DHL. Only 49% high IPI. Median age 61. 2yr EFS 71%, OS 76%.

• Blood 2014 - Retrospect. 300 pts with DHL. Intensive regimens vs R-CHOP. 2yr PFS and OS better with intensive regimens but baseline differences between the two groups not described.

Bortezomib

• REMoDL-B trial

• Bortezomib added to R-CHOP

• Improved PFS in molecular high risk sub-group and improved OS in ABC sub-group

older patients / co-morbidities

Intro

>50% of patients presenting with DLBCL in UK are >70yo

Outcomes are poorer when age / frailty / co-morbidities prevents use of full dose R-CHOP

Historical trials used Old = >60yo. Current trials for older patients use >80yo (e.g. SENIOR)

Holistic care is essential.

Pre-Phase treatment

• Prednisolone 1mg/kg where PS affected by the lymphoma

• Can add vincristine 1mg to the pre-phase

Patient >80 years

• R-mini-CHOP

• Rituximab 375mg/m2, Doxorubicin 25mg/m2, Cyclophosphamide 40mg/m2 and Vincristine 1mg

• SENIOR 2022 - 3yr OS 54% for R-mini-CHOP in >80yo. Steroid pre-phase reduces toxicities.

Non-anthracycline Options

• Include R-Gem-CVP, R-Gem-Ox, R-CEOP - all have similar outcomes in phase 2 trials

Assessing Treatment Response

Intro

End of treatment PET-CT predicts long-term survival, independent of baseline IPI score

But in Blood 2021, 30% of pts not in CMR on EoT PET-CT did not show disease progression, ie. false positives.

Interim PET-CT post 2 cycles (iPET2)

• Change treatment only if no response or progressive disease

• If iPET2 shows CMR, end of treatment imaging can be with conventional CT

• If iPET2 not CMR, then for end of treatment PET-CT

End of Treatment PET-CT

• Timing: 3-6 weeks after the last dose of Rituximab or 12 weeks after radiotherapy completion

• Residual FDG-avid lesions, review at MDT and consider:

  • Biopsy

  • Interval PET-CT in 8-12 weeks

  • Radiotherapy to a single FDG-avid lesion

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

relapse/refractory (bsh 2024 awaited…)

Intro

Aim is to re-attain remission and then proceed to autograft

Position of CAR-T therapy within R/R treatment is currently constantly evolving

Options for 2nd line conventional chemotherapy:

• Clinical trial if available

• R-DHAP / R-ESHAP / R-GDP / R-IVE / R-ICE / R-GemOx

• Choice of regimen dependent on local practice (2019 lit review concluded no diff. between regimens)

Antibody-Drug Conjugates

• Polatuzumab vedotin

  • See details above

  • R-Pola-Benda approved 2nd line onwards for patients not eligible for Autograft (NICE 2020)

• Loncastuximab tersine

  • Anti-CD19 antibody-drug conjugate. SE: Photosensitivity, Oedema.

  • LOTIS-2 2021 - Phase 2 trial. 145 pts. 48% ORR

  • Monotherapy approved 3rd only if already received/contraindicated polatuzumab (NICE 2024)

Bispecific Antibodies - Approved 3rd line in the UK

• Glofitamab - CD3xCD20 - (NICE 2023) (Phase 2, NEJM 2022) (Phase 3, Glofit-Gem-Ox vs R-Gem-Ox underway)

• Epcoritamab - CD3xCD20 - (NICE 2024, published guidance awaited) - subcutaneous admin - (Phase 2, JCO 2022) (Phase 3, Epcorit vs investigators choice underway)

• As with CAR-T, best to avoid bendamustine exposure in 6-12 months prior to bi-specifics

• Combinations being explored, e.g. Glofitamab + Polatuzumab ASH 2023

CAR-T Cells

• Autologous T-cells modified in vitro and then re-infused so as to target tumour cells

• There are different generations of CAR-T in development as the technology progresses, but broadly the CAR-T cells have a new cell surface receptor (the Chimeric Antigen Receptor) that targets the tumour cells (e.g. CD19 for DLBCL) and new internal signalling domains that promote cytotoxic activity when the surface receptor is activated.

• NICE first recommended in 2019 (via cancer drug fund) after 2 or more prior therapies

• Rapidly evolving products / patient eligibility / outcomes

• See this 2020 BMT review paper for a succinct overview of CAR-T in high grade lymphoma

CNS Prophylaxis (BSH 2024)

Intro

~5% of all DLBCL patients treated with R-CHOP relapse in the CNS,

But risk can be 15-30% in high risk subgroups

Usually occurs early post treatment (e.g. median 8.5 months from diagnosis to CNS relapse in GOYA trial).

70-80% of CNS relapses involve the brain parenchyma (i.e. isolated leptomeningeal relapses are a minority)

Prognosis is poor —> median OS <6 months

CNS-IPI Score

One point for each of:

• Age >60

• LDH above upper limit of normal

• Performance Status >1

• Stage III/IV disease

• 2 or more extranodal sites

• Kidney and/or adrenal involvement

It has poor positive and negative predictive values:

• A score of 4-6 (10-20% of all LBCL pts) correlates with a 10% 2-yr CNS relapse rate.

• i.e. although it does identify patients at higher risk it still means that 90% of patients will receive “unnecessary” CNS prophylaxis when using this tool. In addition, 50% of CNS relapses occurs in patients with CNS-IPI <4.

Anatomical & Biological Risk Factors

Anatomical

• Highest risk site is likely testicular involvement, up to 30% CNS relapse risk

• Renal/adrenal involvement has next best evidence as a high risk site

• Other propose high risk sites: Primary breast LBCL, Intravascular lymphoma, 3+ extranodal sites

Biological

• ABC type by gene expression profiling, and MCD / C5 molecular clusters associated with CNS relapse risk although this needs validating in prospective studies

• Double Hit lymphoma is no longer considered a high risk feature

Baseline CNS screening?

• Uniform screening of 500 high risk patients found 11% with baseline CNS disease

• Pts with CNS disease at diagnosis have better out comes than CNS relapse at later date

• Resource implications to uniform screening + potential to delay systemic therapy

• In future, ctDNA of CSF may become clinically useful (research tool at present)

• —> BSH2024 recommends:

  • Consider MRI brain/spine + CSF for high risk patients if achievable w/out delay to systemic chemo

  • High risk = CNS-IPI 5-6, Renal/Adrenal, Testicular, or 3+ EN sites)

High dose Methotrexate (HD-MTX) as CNS Prophylaxis

• Dose: If used, give 3-3.5g/m2, with folinic acid rescue, for 2 cycles

• Dosing rationale: pharmacokinetics suggest dose >3g/m2 needed to treat both parenchyma + CSF

• Toxicity: Need good renal function, CrCl >50ml/min, and good cardiac function due to large vol fluid.

• Timing: If used, give after R-CHOP complete. Retrospective data - no difference in CNS relapse rates in intercalated vs EoT methotrexate. Plus, high rates of delayed R-CHOP in intercalated patients.

• Efficacy: Good summary in the guideline. Overall, very little convincing evidence that it works at all.

Intrathecal Methotrexate (IT-MTX) as CNS Prophylaxis

• Now generally accepted to have a limited role (potential exception for testicular disease)

• 12-15mg x4 during chemotherapy

BSH 2024 Recommends:

• Decisions should involve lymphoma MDT and the patient

• Offer CNS prophylaxis to patients with testicular LBCL using IT-MTX and/or HD-MTX

• Consider CNS prophylaxis for patients with CNS-IPI 5-6, 3+ EN sites, renal/adrenal or breast

• Routine IT-MTX is no longer recommended (except testicular not fit for HD-MTX)

Some of the important papers since 2020:

• Blood 2021 - Retrospective review of 2300 high risk patients. HD MTX did not reduce the rate of CNS relapse in this large retrospective cohort. (CNS relapse rate was 9%)

• Blood Cancer 2021 - Retrospective review of 580 high risk patients. IT MTX showed reduced CNS relapse rate at 1 year (2% vs 7%) but this difference was lost at 5 years (5.6% vs 7%).

• Blood 2022 - Restrospective review of 1400 patients receiving HD MTX. Primary aim of study was to evaluate timeing HD MTX, intercalated vs end of treatment. But it was noted that CNS relapse rates were similar to other cohort studies where less CNS prophylaxis was used.

• Lancet Oncology 2022 - Excellent, detailed review article

• JCO 2023 - Retrospective, observational study of 2400 patients. HD-MTX was not associated with a meaningful reduction in CNS relapse risk.

A few trial notes

POLLARIX Trial 2022

• Phase 3, R-CHOP vs Pola-R-CHP for previously untreated, primary DLBCL.

• >850 patients.

• 2-yr PFS 76% vs 70%.

• No difference in 2-yr OS.

• Heterogenous outcomes in subgroups but study not powered to interrogate this further. Higher rate of febrile neutropenia and diarrhoea vs R-CHOP.

Alliance 2019

• R-da-EPOCH vs R-CHOP for previously untreated DLBCL

• Phase 3, 500 patients

• No difference in PFs or OS. Grade 3-4 AE more common with R-da-EPOCH

• Highest risk DLBCL patients only made up small proportion of patients in trial

GOYA Study 2017

• 1400 patients, previously untreated advanced-stage DLBCL

• R-CHOP vs G-CHOP (G = Obinutuzumab)

• No difference in 3-yr PFS (70 vs 67%). Grade 3-5 sdverse events higher for G-CHOP

• Later retrospective analysis also concludes no benefit for 8x R-CHOP over 6x R-CHOP

CORAL 2010

• 400 patients, 1st relapse after chemo or R-chemo

• R-ICE vs R-DHAP. 3 cycles followed by Autograft

• ORR 63% after chemo (before Autograft)

• 3yr PFS 53% if completed autograft (~50% made it to autograft)

• No difference in ORR or 3yr PFS between the two chemo regimens

• Haem. toxicity more common in R-DHAP group

MInT Trial 2006 (Young patients)

• 6x CHOP-like + Rituximab vs 6x CHOP-like

• >800 pts (18-60yo)

• 3yr EFS 79% vs 59%

• 3yr OS 93% vs 84%