High grade non-hodgkin lymphomas

Dr Catherine OgilvieConsultant Haematologist

Beatson Cancer Centre / Glasgow Royal InfirmaryLymphoma Action MeetingGlasgow, September 2018

Overview

• Lymphoma is a cancer of the lymphatic system; B lymphocytes, T cell lymphocytes and NK cells.

• Occurs when lymphocytes do not die, grow or divide properly due to acquired changes in their genes

• Can occur anywhere in the body

• High grade non-hodgkin lymphoma (NHL) tend to be fast growing

• Need treatment quickly and usually treated with aim to cure

How does lymphoma develop?

• Lymphocytes are always dividing to make new cells to help fight off infection

• Any cells that do not target the infection are not needed and usually die; only the useful lymphocytes survive

• This process is carefully controlled by the body

• Lymphocytes can acquire genetic changes which mean that they no longer respond properly to signals in the body; these cells may then divide and grow when they shouldn’t or may not die when they should

• This breakdown in control means that abnormal lymphocytes can grow and form a lump or tumour

The lymphatic system

• Complex network of lymph vessels, glands (lymph nodes) and other organs e.g. spleen.

• Some are easy to feel and can become enlarged or tender e.g. infection.

• Part of the immune system.

• Lymph nodes are home to large numbers of lymphocytes.

• Lymphoma most commonly occurs in nodes

• Lymphoma can arise in other organs –extra-nodal sites

Symptoms of lymphoma

• Swollen lymph node or lump

• Tiredness

• Weight loss, drenching sweats or fever

• Unexplained itch

• No single symptoms specific to lymphoma

• Abdominal or back pain

• Jaundice

• Chest pain, cough or breathlessness

• Symptoms depend on location of lymphoma and can be non-specific

How is the diagnosis made?

• Biopsy of tissue – usually a lymph node or mass

• Core biopsy

• Excision biopsy

What tests may be required?

• Blood tests e.g FBC, kidney function, liver function, virology

• Imaging e.g CT scan, PET scan, MRI scan

• Bone marrow biopsy

• Lumbar puncture

• Echocardiogram

• Pulmonary function tests

• Assisted conception service (young patients)

CT scanPET/CT scan

Imaging tests

PET scan

How do we stage lymphoma?

Stage 1Stage 2

Stage 3

Stage 4 - lungs, liver, bone marrow, other sites e.g. bowel

B Symptoms ?

Weight loss 10%

PUO

Drenching night sweats

Types of high grade NHL

• B cell high grade NHL

• T cell high grade NHL

• NK/T cell lymphoma

• Important to take time to make the correct diagnosis

• May need more than one biopsy

• Correct diagnosiscorrect treatment

B cell high grade NHL

• Diffuse large B cell lymphoma (DLBCL)

• Most common type of B cell high grade NHL

• Important subtype / related lymphomas– Primary mediastinal B cell lymphoma

– Double or triple hit DLBCL

– Intravascular large B cell lymphoma

– T cell or histiocyte rich large B cell lymphoma

– Grey zone lymphoma

• Burkitt lymphoma

• Mantle cell lymphoma

• Primary central nervous system (CNS) lymphoma

T cell high grade NHL

• Peripheral T cell lymphoma not otherwise specified– Most common

• Anaplastic large cell lymphoma (ALK +/-)– ALK is important prognostically (affects treatment plan)

• Angioimmunoblastic T cell lymphoma– Can be difficult to diagnosis; rash, fevers, low blood counts

• Enteropathy associated T cell lymphoma– Associated with Coeliac disease

• Adult T cell leukaemia / lymphoma– Associated with HTLV-1. Rare in Scotland

• Extranodal NK/T cell lymphoma, nasal type– Rare, palate tumour. Often chemo and radiotherapy concurrently

Treatment

• Chemotherapy – CHOP

• Cyclophosphamide

• Doxorubicin

• Vincristine

• Prednisolone

• Antibody – Rituximab (anti-CD20) – found on B cells

• Used first line in DLBCL, PTCL nos, AITL, anaplastic lymphoma

Treatment – B cell high grade NHL

• DLBCL: R-CHOP; mini R-CHOP

• Double or triple hit DLBCL: consider R-CODOXM/R-IVAC

• PMBCL: R-DA-EPOCH +/- radiotherapy

• Burkitt lymphoma: R-CODOXM/R-IVAC; R-CHOP

• Mantle cell lymphoma: R-AraC, R-CHOP, R-Bendamustine, R-Chlorambucil. Autologous stem cell transplant

• PCNSL: MATRIX chemotherapy; autologous stem cell transplant

Treatment – T cell high grade NHL

• PTCL NOS: CHOP; mini CHOP

• Anaplastic large cell lymphoma: CHOP; role of autologous stem cell transplant

• AITL: CHOP (autologous stem cell transplant if fit, young patient). Less fit – cyclophosphamide and steroid

• EATL: CHOP. More intensive chemotherapy (e.g. ESHAP) if fit, young patient and autologous stem cell transplant.

• Adult T cell leukaemia / lymphoma: CHOP based, may give more intensive treatment

• NK/T cell lymphoma: concurrent chemo and radiotherapy if localised. Intensive chemotherapy e.g. SMILE if more widespread.

Diffuse large B cell lymphoma

• Too many different types of lymphoma to discuss all

• Current treatment and clinical trials in detail

• Focus on DLBCL; happy to discuss others / answer any questions

Focus on DLBCL - aims

• Rationale for current treatment

• Areas of unmet need

• Summarise recent studies

• Potential future treatment developments

• Trials currently open at Beatson WOSCC

Introduction - DLBCL

• DLBCL is the most common subtype of NHL 30-40% of cases.1

• DLBCL is now quite a heterogenous term – morphology, genetics and tumour behaviour.

• 2016 WHO classification – separate entities e.g PMBCL, primary CNS lymphoma.

• Overlap categories – ‘high grade B cell lymphoma with MYC and BCL2 (+/or BCL6) rearrangments’; ‘Gray zone lymphoma’.

1. A Smith et all. Br J Cancer, 2011

Prognosis

• Prognosis - host factors: age, PS, co-morbidities

- Stage (60-70% are stage III / IV)

- disease biology – ABC vs GCB

- response to therapy

• 85-90% respond to chemotherapy; 10-15% are primary refractory

• 20-30% relapse after achieving remission

• Chemo-immunotherapy (e.g R-CHOP) failures occur early

• Outcome can be poor even with autologous stem cell transplant.

R-CHOP: standard of care

• Benefit of adding Rituximab to CHOP.

• Initially shown in elderly patients and then in younger, low risk IPI patients.

• French GELA study.1

• R-CHOP: standard of care for 20 years.

1. Coiffier et al. Blood, 2010.

• Current standard of care: 6 cycles R-CHOP; >50% are cured and if achieve 2 yr EFS, OS is equal to age and sex matched general population.

• Area of unmet need: refractory to R-CHOP or relapse.

• Important negative studies.

• Current and future options.

Improve first line treatment?

• Chemotherapy, monoclonal Ab, radiotherapy, additional agents?

• Established that 8 cycles R-CHOP no better than 6 cycles2; 14 day cycle not better than 21 days3.

2. Pfreundschuh M et al. Lancet Oncol, 2008. 3. Cunningham D et al. Lancet, 2013.

R-CHOP 14 vs R-CHOP 21

• Several studies show no difference in OS or PFS.

• UK study, 20134

• 1080 patients from 119 centres in UK.

• No molecular or clinical subgroup benefited from dose intensification.

4. Cunningham et el, Lancet 2013.

R-CHOEP

• German DSHNHL 2002-1 trial5.

• Large phase 3 study (but comparator arm R-megaCHEOP and ASCT).

• Patients with bulk (>7.5cm) or extranodal disease also received radiotherapy.

• R-CHOEP14: 3 yr EFS 69.5%.

• R-megaCHOEP 3 yr EFS 61.4% (and significantly more toxicity).

• No direct comparison with R-CHOP. Better OS often seen in trials.

5. Schmitz et al. Lancet Onc, 2012.

Radiotherapy

• German RICOVER-60 trial6.

• Patients aged >60 yrs.

• (6xR-CHOP14 + 2xR).

• Value of adding radiotherapy to sites of initial bulk (>7.5cm) or extranodal disease.

6. Held et al. JCO, 2014

Rituximab intensification?

• HOVON-Nordic Lymphoma Group study - phase III, 20167.

• Effect of early intensification of Rituximab followed by R maintenance in combination with 2 weekly CHOP (R-CHOP14 vs R-CHOP14 + extra R on day 8 of cycles 1-4).

• 575 patients.

• Patients in CR1 randomised to R maintenance or not.

• No improvement in CR rate (84% vs 82%) or 3 yr OS in any group (74% vs 71%).

7. Lugtenburg PJ et al. JCO, 2016

Ofatumumab

• Second generation anti-CD20 monoclonal antibody.

• ORCHARRD study8; large, multicentre study, 447 patients recruited.

• R-DHAP vs Ofatumumab-DHAP (followed by ASCT if responding after 2 cycles) in relapsed or refractory DLBCL.

• O-DHAP: RR 38% (CR 15%) vs 42% (CR 22%) in R-DHAP group.

• No sig diff in PFS, EFS or OS.

• OS survival at 2yrs: 41% O arm vs 38% R arm.

8. van Imhoff et al. JCO, 2016

ORCHARRD study

GOYA study

• Obinutuzumab – greater direct cell death induction, Ab-depcellular cytotoxicity than Rituximab.

• Randomised trial of CHOP + Obinutuzumab (G-CHOP) vsCHOP + Rituximab9.

• 1418 patients enrolled.

• 3 yr PFS: 70% vs 67%. CR rate: 57% vs 59%.

• Patients with germinal centre B cell like subtype had a better PFS than patients with activated B cell like subtype irrespective of treatment.

• More grade 3-5 toxicity and SAE with G-CHOP.

9. Vitolo U et al. JCO, 2017

GOYA study: PFS and OS

GOYA study - subgroups

Additional agents

• Select a high risk population to target?

• ABC DLBCL – poorer prognosis: focus of attention

• Some novel agents appear to have preferential activity in ABC type.

• Hypothesis that bortezomib should improve the outcome of patients with non-GC DLBCL as this subtype relies more on the NFκB pathway.

• Other agents – lenalidomide, ibrutinib – in combination with R-CHOP.

• Maintenance – lenalidomide, MTOR inhibitor, PKCβ inhibitor.

REMoDLB study

• Large phase III study10, multicentre, UK.

• Randomised evaluation of molecular guided therapy for DLBCL with Bortezomib.

• 1132 patients from 109 sites.

• First line treatment of DLBCL.

• R-CHOP vs R-CHOP + Bortezomib on days 1+8, cycles 2-6.

• No difference in outcome.

10. AJ Davies et al. Blood, 2015

Lenalidomide

• Investigated in first line (combination with R-CHOP) and maintenance setting.

• REAL07 trial11: Italian study, elderly patients, first line treatment. 49 patients recruited.

• R-CHOP21 x6 and lenalidomide 15mg D1-14.• Grade 3-4 neutropenia 31%; thrombocytopenia 13%. • 94% of planned cycles were completed.• CR 86%, 2 yr PFS 80%, 2 yr OS 92%.

• Appears well tolerated.

• Ongoing phase III study – ROBUST study; lenalidomide+R-CHOP vs R-CHOP in untreated ABC DLBCL.

11. U Vitolo et al. Lancet Oncol, 2014

Ibrutinib

• BTK inhibitor

• Preferential activity in ABC type DLBCL.

• Wilson et al, phase I/II study, Nat Med, 201512.

• 80 patients – relapsed or refractory.

• ABC subtype: CR or PR in 37% (14/38).

• GCB subtype: CR or PR in 5% (1/20).

• ABC – acquires mutations that target the B cell receptor leading to chronic active BCR signalling.

• Ongoing large phase III study in non-GCB DLBCL looking at R-CHOP +/-Ibrutinib (PHOENIX study).

12. W Wilson et al. Nat Med, 2015

Maintenance therapy

• Lenalidomide (REMARC study) – improved PFS but no OS benefit.

• mTOR inhibitor everolimus (RAD-001) – no improvement.

• PRELUDE study (PKCβ inhibitor enzastaurin) – no improvement.

• Currently no benefit to OS with any agent shown.

Immune checkpoint inhibitors

• Checkmate 0139 study.

• Results – clinicaltrials.gov but no published paper.

• Nivolumab in relapsed / refractory DLBCL.

• 161 patients.

• ORR 10.3%; CR 3.4%.

• Ongoing studies in combination with chemotherapy.

• May be a role in subtypes: PMBCL and EBV positive lymphomas – plasmablastic, primary CNS, NK cell, testicular.

CAR T cells

• ZUMA-1 phase 1 study of anti-CD19 CAR T cells in refractory DLBCL.

• USA: multi centre study (111 patients)

• Conditioned with cyclophosphamide and fludarabine.

• DLBCL, n=72, ORR 82% (CR 54%, PR 28%).

• Median duration OR 8.2 months; not reached for those who achieved CR.

• At median follow up of 8 months 39% in CR.

• Median OS not reached; 80% alive at 6 months.

CAR T cells - toxicity

• Grade ≥3 AEs:

– Neutropenia (66%)

– Leucopenia (44%)

– Anaemia (43%)

– Febrile neutropenia (31%)

– Encephalopathy (21%)

• Grade ≥3 cytokine release syndrome and neurologic events seen in 13% and 28% respectively.

• Potentially effective if achieve CR but significant toxicity.

Current trials – Beatson Cancer Centre

• INCA study: Phase II study. Inotuzumab ozogamicin and Rituximab and CVP (IO-R-CVP) vs Gemcitabine and Rituximab and CVP (Gem-R-CVP). Patients not suitable for anthracycline. First line treatment.

• ARGO study: Phase II study. Atezolizumab in combination with Rituximab, Gemcitabine and Oxaliplatin (R-GemOx). RR DLBCL not suitable for high dose chemotherapy.

• AZD3965: phase I study. AZD3965 in patients with advanced cancer. Selective inhibitor of monocarboxylate transporter 1.

• Horizons study: observational study looking at quality of life.

• Cardiac care study: effect of anthracycline chemotherapy on heart function (MRI scans of heart)

• MAPLE study: molecular profiling (DLBCL and FL)

• In set up: MEDI4736: RR DLBCL; phase I study immune checkpoint inhibitor and STAT3 inh

Summary - DLBCL

• R-CHOP remains standard of care and overall outcomes are good.

• Many negative but important studies.

• Additional agents e.g. lenalidomide, ibrutinib under investigation.

• CAR T cells – effective but have important toxicities and currently expensive.

• Checkpoint inhibitors – under investigation.

Thank you for listening, happy to take any questions.