Hematologic Malignancies

Paradigm Shifts in Hodgkin Lymphoma Treatment: From

Frontline Therapies to Relapsed Disease
Cathy Burton, MD1; Pamela Allen, MD, MSc2; and Alex F. Herrera, MD3

DOI https://doi.org/10.1200/EDBK_433502

Accepted March 26, 2024

OVERVIEW
Published May 10, 2024

Combination chemotherapy with or without radiation has served as the primary therapeutic Am Soc Clin Oncol Educ Book
option for classic Hodgkin lymphoma (cHL), leading to durable remission in a majority of 44:e433502
patients with early- and advanced-stage cHL. Patients with relapsed/refractory (RR) cHL could © 2024 by American Society of
still be cured with salvage chemotherapy and autologous stem-cell transplantation. Bren- Clinical Oncology
tuximab vedotin (BV) and the anti–PD-1–blocking antibodies, nivolumab and pem-
brolizumab, are highly effective treatments for cHL and have revolutionized the management
of the disease. Recent studies incorporating BV and PD-1 blockade into salvage therapy for RR
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cHL and into frontline treatment regimens have changed the cHL treatment paradigm. The
novel agents are also useful in the treatment of older patients who have poor outcomes with
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

traditional therapy. This manuscript will review current strategies for approaching the
management of previously untreated, RR, and challenging populations with cHL, including
how to incorporate the novel agents.

INTRODUCTION salvage therapy for RR cHL. Importantly, these well-

For decades, combination chemotherapy with doxorubicin,
bleomycin, vinblastine, and dacarbazine (ABVD) or bleo-
mycin, etoposide, doxorubicin, vincristine, prednisone, and
procarbazine (BEACOPP) with or without radiation therapy
has been the cornerstone of classic Hodgkin lymphoma
(cHL) treatment.1,2 Pediatric patients have received modified
versions of these regimens with more frequent use of
radiation.3,4 Adaptation of therapy using interim positron
emission tomography (PET) results refined treatment on the
basis of dynamic imaging response, but the tools—
chemotherapy and radiation—remained the same.5-7 Pa-
tients not cured by initial treatment had a second chance at
durable remission via salvage chemotherapy and autologous
stem-cell transplantation (ASCT).8
The introduction of effective novel therapies has reshaped
the therapeutic landscape for cHL. The CD30-directed
antibody-drug conjugate brentuximab vedotin (BV) and
PD-1 blocking antibodies, nivolumab and pembrolizumab,
were demonstrated to be safe and effective in patients with
heavily treated relapsed/refractory (RR) cHL.9-13 These
agents have been studied progressively earlier in the course
of therapy, as consolidation treatment after ASCT in high-
risk cHL,14,15 as part of salvage treatment before ASCT,16-21
and most recently, as part of the initial treatment of early-
and advanced-stage disease.22-30 The future has finally ar-
rived: randomized studies now support the use of novel
agents in the frontline management of cHL and there are
abundant data supporting their use as the backbone of
tolerated medications are useful options in the treatment
of older patients or patients with comorbidities who typically
have poorer outcomes than their younger counterparts with
standard treatment. In this review, we will discuss the recent
clinical trial results that have changed the treatment para-
digm in cHL.
PARADIGM CHANGES FOR NEWLY DIAGNOSED
HODGKIN LYMPHOMA
The initial treatment of newly diagnosed cHL is determined
by stage. Patients with early-stage cHL (stage I-II) receive
combined modality therapy (CMT) with chemotherapy and
radiation or chemotherapy alone. Patients with advanced-
stage cHL receive a full course of systemic therapy with
infrequent use of radiation except for pediatric patients,
where a majority of patients receive consolidative radio-
therapy. With modern chemotherapy regimens, the great
majority of patients with cHL are cured with initial therapy,
with long-term remission rates of ≥85% in patients with
early-stage cHL and durable remission in ≥75% in patients
with advanced-stage cHL.31 Here, we will discuss recent trial
results in early- and advanced-stage cHL incorporating
novel agents and how they have shifted the cHL therapy
paradigm.
Early Stage
Standard management of early-stage cHL continues to be
combination chemotherapy with or without radiation, with

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 Burton, Allen, and Herrera
PRACTICAL APPLICATIONS
• Randomized studies support the use of novel agents,
brentuximab vedotin (BV), and PD-1 blockade, as part
of initial therapy for classic Hodgkin lymphoma (cHL).
• In advanced-stage cHL, nivolumab led to improved
progression-free survival compared with BV when
combined with doxorubicin, vinblastine, and
dacarbazine.
• PD-1 blockade has become a cornerstone of salvage
therapy for relapsed/refractory cHL before autologous
stem-cell transplantation, resulting in the most fa-
vorable outcomes observed to date when combined
with chemotherapy.
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• Fit, older patients with cHL are candidates for
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.
curative-intent therapy that may include BV or PD-1
blockade, while unfit patients have effective, novel
therapy options that may lead to durable responses.
• Curative-intent therapy is safe during pregnancy
(second trimester and beyond) and does not require
termination of pregnancy.
the duration of chemotherapy and dose of radiotherapy
determined by clinical risk factors. Patients with favorable
early-stage cHL typically receive fewer cycles of chemo-
therapy (eg, ABVD 3 2-4) and potentially lower doses of
radiation (eg, 20-30 Gy) when receiving CMT, while patients
with unfavorable early-stage cHL receive a longer chemo-
therapy course (eg, ABVD 4-6) and receive higher radiation
doses (eg, 30 Gy) when CMT is administered.32-34 There have
been several, mostly single-arm, clinical trials evaluating
the incorporation of BV and/or PD-1 blockade into man-
agement of early-stage cHL. Studies evaluating BV or PD-1
blockade sequentially or in combination with doxorubicin,
vinblastine, and dacarbazine (AVD) with or without radiation
have demonstrated generally favorable tolerability and
promising efficacy.21-24,26,30 Studies combining BV with AVD
(BV-AVD) did result in increased rates of peripheral neu-
ropathy (PN) and febrile neutropenia/sepsis than typically
observed in the treatment of early-stage cHL.22 Subsequent
studies have omitted vinblastine (eg, BV-AD, BV-
nivolumab-AD) with improved tolerability and similar
efficacy.23 Studies incorporating PD-1 blockade in the
management of early-stage cHL have resulted in particularly
excellent outcomes, with progression-free survival (PFS)
ranging from 96% to 100%.24,26,30 Several randomized
studies are evaluating whether the inclusion of BV and/or
PD-1 blockade improves outcomes compared with PET-
adapted chemotherapy or CMT, aiming to define a new
standard of care. Despite the impressive efficacy observed in
2 | © 2024 by American Society of Clinical Oncology
smaller studies thus far, there is a high bar of success re-
quired to change the standard of care in early-stage cHL. In
the absence of randomized data to support the use of BV and/
or PD-1 blockade, we are left with the same historic treat-
ment paradigm—PET-adapted chemotherapy or CMT re-
main the standard treatment for early-stage cHL.
Advanced Stage
The standard treatment of patients with advanced-stage
cHL has been a course of systemic combination chemo-
therapy, with PET adaptation to refine the components of or
total number of cycles of treatment.5-7,35,36 For example,
when an interim PET scan is negative, the RATHL study
established noninferiority of omitting bleomycin after two
cycles of ABVD,35 while HD18 demonstrated the similar ef-
ficacy of a reduced number of escalated BEACOPP cycles.5 In
adult and pediatric patients, the incorporation of BV into
initial therapy of advanced-stage cHL on the basis of the
ECHELON-1 and AHOD1331 studies led to improved efficacy
and led to the approval of BV as part of standard frontline
therapy. Adult patients treated with BV-AVD for six cycles
had superior modified PFS, PFS, and overall survival (OS)
compared with six cycles of non–PET-adapted ABVD.25,28
Better efficacy was paired with increased toxicity in adult
patients, with BV-AVD resulting in more PN, febrile neu-
tropenia, and sepsis, and necessitating the use of prophy-
lactic granulocyte colony-stimulating factor (G-CSF). In
pediatric patients, BV with doxorubicin, vincristine, eto-
poside, prednisone, and cyclophosphamide led to improved
event-free survival in patients with stage IIB with bulk, IIIB,
and IVA-B cHL without a difference in toxicity compared
with standard treatment.27 However, a majority of pediatric
patients (53.4%) received consolidative radiotherapy even
after incorporation of BV, which can be associated with late
toxic effects in this young, particularly vulnerable
population.37
The randomized HD21 study evaluated the inclusion of BV
into a BEACOPP backbone with additional chemotherapy
refinements aimed at establishing noninferior efficacy while
reducing acute and long-term toxicities such as infertility
and secondary malignancies. Differences between BV, eto-
poside, doxorubicin, cyclophosphamide, dacarbazine, and
dexamethasone (BrECADD) and the escalated BEACOPP
regimen include reduced etoposide dosing, substitution of
BV for vincristine, omission of bleomycin, substitution of
dacarbazine for procarbazine, and substitution of a shorter
course of dexamethasone for prednisone. The primary safety
end point, reduction of treatment-related morbidity, was
met, with BrECADD resulting in less Common Terminology
Criteria for Adverse Events grade 3-4 organ toxicity or grade
4 anemia, thrombocytopenia, or infection (42% v 59% with
BEACOPP; P < .0001). Fewer transfusions (8% v 22% red cell
transfusion, 6% v 13% platelet transfusion) were necessary
with BrECADD and there was also less sensory PN (38% v
49%) than with BEACOPP. Notably, there appeared to be
better residual ovarian function after BrECADD, with post-
 Paradigm Shifts in Hodgkin Lymphoma
treatment mean follicle stimulating hormone (FSH) levels in
female and male patients in the normal range compared with
abnormal mean post-treatment FSH levels after BEACOPP.
At 3 years, the PFS in patients with advanced-stage cHL
treated with BrECADD (94.9%) was excellent and non-
inferior to the 3-year PFS after escalated BEACOPP
(92.3%).38 With reduced acute toxicity, noninferior efficacy,
and early signals that there will be less long-term toxicity,
BrECADD supplants BEACOPP as a standard treatment for
advanced-stage cHL when intensified therapy is desired.
The S1826 study, led by SWOG Cancer Research Network, was
the first randomized phase III study to examine PD-1
blockade as initial treatment of advanced-stage (III-IV) cHL.
S1826 was also the first collaborative study between the adult
National Cancer Institute–funded National Clinical Trials
Network groups and the Children’s Oncology Group with the
goal of evaluating a harmonized cHL therapy regimen across
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the pediatric and adult age spectrum. Patients age 12 years or
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.
older were randomly assigned 1:1 to receive six cycles of
either nivolumab combined with AVD chemotherapy
(N-AVD) or standard BV-AVD and could receive radiation to
residually metabolically active lesions on end of treatment
(EOT) PET. Patients were stratified on the basis of age, in-
ternational prognostic score (IPS), and the intent to use EOT
consolidative radiation. Patients receiving BV-AVD were
required to receive G-CSF, while growth factor support was
optional for patients receiving N-AVD.
The S1826 study accrued nearly a year ahead of schedule
despite the COVID-19 pandemic; 994 patients were enrolled.
The study population was diverse; nearly one fourth of
patients were younger than 18 years, 10% were older than
60 years, and about one fourth of patients were from un-
derrepresented racial/ethnic backgrounds. Less than 1% of
patients received per-protocol EOT radiation. At the second
planned interim analysis, the SWOG Data and Safety Mon-
itoring Committee determined that the study had met its
primary end point. With a median of 12.1 months of follow-
up time, N-AVD resulted in superior PFS compared with BV-
AVD (hazard ratio, 0.48 [99% CI, 0.27 to 0.87], one-sided P 5
.0005). The 1-year PFS after N-AVD was 94% compared with
86% after BV-AVD. The PFS benefit with nivolumab was
consistent across patient subgroups regardless of age, IPS
score, and stage. There were 11 deaths in the BV arm com-
pared with four in the nivolumab arm. N-AVD was better
tolerated than BV-AVD, with a higher treatment discon-
tinuation rate in the BV arm and low rates of immune-related
adverse events experienced in the nivolumab group. Neu-
tropenia was more frequent in the nivolumab group because
of lack of mandated G-CSF prophylaxis; however, the rates
of febrile neutropenia, sepsis, and infection were not in-
creased.39 On the basis of the superior efficacy, improved
tolerability, and low rate of radiation usage, S1826 has
changed the treatment paradigm for patients with
advanced-stage cHL. N-AVD is a new standard of care,
establishing the key role of PD-1 blockade in the initial
treatment of cHL (Table 1).
ASCO Educational Book
PARADIGM CHANGES FOR RELAPSED
HODGKIN LYMPHOMA
Patients with relapsed/refractory (RR) cHL were tradition-
ally treated with non–cross-resistant regimens of cytotoxic
chemotherapy followed by ASCT in chemosensitive patients.
The most common regimens included platinum-based
chemotherapy with ifosfamide, carboplatin, and etoposide
(ICE)44 or gemcitabine-containing regimens such as gem-
citabine, vinorelbine, and liposomal doxorubicin (GVD).45
These regimens were highly effective when paired with
ASCT, resulting in approximately 50% long-term cure
rates.46 The introduction of BV and anti–PD-1 antibodies
significantly improved outcomes in the relapsed setting,
with 2- and 5-year OS rates after ASCT reaching 75% and
59%, respectively.47 However, now that BV and PD-1
blockade are routinely used in the frontline setting, the role
of traditional chemotherapy versus anti–PD-1 versus BV for
relapsed patients is less clear. The remarkable efficacy of the
novel therapies in the salvage setting has further called into
question the role of transplantation. Although the data are
evolving, transplantation remains a cornerstone of therapy
for initial relapsing patients who are eligible. Multiple
studies have now shown that salvage therapy containing PD-
1 blockade consistently demonstrates improved outcomes
among patients proceeding to transplant regardless of
preceding therapy (Table 2).
Role of Brentuximab in Relapsed Therapy
BV was initially approved as a single agent among patients
with cHL who relapsed after multiple lines of therapy,
demonstrating a single-agent efficacy of 75% overall re-
sponse rate (ORR) and 34% complete remission (CR) with a
median PFS of 9.3 months.10 Subsequently, BV has been
studied as a single agent and in combination with chemo-
therapy in the pre-ASCT setting. BV was studied as mono-
therapy in the pre-ASCT setting, resulting in an ORR of 75%
and a CR rate of 43%, nearly identical to the post-ASCT
setting.17 Patients not in CR (Deaville score 1-3) after BV
alone received sequential chemotherapy and approximately
half of the patients proceeded to ASCT without salvage
chemotherapy. The outcomes of transplanted patients were
favorable, with a 2-year PFS of 77%. Moskowitz et al also
evaluated a PET-driven protocol that incorporated aug-
mented ICE chemotherapy for patients failing to achieve a CR
to BV alone. Only 27% of patients achieved a CR (Deauville
score 1-2) to BV alone, and the remainder received two cycles
of augmented ICE. Overall, 76% of patients achieved CR
before ASCT with this approach.19 Post-transplant outcomes
were excellent, with a 2-year PFS of 80%. Importantly, there
was no significant difference in outcomes between patients
achieving CR from BV alone versus after BV and augmented
ICE. Lynch et al48 achieved similar outcomes with a study of
combined dose-dense BV and ICE. However, there was
significant toxicity, both hematologic and nonhematologic,
and one treatment-related death. In addition to ICE, BV has
been combined with many other chemotherapy regimens,
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 4 | © 2024 by American Society of Clinical Oncology
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TABLE 1. Studies Incorporating Novel Agents as Initial Treatment of Advanced-Stage Classic Hodgkin Lymphoma
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

Median Age, Therapy Received/Arms Median Follow-Up,

Trial No. Clinical Disease Features Years of Treatment Years Response PFS OS
ECHELON 140 1,334 Stage III or IV 36 ABVD 36 5.1 BV-AVD BV-AVD
BV-AVD 36 6-year PFS 82.3% 6-year OS 93.9%
ABVD ABVD
5-year PFS 74.5% 6-year OS 89.4%
CHECKMATE 20541 51 Stage III, IV, or IIB with 37 Nivo 34 → nivo 1 AVD 36 0.93 84% ORR, 67% CR 9-month PFS 92% 9-month OS 98%

Burton, Allen, and Herrera

unfavorable risk factors
Sequential pembro and 30 Stage I/II unfavorable only, 29 Pembro 33 → AVD 34-6 1.9 CMR after pembro 37%, Median PFS not reached, Median OS not reached,
AVD42 stage III/IV (four cycles for early- CMR after AVD 100%, 2-year PFS 100% 2-year OS 100%
stage, six cycles for EOT CMR 100%
advanced-stage or
early-stage bulky)
Pembro 1 AVD30 30 Stage I, II, III, IV 32 Pembro 1 AVD (2-6 0.86 68% PET 2 neg, 78% EOT 1-year PFS 96% 1-year OS 100%
cycles) PET neg
S1826 994 Stage III-IV 27 N-AVD 36 BV-AVD 36 1 N-AVD: 1-year PFS 94% N-AVD: 1-year OS 99%
N-AVD v BV-AVD39 BV-AVD BV-AVD
1-year PFS 86% 1-year OS 98%

Abbreviations: ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AVD, doxorubicin, vinblastine, and dacarbazine; BV, brentuximab vedotin; BV-AVD, BV with AVD; CMR, complete metabolic
response; CR, complete remission; EOT, end of treatment; N-AVD, nivolumab combined with AVD; neg, negative; NIVO, nivolumab; ORR, overall response rate; OS, overall survival; Pembro,
pembrolizumab; PET, positron emission tomography; PFS, progression-free survival.
 ASCO Educational Book

TABLE 2. Novel Salvage Regimens for Relapsed/Refractory Classic Hodgkin Lymphoma

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Regimen Phase No. Primary Refractory, No. Relapsed, No. CMR, % PFS (all patients) PFS (ASCT cohort) Reference
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

BV-based salvage regimens

BV→augmented ICE II 45 25 20 761 82% at 3 years 82% at 3 years Moskowitz et al19
2
BV→salvage therapy II 57 35 22 74 71% at 2 years 71% at 2 years Herrera et al17
BV 1 ICE II 45 29 16 74 80% at 2 years Not reached Lynch et al48

Paradigm Shifts in Hodgkin Lymphoma

BV 1 ESHAP I/II 66 40 26 70 71% at 30 months Not reached Garcia-Sanz et al49
BV 1 DHAP II 61 23 38 79 76% at 2 years Not reached Hagenbeek et al50
BV 1 gemcitabine I/II 454 29 16 67 Not reached Not reached Cole et al51
BV 1 bendamustine I/II 55 28 27 74 62.6% at 2 years 70% at 2 years LaCasce et al52
Anti–PD-1–based salvage regimens
N 6 ICE5 II 39 18 21 91 72% at 2 years 94% at 2 years Mei et al18
Pem-ICE II 42 16 26 86.5 87.2% at 2 years Not reached Bryan et al21
7
Pem-GVD II 39 16 23 95 100% at 13.5 months 100% at 13.5 months Moskowitz et al20
BV 1 nivolumab I/II 91 38 53 67 78% at 2 years 91% at 3 years Herrera et al, Moskowitz et al16,53
BV 1 ipilimumab I/II 64 35 29 57 61% at 1 year 100% at 1 yeara Diefenbach et al54,55
BV 1 nivolumab 61 70% at 1 year Approximately 85% at 1 yeara
BV 1 ipilimumab 1 nivolumab 73 80% at 1 year Approximately 80% at 1 yeara

Abbreviations: ASCT, autologous stem-cell transplantation; BV, brentuximab vedotin; CMR, complete metabolic response by PET; DHAP, dexamethasone, cytarabine, cisplatin; ESHAP, etoposide,
cytarabine, cisplatin, methylprednisolone; GVD, gemcitabine, vinorelbine, and liposomal doxorubicin; ICE, ifosfamide, carboplatin, and etoposide; N 6 ICE, nivolumab with or without ICE; Pem,
asco.org/edbook | Volume 44, Issue 3 | 5

pembrolizumab; PET, positron emission tomography; PFS, progression-free survival.

a
Approximate number deduced from Kaplan-Meier estimates provided in the supplement.
 Burton, Allen, and Herrera
with high CR rates of 70%-79% and 2-year PFS rates of
70%-76% after ASCT.49,56,57
Anti–PD-1–Based Relapsed Therapy
Anti–PD-1–based therapy has been shown to be superior to
BV in multiple settings, including frontline and relapse. The
randomized phase III study, KEYNOTE-204, demonstrated
definitively the superiority of pembrolizumab versus BV in a
head-to-head comparison.58 Pembrolizumab resulted in a
median PFS of 13.2 months versus 8.3 months for BV. Sub-
sequently, trials have assessed multiple anti–PD-1 combi-
nations in transplant-eligible patients in combination with
chemotherapy, BV, and ipilimumab among others. Receipt of
PD-1–based salvage therapy at any point before ASCT is
associated with significantly improved PFS compared with
either BV or chemotherapy-based salvage treatments.59
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Pembro-GVD20 represents a fully outpatient-administered
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.
pretransplant regimen that was studied in a phase II clinical
trial of transplant-eligible patients with RR cHL (Clinical-
Trials.gov identifier: NCT03618550). Patients received 2-4
cycles and those who achieved CR by PET (Deauville ≤3) after
2-4 cycles proceeded to ASCT. Maintenance therapy after
ASCT was permitted, and approximately one third of patients
received maintenance BV. Most patients achieved a CR after
just two cycles of therapy (n 5 31), and the remainder re-
ceived four cycles (n 5 8). Thirty-six (95%) patients pro-
ceeded to ASCT. Pembro-GVD resulted in the best efficacy
reported to date, with overall and CR rates of 100% and 95%,
respectively. All transplanted patients remained in remission
at last follow-up. A similar approach but requiring inpatient
therapy was evaluated in a phase II study of pembrolizumab
with ICE resulting in 2-year estimates for PFS and OS of
87.2% and 95.1, respectively.21 New areas of FDG-PET
positivity in two patients were biopsied and not involved
with lymphoma, highlighting the challenge of false-positive
PET scans in the setting of immunotherapy.
ICE has also been combined with nivolumab in a sequential
fashion (Nivo-ICE). This PET-directed trial allowed
responding patients to receive nivolumab-only treatment
before transplant.18 Treatment included six cycles of nivolu-
mab followed by ASCT if CR was achieved. Those who did not
achieve a CR received Nivo-ICE chemotherapy for two cycles.
Most patients were able to receive ASCT with nivolumab alone
(n 5 34), while a minority (n 5 9) patients received nivolumab
followed by Nivo-ICE. The end-of-protocol-therapy CR rate
was 91%. Outcomes were excellent overall with most patients
proceeding directly to transplant and a 2-year PFS of 94% in
patients who proceeded to ASCT.
Finally, there have been novel-novel immunotherapy
combinations, all with excellent results. BV and nivolumab
for four cycles resulted in an ORR of 85%, a CR rate of 67%,
and an estimated 3-year PFS of 77%. The 3-year PFS was
high for those undergoing ASCT directly after BV 1 Nivo at
91%.60 A phase I study evaluated immunotherapy
6 | © 2024 by American Society of Clinical Oncology
combinations with BV, demonstrating similar results and
further demonstrating the superiority of PD-1 versus non–
PD-1–based therapy in this setting.54,55 Notably, the addition
of PD-1 therapy did not negatively affect stem-cell mobi-
lization or collection or engraftment in any of these studies.
Although there has not been a definitive randomized study
establishing the optimal salvage regimen for R/R cHL, on the
basis of the outstanding efficacy observed, anti–PD-1–
based salvage has been incorporated into routine practice
as a standard pretransplant strategy. A practical concern
with pretransplant anti–PD-1 therapies includes a possible
increased risk of engraftment syndrome, which should be
monitored closely and treated promptly with corticosteroids.
Given the abundance of data favoring anti–PD-1 salvage
therapy, we generally recommend incorporating a PD-1
antibody in combination with non–cross-resistant che-
motherapy or BV as salvage therapy ahead of ASCT for pa-
tients with R/R cHL after first-line therapy.61
With multiple studies demonstrating such excellent outcomes
after anti–PD-1–based salvage therapy in R/R cHL, recent
studies have evaluated PD-1 blockade combined with che-
motherapy or BV, often followed by anti–PD-1 maintenance,
and without subsequent ASCT (ClinicalTrials.gov identifier:
NCT05595447, NCT05675410, NCT02927769). The median
follow-up of these studies is too short thus far to draw any
conclusions, but it remains plausible that there may be a
subset of patients who may experience durable remission
after anti–PD-1–based salvage therapy without ASCT.
Post-Transplant Maintenance
To improve post-transplant remission, maintenance strate-
gies incorporating BV or PD-1 blockade have been studied.
Maintenance with brentuximab in the phase III AETHERA trial
demonstrated superior 5-year PFS of 59% versus 41%
compared with placebo.15 Eligibility was restricted to BV-
naı̈ve, high-risk patients with one or more of the following:
primary refractory disease, relapse <1 year after initial
therapy, or extranodal disease at relapse. Although this was a
practice-changing study at the time of its publication, sub-
sequent retrospective studies in the current novel therapy era
suggest the benefit of BV maintenance may be restricted to
patients who received no novel agents before ASCT.62
Anti–PD-1–based maintenance has been evaluated in three
single-arm phase II studies. Pembrolizumab was adminis-
tered for up to eight cycles within 60 days after ASCT in
patients with RR cHL (90% with high-risk factors per
AETHERA).63 Ultimately, therapy resulted in excellent long-
term outcomes, with an 18-month PFS for evaluable patients
of 82% and OS of 100%. There was increased toxicity, with
having 40% at least 1 grade 2 or higher immune-related AE.
Similar outcomes were seen with nivolumab monotherapy
and in a trial of nivolumab combined with BV. Preliminary
data from the trial of nivolumab monotherapy maintenance
reported a 6-month PFS of 92% and an OS of 100%.64 The
 Paradigm Shifts in Hodgkin Lymphoma
combination of BV 1 nivolumab as post-transplant main-
tenance resulted in an 18-month PFS of 94%.65 However,
dual therapy was associated with higher rates of toxicity,
including 53% rate of PN, 29% requiring corticosteroids for
an immune-related AE, and 24% discontinuing treatment
early. Nevertheless, this is one of the few modern studies to
report data on patients receiving previous novel agents; 51%
of patients had previous BV and 42% had previous anti–PD-1
therapy, suggesting that unlike BV, previous exposure did
not diminish efficacy of PD-1–based therapy in the post-
transplant setting.
The practical application of maintenance in the current era
includes consideration in high-risk patients with the novel
agent to which patients have either not been exposed or had
the best response and least toxicity.
Summary
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Copyright © 2024 American Society of Clinical Oncology. All rights reserved.
Salvage therapy followed by ASCT remains the standard
treatment for RR cHL after frontline therapy. On the basis of
the superb outcomes observed with the incorporation of
PD-1 blockade into salvage therapy, using anti–PD-1
therapy combined with chemotherapy or BV has become a
common practice. However, with the evolution of cHL
frontline therapy and routine incorporation of BV and PD-1
blockade, salvage regimens will need to be adapted according
to the agents received as initial treatment. Similarly, the
utility of maintenance therapy with novel agents is unclear
as BV and PD-1 blockade are used in frontline treatment and
pretransplant salvage therapy. A logical strategy for initial
management of RR cHL is to use the novel agents that have
not been used previously (eg, anti–PD-1–based therapy
after BV-AVD); however, future studies will be necessary to
evaluate the optimal salvage approach of RR cHL in the era of
frontline novel therapies.
TREATMENT CONSIDERATIONS FOR CHALLENGING
POPULATIONS WITH HODGKIN LYMPHOMA
Older patients have poorer outcomes with conventional
treatment, but with the advent of new targeted therapies for
cHL, there is increased attention on this challenging patient
population. There has also been increased focus on patient
comorbidities that can occur in both older and younger
patients, and proactive medical management and pre-
habilitation allows the most effective treatment for cHL to be
delivered. One other challenging patient population is the
occurrence of cHL during pregnancy, also requiring specific
managerial considerations.
Older Patients
Older patients age 60 years and older represent approxi-
mately 20% of cHL cases.66,67 Survival rates for older patients
with cHL are worse compared with younger patient
populations,68-72 and age- and sex-matched controls.66,73
Poorer outcomes are multifactorial and related to
ASCO Educational Book
comorbidities, poor performance status, histologic differ-
ences, and advanced stage. In addition, treatment-related
factors including inability to tolerate full-dose chemo-
therapy on schedule and increased incidence of treatment-
related toxicity affect outcome. Historically, older patients
have been underrepresented in clinical trials.69,74-76 How-
ever, there have been significant endeavors globally to
generate, collate, and study data on this patient population
as well as efforts to improve assessments of frailty and
functionality.
Frailty, as assessed by formal scores such as the cumulative
illness rating score and instrumental activities of daily living
(ADLs), at baseline diagnosis are strong predictors of OS in
elderly cHL.77-83 The UK Study of Hodgkin in the Elderly/
Lymphoma Database (SHIELD) registration study showed
that achievement of CR strongly predicted survival.84 Factors
associated with achieving CR were related to comorbidity
score and ADLs, and frail patients were consistently unable
to complete treatment. However, more research is needed to
delineate more comprehensive geriatric assessments rele-
vant to and prognostic for older patients with cHL.
Chemotherapy Approaches
In early-stage older cHL patients, the German Hodgkin
Study Group have analyzed outcomes with ABVD within the
HD10 and HD11 trials.85,86 They observed excellent 5-year
PFS estimated at 75%, but mean delay of treatment was
twice as high in the older patients (2.2 v 1.2 weeks), and WHO
grade 3 and 4 toxicity was also more frequent in this group
(68% v 50%), resulting in a treatment-related mortality of
5% in older patients. These trials suggested a reduction in
pulmonary toxicity with 2 versus four cycles of bleomycin-
containing treatment. The HD13 trial found that removing
bleomycin from two cycles of ABVD resulted in only a 4%
reduction in freedom from treatment failure 86,87 and further
retrospective data suggested that OS was not affected if
bleomycin dosing was reduced in older patients.83 Therefore,
in view of the high rate of pulmonary toxicity and associated
treatment-related mortality, bleomycin should generally be
omitted or used with great caution in older patients with cHL.
Alternative anthracycline-containing regimens including
cyclophosphamide, doxorubicin, vincristine, and predniso-
lone, and doxorubicin, cyclophosphamide, vincristine,
procarbazine, and prednisolone (ACOPP) have both been
used in older patients. A retrospective UK study of 41 older
patients with cHL demonstrated that ACOPP with dose-
reduced cyclophosphamide yielded 2-year PFS and OS of
73% and 93%, respectively, and was tolerated without severe
side effects, although nearly 60% of the population required
hospitalization during the treatment process.88
Approaches Using Brentuximab
Studies using BV-based treatment for older untreated pa-
tients with cHL deemed ineligible for conventional
asco.org/edbook | Volume 44, Issue 3 | 7
 Burton, Allen, and Herrera
combination chemotherapy have been conducted.88,89 The
UK study used single-agent BV for patients with cHL age
60 years and older or patients with cHL younger than
60 years, unfit or ineligible for combination chemotherapy
by cardiac ejection fraction <50%, significant cardiac
morbidity, and/or compromised lung function. Although BV
was reasonably well tolerated, response and durability were
limited, with a CR rate of 26% and median PFS of 7.3 months.
Additionally, 29% of patients stopped treatment because of
unacceptable toxicity, predominantly due to sensory
neuropathy.
In advanced-stage patients, the phase III ECHELON-1 study
A 1 AVD versus ABVD included 186 patients age 60 years and
older.40 With a median follow-up of 61 months, the 5-year
PFS rates with A 1 AVD versus ABVD were 67.1% versus
61.6%, respectively. Pulmonary adverse events were higher
with ABVD versus A-AVD (13% v 3%, respectively). The
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incidence of PN (any-grade 29% v 17%, respectively) and the
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.
incidence of severe PN (5% v <1%, respectively) were higher
in the A 1 AVD arm, although rates of resolution were similar
(85.6% v 87%, respectively).
BV has been used sequentially before and after standard AVD
in older patients with cHL.90 After two lead-in doses of
single-agent BV, patients received six cycles of AVD che-
motherapy followed by four consolidative doses of BV in
responding patients. Seventy-seven percent of 48 patients
completed six cycles of AVD and 73% received at least one BV
consolidation. ORR and CR rates after the initial BV lead-in
dose were 82% and 36%, respectively, and 2-year event-free
survival PFS and OS rates were 80%, 84% and 93%, re-
spectively. The study demonstrated that sequential BV-AVD
was well tolerated and was associated with favorable out-
comes for those older patients who can tolerate anthracy-
cline and combination chemotherapy, and geriatric-based
measures were strongly associated with patient survival.
However, 33% had grade 2 PN, and delivery of the treatment
occurred over a long time period.
In phase II, nonrandomized studies, BV monotherapy, BV
plus dacarbazine (DTIC), and BV plus bendamustine have
been evaluated.91,92 For patients receiving BV monotherapy,
the ORR was 92% (CR, 72%), but the relapse rate was high.
Twenty-two patients received 1.8 mg/kg BV and 375 mg/m2
DTIC for up to 12 cycles. Ninety-five percent achieved an
objective response, and 64% achieved CR. With a median
follow-up of 63.6 months, median duration of response
was 46.0 months. Median PFS was 47.2 months; median
OS was not reached. Ten patients (45%) experienced
grade ≥3 treatment-emergent adverse events, sensory PN
(27%) and neutropenia (9%), but overall it was well toler-
ated. Conversely, the addition of concurrent bendamustine
caused increased toxicity, including several treatment-
related deaths. For older patients with cHL, BV plus DTIC
may be a frontline option on the basis of tolerability and
response duration.
8 | © 2024 by American Society of Clinical Oncology
Anti–PD-1–Based Approaches
Two recently presented studies investigated PD-1 blockade as
frontline therapy for older patients with cHL.93,94 The pro-
spective Lysa phase II study assessed the safety and efficacy of
nivolumab alone or in combination with vinblastine in un-
treated patients age 61 years and older with cHL and coex-
isting medical conditions.93 Patients were given an induction
phase of six cycles of nivolumab. Patients who achieved
complete metabolic response (CMR) continued nivolumab
monotherapy with 18 additional cycles. Patients who achieved
a partial metabolic response (PMR) or worse received nivo-
lumab and vinblastine for 18 cycles. Overall, the efficacy was
disappointing: at EOT, 16 (28.6%) patients achieved CMR, 10
(17.9%) achieved PMR, 10 (17.9%) had no response, and
progressive disease was observed in 17 (30.4%) patients.
Fifteen (23.4%) patients died during treatment.
A recent Australian study used pembrolizumab as mono-
therapy for older patients with cHL unfit for chemother-
apy.94 Twenty-five patients received a median of 11 cycles
with 72% ORR with 32% CR rate. Although 5 patients died,
there were no treatment-related deaths. Immune-mediated
AEs were the commonest side effect, demonstrating that the
treatment was feasible with reasonable activity.
In the S1826 study, 97 patients age 60 years and older were
randomly assigned between N-AVD or BV-AVD.39 Grade 3
hematologic toxicity occurred in 52% of patients on N-AVD
and 38% on BV-AVD, but febrile neutropenia, sepsis, and
infections were lower for patients who received N-AVD
versus BV-AVD. PN was much less frequent with N-AVD than
BV-AVD in overall incidence and severity. One-year PFS was
93% for N-AVD and 64% for BV-AVD. Nonrelapse mortality
was 4% for N-AVD and 14% for BV-AVD. Treatment was
discontinued early in 10% of patients treated with N-AVD
and 33% of patients treated with BV-AVD. N-AVD improved
PFS and EFS and was better tolerated than BV-AVD in pa-
tients age 60 years and older, suggesting N-AVD is likely to
become a primary option in older patients who can tolerate
combination chemotherapy. The S1826 data suggested that
combined BV-AVD should be avoided in patients older than
60 years because of the high risk of sepsis/infection and
resulting treatment-related mortality.
Approaches Using BV and Anti–PD-1 Combination
BV has also been investigated with nivolumab as upfront
therapy in older patients.95,96 In a phase II trial of 46 patients,
BV 1 nivolumab for a maximum eight cycles produced a CMR
in 22 (48%) patients and PMR in six (13%) patients (ORR
61%). Another study evaluated a longer course of upfront BV
1 nivolumab (max 16 cycles) in older patients resulting in
86% ORR and a CR rate of 67% and more durable responses.
With 51.6 months of median follow-up, mDOR, mPFS, and
mOS were not reached. Seventy-six percent with BV-
nivolumab experienced grade ≥3 treatment-emergent ad-
verse events, and increased lipase (24%), motor PN (19%),
 ASCO Educational Book

TABLE 3. Studies Incorporating Novel Agents Into Initial Therapy of Older Adults With cHL

Median Age, Therapy Received/Arms of Median Follow-Up,

Trial No. Clinical Disease Features Years Treatment Years Response PFS OS
BV (BREVITY)89 38 Stage II with B symptoms or 77 BV monotherapy 316 cycles 3 ORR 83.9%, CR Median PFS 7.3 Median OS 19.5
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bulky disease, stage III, stage 25.8% months months

IV unfit for standard
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

chemotherapy
BV97 27 Age ≥60 years cHL 78 BV monotherapy 316 cycles ORR 92%, CR 73% Median PFS 10.5 Median OS not
months reached
Sequential BV→AVD in 69 Stage I, II, III, IV age ≥60 years 69 BV 32 → AVD 36 → BV 34 0.52 ORR 82%, CR 36% 2-year PFS 84% 2-year OS 93%
elderly90

Paradigm Shifts in Hodgkin Lymphoma

BV 1 bendamustine 59 Stage III, IV elderly cHL 70.3 BV 1 bendamustine 1.7 2-year PFS 54% 2-year OS 83%
(HALO)91
BV 1 DTIC92 19 Stage I-IV, age ≥60 years 69 BV 1 dacarbazine 4.83 ORR 100%, CR 68% Median PFS 46.8 Median PFS 64
months months
BV 1 bendamustine92 20 Stage I-IV, age ≥60 years 75 BV 1 bendamustine 4.3 ORR 100%, CR 88% Median PFS 40.3 Median OS 46.9
months months
BV 1 NIVO (≤16 cycles)92 21 Stage I-IV, age ≥60 years 72 BV 1 NIVO for up to 16 cycles 1.6 ORR 95%, CR 79% Median PFS not Median OS not
reached reached
NIVO (eight cycles) 64 Stage I, II, III, IV age ≥61 years 75 NIVO for 6 cycles 1.7 ORR 51.9% Median PFS 9.8 2-year OS 76.7%
6 vinblastine with coexisting medical If CMR, further 18 cycles of CR 28.6% months
NIVINIHO93 conditions NIVO
If PMR or worse, NIVO and
vinblastine for 18 cycles
Pembro94 27 Stage I, II, III, IV age ≥65 years or 77 Pembro up to 35 cycles 2.1 ORR 72% Median DOR 10.6 Median 2-year OS
unsuitable for standard CRR 32% months 83%
chemotherapy
BV 1 NIVO (eight cycles) 46 Stage I, II, III, IV age ≥60 years or 71.5 BV 1 NIVO for eight cycles 1.8 ORR 64%, CR 52% Median PFS 18.3 Median OS not
asco.org/edbook | Volume 44, Issue 3 | 9

(ACCRU RU051505I)95 unsuitable for standard months reached

chemotherapy

Abbreviations: AVD, doxorubicin, vinblastine, and dacarbazine; BV, brentuximab vedotin; cHL, classic Hodgkin lymphoma; CMR, complete metabolic response; CR, complete remission; DOR, duration
of response; DTIC, dacarbazine; NIVO, nivolumab; ORR, overall response rate; OS, overall survival; Pembro, pembrolizumab; PFS, progression-free survival; PMR, partial metabolic response.
 Burton, Allen, and Herrera
and sensory PN (19%) were most common with BV-
nivolumab. Further validation is needed, but these studies
suggest BV 1 nivolumab may be a useful option in older
patients with cHL who are unable to tolerate chemotherapy
(Table 3).
Patients With Comorbidities
Cardiac
Patients with preexisting heart disease or multiple cardiac risk
factors have an increased risk of heart failure with anthra-
cyclines. Among patients with preexisting cardiomyopathy or
heart failure, cHL-related mortality was fourfold higher than
cardiovascular mortality (37% v 8%) in a SEER-Medicare
analysis.98 The high mortality related to cHL was likely
partly due to less anthracycline use. In patients with estab-
lished cardiac disease, close collaboration with cardiology or
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cardio-oncology is necessary, so that with optimization of
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.
medical therapy, screening, surveillance echocardiograms,
and other strategies, it can be determined whether
anthracycline-containing regimens can be safely delivered.
Renal
The incidence of bleomycin lung toxicity ranges from 5% to
32%, with associated mortality rates of 10% to 25%.76,78,83,85
The primary risk factor is age, but the risk with increasing
age is due in part to declining creatinine clearance as
bleomycin is primarily metabolized renally. For patients with
renal impairment, there should be caution regarding the
administration of bleomycin. For patients with end-stage
renal failure, there are some case reports describing the safe
administration of BV in this scenario.99-101
Pregnancy
For the management of cHL in pregnancy, there are no
prospective trials. However, a number of case reports, series,
and cohorts have been published.102-107 The priority is the
mother’s health, and the patient should be managed jointly
with a specialist obstetric team.
Delaying therapy until postpartum can be considered
depending on timing, but in most circumstances, chemo-
therapy can be safely delivered in the second and third tri-
mesters, and maternal and fetal outcomes are excellent.
Termination of pregnancy only needs to be considered in
rare circumstances. Radiation-based imaging should be
AFFILIATIONS
1
Department of Haematology, St James’s University Hospital, Leeds,
United Kingdom
2
Department of Hematology and Oncology, Winship Cancer Institute of
Emory University, Atlanta, GA
3 C.B. and P.A. contributed equally to this work.
Division of Lymphoma, Department of Hematology and Hematopoietic
Cell Transplantation, City of Hope, Duarte, CA
10 | © 2024 by American Society of Clinical Oncology
avoided, and instead magnetic resonance imaging and ul-
trasound should be used for staging and response
assessment.
ABVD is the regimen of choice and has been used in all three
trimesters. The potential risk to fetal development is highest
in the first trimester with organogenesis occurring and
higher potential for teratogenicity, so exposure to chemo-
therapy in the first trimester should be avoided. For novel
agents such as brentuximab, there are no data regarding
their use in pregnancy, and their potential teratogenic and
toxic effects are unknown. Where possible, radiotherapy
should be delayed until after delivery.
Summary
Treatment for older, fit cHL patients should be given with
curative intent. In the majority of cases, this will include the
use of anthracyclines with reduction or omission of bleo-
mycin. Novel agents such as BV and PD-1 blockade can be
considered if available. Therapy for unfit or frail patients
depends on comorbidities and should be tailored to the
individual patient accordingly with attenuated or omission
of anthracycline-based therapy and potentially with use of
BV and/or checkpoint inhibitors. For older patients with cHL
or patients with comorbidities, there should be careful
clinical oversight with close monitoring of potential
treatment-related toxicities, including infectious compli-
cations and organ damage. For pregnant patients, it is im-
portant to prioritize the health of the mother and ABVD
chemotherapy can be safely delivered during the second and
third trimesters.
CONCLUSIONS
In recent years, the cHL treatment landscape has under-
gone dramatic shifts because of the incorporation of BV and
anti–PD-1–blocking antibodies. Randomized studies now
support the use of these novel agents as part of initial
therapy for advanced-stage cHL and there is abundant
evidence to support their use as part of salvage therapy
ahead of ASCT for RR cHL. Even in older patients and in
other challenging situations, curative-intent therapy can
be delivered, often with incorporation of novel therapies to
allow omission of bleomycin and/or reduce toxicity. From
upfront therapy to treatment of relapsed disease, BV and
PD-1 blockade have evolved the therapeutic paradigm for
cHL beyond reliance on our historic tools of chemotherapy
and radiation.
CORRESPONDING AUTHOR
Alex F. Herrera, MD; e-mail: aherrera@coh.org.
EQUAL CONTRIBUTION
 Paradigm Shifts in Hodgkin Lymphoma

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS Pamela Allen

OF INTEREST AND DATA AVAILABILITY STATEMENT
The following represents disclosure information provided by authors of
this manuscript. All relationships are considered compensated.
Relationships are self-held unless noted. I 5 Immediate Family
Member, Inst 5 My Institution. Relationships may not relate to the
subject matter of this manuscript. For more information about ASCO’s
conflict of interest policy, please refer to www.asco.org/rwc.
Cathy Burton
Honoraria: Takeda, Roche
Consulting or Advisory Role: Celgene, Bristol Myers Squibb, Takeda, Roche
Speakers’ Bureau: Roche, Celgene, Takeda, Gilead Sciences
Travel, Accommodations, Expenses: Takeda Science Foundation, Roche
Consulting or Advisory Role: Seattle Genetics/Astellas, Daichii Sankyo,
Kyowa Kirin International, BostonGene
Alex F. Herrera
Consulting or Advisory Role: Bristol Myers Squibb, Seagen, Merck,
Genentech/Roche, AstraZeneca/MedImmune, Karyopharm Therapeutics,
ADC Therapeutics, Takeda, Regeneron, Genmab, Tubulis GmbH, Pfizer,
Adicet Bio, Caribou Biosciences, AbbVie, Alimera Sciences
Research Funding: Bristol Myers Squibb (Inst), Merck (Inst), Genentech/
Roche (Inst), Kite, a Gilead company (Inst), AstraZeneca (Inst), Seagen (Inst),
Gilead Sciences (Inst), ADC Therapeutics (Inst)
No other potential conflicts of interest were reported.

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