Abstract
Classic Hodgkin lymphoma (cHL) is highly curable with risk-adapted first-line treatment. Due to exceptional efficacy, antiprogrammed cell death protein 1 antibodies (aPD1) are increasingly incorporated into first-line treatment. However, the short- and long-term immune-related adverse event burden in this setting is insufficiently understood. Here, we review the currently available evidence on the feasibility and safety of aPD1 first-line cHL treatment. A more harmonized and complete reporting is critical to enable a detailed understanding and comprehensive assessment of aPD1-related morbidity.
References
1.
Ansell
SM
, Bröckelmann
PJ
, von Keudell
G
, et al. Nivolumab for relapsed/refractory classical Hodgkin lymphoma: 5-year survival from the pivotal phase 2 CheckMate 205 study
. Blood Adv
. 2023
;7
(20
):6266
-6274
.2.
Armand
P
, Zinzani
PL
, Lee
HJ
, et al. Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma
. Blood
. 2023
;142
(10
):878
-886
.3.
Borchmann
P
, Ferdinandus
J
, Schneider
G
, et al; German Hodgkin Study Group
Swiss Group for Clinical Cancer Research
Arbeitsgemeinschaft Medikamentöse Tumortherapie
Nordic Lymphoma Group
Australasian Leukaemia and Lymphoma Group
. Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial
. Lancet
. 2024
;404
(10450
):341
-352
.4.
Sasse
S
, Bröckelmann
PJ
, Goergen
H
, et al. Long-term follow-up of contemporary treatment in early-stage Hodgkin lymphoma: updated analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 Trials
. J Clin Oncol
. 2017
;35
(18
):1999
-2007
.5.
Ansell
SM
, Radford
J
, Connors
JM
, et al; ECHELON-1 Study Group
. Overall survival with brentuximab vedotin in stage III or IV Hodgkin's lymphoma
. N Engl J Med
. 2022
;387
(4
):310
-320
.6.
Bröckelmann
PJ
. Hodgkin lymphoma: great progress with room for improvement
. Nat Rev Clin Oncol
. 2025
;22
(6
):379
-381
.7.
Kreissl
S
, Goergen
H
, Buehnen
I
, et al; German Hodgkin Study Group
. PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial
. Lancet Haematol
. 2021
;8
(6
):e398
-e409
.8.
Bröckelmann
PJ
, Müller
H
, Fuchs
M
, et al. Correlation between progression-free and overall survival in patients with Hodgkin lymphoma: a comprehensive analysis of individual patient data from randomized German Hodgkin Study Group (GHSG) trials
. Ann Oncol
. 2025
;36
(4
):393
-402
.9.
Kuderer
NM
, Desai
A
, Lustberg
MB
, Lyman
GH
. Mitigating acute chemotherapy-associated adverse events in patients with cancer
. Nat Rev Clin Oncol
. 2022
;19
(11
):681
-697
.10.
Lustberg
MB
, Kuderer
NM
, Desai
A
, Bergerot
C
, Lyman
GH
. Mitigating long-term and delayed adverse events associated with cancer treatment: implications for survivorship
. Nat Rev Clin Oncol
. 2023
;20
(8
):527
-542
.11.
Tison
A
, Garaud
S
, Chiche
L
, Cornec
D
, Kostine
M
. Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases
. Nat Rev Rheumatol
. 2022
;18
(11
):641
-656
.12.
Goodman
RS
, Lawless
A
, Woodford
R
, et al. Extended follow-up of chronic immune-related adverse events following adjuvant anti-PD-1 therapy for high-risk resected melanoma
. JAMA Netw Open
. 2023
;6
(8
):e2327145
.13.
Jayathilaka
B
, Mian
F
, Franchini
F
, Au-Yeung
G
, IJzerman
M
. Cancer and treatment specific incidence rates of immune-related adverse events induced by immune checkpoint inhibitors: a systematic review
. Br J Cancer
. 2025
;132
(1
):51
-57
.14.
Gougis
P
, Jochum
F
, Abbar
B
, et al. Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective
. EClinicalMedicine
. 2024
;70
:102536
.15.
Postow
MA
, Sidlow
R
, Hellmann
MD
. Immune-related adverse events associated with immune checkpoint blockade
. N Engl J Med
. 2018
;378
(2
):158
-168
.16.
Yin
Q
, Wu
L
, Han
L
, et al. Immune-related adverse events of immune checkpoint inhibitors: a review
. Front Immunol
. 2023
;14
:1167975
.17.
Johnson
DB
, Nebhan
CA
, Moslehi
JJ
, Balko
JM
. Immune-checkpoint inhibitors: long-term implications of toxicity
. Nat Rev Clin Oncol
. 2022
;19
(4
):254
-267
.18.
Naidoo
J
, Murphy
C
, Atkins
MB
, et al. Society for Immunotherapy of Cancer (SITC) consensus definitions for immune checkpoint inhibitor-associated immune-related adverse events (irAEs) terminology
. J Immunother Cancer
. 2023
;11
(3
):e006398
.19.
Owen
CN
, Bai
X
, Quah
T
, et al. Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma
. Ann Oncol
. 2021
;32
(7
):917
-925
.20.
Schulz
TU
, Zierold
S
, Sachse
MM
, et al. Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: prevalence and impact on patients' health-related quality of life
. Eur J Cancer
. 2022
;176
:88
-99
.21.
Iyer
PC
, Cabanillas
ME
, Waguespack
SG
, et al. Immune-related thyroiditis with immune checkpoint inhibitors
. Thyroid
. 2018
;28
(10
):1243
-1251
.22.
Mosaferi
T
, Tsai
K
, Sovich
S
, et al. Optimal thyroid hormone replacement dose in immune checkpoint inhibitor-associated hypothyroidism is distinct from Hashimoto's Thyroiditis
. Thyroid
. 2022
;32
(5
):496
-504
.23.
Allen
PB
, Savas
H
, Evens
AM
, et al. Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma
. Blood
. 2021
;137
(10
):1318
-1326
.24.
Allen
PB
, Lu
X
, Chen
Q
, et al. Sequential pembrolizumab and AVD are highly effective at any PD-L1 expression level in untreated Hodgkin lymphoma
. Blood Adv
. 2023
;7
(12
):2670
-2676
.25.
Bröckelmann
PJ
, Goergen
H
, Keller
U
, et al. Efficacy of nivolumab and AVD in early-stage unfavorable classic Hodgkin lymphoma: the randomized phase 2 German Hodgkin Study Group NIVAHL Trial
. JAMA Oncol
. 2020
;6
(6
):872
-880
.26.
Bröckelmann
PJ
, Bühnen
I
, Meissner
J
, et al. Nivolumab and doxorubicin, vinblastine, and dacarbazine in early-stage unfavorable Hodgkin lymphoma: final analysis of the randomized German Hodgkin Study Group Phase II NIVAHL trial
. J Clin Oncol
. 2023
;41
(6
):1193
-1199
.27.
Bröckelmann
PJ
, Bühnen
I
, Herhaus
P
, et al. Quality of life with nivolumab and AVD first-line treatment in Hodgkin lymphoma: patient-reported outcomes from the phase II GHSG Nivahl trial [abstract]
. Blood
. 2023
;142
(suppl 1
):1710
.28.
Dickinson
M
, Berkahn
L
, Trotman
J
, et al. P1066: pembrolizumab monotherapy as a first therapy for Hodgkin Lymphoma is deliverable in older or ABVD ineligible patients, does not preclude subsequent therapy, and provides adequate survival
. Hemasphere
. 2023
;7
(S3
):e691267e
.29.
Dickinson
MJ
, Trotman
J
, Berkahn
L
, et al. Pembrolizumab as first therapy for Hodgkin Lymphoma is deliverable in older or ABVD-ineligible patients, allows subsequent therapy, and gives adequate survival
. Hematological Oncol
. 2023
;41
(S2
):160
-161
.30.
Dickinson
M
. Pembrolizumab Monotherapy for Older/ABVD-Ineligible Patients With Hodgkin Lymphoma. VJHEMONC
; 2023
Accessed 6 November 2025. https://www.vjhemonc.com/video/kcqjhmelcpe-pembrolizumab-monotherapy-for-olderabvd-ineligible-patients-with-hodgkin-lymphoma/.31.
Friedberg
JW
, Bordoni
R
, Patel-Donnelly
D
, et al. Brentuximab vedotin with dacarbazine or nivolumab as frontline cHL therapy for older patients ineligible for chemotherapy
. Blood
. 2024
;143
(9
):786
-795
.32.
Herrera
AF
, LeBlanc
M
, Castellino
SM
, et al. Nivolumab+AVD in advanced-stage classic Hodgkin's lymphoma
. N Engl J Med
. 2024
;391
(15
):1379
-1389
.33.
Rutherford
SC
, Li
H
, Herrera
AF
, et al. Nivolumab-AVD versus brentuximab vedotin-AVD in older patients with advanced-stage classic Hodgkin lymphoma enrolled on S1826
. J Clin Oncol
. 2025
;43
(27
):2968
-2973
.34.
Lazarovici
J
, Amorim
S
, Bouabdallah
K
, et al. Nivolumab first-line therapy for elderly, frail Hodgkin lymphoma patients: Niviniho, a Lysa phase II study [abstract]
. Blood
. 2021
;138
(suppl 1
):232
.35.
Lee
HJ
, Ramchandren
R
, Friedman
J
, et al. Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for advanced-stage classical Hodgkin lymphoma
. Blood
. 2025
;145
(3
):290
-299
.36.
Lynch
RC
, Ujjani
CS
, Poh
C
, et al. Concurrent pembrolizumab with AVD for untreated classic Hodgkin lymphoma
. Blood
. 2023
;141
(21
):2576
-2586
.37.
Kuczmarski
TM
, Ujjani
CS
, Poh
C
, et al. Potential delayed immune-related adverse events in patients treated with frontline pembrolizumab + AVD for classic Hodgkin lymphoma [abstract]
. Blood
. 2024
;144
(suppl 1
):1667
.38.
Ramchandren
R
, Domingo-Domènech
E
, Rueda
A
, et al. Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 study
. J Clin Oncol
. 2019
;37
(23
):1997
-2007
.39.
Torka
P
, Feldman
T
, Savage
KJ
, et al. Phase II trial of nivolumab plus doxorubicin, vinblastine, dacarbazine as frontline therapy in older adults with Hodgkin lymphoma
. J Clin Oncol
. 2025
;43
(8
):985
-993
.40.
Bröckelmann
PJ
, Cliff
ERS
, Iacoboni
G
, et al. Beyond maximum grade: tolerability of immunotherapies, cellular therapies, and targeted agents in haematological malignancies
. Lancet Haematol
. 2025
;12
(6
):e470
-e481
.41.
Zhang
Z
, Sharma
R
, Hamad
L
, Riebandt
G
, Attwood
K
. Incidence of diabetes mellitus in patients treated with immune checkpoint inhibitors (ICI) therapy - a comprehensive cancer center experience
. Diabetes Res Clin Pract
. 2023
;202
:110776
.42.
Ferdinandus
J
, Schneider
G
, Moccia
A
, et al. Fertility in patients with advanced-stage classic Hodgkin lymphoma treated with BrECADD versus eBEACOPP: a secondary analysis of the multicentre, randomised, parallel, open-label, phase 3 HD21 trial
. Lancet Oncol
. 2025
;26
(8
):1081
-1090
.43.
Bröckelmann
PJ
, Bühnen
I
, Herhaus
P
, et al. Fertility and gonadal function after first-line treatment with nivolumab-AVD in Hodgkin lymphoma patients: an analysis from the phase II GHSG Nivahl trial [abstract]
. Blood
. 2023
;142
(suppl 1
):4456
.44.
Winship
AL
, Alesi
LR
, Sant
S
, et al. Checkpoint inhibitor immunotherapy diminishes oocyte number and quality in mice
. Nat Cancer
. 2022
;3
(8
):1
-13
.45.
Özdemir
BC
. Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology
. J Immunother Cancer
. 2021
;9
(2
):e002220
.46.
Ferdinandus
J
, Kaul
H
, Fosså
A
, et al. PET-guided Brecadd in older patients with advanced-stage classic Hodgkin lymphoma: results of the phase 2 part of the GHSG HD21 trial [abstract]
. Blood
. 2024
;144
(suppl 1
):568
.© 2025 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
2025
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