Classical Hodgkin Lymphoma- relapse

Rifca Le DieuClinical Reader/Honorary Consultant

Learning Objectives

• To understand the relevance of prognostic factors at relapse• To understand the treatment pathway in R/R Hodgkins• To appreciate the (lack of) evidence base for what is done• To understand how new agents are changing the treatment

paradigm in relapsed disease

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Scale of the problem

• 10% early stage and 15-30% of advanced stage will have primary refractory disease or experience relapse

• ~70% of relapses occur within 2 years of primary therapy• Of these, ~50% will be cured with salvage therapy

Primary refractory disease: Progression or non-response during induction treatment or within 90 days of completion

Kuruvilla 2011

Relapsed/refractory disease

• Small but challenging population• Repeat biopsy recommended

• In all relapse ?change in histology • Consider in those with residual FDG-avid lesions post therapy -

confirm active disease

• Tissue type patient and siblings

Collins 2013

Prognostic factors at relapse

• Intensity of 1st line therapy (Josting 2010)

• Relapse post BEACOPP more challenging than relapse post ABVD

• Time to relapse (Josting 2000, Pfreundschuh 1994)

• 5y OS• Primary refractory: 26%• Early relapse (<12m): 46% • Late relapse (>12m): 71%

• Extranodal involvement prior to salvage (Martin 2001)

• Presence/absence of systemic symptoms prior to salvage (Moskowitz 2001)

• PS at time of salvage (Ferme 1995)

Allow informed consent onlyDo not impact on therapy decisions

Prognostic factorsPET status post salvage:

probably the most important predictor of outcome

PET –ve post salvage – 3-5y PFS of > 70%PET +ve post salvage – 3-5y PFS 25-30%

Jabbour 2007, Moskowitz 2010

First line salvage treatment

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Salvage chemotherapy

induce PET –ve CR (Deauville score 1-3)

minimize toxicity to stem cell compartmentCollins 2013

Aim of treatment in younger patients with no significant comorbidities : induce remission and proceed to ASCT

Meta-analysis of 11 studies – overall survival: pre-transplant PET positive: 17-77% pre-transplant PET negative: 78-100%

Adams & Kwee, 2016

Salvage chemotherapy

• First-line salvage – all single arm phase II trials

ORR:70-89%CRR: 21-54%

Salvage – how do you choose?

• Use an established regimen which is familiar to treating centre

• Tailor to individual patient needs– Avoid cisplatin in renal impairment– Avoid ifosfamide in patients at high risk of ifosphamide-induced

encephalopathy (previous cisplatin / concomitant opioids or CYP2B6 inhibitors)

Collins 2013

Salvage – how much?

• No published evidence

• Consensus: 2 cycles of a multi-agent regimen then re-evaluation using CT-PET

Collins 2013

Salvage – what next?

PET –ve stem cell harvest (?after #3 salvage) and ASCT

PET +ve 2nd line salvage

Second line salvage…introducing the novel agents

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Which second line salvage regimen?

• No difference in outcome in those achieving a –ve pre-ASCT PET irrespective of whether 1 or 2 lines required to achieve it (EFS>80%)

• Choose another – GEM-P, ICE, DHAP….– Original paper (Moskowitz 2012) used standard or augmented dose

ICE and if PET +ve – GVD

• Brentuximab vedotin (BV)

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Brentuximab vedotin

Anti-CD30 monoclonal antibody conjugated to MMAE (= vinca alkaloid)1.8mg/kg IV D1 every 21 days up to 16 cyclesRe-evaluate after 3-4 cyclesSEs: peripheral neuropathy, bone marrow toxicity, lung toxicity (don’t give with gemcitabine/bleomycin or concurrently with mediastinal RT)

Monomethyl auristatin EIn 2011, first new drug to be approved in Hodgkins since 1977

Efficacy of BV as bridge to ASCT• Eyre, BJH 2017

– UK-wide retrospective study– 99 SCT-naïve R/R– Non-toxic bridge to SCT in 34%– Deferred SCT (inadequate response to BV) in 27%– 39% never reached SCT with PFS of 3.0 months

• Approved by NICE for R/R HL after at least 2 previous therapies when ASCT or multi-agent chemotherapy not an option (pre-SCT)(as of June 2018)

BV Combinations

• Combination Benda + BV as 1st line salvage (LaCasce Blood 2018)

– Phase I/II single arm study– N=55– ORR 92.5%, CR 73.6%– Infusion-related reactions 56.4% (severe in 14.5%)

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Not approved by NICE. As of Oct 2020, Bendamustine not funded by NHSE for R/R Hodgkins.

Only in the context of a clinical trial

Checkpoint Inhibitors (CPI)• Remove the T cell inhibition

induced by tumour cells

• Anti-PD1 monoclonal antibodies:• Nivolumab• Pembrolizumab

• Anti-PD-L1 monoclonal antibodies:• Avelumab

• Genetically determined vulnerability in HL – consistent amplification of 9p seen. Locus for PD-L1 and PD-L2 genes

Data on CPIs in R/R HL

Antibody ORR (%) CR (%) PFS Follow-up Reference

NivolumabN=243

69 (63-75) 16 (NR) mPFS 14.7m(11.3-18.5)

18m Armand JCO 2018

CheckMate 205

PembrolizumabN=210

69 (62-75) 22 (17-29) PFS@9m 63% At 12m Chen JCO 2017KEYNOTE 087

EHA Education Session 2018

Excellent single agent activity (lower CR rate) with favourable toxicity

Side effects of CPINivolumab• Fatigue (25%)• Infusion-related reactions (20%)• Rash (16%)• Pyrexia (14%• Arthralgias (14%)• Pruritus (10%)• Diarrhoea (10%)

• Asymptomatic lipase elevation• Neutropenia

• Pneumonitis in 2 patients that resolved with steroids

Pembrolizumab• Pyrexia (11%)• Hypothyroidism (10.5%)• Diarrhoea (6.7%)• Fatigue (6.7%)• Headache (6.2%)• Rash (6.2%)• Nausea (5.7%)

• Grade 3/4: neutropenia, dyspnoea, diarrhoea

• 4.3% discontinued due to TR-AEs: myocarditis, myelitis, myositis, pneumonitis, CRS

No deaths attributable to treatment in either study

Pembrolizumab

• Subgroup analysis showed that even in the 23 patients who were refractory to all prior lines of therapy, a response rate of 56% was observed

• NICE recommended as an option for patients who are unsuitable for SCT due to a failure to reach a suitable remission, co-morbidities or age and have failed BV

• 200mg IV every 3w

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Brentuximab or Pembrolizumab?

• Keynote-204 (EHA 2020)– Open-label, randomised, phase 3 study – N=300 R/R– Pembrolizumab resulted in improved PFS

• 13.2m vs 8.3m• 12m PFS 53.9% vs 35.6%

– No statistical difference in ORR– Authors stated pembrolizumab should be the new standard of care at

relapse post ASCT or in those ineligible for ASCT

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Brentuximab or Pembrolizumab?

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Patients on Pembro also had improved HRQoL compared with

patients on BV (Zinzani, ASH 2020)

Autologous stem cell transplantation

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Autologous stem cell transplantation

2 randomised trials demonstrated significant benefit of ASCT over chemo alone (FFTF not OS) • Linch, Lancet 1993

• BNLI: 3y EFS 53% vs 10%

• Schmitz, Lancet 2002• GHSG: FFTF at 3y 55% vs 34%

• Conditioning regimen: BEAM most popular worldwide

Maintenance post ASCT?• Brentuximab

– licensed for this indication if high risk features present (AETHERA study Moskowitz, Blood 2018 ):

• Primary refractory disease• Relapse within 1y of initial therapy• Extra-nodal disease pre-salvage

– 3y PFS 61% vs 43%– No OS advantage (?due to cross-over between arms)– Not approved by NICE for this indication

• Pembro + BV (ASH 2020)

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If unfit for ASCT (and failed BV and pembro)…

• No prospective studies• Survival without ASCT (if in CR post salvage) (Longo 1992, Bonfante 1997)

• Primary refractory: 0-8% survive >8y• Early relapse (<12m): 11% 20y OS• Late relapse (>12m): 22% 20y OS

• Combined modality therapy• Single agent chemotherapy (vinblastine, lomustine, etoposide, gemcitabine)• Multiagent oral regimens

• PECC (Prednisolone, etoposide, CCNU (lomustine), chlorambucil)• ChlVPP (chlorambucil, vinblastine, procarbazine, prednisolone)• LD56 (Vinblastine, methotrexate, lomustine, chlorambucil, dexamethasone, bleomycin)

• Consider clinical trial options

Other potential agentsN ORR, % CR, % Median

PFSReference

Lenalidomide Immuno-modulatory agent

38 19% 3% 4 months Fehniger, Blood 2011

Everolimus mTORinhibitor

57 42% 8% 9 months JohnstonBlood 2012

Panobinostat HDAC inhibitor 129 23% 4% 6.1months

YounesJCO 2012

Adapted from LaCasce, Hematol Oncol 2019

Relapse post ASCT

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• Outcomes poor, especially if within 6-12 m• Median OS 25-32 months• Aim: to attain sufficient response to allow alloSCT

Collins 2013

Options now:(1) Brentuximab if you haven’t used it before(2) Re-use of brentuximab(3) Nivolumab if previous brentuximab (and no pembro)

Brentuximab for relapse post ASCT

• Pivotal phase II study (Younes 2012)

• In 102 CD30+ relapsed patients post SCT• Objective responses in 75%• CR in 34% (median duration of response 20.5 m in this group)• Median PFS 5.6m• Of note, patients who did not achieve CR at first re-staging were unlikely to achieve CR with further

therapy• Only 8 proceeded to alloSCT

• Chen, Blood 2012• Retrospective cohort of patients (n=18) who proceeded to RIC alloSCT after BV

• One yr PFS and OS 92% and 100%; TRM 0%

Re-treatment with Brentuximab

• Bartlett 2014– Phase 2 – N=21– ORR 60%, CR 30%– Median duration of response 9.5 months– If in CR, 45% had response durations>1y– Higher rate of peripheral neuropathy – 28%

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Nivolumab

• Nivolumab: – 3mg/kg IV every 2w for up to 2y– NICE approved in July 2017 for R/R Hodgkins after treatment with

ASCT and BV

Response assessment post CPI

• Use LyRIC (Lymphoma response to immunologic therapy) criteria in PET assessment– ‘indeterminate’ response due to pseudo-progression (Cheson 2016)

• Concept of ‘treatment beyond progression’• If clinical response and no significant SEs• Of 70 patients treated beyond conventional PET-defined progression, 61%

had stabilisation or reduction of their target lesions at the subsequent response assessment (Armand, 2018)

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The future for new agents• Lots of combination studies ongoing• Durability of responses and toxicities need further investigation• ?Is this really a better strategy than sequential use

– BV + Nivolumab (Herrara, ASH 2018)• 62 R/R patients• ORR 82%, CR 61%• IRRs in 44% • 8% treated with steroids for immune-related AEs

– BV + Ipilumumab + Nivolumab (Diefenbach, ASH 2018)• 22 R/R patients• ORR 82%, CR 68%• in 9 patients post ASCT, ORR 95% and CR 79%• Large number of grade 3 AEs

Randomised phase 2 study of doublet vs triplet

ongoing

Allogeneic stem cell transplantation• Reduced intensity conditioning• Chemo-sensitivity at time of transplant most important

prognostic indicator• TRM has improved over time

• <10% in <50y• 15% in 50-70y

• PFS 20-40% at 2-4 yrs; OS 35-60% 2y post • Donor availability: no significant difference in PFS/OS between

donor types (EBMT Registry study, Martinez JCO 2017)

Collins 2013

CPI and alloSCT• Possibility of increased GvHD due to modulation of antigen-specific T cell responses• Multicentre retrospective study (Merryman Blood 2017)

– n=39 (79% with HL)– Median of 62d (range 7-260) between last dose CPI and allo– Grade 2-4 aGVHD in 44%; Grade 3-4 aGVHD in 23%– cGVHD in 41% by 1y– 1 year non-relapse mortality 11%

• Meta-analysis 2019: does not increase mortality but does increase grade 3-4 GvHD• ICML-15: stop CPI 2m pre allo and give cyclo as additional GvHD prophylaxis

Remain vigilant

CAR T cells• Ramos JCO Nov 2020

• CD30 CAR-T• Fludarabine-based lymphodepletion• N=41• Median 7 prior lines of therapy• ORR in 32 patients with active disease 72%• 19 patients in CR• 1y PFS 36%; OS 94%• 10 CRS (all grade 1), no neurotoxicity

• Other trials underway:2018 – 3, 2019 – 9, 2020 –13, 2021 – 21• None currently in the UK

Microenvironment/tumourimmunology clearly different to B NHLs

Current clinical trials open in the UKANIMATE:Nivolumab monotherapy in patients failing to achieve CMR following 2 cycles of salvageNCT03337919

Phase II UCL CTC/BMS Numerous sites

CheckMate 744: Nivolumab + BV after failure of first line therapy followed by BV + Benda in those with sub-optimal responseNCT02927769

Phase IIAge 5-3080 patients

BMS Numerous sites

ADCT-301:Following 3 lines of therapy inc BV and CPINCT04052997

Phase II100 patients

ADC Therapeutics Manchester, Oxford, UCL, Plymouth

SEA-TGT:Advanced cancer inc HodgkinsNCT04254107

Phase I Seagen Inc Royal Marsden

https://clinicaltrials.gov

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We are getting better at this….

Outcomes in patients relapsing post ASCT

R/R HL Combination chemoeg IGEV x 2

D1-3

D4-5

#3 then SC harvest ASCT

BV x 4 (But maybe now Pembro?)

Pembrox 3

(up to 2 years)

D1-3

D4-5

R/R Hodgkins Lymphoma: A 2021 treatment algorithm in the UK

Don’t forget to biopsy…and re-biopsy

Register for Animate

<30yrs: consider CheckMate 744

Relapse post ASCT

BV x 4 ?AlloSCT

D1-3

D4-5 Nivo x 4(up to 2 years)

??AlloSCT at time of D1-3 response leaving 2 month gap

?Continue BV to 16 cycles then stop

Key messages

• Cure is currently possible in 50% of R/R patients • PET post salvage most important predictor of outcome• No data to support one salvage regimen over another• Aim to induce remission and proceed to ASCT• Relapse post ASCT: new drugs – BV and Nivolumab; aim for

allo• Non-transplant candidates: BV, Pembro, single agents, multi-

agent PO regimens

Challenges• The lack of evidence!

– How do we integrate the data out there to direct patient care?• The need for validated biomarkers to aid clinical decision making

– Can we predict who will get R/R disease? And then how they will respond to salvage?

– (But if we could, would we treat them differently?)• Improving our CR rate with salvage (…to get more to ASCT)• Better understanding of the roles of BV/CPI

– More may not necessarily be better….• Optimal timing of alloSCT…is it wise to delay?

Thank you for your attention