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How we incorporate novel agents into the treatment of classic Hodgkin lymphoma
Tracking no: BLD-2020-007900-CR2

Narendranath Epperla (The Ohio State University, United States) Alex Herrera (City of Hope National
Medical Center, United States)

Abstract:
The introduction of targeted immunotherapies specifically, brentuximab vedotin (BV) and programmed
death-1 (PD-1) blocking antibodies (nivolumab and pembrolizumab), has reshaped the therapeutic landscape
of classic Hodgkin lymphoma (cHL) in the past decade. Targeting specific biologic features of cHL, these
novel agents have expanded treatment options for patients with multiply rel/ref cHL and have
increasingly been studied at earlier points in a patient’s disease course. With the plethora of studies
evaluating BV and PD-1 blockade as part of cHL therapy, often in non-randomized, controlled studies,
more questions than answers have arisen about how to optimally integrate these drugs into clinical
practice. In this article, we use a case-based format to offer practical guidance on how we incorporate
BV and anti-PD1 antibodies into the management of cHL and review the data supporting those
recommendations.

Conflict of interest: COI declared - see note

COI notes: Consulting or Advisory Role - Bristol-Myers Squibb; Merck; Seattle Genetics; Karyopharm;
Gilead/Kite Pharma Research Funding - Bristol-Myers Squibb (Inst); Genentech/Roche (Inst); Merck (Inst);
Seattle Genetics (Inst); Gilead/Kite Pharma (Inst); ADC Therapeutics (Inst)

Preprint server: No;

Author contributions and disclosures: N.E. and A.F.H. wrote and edited the manuscript.

Non-author contributions and disclosures: No;

Agreement to Share Publication-Related Data and Data Sharing Statement:

Clinical trial registration information (if any):

How we incorporate novel agents into the treatment of classic Hodgkin
lymphoma

Narendranath Epperla1, Alex F. Herrera2

1
Division of Hematology, The James Cancer Hospital and Solove Research Institute, The Ohio
State University, Columbus.
2
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National
Medical Center, Duarte, California.

Corresponding Author:
Alex F. Herrera, MD
City of Hope
1500 E. Duarte Road
Duarte, CA 91010
ph: 626-256-4673 x62405
f: 626-218-8256
e: aherrera@coh.org

Key words: Classic Hodgkin lymphoma, brentuximab vedotin, nivolumab, pembrolizumab, PD-

1 blockade

1
Abstract

The introduction of targeted immunotherapies specifically, brentuximab vedotin (BV) and

programmed death-1 (PD-1) blocking antibodies (nivolumab and pembrolizumab), has reshaped

the therapeutic landscape of classic Hodgkin lymphoma (cHL) in the past decade. Targeting

specific biologic features of cHL, these novel agents have expanded treatment options for

patients with multiply rel/ref cHL and have increasingly been studied at earlier points in a

patient’s disease course. With the plethora of studies evaluating BV and PD-1 blockade as part

of cHL therapy, often in non-randomized, controlled studies, more questions than answers have

arisen about how to optimally integrate these drugs into clinical practice. In this article, we use a

case-based format to offer practical guidance on how we incorporate BV and anti-PD1

antibodies into the management of cHL and review the data supporting those

recommendations.

2
Introduction

Classic Hodgkin lymphoma (cHL) is curable in the majority of patients, but 10-30% of patients

who receive standard therapy will develop relapsed or refractory (rel/ref) cHL 1-5. While high-

dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) is the

standard treatment for chemotherapy-sensitive patients with rel/ref cHL, only about half of

patients will attain durable disease control 6-10.

The advent of novel treatment options for cHL has revolutionized the cHL therapeutic

landscape. Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) with a microtubule

toxin payload (monomethyl auristatin E) directed against CD30 on the surface of Hodgkin

Reed–Sternberg cells that is approved by the United States Food and Drug Administration (US

FDA) for the treatment of advanced stage and rel/ref cHL 11. Also approved for use in rel/ref cHL

by the US FDA, the programmed death-1 (PD-1) blocking antibodies nivolumab and

pembrolizumab interrupt the interaction between PD-1 and its ligands PD-L1 and PD-L2, which

are overexpressed in cHL due to aberrations of chromosome 9p24.1 (containing the PD-L1 and

PD-L2 loci) and play a fundamental role in the pathogenesis of the disease 12. These

immunotherapies targeting specific biologic features of cHL have expanded the therapeutic

armamentarium for patients with multiply rel/ref cHL and have now been studied in various

settings throughout a patient’s disease course – from initial therapy to post-transplant

consolidation. With the abundance of studies evaluating BV and PD-1 blockade as part of cHL

therapy, often in non-randomized, controlled studies, the dilemma of how to optimally integrate

these drugs into clinical practice has arisen. In this article, we use a case-based format to offer

practical guidance on how to incorporate BV and anti-PD1 antibodies into the management of

cHL.

3
Case-1

A 24-year-old man with stage III cHL was treated with 2 cycles of doxorubicin, bleomycin,

vinblastine, and dacarbazine (ABVD) followed by 4 cycles of AVD after a post-cycle 2 PET-CT

demonstrated a complete metabolic response (CMR) 13. End of treatment (EOT) PET-CT

confirmed CMR. 14 months after treatment, he noticed right cervical node enlargement.

Restaging PET-CT showed hypermetabolic adenopathy (cervical, mediastinal and bilateral

axillary nodes) and lymph node biopsy showed Reed-Sternberg cells with bilobed nuclei that

were positive for CD15, CD30, dim PAX5, and negative for CD45 and CD3 among abundant

non-malignant inflammatory cells. He received 2 cycles of ifosfamide, carboplatin, and

etoposide (ICE) with CMR and subsequent auto-HCT. Six months later, he felt a palpable right

axillary node and restaging PET-CT showed hypermetabolic bilateral axillary and mediastinal

lymph nodes. Biopsy confirmed relapsed cHL.

BV and PD-1 blockade in multiply rel/ref cHL

A pivotal phase II study in patients (n=102) with rel/ref cHL after auto-HCT demonstrated that

BV (1.8 mg/kg every 3 weeks, maximum 16 cycles) produced an overall response rate (ORR) of

75% and CR rate of 34% 14. Among patients with CR, responses were durable with a 5-year

overall survival (OS) and progression-free survival (PFS) of 64% and 52%, respectively 15. The

most common adverse event (AE) was peripheral neuropathy (56%)14.

PD-1 blockade is also effective in patients who progress following auto-HCT. In the pivotal

phase II CheckMate 205 study, nivolumab (3 mg/kg every 2 weeks) produced an ORR of 69%

and CR rate of 16% in rel/ref cHL patients who failed prior auto-HCT and/or prior BV 16,17.

Pembrolizumab (200mg every 3 weeks) had similar efficacy in a pivotal phase II study of

patients with rel/ref cHL who failed auto-HCT or in patients refractory to salvage therapy and BV

4
with an ORR of 72% and CR rate of 28% 18,19. Both anti-PD-1 antibodies produced similar

response rates across patient subgroups regardless of the number of prior lines of therapy or

receipt of prior auto-HCT or BV. In both studies, response duration was associated with depth of

response to anti-PD1 monotherapy (e.g. CM205: median duration of response (DOR) 20.3

months after CR, 12.8 months after partial response (PR) 19.

Anti-PD-1 monotherapy is well tolerated but is associated with immune-related AEs (irAEs) that

result in therapy discontinuation in 5-7% of patients. Most irAEs are grade 1-2, including

hypo/hyperthyroidism (12%-16%), rash (9%), hepatitis (5%), and pneumonitis (3%-4%) 17,18.

Anti-PD-1 therapy can be continued if asymptomatic endocrinopathy occurs, though should be

discontinued for severe irAEs, which are managed with corticosteroids +/- other

immunosuppressive therapies. Re-challenge with PD-1 blockade after irAE resolution and

corticosteroid taper can be considered in certain circumstances.20,21

How do we incorporate novel agents for patients with multiply rel/ref cHL?

1. Multiply rel/ref cHL including post auto-HCT relapse (novel agent naïve)

Although both BV and PD-1 inhibitors are effective in multiply rel/ref cHL, there is no consensus

on the optimal timing and sequencing of these drugs. The phase 3 randomized KEYNOTE-204

study comparing pembrolizumab 200mg (n = 148) to BV 1.8 mg/kg (n = 152) every 3 weeks for

up to 35 cycles in patients with rel/ref cHL 22 showed that pembrolizumab was associated with

significantly longer PFS compared to BV (HR=0.65, 95% CI=0.48-0.88; median 13.2 vs 8.3

months). The benefit was noted across subgroups, including primary refractory cHL (HR=0.52)
22
. Pembrolizumab and BV were associated with a similar incidence of grade ≥ 3 AEs (19.6%

versus 25%) but pembrolizumab was associated with a higher incidence of irAEs

(hypothyroidism [15.5% vs 1.3%], pneumonitis [10.8% vs 2.6%]), while BV was associated with

5
more nausea (13.2% vs 4.1%) and peripheral neuropathy (18.4% vs 2%). In the vignette above,

the patient received chemotherapy-based initial and salvage therapy and did not receive

consolidation after auto-HCT, and thus is naïve to BV and PD-1 blockade. In patients with

multiply rel/ref cHL who have not received either agent, we recommend using PD-1 blockade

before BV, based on the preliminary results from KEYNOTE-204, though publication of the final

analysis is awaited to confirm this recommendation.

Based on available evidence there is no clear difference in the efficacy or toxicity between

pembrolizumab and nivolumab. They are administered using different schedules (q2 or 4 weeks

for nivolumab, q3 or 6 weeks with pembrolizumab) and the duration of therapy was different in

clinical trials (until PD with nivolumab, until PD for maximum of 2 years with option to

discontinue early after CR with pembrolizumab). We typically use a personalized approach to

antibody and schedule selection, tailored to the patient’s wishes, clinical status, and depth of

response. For patients who need closer monitoring, we choose a q2 week nivolumab or q3

week pembrolizumab schedule. In patients who achieve CR, we treat until progression with

consideration of discontinuation after 6 months (at the earliest) and usually discontinue after 2

years. In preliminary reports, re-treatment with PD-1 blockade after discontinuation is

associated with an ORR ranging from 67-100%; 23-26 therefore, this may be a logical approach

for patients who wish to pause therapy although results are unpublished and in a small number

of patients. For patients with PR or SD to PD-1 blockade we usually treat until progression. In

CM205, patients treated beyond progression (TBP) had a longer median time between PD and

next systemic therapy (8.8 months versus 1.5 months) and a longer median OS from the time of

PD (not reached versus 13.2 months), so we continue treatment beyond progression if the

patient is clinically well and the disease burden is not high.17 Follow-up imaging is critical to

distinguish between “pseudoprogression” and true PD 27. In patients with multiply rel/ref cHL

6
who have progressed on anti-PD-1 therapy, we recommend BV for up to 16 cycles depending

on tolerance of AEs (i.e. peripheral neuropathy).

2. Multiply rel/ref cHL including post auto-HCT relapse with prior exposure to novel

agents

For patients who have multiply rel/ref cHL or relapse after auto-HCT with prior BV or anti-PD-1

exposure, we recommend selecting the agent that has not been used previously. Although the

ORR to BV or anti-PD1 monotherapy is high, the CR rate and ultimate curative potential with

either type of agent is relatively low 15,17,28. To improve the depth and duration of response,

combination strategies are currently being evaluated in clinical trials with promising results thus

far, although these approaches are not standard and not recommended in routine practice at

this time (Table 1). 29-34

Case 2

A 30-year-old woman was diagnosed with stage IV cHL and received ABVDx2/AVDx4,

achieving a CMR at EOT. Seven months later, the patient developed fever and night sweats.

PET-CT showed hypermetabolic adenopathy above and below the diaphragm and FDG-uptake

in multiple vertebrae. Lymph node biopsy confirmed relapsed cHL.

Novel agent-based salvage therapy for rel/ref cHL following frontline therapy

There are many salvage therapy options for rel/ref cHL with no randomized, controlled trials in

the modern era to guide practice. The efficacy of conventional platinum- or gemcitabine-based

chemotherapy regimens is similar, with ORR and CR rates by PET ranging between 70- 89%

and 54-73%, respectively 35-40. Achievement of a CMR prior to transplant is a critical prognostic

7
factor for auto-HCT outcome 41-44. Several studies incorporating BV and/or PD-1 blockade into

initial salvage therapy have aimed to improve the CMR rate prior to auto-HCT.

Sequential and combination BV-based salvage regimens have been studied (see Table 2) 45-53.

Although a minority of patients will have a CR with BV alone as initial salvage therapy (27-43%)
45,47
, the CMR rates after sequential BV-chemotherapy or combined BV/chemotherapy range

from 68-83%. The primary toxicities observed with these regimens are hematologic.

BV (1.8 mg/kg) and nivolumab (3 mg/kg) combined as initial salvage therapy q3 weeks for 4

cycles (n=91) yielded an ORR of 85% and CR rate of 67% 54 with excellent durability of

responses (2-year PFS of 79% in all patients), including a 2-year PFS of 92% among patients

who proceeded directly to auto-HCT after BV-nivolumab. The combination was well tolerated

with 14% of patients requiring systemic steroids for irAEs and no treatment discontinuation due

to irAEs. Infusion-related reactions were common (44%), but most were grade 1-2 54,55.

Preliminary results of BV+nivolumab as first salvage therapy in children, adolescents, and

young adults (NCT02927769) followed by BV-bendamustine in patients not in CR demonstrated

a promising CR rate of 89% prior to auto-HCT (n=44) 56.

How do we incorporate novel agents into salvage therapy for rel/ref cHL?

1. Relapsed cHL (novel agent naïve)

There are no randomized, controlled data to guide decisions about first salvage therapy for

patients with rel/ref cHL and regimens are selected based on physician or patient preference

(e.g. desire to avoid chemotherapy or inpatient hospitalization). In the case above, the patient

has early relapse of cHL after receiving PET-adapted A(B)VD therapy and has not previously

received novel agents. Salvage combination chemotherapy remains the standard approach;

however, we would also consider use of BV-nivolumab based on the high likelihood of achieving

8
CR, excellent PFS, outpatient administration, and its favorable toxicity profile. This is not an

approved use of BV or nivolumab, but is supported by guidelines.57

2. Primary refractory cHL (novel agent naïve)

Some salvage regimens are associated with lower CR rates in patients with primary refractory

cHL compared to relapsed cHL, including some chemotherapy regimens (BeGeV: 59%

refractory vs 84% relapsed) 40, BV+chemo regimens (BV+bendamustine: 64% refractory vs 84%

relapsed) 53, and BV+Nivo (48% refractory vs 71% relapsed). While PFS has not been different

between patients with primary refractory cHL versus relapsed cHL after most salvage therapies

(and ASCT), the 21-month PFS in patients with primary refractory cHL following BV+nivolumab

as first salvage therapy was 65% versus 97% in patients with relapsed cHL. At present,

chemotherapy-based salvage remains the standard for these patients, although novel salvage

approaches remain satisfactory options supported by guidelines 57,58.

3. Rel/ref cHL with prior exposure to novel agents

Some patients will have received novel agents as part of frontline therapy. In these patients, we

would use a standard chemotherapy-based salvage regimen at the present time. However, with

promising early data on anti-PD1 based salvage independent of BV 59-62, anti-PD1-based

salvage may be a future option for patients with frontline BV failure. Of note, the duration of

salvage therapy with novel salvage regimens are typically longer (e.g. 4 cycles/12 weeks with

BV+Nivo) compared to conventional chemotherapy (e.g. 3 cycles/9 weeks with ICE). Priorities

regarding therapy duration and toxicities should be considered when selecting a salvage

regimen.

Novel agents as post auto-HCT consolidation therapy

9
In the phase III double-blind randomized AETHERA study, patients with high-risk (defined as

primary refractory, relapse <12 months after initial therapy, or extranodal relapse) rel/ref cHL

(n=329, all BV naïve) received BV (1.8 mg/kg every 3 weeks) or placebo for up to 16 cycles as

consolidation after auto-HCT 9. The median PFS was 42.9 months after BV compared to 24.1

months with placebo (HR=0.57) and sustained PFS benefit was observed with long-term follow-

up (5-year PFS 59% versus 41%, HR=0.52) 9,10, resulting in US FDA approval for BV as post

auto-HCT consolidation therapy. Patients with ≥2 adverse risk factors (eligibility factors, B

symptoms at relapse, <CR at auto-HCT, ≥2 salvage therapies) benefitted most from BV

consolidation (HR=0.42) 9,10. PD-1 blockade has also been evaluated as post auto-HCT

consolidation in rel/ref cHL patients alone or in combination with BV. In separate phase II

studies, pembrolizumab (8 cycles, n=30) or BV+Nivo (8 cycles, n=59) resulted in 81% and 92%

19-month PFS, respectively 63,64.

How do we incorporate novel agents as post-auto-HCT consolidation therapy for rel/ref

cHL?

BV consolidation after auto-HCT is approved for use in high-risk cHL patients with primary

refractory disease, relapse within 12 months of frontline therapy completion, or extranodal

relapse. In the case above, the patient had 3 modified AETHERA high-risk factors (early

extranodal relapse with B symptoms). We would recommend BV consolidation for this BV-naïve

patient, especially due to the benefit observed in the post-hoc analysis of patients with ≥2

modified AETHERA risk factors. AETHERA only enrolled BV-naïve patients, so the benefit of

BV consolidation is unclear in patients with prior BV exposure. We do not recommend BV

consolidation in patients who have demonstrated BV resistance (e.g. best response SD/PD or

PD <3 months after BV) prior to auto-HCT. In high-risk patients who remain BV-sensitive after a

short course of BV before auto-HCT (e.g. CR to BV-based salvage), we consider BV

10
consolidation, although there are no data to support its use 65. We recommend counting salvage

BV cycles towards the maximum 16 cycles of consolidation (i.e. maximum 12 consolidation

cycles after 4 cycles of salvage BV). Although results are promising thus far, due to limited

available data, we do not currently recommend post-auto-HCT consolidation with PD1 blockade.

Case 3

A 22-year-old man presented with a 7-week history of pruritus, fatigue, fevers, night sweats, and

a neck mass. On examination, he had palpable bilateral cervical and axillary lymphadenopathy.

Laboratory values demonstrated: WBC 11K/µL, absolute lymphocyte count 0.4K/µL,

hemoglobin 9 g/dL, and albumin 2.8 gm/dL. PET-CT demonstrated hypermetabolic cervical,

axillary, and mediastinal lymphadenopathy and multiple FDG-avid bone lesions. Lymph node

biopsy confirmed a diagnosis of nodular sclerosing cHL.

Standard frontline therapy of cHL

Combination chemotherapy +/- radiotherapy is standard treatment of newly diagnosed cHL.

PET-adapted approaches allow for de-escalation of therapy in patients with a negative interim

PET and therapy intensification in patients with early evidence of chemoresistance. In early

stage cHL, ABVD with radiotherapy or PET-adapted chemotherapy yields cure rates of over 85-

90%5,66,67, depending on disease bulk and other risk factors. In patients with advanced stage

cHL, PET-adapted approaches starting with ABVD or escalated-BEACOPP (bleomycin,

etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), are

associated with 75-90% long-term PFS 68-70.

11
BV in frontline treatment of cHL

ECHELON-1 (n=1334) was a randomized phase III trial comparing 6 cycles of BV+AVD to

ABVD (non-PET adapted) in newly diagnosed advanced-stage cHL. The primary endpoint was

2-year modified PFS (mPFS), with events defined as death, disease progression, or <CR at

EOT followed by subsequent anti-lymphoma therapy. The FDA approved BV+AVD as front-line

treatment of advanced-stage cHL as BV+AVD resulted in a 2-year mPFS of 82.1% compared to

77.2% following ABVD. In a post-hoc analysis, traditional 3-year PFS was higher after BV+AVD

(83% versus 76.1% with ABVD). Notable toxicities with BV+AVD compared to ABVD included

more neuropathy (all grades, 67% versus 43%; grade 3, 11% versus 2%), febrile neutropenia

(19% versus 8%), and grade ≥ 3 infection (18% versus 10%), but less pulmonary toxicity (2%

versus 7%). Prophylactic granulocyte colony-stimulating factor (G-CSF) with BV+AVD reduced

the rate of grade ≥3 neutropenia to 29% from 70% and febrile neutropenia to 11% from 21%

and is recommended 71. Among patients randomized to BV+AVD arm who developed peripheral

neuropathy, 62% had complete resolution and 17% had improvement without resolution of

symptoms at the time of last follow-up. Preliminary results of the 5-year data on fertility and

secondary malignancies have been presented without concerning signals72, but longer follow-up

and additional data are needed 73,74. BV has also been studied as part of frontline treatment of

early-stage cHL in combination with AVD (n = 34, 3y PFS 94%) or as consolidation after ABVD
75,76
(n = 41, 3y PFS 92%) with promising results observed in phase II studies . The randomized

phase III UK RADAR study is a PET-adapted trial that will determine if BV+AVD +/- radiotherapy

improves the PFS and CMR rate compared to ABVD +/- radiotherapy in early stage cHL.

Finally, BV has been studied in combination with variations of escalated-BEACOPP in frontline

therapy of advanced-stage cHL. BreCADD (BV, etoposide, doxorubicin, cyclophosphamide,

vincristine, dacarbazine, and dexamethasone) had a more favorable toxicity profile 77 and is

12
being evaluated against escalated-BEACOPP in the randomized phase III HD21 trial

(NCT02661503).

PD-1 blockade in frontline treatment of cHL

Increasing degrees of 9p24.1 aberration are associated with a higher probability of frontline

chemotherapy failure in cHL 78. Hence, incorporating PD-1 blockade into frontline therapy may

overcome adverse biological features and potentially improve outcomes. In CheckMate 205

(cohort D, n=51), patients with newly diagnosed stage IIB- IV cHL received nivolumab for 4

doses q2 weeks followed by nivolumab plus AVD (N+AVD) for 12 doses q2 weeks. After

N+AVD combotherapy, the CR rate was 67% by central review and 80% by investigators. The

9-month mPFS was 92% and subsequent follow-up showed that 21-month investigator-

assessed PFS was 83%. Grade ≥3 AEs were uncommon except for neutropenia (49%) and

febrile neutropenia (10%) and the most common irAEs were hypo/hyperthyroidism (26%), all

grade 1-2 79,80.

Sequential pembrolizumab followed by AVD was evaluated in a phase II study of newly

diagnosed cHL (n=30; early-stage unfavorable=12, advanced=18), with 3 cycles of

pembrolizumab q3 weeks followed by 4-6 cycles of AVD. The CMR was 37% following

pembrolizumab monotherapy and 100% following 2 cycles of AVD 81. A randomized phase II

study evaluated combination (N+AVDx4) versus sequential (nivolumabx4, N+AVDx2, AVDx2)

nivolumab with AVD in patients with early-stage unfavorable cHL with similar 12-month PFS

following concomitant (100%) and sequential (98%) therapy 82 (Table 3).

Novel agents in frontline treatment of elderly/frail cHL patients

13
Conventional chemotherapy is associated with inferior outcomes in newly diagnosed elderly/frail

cHL patients, due to toxicity and higher rates of relapse 83,84. In the E2496 study comparing

Stanford V to ABVD in advanced stage cHL, patients ≥ 60 years old had 9% treatment-related

mortality, 48% 5-year failure-free survival, and 58% 5-year OS compared to 0.3%, 74%, and

90% in younger patients, respectively 84.

BV monotherapy, sequential BV/chemotherapy, combination BV+chemotherapy, and

BV+nivolumab have been studied in newly diagnosed elderly (≥ 60 years)/frail patients, though

studies have employed variable enrollment criteria (i.e. elderly and/or frail and/or ineligible for

chemotherapy), impacting interpretation and application of these data (Table 4). BV

monotherapy is associated with ORR and CR rates of 84-92%/26-73% in newly diagnosed

elderly/frail cHL patients, with a median PFS of 7.3-10.5 months 85,86. The most common toxicity

in both studies was neuropathy. BV+dacarbazine (375 mg/m2) and BV+bendamustine (90 or 70

mg/m2) resulted in similar ORR/CR rates (BV+dacarbazine, 100%/62-69%; BV+bendamustine

100%/88%), but BV+bendamustine is associated with increased toxicity in elderly patients with

standard BV dosing (1.8mg/kg dose, 65% serious AE) 87. The durability of responses is

improved when single-agent chemotherapy is added to BV with a median PFS of 46.8 months

after BV+dacarbazine, 40.3 months after BV (1.8mg/kg)+bendamustine, and 2-year PFS of 54%

after BV (1.2mg/kg)+bendamustine 87-89.

Frontline BV+nivolumab has been evaluated in two phase II studies and is associated with best

ORR/CR rates of 91-95% and 65-79%, respectively. More grade ≥3 AEs were observed in

elderly patients, most commonly elevated lipase (19%), neutropenia (17%), and peripheral

neuropathy (11-14%, 48% all grades) 89. In one study of fixed-duration BV+nivolumab (8 cycles,

n=46), the median PFS was18.3 months, but the study did not meet its pre-specified goal of

65% ORR at EOT, with only 61% and 48% of patients remaining in response and CR,

respectively 90.

14
Finally, a phase II study evaluated 2 cycles of BV followed by six cycles of AVD and then 4

cycles of BV consolidation in elderly patients with newly diagnosed cHL (n=48). The ORR/CR

rate after BVx2/AVDx6 were 95% and 90% with a 2-year PFS/OS of 84% and 93%,

respectively. 77% of patients completed AVDx6, 73% received ≥1 dose of BV consolidation, and

42% of patients experienced a serious AE (most commonly neutropenia or infection) 91.

How do we incorporate novel agents for patients with newly diagnosed cHL?

1. Early stage cHL

In young, fit patients with early-stage cHL, we do not recommend incorporation of BV or PD-1

blockade due to the dearth of randomized, controlled data with sufficient long-term follow-up at

this time.

2. Advanced stage cHL

In patients with newly diagnosed advanced-stage cHL, treatment selection requires

consideration of the risks and benefits of the various options available in discussion with the

patient. ABVD has been the standard in North America and bleomycin can be safely dropped

after 2 cycles in patients with a negative interim PET 13. However, patients with a positive

interim PET scan have dismal outcomes with ABVD continuation 67 and the alternative is

escalation to BEACOPP, a regimen associated with increased toxicity compared with ABVD.

Although BV+AVD was compared to ABVD without PET-adaptation and the primary endpoint of

the ECHELON-1 study was the unfamiliar mPFS, both the mPFS and traditionally-defined PFS

were higher than the control arm.92 Without escalation to BEACOPP, PET2+ patients had a 3-

year PFS of 67.7% in ECHELON-1 (58% 2y mPFS) 74 compared to PET2+ patients with 5-year

PFS of 70.7% and 66% in the AHL2011 and S0816 studies, respectively, and a 67.5% 3-year

PFS in RATHL 13,74,93. Major drawbacks of BV+AVD include increased toxicity compared to

15
ABVD (i.e. peripheral neuropathy, neutropenia/ infections), the requirement for G-CSF use, and

high cost.

In the vignette above, the patient has stage IV cHL with several high-risk features and an

international prognostic score (IPS) of 6. PET-adapted ABVD- (e.g. RATHL) or BEACOPP-

based approaches (e.g. AHL2011) remain standard options for this patient. However, in

secondary analyses of the ECHELON-1 study, younger patients with higher risk disease

appeared to benefit the most from BV+AVD. Therefore, the high-risk patient described above is

the type of patient in whom we strongly consider use of BV+AVD. Currently, we do not

recommend use of PD-1 blockade as part of initial frontline therapy for young, fit patients with

advanced-stage cHL based on lack of supporting data. The phase III randomized S1826 study

is evaluating BV+AVD versus N+AVD as frontline treatment of advanced-stage cHL

(NCT03907488).

3. Elderly cHL

In elderly, frail, or comorbid patients, we base decision-making on whether the patient can

tolerate combination chemotherapy. If yes – for early stage favorable elderly/unfit patients, 2

cycles of ABVD followed by radiation therapy 94 is relatively well tolerated and associated with

excellent outcomes. For non-bulky early-stage patients, PET adapted ABVD (3-4 cycles as per

RAPID or CALGB 50604) 5,67 can be considered but 4 cycles of bleomycin is associated with

increased toxicity and the risks versus benefits of using bleomycin in elderly or co-morbid

patients must be weighed 95. For advanced stage patients or those who can tolerate

chemotherapy but not bleomycin, we utilize the sequential BV-AVD regimen 91 due to its

curative potential as a full systemic course of therapy compared to BV monotherapy or doublets.

If the patient cannot tolerate combination chemotherapy, we recommend BV-based therapy --

preferably BV+DTIC since it is associated with a longer DOR or BV monotherapy for very

16
elderly/unfit patients. If the patient’s performance status improves upon treatment of the HL with

BV monotherapy, it is reasonable to transition to sequential BV-AVD.

Conclusions

The above scenarios represent our management recommendations for common questions that

currently arise regarding how to integrate novel therapies into the treatment of cHL. Dilemmas

remain because the field is evolving so rapidly that a cHL patient encountered in the clinic may

have multiply rel/ref cHL with no prior exposure to novel agents or may have received a novel

agent as frontline or salvage treatment, which prevents uniform recommendations for all

patients at a particular time point. There is also a lack of randomized, controlled data to guide

decisions, although studies like KEYNOTE-204 are aiming to bridge the gap. A critical question

for the future of cHL management will be how to optimally time the use of BV and PD-1

blockade and what the best combination partners will be. As we treat more patients with these

drugs earlier in the disease course, patients with rel/ref cHL will increasingly have BV- or anti-

PD1 resistant cHL and approaches to overcoming resistance will be necessary. As we better

understand the biology of the novel agents we may identify targetable mechanisms of

resistance, and some BV- and anti-PD1-based combinations have demonstrated early promise
33,34,96
. We must also accept that many patients have cHL not cured by the current “novel”

agents and that newer targeted therapies for cHL are needed.

As we await data to clarify the optimal role and timing of BV and PD-1 blockade in cHL, a

proposed algorithm for how to incorporate novel agents into the management of cHL is shown in

Figure 1.

17
Acknowledgments

The authors would like to thank Dr. Philippe Armand for his thoughtful review of the manuscript.

AFH is supported by the Emmet and Toni Stephenson Leukemia and Lymphoma Society

Scholar Award and the Lymphoma Research Foundation Larry and Denise Mason Clinical

Investigator Career Development Award.

Author Contributions
N.E. and A.F.H. wrote and edited the manuscript.
Conflicts of Interest
Consulting or Advisory Role - Bristol-Myers Squibb; Merck; Seattle Genetics; Karyopharm;
Gilead/Kite Pharma Research Funding - Bristol-Myers Squibb (Inst); Genentech/Roche (Inst);
Merck (Inst); Seattle Genetics (Inst); Gilead/Kite Pharma (Inst); ADC Therapeutics (Inst)

18
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Regimen Phase N ORR (%) CRR (%) NCT# Reference
BV monotherapy and combination therapy in rel/ref cHL
BV II 102 75 34 NCT00848926 Younes 14
BV-ibrutinib II 39 69 46 NCT02744612 Chen 29
BV-bendamustine I/II 64 71 32 NCT01657331 O'Connor 30
BV-ipilimumab I 21 76 57 NCT01896999 Diefenbach 31
BV-nivolumab I 18 88 61 NCT01896999 Diefenbach 31
BV-nivolumab- I 22 82 73 NCT01896999 Diefenbach 31
ipilimumab
Anti PD-1 monotherapy and combination therapy in rel/ref cHL
Nivolumab II 243 69 16 NCT02181738 Armand 17
Pembrolizumab II 210 69 22 NCT02453594 Chen 19
Nivolumab + Ib 31 74 23 NCT01592370 Armand 32
ipilimumab
Pembrolizumab + I 9* 100 44 NCT03150329 Herrera 33
vorinostat
Camrelizumab + II NCT03250962 Nie 34
decitabine
anti-PD-1-naïve 42 95 71
prior anti-PD-1 25 52 28
Table 1: Studies of BV and PD-1 blockade in multiply relapsed/refractory cHL

Abbreviations: BV=brentuximab vedotin, ORR=overall response rate, CRR=complete response rate

*Includes patients with both prior PD1 blockade and PD1 refractory

32
Regimen Phase N Primary Relapsed CMR PFS Reference
Refractory (n) (n) (%)
BV based salvage regimens
Sequential BV and chemotherapy
BVaugmented ICE II 45 25 20 761 82% at 3 yrs Moskowitz 45
2
BVsalvage therapy II 57 35 22 74 71% at 2 yrs Herrera 47
Combination BV and chemotherapy/novel agents
BV + ICE
BV-ICE x 2 I/II 16 11 5 69 Not reported Cassaday 48
BV-ICE x 2-3 II 423 12 30 69 69% at 1 yr Stamatoullas 49
BV + ESHAP I/II 66 40 26 70 71% at 30 mo Garcia-Sanz 50
BV + DHAP II 61 23 38 79 76% at 2 yrs Hagenbeek 51
BV + Gemcitabine I/II 454 29 16 67 Not reached Cole 52
BV + Bendamustine I/II 55 28 27 74 62.6% at 2 yrs LaCasce 53
BV + Nivolumab I/II 91 38 53 67 78% at 2 yrs Herrera,
Moskowitz 54,55
Anti PD-1 based salvage regimens
N+/-ICE5 II 39 18 21 866 79% at 1 yr Herrera 59
Pem-ICE II 23 8 15 96 Not reported Bryan 60
Pem-GVD7 II 39 16 23 95 Not reached Moskowitz 61,62
Table 2: Novel agents based salvage regimens in second-line therapy in cHL
Abbreviations: BV=brentuximab vedotin, ICE=ifosfamide, carboplatin and etoposide, ESHAP=etoposide,
cytarabine, cisplatin, methylprednisolone, DHAP=dexamethasone, cytarabine, cisplatin, N+/-ICE=nivolumab with or
without ICE, yrs=years, mo=months, CMR=complete metabolic response by PET
1
27% achieved CMR to BV alone, and 76% to both
2
43% achieved CMR to BV alone, and 74% to both
3
Only 39 patients were evaluable for efficacy
4
Only 42 patients were evaluable for efficacy
5
Patients received Nivolumab 3 mg/kg every 2 weeks for 6 cycles. Patients in CR at cycle 6 proceeded to auto-HCT;
those not in CR received N+ICE for 2 cycles.
6
End of nivolumab alone, CR rate=70%; end of NICE, CR rate=86%
7
37 patients were evaluable for response

33
 Table 3: Novel agents based treatment in newly diagnosed cHL

Regimen Phase N Stage Median CRR (%) PFS Reference

age (yrs)
BV and anti PD-1 therapies in newly diagnosed cHL
BV+AVD vs ABVD III 1334 III-IV 35 vs 37 73 vs 71 3-yr PFS 83% vs 76.1% Connors, Straus 73,74
NivoN+AVD II 51 IIB*-IV 37 671 21 mo PFS 83% Ramchandren,
Ansell 79,80
PemAVD II 30 IIB*-IV 30 1002 At a median f/up of 6.5 Allen 81
mo, PFS 100%
N+AVD concomitant II 110 I-II 26 vs 27 83 vs 84 12 mo PFS 100% vs 98% Bröckelmann 82
vs sequential3 (unfavorable)
BV+AVD II 34 I-II* 36 91 3-yr PFS 94% Abramson 75
(non-bulky)
ABVDBV II 40 I-II* 29 95 3-yr PFS 92% Park 76
(non-bulky)
Abbreviations: BV=brentuximab vedotin, ABVD=doxorubicin, bleomycin, vinblastine and dacarbazine,
Nivo=nivolumab, Pem=pembrolizumab, DTIC=dacarbazine, yr=year, mo=months, CRR=complete response rate,
PFS=progression-free survival

*Includes unfavorable cHL

1- CR rate 67% by central review and 80% by investigators

2- PET-CR rate was 37% following pembrolizumab monotherapy and 100% following AVD x 2 cycles
3- Concomitant N-AVD received 4 cycles of N-AVD; sequential arm received Nivolumab x 4 cyclesN-AVD x
2 cyclesAVD x 2 cycles followed by 30-Gy involved site radiation therapy

34
1 Table 4: Treatment in newly diagnosed elderly/frail cHL

Regimen Phase N Stage Median CRR PFS Frail Reference

age (yrs) (%)
BV and anti PD-1 therapies in elderly/frail patients
BV II 27 I-IV 78 73 Median PFS 10.5 mo 81% were impaired ≥ 1 Forero-Torres 85
aspect of GA
BV (BREVITY) II 38 II-IV 76 26 Median PFS 7.3 mo Median CIRS-G score Gibb 86
was 6 in evaluable pts
BV (1.2 mg/m2) + I/II 59 II-IV 70 63 2-yr PFS 54% 79% Colella 88
bendamustine (HALO)
BV+DTIC II 19 I-IV 69 68 Median PFS 46.8 mo 50% Friedberg,
Yasenchak 87,89
BV (1.8 mg/m2) + II 20 I-IV 75 88 Median PFS 40.3 mo 45% Friedberg,
bendamustine (70 mg/m2) Yasenchak 87,89
BV+Nivo (≤ 16 cycles) II 21 II-IV 72 79 Median PFS not GA not reported* Yasenchak 89
reached
BV+Nivo (8 cycles) II 46 II-IV 71 68 Median PFS 21.8 mo GA not assessed** Cheson 90
Sequential BVAVD1 II 48 II-IV 69 81 2-yr PFS 85% Median CIRS-G score Evens 91
was 7
Standard chemotherapies in elderly/frail patients
ABVD x 6-82 III2 23 II-IV 66 65 5-yr PFS 64% - Evens84
Stanford V2 III2 21 II-IV 64 62 5-yr PFS 51% - Evens84
ABVD x 2 + IFRT3 III3
70 I-II 64 96 5-yr PFS 79% - Boll95
AVD x 2 + IFRT4 III4 82 I-II 66 98 5-yr PFS 79% - Boll95
PVAG x 6-8 II 59 II-IV 68 78 3-yr PFS 58% - Boll97
2 Abbreviations: BV=brentuximab vedotin, ABVD=doxorubicin, bleomycin, vinblastine and dacarbazine, AVD=doxorubicin, vinblastine and dacarbazine,
3 Nivo=nivolumab, DTIC=dacarbazine, yr=year, mo=months, CRR=complete response rate, PFS=progression-free survival, GA=geriatric assessment, CIRS-G=
4 Cumulative Illness Rating Scale-Geriatric comorbidity score, IFRT=involved field radiation therapy

5
6 1- Patients received 2 cycles of BV followed by six cycles of AVD and then 4 cycles of BV consolidation in responding patients
7 2- Secondary analysis of E2496
8 3- Secondary analysis of GHSG HD10

1
 9 4- Secondary analysis of GHSG HD13

10

11 *≥60 years who were considered unfit for conventional chemotherapy were included in the study

12 **Patient were selected based on abnormal organ function that would render them poor candidates for standard chemotherapy

2
13 Figure Legends
14 Figure 1: How we incorporate novel agents into treatment of classic Hodgkin lymphoma
15