Received: 16 February 2024 Revised: 22 July 2024 Accepted: 25 July 2024
DOI: 10.1002/pbc.31250 Pediatric
Blood &
Cancer The American Society ofPediatric Hematology/OncologyR E S E A RCH ART I C L E
Symptomatic osteonecrosis in children treated for Hodgkin
lymphoma: A population-based study in Sweden, Finland, and
Denmark
Mia Giertz1,2 Henri Aarnivala3,4 SaschaWilkMichelsen5
Caroline Björklund6 Annika Englund1,2 Marika Grönroos7
Lisa Lyngsie Hjalgrim5 Pasi Huttunen8 TuukkaNiinimäki4,9 Eva Penno10
Tuuli Pöyhönen11 Päivi Raittinen12 Susanna Ranta13,14 Johan E. Svahn15
Lisa Törnudd16,17 Riitta Niinimäki3,4 Arja Harila1,2
1Department ofWomen’s and Children’s Health, Uppsala University, Uppsala, Sweden
2Department of Pediatric Oncology andHematology, Uppsala University Hospital, Uppsala, Sweden
3Department of Paediatrics, Oulu University Hospital, Oulu, Finland
4Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland
5Department of Pediatric Hematology andOncology, Department of Pediatric and AdolescenceMedicine, JulianeMarie Centret, University Hospital Copenhagen,
Copenhagen, Denmark
6Department of Pediatric Hematology andOncology, UmeåUniversity Hospital, Umeå, Sweden
7Department of Pediatrics, Turku University Hospital, Turku, Finland
8Department of Pediatric Hematology, Oncology and StemCell Transplantation, NewChildren’s Hospital, Helsinki University Hospital, Helsinki, Finland
9Department of Surgery, Oulu University Hospital, Oulu, Finland
10Department of Surgical Sciences, Unit of Radiology, Uppsala University, Uppsala, Sweden
11Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland
12Centre for Child Health Research, Tampere University and University Hospital, Tampere, Finland
13Department ofWomen’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
14Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
15Department of Paediatric Oncology, Skåne University Hospital, Lund University, Lund, Sweden
16Division of Children’s andWomen’s Health, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
17Department of Pediatrics, H.R.H Crown Princess Victoria’s Children’s and Youth Hospital, Linköping, Sweden
Correspondence
Mia Giertz, Akademiska sjukhuset, 751 85
Uppsala, Sweden.
Email: mia.giertz@uu.se
Previous publication: Part of these data has
been presented as ameeting abstract and oral
Abstract
Background: Osteonecrosis (ON) is a potentially disabling skeletal complication of
cancer treatment. Although symptomatic osteonecrosis (sON) is well-known in acute
lymphoblastic leukemia (ALL),with an incidencearound6%, studies on sON inpediatric
Abbreviations: ABVD, doxorubicin hydrochloride (adriamycin), bleomycin sulfate, vinblastine sulfate, and dacarbazine; ALL, acute lymphoblastic leukemia; BMI, bodymass index; CI, confidence
interval; EOT, end of treatment; EuroNet-PHL, EuropeanNetwork for Paediatric Hodgkin Lymphoma; GC, glucocorticoids; GPOH-HD, German Society of Pediatric Oncology and
Hematology-Hodgkin’s Disease; HL, Hodgkin lymphoma; IOTF, International Obesity Task Force;MRI, magnetic resonance imaging; NLPHL, nodular lymphocyte-predominant Hodgkin lymphoma;
ON, osteonecrosis; OR, odds ratio; SDS, standard deviation score; sON, symptomatic osteonecrosis; TJA, total joint arthroplasty.
Mia Giertz andHenri Aarnivala contributed equally as first authors.Riitta Niinimäki and Arja Harila contributed equally as last authors.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2024 The Author(s). Pediatric Blood &Cancer published byWiley Periodicals LLC.
Pediatr Blood Cancer. 2024;e31250. wileyonlinelibrary.com/journal/pbc 1 of 11
https://doi.org/10.1002/pbc.31250
2 of 11 GIERTZ ET AL.
presentation at the virtual NOPHO39th
Annual meeting onMay 9, 2022, with the title,
“Osteonecrosis in paediatric Hodgkin lymphoma,
preliminary results from a cohort study in Sweden,
Finland and Denmark.”Not published at any
official site.
Funding information
Mary Beve’s Foundation; Gerd Ahlman’s Fund;
Swedish Childhood Cancer Fund; Alma and K.
A. Snellman Foundation; Väre Foundation for
Pediatric Cancer Research; Danish Childhood
Cancer Foundation, Grant/Award Number:
2021-7439; Lion’s Cancer Research Fund of
Middle Sweden
Hodgkin lymphoma (HL) are scarce. The aimof this studywas to examine the incidence,
risk factors, and outcome of sON in children treated for HL.
Procedure: A total of 490 children under 18, diagnosed with HL between 2005
and 2019 in Sweden, Finland, and Denmark were eligible for the study. Data on
patient characteristics, HL treatment, and development of sON were collected from
patients’ medical records. Magnetic resonance imaging scans were used to establish
ON diagnosis and gradeON according to the Niinimäki grading system.
Results: Cumulative 2-year incidence of sON among the 489 included patients was
5.5% (n = 30). The risk for developing sON was higher for those with older age (odds
ratio [OR] 1.25, 95% confidence interval [CI]: 1.05–1.49, p< .010), female sex (OR4.45,
CI 1.87–10.58,p< .001), high total cumulative glucocorticoid (GC)doses (OR1.76, 95%
CI: 1.21-2.56, p= 0.003), and advancedHL (OR 2.19, 95%CI: 1.03-4.65, p= .042). Four
(13.3%) patients underwent major surgical procedures and 13 (43.3%) had persistent
symptoms due toON at follow-up.
Conclusions: This study shows that sON is as common in pediatric HL as in pediatric
ALL, with risk factors such as older age, female sex, high cumulative GC doses, and
advancedHL. FutureHL protocol development should aim to reduce the burden ofON
bymodifying GC treatment.
KEYWORDS
children, Hodgkin lymphoma, osteonecrosis
1 INTRODUCTION
Hodgkin lymphoma (HL) is one of the most common malignancies
in teenagers and young adults aged 12–29, with approximately 80
new pediatric cases in the Nordic countries each year.1–3 Over the
past decades, treatment for pediatric HL has been adjusted to mini-
mize toxicities and late complications, with a special focus on reducing
radiation burden, without compromising the excellent 5-year survival
of over 95%.1,4–6 Treatment in the Nordic countries has for the last
15 years followed the European Network for Paediatric Hodgkin Lym-
phoma (EuroNet-PHL) protocols.7 This treatment consists of intensive
chemotherapy including high doses of glucocorticoids (GC) combined
with consolidating radiation therapy (RT) for those with inferior
positronemission tomography (PET) response to induction chemother-
apy. There are numerous side effects to intensive GC treatment, one
being osteonecrosis (ON).8–10 ON is thought to be caused by compro-
mised blood circulation to the bone that leads to degenerative changes
and destruction of the joints, primarily the knees and hips.11–13 Multi-
ple sites are often affected, and symptoms range from asymptomatic
to immobilizing pain, occasionally leading tomajor surgical procedures
such as total joint arthroplasty (TJA).9,14,15
Although there are numerous studies describing ON in pediatric
acute lymphoblastic leukemia (ALL), showing incidence rates around
6% in northern European cohorts,13,14 studies analyzing ON in larger
pediatric HL cohorts are lacking.10,16–18 The German HL Study group
reported a cumulative incidence of ON of 0.2%–1.0% (depending on
HL stage) in patients 16–60 years of age. In their study, younger age
at diagnosis, male sex, and higher cumulative GC were risk factors for
ON.18 Conversely, risk factors for ON in pediatric ALL have included
higher age, female sex, and higher body mass index (BMI).13,14,19 The
risk of ON appears especially high in patients with cancer who were
treated with high doses of GC from the start of puberty to early
adulthood.20 Most pediatric patientswithHL are older than 10 at diag-
nosis and receive high doses of GC, suggesting that the risk of ON in
children with HLmay be higher than reported in adults.
The aim of this study was to systematically explore the incidence,
risk factors, treatment, and outcome of symptomatic ON (sON) in a
population-based Nordic cohort of children and adolescents treated
for HL.
2 METHODS
2.1 Study design
This study was conducted as a population-based retrospective obser-
vational cohort study. All children under 18 who were diagnosed with
HL from 2005 to 2019 in Sweden, Finland, and Denmark were eli-
gible for the study. Diagnosis of HL was based on the World Health
Organization (WHO) classification, including classic nodular sclerosis
HL, lymphocyte-rich classical HL, mixed cellularity HL, lymphocyte-
depletedHL, andnodular lymphocyte-predominantHL (NLPHL).21 The
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GIERTZ ET AL. 3 of 11
study was approved by the Ethical Review Authority in each partici-
pating country (Sweden: 2020-00174, 2021-03247, 2023-01174-02;
Finland: 271/2019; Denmark: R-20073404). All data collection and
analysis weremanaged according to the Declaration of Helsinki.
2.2 Data collection
Patients were identified from either the National Childhood Cancer
Registry (Sweden and Denmark) or hospital medical records (Fin-
land) based on the International Classification of Disease—Tenth
revision (ICD-10) for HL (C81.0-C81.9). Patient characteristics, HL
diagnosis, and treatment, as well as presenting symptoms, diagnosis,
and management of sON, were obtained from the registries and
medical records between August 2020 and October 2022. Data were
collected by a local clinician or research nurse, using a case report form
(CRF).
All reportedONhadbeendiagnosedwithmagnetic resonance imag-
ing (MRI) at the local treatment center. The MRI scans were collected
for centralized review by a pediatric radiologist (Eva Penno) and an
orthopedic surgeon (Tuukka Niinimäki) to both confirm ON diagnosis
and grade ON lesions sync the Niinimäki classification system (Table
S1).22 The two reviewers worked independently and were blinded to
all patient data. The radiographic definition of ONwas a circumscribed
lesionwith a distinct rim of low signal intensity on T1-weighted images
(band sign), and high signal intensity on short tau inversion recovery
images (double-line sign).23 The definition of sON was persistence of
pain in one or more locations of an extremity, in combination with
confirmed osteonecrotic lesions onMRI.11,24
Date of developing sON was registered as the date of radiological
confirmation of ON lesions in patients reporting pain or other symp-
toms leading to radiological examination. Date of last follow-upwas set
as date of last contact with healthcare, as documented in the patients’
medical records at the local treatment center. For six patients, date for
last follow-up was missing, and therefore end of treatment (EOT) was
considered as last follow-up.
Cumulative GC doses given as part of HL treatment were calcu-
lated as prednisolone equivalents in mg/m2. Dexamethasone doses
were converted to GC equivalent of prednisolone by conversion fac-
tor 6.67.25 Possible extra doses of GC given outside of the treatment
protocol were not considered.
The International Obesity Task Force (IOTF) BMI cutoffs were
used to assess BMI, in which BMI less than 17 kg/m2 corresponds
to underweight, BMI 17−25 as normal, BMI greater than 25 over-
weight, and greater than 30 obesity.26 To compare changes in BMI at
different time points, such as diagnosis of HL, diagnosis of sON and
EOT, IOTF-BMI was transformed to standard deviation scores (SDS).
Children under 5 years were defined as overweight or obese for SDS
+2.27 Children 5−18 years were defined as overweight for SDS +1,
and obese for SDS +2.28 Pubertal status was categorized as “not in
puberty” or “in/completed puberty.” For 99 patients (20.2%), puber-
tal status at HL diagnosis had not been reported, and it was therefore
estimated when possible. Females ≥13 and males ≥14 were listed
as “in/completed puberty” and females ≤8 and males ≤9 as “not in
puberty.”
2.3 Data analysis and statistics
All data were analyzed with the Statistical Program for Social Sciences
(SPSS), version 28.0.1.0. Patient characteristics were summarized by
descriptive statistics. Categorical datawere presented as numbers and
fractions (%). Continuous data were presented as means and medi-
ans. Continuous variables were compared using the Mann–Whitney
test, and categorical variables using the chi-square test. A competing
risks analysis (for death prior to sON diagnosis) was not performed,
as the single patient who died did so after being diagnosed with sON.
Therefore, death was not a competing risk for observing sON in this
group of patients. As the dependent variable (sON) is binary, simple
and multiple logistic regression was used. All independent variables
(age, sex, HL stage, GC doses, BMI, pubertal status, and radiotherapy)
were analyzed separately to get unadjusted results (simple regression).
Due to the small cohort and risk for overfitting, we could only adjust
for age, sex, and HL stage (multiple regression). The independent vari-
ables were checked for multicollinearity, and showed no strong linear
correlations. Kaplan–Meier survival analysis was performed to esti-
mate cumulative incidence of sON. Associations with p < .05 were
considered significant.
3 RESULTS
3.1 Patient characteristics
In total, 490 children were eligible for the study in Sweden (n = 255),
Finland (n = 122), and Denmark (n = 113). Data were incomplete
for one patient from Sweden; thus, 489 patients were included in
the analyses (Figure 1). Descriptive data are presented in Table 1.
All patients had been treated according to protocols as part of Euro-
pean clinical trials (GPOH-HD [German Society of Pediatric Oncol-
ogy and Hematology-Hodgkin’s Disease] 95, GPOH-HD 2002 pilot,
EuroNet-PHL-C1 and EuroNet-PHL-C2, EuroNet-PHL-LP1), including
combinations of different chemotherapeutic agents, with or without
prednisone. Prednisone doses were given based on body surface, and
varied both in total doses and treatment duration between patients,
due to different HL stages and protocols. Radiotherapy was given to
thosewith inadequate response to therapyanddosesdifferedbetween
protocols due to gradual reductions over time. Detailed information on
treatment regimens are shown in Table S2.
3.2 Incidence and timing of sON
ON lesions were reported in 44 (9%) patients. However, ON lesions in
14 patients were incidental findings detected by MRI performed due
to other indications, and these asymptomatic ON cases were excluded
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4 of 11 GIERTZ ET AL.
F IGURE 1 Study flowchart. Osteonecrosis (ON).
from further analysis. Hence, a total of 30 (6.1%) patients with sON
were included in the statistical analyses. The cumulative 2- and 5-year
incidence of sON was 5.5% (95% confidence interval [CI]: 3.34–7.66)
and6.4% (95%CI: 4.05–8.75), respectively.As shown inTable2,median
time from HL diagnosis to sON diagnosis by MRI was 9.3 months
(range: 1.5–118.8). Eleven (36.7%) patients (eight females, threemales)
were diagnosed with sON during HL treatment, with a median time
to sON of 4.1 months (range: 1.5–7.9). Out of the 19 (63.3%) patients
who were diagnosed with sON after end of HL therapy, six patients
reported symptoms consistent with sON already during therapy. One
patient complained of knee pain already during HL treatment, but was
not diagnosed with sON in the knees until 9 years later at a follow-up
clinic.
3.3 Sites and severity of sON
Joint ON was present in 23 (76.7%) patients. Two (6.7%) patients
already had Niinimäki grade 5 ON (joint collapse) at initial diagnosis
of sON. Details regarding sON location and severity are presented in
Table 2.
3.4 Age and puberty
Mean age of patients with sON was higher than in patients without
sON (15.3 ± 1.6 vs. 13.8 ± 3.2 years, p < .001). One sON patient was
10.8 years old, while all others were older than 12. In multiple analysis,
the odds of developing sONwas 25%higher for each added year of age
(odds ratio [OR] 1.25, 95%CI: 1.04–1.51, p= .016) (Table 3). Out of the
30 patients with sON, 27 were in puberty or had completed puberty.
There were no differences in pubertal status between patients with or
without sONwith either chi-square test or logistic regression.
3.5 Sex distribution
Females had a higher risk of developing sON thanmales, 23/218 versus
7/271 (10.6% vs. 2.6%, p< .001). The difference in sON incidence over
time is visualized in Figure 2, which demonstrates a 2-year cumulative
incidence in females of 9.5% (95% CI: 5.58–13.42) compared to 2.3%
inmales (95%CI: 0.54–4.06, p< .001). In the whole cohort, the odds of
developing sONwere four times higher for females than for males (OR
4.45, 95%CI: 1.87–10.58, p< .001), and 22 out of 177 (12.4%) pubertal
females developed sON (Table 3).
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GIERTZ ET AL. 5 of 11
TABLE 1 Descriptives of the cohort.
All patients (N= 489) No sON (N= 459) sON (N= 30)
Mean ± SD Mean ± SD Mean ± SD pa
Age at diagnosis 13.86 ± 3.13 13.76 ± 3.18 15.31 ± 1.59 <.001
Cumulative GC dose inmg 2857 ± 1280 2807 ± 1290 3623 ± 809 .002
BMI SDS at diagnosisb 0.26 ± 1.18 0.27 ± 1.17 0.09 ± 1.32 .431
BMI SDS change from diagnosis to end of
therapyc
0.64 ± 0.76 0.63 ± 0.75 0.81 ± 0.71 .242
N (%) N (%) N (%)
Sex <.001
Male 271 (55.4%) 264 (57.5%) 7 (23.3%)
Female 218 (44.6%) 195 (42.5%) 23 (76.7%)
Country .038
Sweden 254 (51.9%) 245 (53.4%) 9 (30.0%)
Denmark 113 (23.1%) 104 (22.7%) 9 (30.0%)
Finland 122 (24.9%) 110 (24.0%) 12 (40.0%)
BMI at diagnosis .392
Underweight 17 (3.5%) 13 (2.8%) 4 (13.3%)
Normal 355 (72.6%) 333 (72.6%) 18 (60.0%)
Overweight 73 (14.9%) 69 (15.0%) 4 (13.3%)
Obese 22 (4.5%) 21 (4.6%) 1 (3.3%)
Unknown 22 (4.5%) 23 (5.0%) 3 (10.0%)
BMI at end of therapy .540
Underweight 9 (1.8%) 8 (1.7%) 1 (3.3%)
Normal 230 (47.0%) 217 (47.3%) 13 (43.3%)
Overweight 104 (21.3%) 96 (20.9%) 8 (26.7%)
Obese 46 (9.4%) 43 (9.4%) 3 (10.0%)
Unknown 100 (20.4%) 95 (20.7%) 5 (16.7%)
Pubertal status at diagnosis .076
Not in puberty 112 (22.9%) 109 (23.7%) 3 (10.0%)
In/completed puberty 348 (71.2%) 322 (70.2%) 26 (86.7%)
Unknown 29 (5.9%) 28 (6.1%) 1 (3.3%)
Subtype .218
Nodular sclerosis 357 (73%) 335 (73.0%) 22 (73.3%)
Mixed cellularity 51 (10.4%) 46 (10.0%) 5 (16.7%)
NLPHL 43 (8.8%) 43 (9.4%) 0 (0%)
HLNOS 38 (7.8%) 35 (7.6%) 3 (10.0%)
Stage .118
I 36 (7.4%) 36 (7.8%) 0 (0%)
II 246 (50.3%) 234 (51.0%) 12 (40%)
III 100 (20.4%) 92 (20.0%) 8 (26.7%)
IV 103 (21.2%) 93 (20.3%) 10 (33.3%)
Unknown 4 (0.8%) 4 (0.9%) 0 (0%)
Protocol .210
EuroNet PHL C1/C2 364 (74.4%) 337 (73.4%) 27 (90%)
GPOH-HD 95/2002 66 (13.5%) 65 (14.2%) 1 (3.3%)
ABVD 22 (4.5%) 22 (4.8%) 0
(Continues)
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 of 11 GIERTZ ET AL.
TABLE 1 (Continued)
N (%) N (%) N (%)
EuroNet PHL LP1 12 (2.5%) 12 (2.6%) 0
Other 25 (5.1%) 23 (5.0%) 2 (6.7%)
Radiotherapy .813
Yes 183 (37.4%) 171 (37.3%) 12 (40%)
No 299 (61.2%) 281 (61.2%) 18 (60%)
Unknown 7 (1.4%) 7 (1.5%) 0 (0%)
Relapse N/A
Yes 64 (13.1%) 62 (13.5%) 2 (6.7%)
No 425 (86.9%) 397 (86.5%) 28 (93.3%)
Overall survival N/A
Alive 477 (97.5%) 448 (97.6%) 29 (96.7%)
Dead 12 (2.5%) 11 (2.4%) 1 (3.3%)
Abbreviations: ABVD, doxorubicin hydrochloride (Adriamycinadriamycin), bleomycin sulfate, vinblastine sulfate, and dacarbazine; BMI SDS, body bodymass
index standard deviation score; EuroNet PHL, European Network Pediatric Hodgkin Lymphoma Study Group; GC, glucocorticoids; GPOH-HD, the German
Society of PediatricOncology and Hematology–-Hodgkin’s Disease; N/A, not assessed due to small numbers of patients who relapsed/died in the sON group;
NLPHL, nodular lymphocyte-predominant HL; NOS, not otherwise specified; SD, standard deviation; sON, symptomatic osteonecrosis.
aSignificance level p< .05 withMann–WhitneyU or X2 test.
bData available for 464 patients.
cData available for 387 patients.
3.6 Treatment and stage of HL
There was no significant difference in the risk of developing sON
between different treatment protocols (Table 1). GC was part of HL
treatment and/or pre-phase in 464 patients (94.9%).Of the 25 patients
who did not receive GC, 18 patients were treated with only ABVD
(doxorubicin hydrochloride [adriamycin], bleomycin sulfate, vinblastine
sulfate, and dacarbazine) courses, and the remaining seven patients
had NLPHL treated with various regimens.
All sON patients were treated with GC, and they received signifi-
cantly higher totalGCdosesduringHL treatment compared topatients
who did not develop sON (mean 3623 ± 809 vs. 2800 ± 1290 mg/m2,
p = .002). As seen in Table 3, the odds for sON were nearly doubled
for each 1000 mg of total cumulative GC given during the whole HL
treatment (OR 1.76, 95%CI: 1.21–2.56, p= .003).
There were no differences in sON when comparing the specific
HL stages I–IV. However, when grouping HL stages into low stage
(I+II) and advanced stage (III+IV), logistic regression analysis (Table 3)
showed that patients with low stage HL had twofold increased odds
of developing sON than patients with advanced stage HL (OR 2.19,
95% CI: 1.03–4.65, p = .042). The difference in cumulative 2-year inci-
dence of sON between low and advanced HL stage is visualized in
Figure 3.
3.7 BMI
Information on BMI categories was available for 467 patients (94.7%)
at HL diagnosis and for 389 (79.6%) patients at EOT. As seen in
Table 1, there were no differences between patients who developed
sONcompared to thosewhodid not develop sON, regarding IOTF-BMI
categories at diagnosis, mean IOTF-BMI SDS at diagnosis, nor in the
mean IOTF-BMI SDS change from diagnosis to EOT.
3.8 Symptoms and management of ON
Pain was the first symptom of ON in 29 (96.7%) patients. One patient
experienced fatigue in the shoulders. Treatment and recommendations
at sONdiagnosis are presented in Table 2. Four patients (three females,
one male) underwent bilateral hip replacement. Of note, the sole male
patient requiring hip TJA had undergone allogenic hematopoietic stem
cell transplantation (HSCT) prior to HL treatment. HL treatment was
modified in two patients, one who discontinued steroid treatment and
onewhowas switched to ABVD treatment.
3.9 Follow-up
In all patients, median follow-up time from diagnosis to last contact
with healthcare was 5.1 years (range: 0.2–16.7). There were no dif-
ferences in follow-up time between females (median 5.0 years, range:
0.2–13.8) and males (median 5.1 years, range: 0.3–16.7). Median time
for follow-up concerning sON symptoms and radiographic evaluation
was 3.8 years (range: 0.3–11.5). At last sON follow-up, symptoms
persisted in nine females and four males (13 patients, 43.3%). Two
patients relapsed after sON diagnosis, at 1 and 3 years, respectively.
One patient died 5 years after sON diagnosis (death caused by large
diffuse B-cell lymphoma).
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GIERTZ ET AL. 7 of 11
TABLE 2 Characteristics of patients (N= 30) with HL and sON,
severity and location of sON lesions, and therapeutic implications of
sON.
Characteristics Median (range)
Time to sON inmonths 9.3 (1.5–118.8)
Follow-up time (sON) in years 3.8 (0.3–11.5)
Total number of ON lesions per patient 3.6± 2.4
n (%)
Age
<10 years 0 (0%)
10–13.9 years 6 (20%)
14–17.9 years 24 (80%)
Timing of sON
During treatment 11 (36.7%)
After EOT 19 (63.3%)
Most common sites affected withON
Femur 20 (66.7%)
Tibia 17 (56.7%)
Knee 15 (50%)
Hip 11 (36.7%)
Highest Niinimäki grade at sON dx
Grade 5 2 (6.7%)
Grade 4 9 (30%)
Grade 3 10 (33.3%)
Grade 2 9 (30%)
Modified HL treatment
Yes 2 (6.7%)
No 21 (70%)
Unknown 7 (23.3%)
Weight-bearing restrictions
Yes 12 (40%)
No 17 (56.7%)
Unknown 1 (3.3%)
Crutches for mobility
Yes 7 (23.3%)
No 23 (76.7%)
Physiotherapy
Yes 18 (60.0%)
No 11 (36.7%)
Unknown 1 (3.3%)
Painmedication other than opioids
Yes 18 (60%)
No 11 (36.7%)
Unknown 1 (3.3%)
(Continues)
TABLE 2 (Continued)
Characteristics Median (range)
Oral opioids
Yes 10 (34.5%)
No 18 (62.1%)
Unknown 1 (3.4%)
Bisphosphonate treatment
Yes 6 (20%)
No 24 (80%)
Surgical interventionb
Yes 7 (23.3%)
No 23 (76.7%)
Symptoms at last follow-up
Yes 13 (43.3%)
No 13 (43.3%)
Unknown 4 (13.3%)
Abbreviations: HL, Hodgkin lymphoma; ON, osteonecrosis; sON, symp-
tomatic osteonecrosis.
aNumbers (n) do not add up to 100% as most patients had multiple ON
lesions at different sites.
bIncluding total joint arthroplasty (TJA), core decompression, arthroscopy,
lengthening of tragus tendon.
4 DISCUSSION
This systematic population-based study describes the largest complete
pediatric HL cohort to date, assessing sON and risk factors in 489 chil-
dren under 18 treated for HL in three Nordic countries. We report a
5.5% 2-year and a 6.4% 5-year cumulative incidence of sON. Risk fac-
tors for sON were older age, female sex, high GC doses, and advanced
HL. Out of the patients with sON, as many as 43.3% had persisting
symptoms at last follow-up, and 13% had undergonemajor hip surgery
by the time of data collection.
Reports of sON in children with HL are scarce.10,17,18,29 In the
only cohort study consisting exclusively of children and adolescents
with HL, ON was found by MRI screening in 10 of 24 patients (42%),
but only one presented with symptoms.17 Niinimaki et al. used MRI
screening at EOT in 32 children with cancer, and found four of seven
patients (57%) with HL to have ON, of whom two presented with
symptoms.10 In a retrospective study including mainly adults, Albano
et al. found ON using MRI screening in seven of 42 patients (17%).29
In a large study by Borchman et al. including 11,330 patients with HL
aged16−60years, 0.2%–1.0%developed sON (depending on the grade
of HL).18
Previous studies have not been able to define any specific risk fac-
tors forON in childrenwithHL, althoughhigherGCdosewasdescribed
as themain risk factor for ON in the aforementioned studies by Borch-
man et al. and Albano et al.18,29 Borchman et al. also found teenagers
and young adults to be at a higher risk of developing ON than older
adults. Interestingly, male sex was described as a risk factor for ON in
their cohort.18 Rather, our results on incidence and risk factors of ON
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 of 11 GIERTZ ET AL.
TABLE 3 Analysis of risk factors for symptomatic osteonecrosis.
Unadjusted Adjusted
95%CI 95%CI
OR Lower Upper pa OR Lower Upper pa
Age at diagnosis 1.25 1.05 1.49 .010 1.25 1.04 1.50 .016
Male (ref) <0.001 .001
Female 4.45 1.87 10.58 4.21 1.76 10.11
HL stage I+II (ref) 0.042 0.031
HL stage III+IV 2.19 1.03 4.65 2.34 1.08 5.08
Cumulative GC doseb 1.76 1.21 2.56 .003 N/A
BMI SDS change 1.39 0.80 2.39 .240 N/A
Not in puberty (ref) 0.072 N/A
In/completed puberty 0.33 0.99 1.1
No radiotherapy (ref) .813 N/A
Radiotherapy 0.91 0.43 1.194
Note: Unadjusted results analyzedwith simple logistic regression. Adjusted results analyzedwithmultiple logistic regression.
Abbreviations: BMI SDS change, change in body mass index standard deviation score from diagnosis to end of treatment; CI, confidence interval; N/A, not
assessed; OR, odds ratio.
aSignificance level p< .05.
bCumulative glucocorticoid doses in 1000mg.
F IGURE 2 Incidence of symptomatic osteonecrosis (sON) in
females versus males. CI, confidence interval.
are in accordance with those reported by Mogensen et al. in children
with ALL.14 Mogensen et al. found a 5-year 6.3% cumulative incidence
in pediatric ALL patients treated according to the Nordic Society of
Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol
and a 28% incidence in females over 10, which is higher than the 12.4%
incidence in pubertal females presented here. The elevated risk of sON
in pubertal females might be explained by increased estrogen levels
F IGURE 3 Incidence of symptomatic osteonecrosis (sON) in low
versus advanced stages of Hodgkin lymphoma (HL). CI, confidence
interval.
that promote intracortical bone remodeling, increase bone mass gain,
and have procoagulatory effects.30,31 All this can lead to an imbalance
between osseous metabolic/blood supply demands and real osseous
blood supply.12,20,31
Most treatment regimens for childhood HLworldwide include GC.7
However, young adults with early stage HL have often been treated
according to adult protocols generally consisting of ABVD courses
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GIERTZ ET AL. 9 of 11
without GC. These patients appear to have a much lower risk for ON
than young adults treated according to pediatric protocols containing
GC.17,18 In the present study, only patients who received GC within
their treatment developed sON, which is in accordance with litera-
ture. GC have a lipid-altering effect that is thought to induce ON and
hyperlipidemia has also been shown, by Mogensen et al., to be a risk
factor for ON in children with ALL.32–34 This suggests that patients
with a lower BMI might have a lower risk for ON, as they usually have
lower lipid levels than those with higher BMI. In our study, we did not
observe any association between BMI at diagnosis and risk of devel-
oping sON. Nevertheless, as nine patients were diagnosed with sON
already during chemotherapy, it is evident that not only the cumulative
GC dose, but also host-related factors play a role in the development
of sON. Differences in GC metabolism resulting in different GC expo-
sure and side effects are an example of such factors, and there are
some data on genetic variations predisposing to metabolic side effects
of dexamethasone.35
As many as 14 incidental cases of asymptomatic ON were found,
although no systematic screening for ON was performed. This high-
lights that asymptomatic ON is common, as shown in screening
studies.10,17,36 As asymptomatic ON does not always progress to sON,
and can only be found at actual screening or incidentally through other
MRI follow-up, there are no current recommendations for managing
or treating asymptomatic ON.15,36,37 According to present literature,
there is little to be done to prevent ON progression, regardless of
whether the lesions are symptomatic. This is supported in a review
from 2014, in which Te Winkel et al. stated that there is no conclusive
evidence to support the effectiveness of any specific intervention such
as weight-bearing restrictions, bisphosphonates, hyperbaric oxygen
therapy, or prostacyclin analogs. Te Winkel and colleagues there-
fore recommend only clinical screening of ON, focusing on persistent
pain or limited joint mobility.38 As no evidence-based conservative
treatment alternatives are available, management of sON in children
is mainly symptomatic and given on a case-by-case basis. Accord-
ingly, treatment of sON within our cohort consisted of weight-bearing
restrictions, pharmacological pain relief, and physiotherapy. All but two
sON patients diagnosed during chemotherapy carried through their
therapy with full GC doses.
With lack of options on secondary prevention and conservative
treatment, the most appealing way to decrease the impact of sON
would be to reduce GC doses in HL treatment protocols. Even in the
present study, it was observed that patients receivingABVD treatment
without GCdid not develop sON.However, ABVD carries a high risk of,
for example, cardiac and pulmonary toxicity.39–42 Hence, there should
be an attempt to compare theoverall toxicity profiles of different treat-
ment protocols rather than single toxicities when deciding on future
directions in HL therapy. This would require systematic registration
and reporting of treatment-associated toxicities, where there still is
much to be improved in clinical practice. Our results highlight the need
for new treatment strategies for HL to reduce sON risk, especially con-
sidering the excellent outcome in bothprimary and relapsedHL. Future
studies should focus on diminishing the risk of ON, either bymodifying
current chemotherapy alternatives or using targeted therapies already
used in adultswithHL.43–45 For example, a recent adult study reported
promising results on overall survival of early stage unfavorable HL,
and reported no ON when combining nivolumab with conventional
chemotherapy without GC, as well as nivolumab in monotherapy.44
Furthermore, a recently published abstract from an American study
including 976/994 adults and children from 12 years with stage III–IV
HL, showed that nivolumab in combination with doxorubicin, vinblas-
tine, and dacarbazine (AVD) was superior in progression-free survival
after 1 year, compared to brentuximab vedotin combined with AVD
(94% vs. 86%).46
Themost important strength of the present study is the population-
based design, including all HL patients treated in the three Nordic
countries over the study period, thereby minimizing selection bias.
Information from medical records were individually and thoroughly
evaluated for all cases, which minimized information bias. Further-
more, due to an established Nordic collaboration and common pedi-
atric oncology and hematology education system, clinical practice is
similar in Sweden, Finland, andDenmark. Details on almost all patients’
treatment regimens were available, and GC treatment was evalu-
ated as total cumulative doses, regardless of treatment strategy. Even
though patients were treated according to different protocols, the
cohort was quite homogenous in terms of the used steroid regime,
as it was the same for 88% of the patients (EuroNet PHL C1/C2 and
GPOH-HD 95/2002).
Study limitations include its retrospective design, possible differ-
ences in data registration and ON awareness, as well as relying on
documentation in patient medical records. Although cumulative GC
doses for the whole treatment period were attained, exact doses of
GC received at sON diagnosis were not available. However, higher
HL stage reflects higher total cumulative GC doses, hence both vari-
ables are analyzed in this study. Finally, the median follow-up time of
5.1 yearsmayhave led toanunderestimationof thenumberof late sON
cases, although their number would likely have been small considering
that sON generally developed during or the first years after treatment.
Still, longer follow-up studies, preferably with prospective registration
of sONwithin treatment protocols, are needed to elucidate the role of
sON in children and young adults with HL in the very long-term.
Taken together, this study establishes the cumulative incidence
of sON in pediatric HL, showing that sON is a common and rele-
vant treatment complication. ON should be suspected, and screened
for with MRI, in children reporting persisting skeletal pain during or
after HL treatment. Reducing GC in HL therapy should be one of the
main focuses in future HL protocol development, to minimize risk of
developing ON, especially in patients at risk—adolescent females.
ACKNOWLEDGMENTS
We would like to thank Olle Lindinger, Umeå University Hospital
(Sweden), Yvonne Håkansson, Lund University Hospital (Sweden), and
Lars Kawan, Queen Silvia’s Hospital in Gothenburg (Sweden), Steen
Roshoej, Margrethe Ottosen Møller, and Hilde Dragland Galsgaard
Aalborg, Aarhus and Odense (Denmark), for assistance in collecting
data for the study. This study was supported by grants from theMary
Beve’s Foundation, Gerd Ahlman’s Fund, Swedish Childhood Cancer
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 of 11 GIERTZ ET AL.
Fund, Alma and K. A. Snellman Foundation, and the Väre Foundation
for Pediatric Cancer Research, Danish Childhood Cancer Foundation
(no. 2021-7439), Lion’s Cancer Research Fund ofMiddle Sweden.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ORCID
MiaGiertz https://orcid.org/0009-0005-2767-1714
Henri Aarnivala https://orcid.org/0000-0002-2025-3676
AnnikaEnglund https://orcid.org/0000-0001-5678-3719
SusannaRanta https://orcid.org/0000-0001-7854-0371
RiittaNiinimäki https://orcid.org/0000-0003-0190-5664
REFERENCES
1. Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and ado-
lescent cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):83-103.
doi:10.3322/caac.21219
2. Larønningen SFJ, Beydogan H, Bray F, et al. NORDCAN: cancer inci-
dence, mortality, prevalence and survival in the Nordic countries. NORD-
CAN; 2022. AccessedMarch 2, 2023. https://nordcan.iarc.fr/
3. Hjalgrim LL, Rostgaard K, Engholm G, et al. Aetiologic heterogeneity
in pediatric Hodgkin lymphoma? Evidence from the Nordic countries,
1978–2010. Acta Oncol. 2016;55(1):85-90. doi:10.3109/0284186x.
2015.1049660
4. Mauz-Korholz C, Hasenclever D, Dorffel W, et al. Procarbazine-free
OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in
females have comparable effectiveness in pediatric Hodgkin’s lym-
phoma: the GPOH-HD-2002 study. J Clin Oncol. 2010;28(23):3680-
3686. doi:10.1200/JCO.2009.26.9381
5. Smith MA, Altekruse SF, Adamson PC, Reaman GH, Seibel NL.
Declining childhood and adolescent cancer mortality. Cancer.
2014;120(16):2497-2506. doi:10.1002/cncr.28748
6. Mauz-Körholz C, Landman-Parker J, Fernández-Teijeiro A, et al.
Response-adapted omission of radiotherapy in children and ado-
lescents with early-stage classical Hodgkin lymphoma and an ade-
quate response to vincristine, etoposide, prednisone, and doxorubicin
(EuroNet-PHL-C1): a titration study. Lancet Oncol. 2023;24(3):252-
261. doi:10.1016/s1470-2045(23)00019-0
7. Mauz-Körholz C, Metzger ML, Kelly KM, et al. Pediatric Hodgkin lym-
phoma. J Clin Oncol. 2015;33(27):2975-2985. doi:10.1200/jco.2014.
59.4853
8. Mattano LA Jr, Devidas M, Nachman JB, et al. Effect of alternate-
week versus continuous dexamethasone scheduling on the risk
of osteonecrosis in paediatric patients with acute lymphoblastic
leukaemia: results from theCCG-1961 randomised cohort trial. Lancet
Oncol. 2012;13(9):906-915. doi:10.1016/S1470-2045(12)70274-7
9. Mattano LA Jr, Sather HN, Trigg ME, Nachman JB. Osteonecro-
sis as a complication of treating acute lymphoblastic leukemia in
children: a report from the Children’s Cancer Group. J Clin Oncol.
2000;18(18):3262-3272. doi:10.1200/JCO.2000.18.18.3262
10. Niinimaki RA, Harila-Saari AH, Jartti AE, et al. Osteonecrosis in chil-
dren treated for lymphoma or solid tumors. J Pediatr Hematol Oncol.
2008;30(11):798-802. doi:10.1097/MPH.0b013e31818ab29d
11. Niinimäki T, Harila-Saari A, Niinimäki R. The diagnosis and classifica-
tionof osteonecrosis in patientswith childhood leukemia.Pediatr Blood
Cancer. 2015;62(2):198-203. doi:10.1002/pbc.25295
12. Toksvang LN, Andrés-Jensen L, Rank CU, et al. Maintenance therapy
and risk of osteonecrosis in children and young adults with acute lym-
phoblastic leukemia: a NOPHOALL2008 sub-study.Cancer Chemother
Pharmacol. 2021;88(5):911-917. doi:10.1007/s00280-021-04316-z
13. teWinkelML, PietersR,HopWC, et al. Prospective studyon incidence,
risk factors, and long-termoutcomeof osteonecrosis in pediatric acute
lymphoblastic leukemia. J Clin Oncol. 2011;29(31):4143-4150. doi:10.
1200/jco.2011.37.3217
14. Mogensen SS, Harila-Saari A, Mäkitie O, et al. Comparing osteonecro-
sis clinical phenotype, timing, and risk factors in children and young
adults treated for acute lymphoblastic leukemia. Pediatr Blood Cancer.
2018;65(10):e27300. doi:10.1002/pbc.27300
15. Niinimäki R, Suo-Palosaari M, Pokka T, Harila-Saari A, Niinimäki
T. The radiological and clinical follow-up of osteonecrosis in can-
cer patients.ActaOncol. 2019;58(4):505-511. doi:10.1080/0284186x.
2019.1566769
16. Hanif I, Mahmoud H, Pui CH. Avascular femoral head necrosis in
pediatric cancer patients.Med Pediatr Oncol. 1993;21(9):655-660.
17. Littooij AS, Kwee TC, Enriquez G, et al. Whole-body MRI reveals high
incidence of osteonecrosis in children treated for Hodgkin lymphoma.
Br J Haematol. 2017;176(4):637-642. doi:10.1111/bjh.14452
18. Borchmann S,MüllerH, HaverkampH, et al. Symptomatic osteonecro-
sis as a treatment complication in Hodgkin lymphoma: an analysis of
theGermanHodgkin StudyGroup (GHSG). Leukemia. 2019;33(2):439-
446. doi:10.1038/s41375-018-0240-8
19. Niinimaki RA, Harila-Saari AH, Jartti AE, et al. High body mass index
increases the risk for osteonecrosis in childrenwith acute lymphoblas-
tic leukemia. J Clin Oncol. 2007;25(12):1498-1504. doi:10.1200/jco.
2006.06.2539
20. Kunstreich M, Kummer S, Laws HJ, Borkhardt A, Kuhlen M.
Osteonecrosis in children with acute lymphoblastic leukemia.
Haematologica. 2016;101(11):1295-1305. doi:10.3324/haematol.
2016.147595
21. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition
of the World Health Organization classification of haematolym-
phoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720-
1748. doi:10.1038/s41375-022-01620-2
22. Niinimäki TNJ, Halonen J, Hänninen P, Harila-Saari A, Niinimäki R.
The classification of osteonecrosis in patients with cancer: validation
of a new radiological classification system. Clin Radiol. 2015;70:1439-
1444.
23. Karimova EJ, Rai SN, Deng X, et al. MRI of knee osteonecrosis in chil-
dren with leukemia and lymphoma: part 1, observer agreement. AJR
Am J Roentgenol. 2006;186(2):470-476. doi:10.2214/AJR.04.1598
24. Saini A, Saifuddin A. MRI of osteonecrosis. Clin Radiol.
2004;59(12):1079-1093. doi:10.1016/j.crad.2004.04.014
25. Mager DE, Lin SX, Blum RA, Lates CD, Jusko WJ. Dose equiva-
lency evaluation of major corticosteroids: pharmacokinetics and cell
trafficking and cortisol dynamics. J Clin Pharmacol. 2003;43(11):1216-
1227. doi:10.1177/0091270003258651
26. Cole TJ, Lobstein T. Extended international (IOTF) body mass
index cut-offs for thinness, overweight and obesity. Pediatr Obes.
2012;7(4):284-294. doi:10.1111/j.2047-6310.2012.00064.x
27. WHO child growth standards based on length/height, weight and age.
Acta Paediatr Suppl. 2006;95:76-85. doi:10.1111/j.1651-2227.2006.
tb02378.x
28. deOnisM, Lobstein T. Defining obesity risk status in the general child-
hood population: which cut-offs should we use? Int J Pediatr Obes.
2010;5(6):458-460. doi:10.3109/17477161003615583
29. Albano D, Patti C, La Grutta L, et al. Osteonecrosis detected by
whole body magnetic resonance in patients with Hodgkin lymphoma
treatedbyBEACOPP. Eur Radiol. 2017;27(5):2129-2136. doi:10.1007/
s00330-016-4535-8
30. Schoenau E. Bone mass increase in puberty: what makes it happen?
Horm Res. 2006;65(2):2-10. doi:10.1159/000091748
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GIERTZ ET AL. 11 of 11
31. Nowak-Göttl U, Kenet G. Challenging aspects of managing hemostasis
in adolescents. Acta Haematol. 2014;132(3-4):326-330. doi:10.1159/
000360237
32. Wang GJ, Cui Q, Balian G. TheNicolas Andry award. The pathogenesis
and prevention of steroid-induced osteonecrosis.ClinOrthop Relat Res.
2000;370:295-310. doi:10.1097/00003086-200001000-00030
33. ChangC, GreenspanA, GershwinME. The pathogenesis, diagnosis and
clinical manifestations of steroid-induced osteonecrosis. J Autoimmun.
2020;110:e102460. doi:10.1016/j.jaut.2020.102460
34. Mogensen SS, Schmiegelow K, Grell K, et al. Hyperlipidemia is a risk
factor for osteonecrosis in children and young adults with acute lym-
phoblastic leukemia. Haematologica. 2017;102(5):e175-e178. doi:10.
3324/haematol.2016.160507
35. HuW, Jiang C, KimM, et al. Individual-specific functional epigenomics
reveals genetic determinants of adverse metabolic effects of gluco-
corticoids. Cell Metab. 2021;33(8):1592-1609.e7. doi:10.1016/j.cmet.
2021.06.004
36. Kawedia JD, Kaste SC, Pei D, et al. Pharmacokinetic, pharmaco-
dynamic, and pharmacogenetic determinants of osteonecrosis in
childrenwith acute lymphoblastic leukemia.Blood. 2011;117(8):2340-
2347; quiz 2556. doi:10.1182/blood-2010-10-311969
37. Ojala AE, Paakko E, Lanning FP, Lanning M. Osteonecrosis during the
treatment of childhood acute lymphoblastic leukemia: a prospective
MRI study.Med Pediatr Oncol. 1999;32(1):11-17.
38. Te Winkel ML, Pieters R, Wind EJ, Bessems JH, van den Heuvel-
Eibrink MM. Management and treatment of osteonecrosis in children
and adolescents with acute lymphoblastic leukemia. Haematologica.
2014;99(3):430-436. doi:10.3324/haematol.2013.095562
39. Policiano C, Subirá J, Aguilar A, Monzó S, Iniesta I, Rubio Rubio
JM. Impact of ABVD chemotherapy on ovarian reserve after fertility
preservation in reproductive-aged women with Hodgkin lymphoma.
J Assist Reprod Genet. 2020;37(7):1755-1761. doi:10.1007/s10815-
020-01844-0
40. Amin MSA, Brunckhorst O, Scott C, et al. ABVD and BEACOPP reg-
imens’ effects on fertility in young males with Hodgkin lymphoma.
Clin Transl Oncol. 2021;23(6):1067-1077. doi:10.1007/s12094-020-
02483-8
41. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided
by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J
Med. 2016;374(25):2419-2429. doi:10.1056/NEJMoa1510093
42. Taparra K, Liu H, Polley MY, Ristow K, Habermann TM, Ansell SM.
Bleomycin use in the treatment of Hodgkin lymphoma (HL): toxicity
and outcomes in the modern era. Leuk Lymphoma. 2020;61(2):298-
308. doi:10.1080/10428194.2019.1663419
43. Davis KL, Fox E, Merchant MS, et al. Nivolumab in children and
young adults with relapsed or refractory solid tumours or lym-
phoma (ADVL1412): a multicentre, open-label, single-arm, phase 1–2
trial. Lancet Oncol. 2020;21(4):541-550. doi:10.1016/s1470-2045(20)
30023-1
44. Bröckelmann PJ, Goergen H, Keller U, et al. Efficacy of nivolumab and
AVD in early-stage unfavorable classic Hodgkin lymphoma: the ran-
domized phase 2 German Hodgkin Study Group NIVAHL trial. JAMA
Oncol. 2020;6(6):872-880. doi:10.1001/jamaoncol.2020.0750
45. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with
chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med.
2018;378(4):331-344. doi:10.1056/NEJMoa1708984
46. HerreraAF, LeBlancML, Castellino SM, et al. SWOGS1826, a random-
ized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-
AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). J Clin
Oncol. 2023;41(17 suppl):LBA4. doi:10.1200/JCO.2023.41.17_suppl.
LBA4
SUPPORTING INFORMATION
Additional supporting information can be found online in the Support-
ing Information section at the end of this article.
How to cite this article: GiertzM, Aarnivala H,WilkMichelsen
S, et al. Symptomatic osteonecrosis in children treated for
Hodgkin lymphoma: A population-based study in Sweden,
Finland, and Denmark. Pediatr Blood Cancer. 2024;e31250.
https://doi.org/10.1002/pbc.31250
 15455017, 0, D
ow
nloaded from
 https://onlinelibrary.w
iley.com
/doi/10.1002/pbc.31250 by D
uodecim
 M
edical Publications Ltd, W
iley O
nline Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on W
iley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License