REVIEW

CURRENT
OPINION Current developments in the treatment of
early-stage classical Hodgkin lymphoma
Sven Borchmann, Bastian von Tresckow, and Andreas Engert

Purpose of review
After presenting the current treatment recommendations for early-stage Hodgkin lymphoma, we give an
overview on recently published clinical trials in this setting. Furthermore, the potential influence of current
trials on the treatment of early-stage Hodgkin lymphoma and integration of newly emerging drugs into
treatment protocols will be discussed.
Recent findings
Trials attempting treatment de-escalation and omission of radiotherapy on the basis of early interim PET-
scans have been disappointing so far, but results of some large trials employing this strategy are still
awaited. In contrast, a more defensive strategy of starting treatment with less aggressive doxorubicine,
bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy and intensifying treatment in early interim
PET-positive patients has shown encouraging results. New drugs such as brentuximab vedotin and immune
checkpoint inhibitors have shown promising results in relapsed and refractory Hodgkin lymphoma. Clinical
trials of brentuximab vedotin in early-stage Hodgkin lymphoma have been initiated. Additionally,
biomarker-based treatment de-escalation might be a possible route for future improvements.
Summary
The challenge for future clinical research in early-stage Hodgkin lymphoma is to continue to cure the
majority of patients with first-line treatment while reducing long-term toxicity. New strategies to
achieve that goal are currently being developed and will further refine treatment of early-stage Hodgkin
lymphoma.
Keywords
clinical trials, early-stages, Hodgkin lymphoma, treatment

INTRODUCTION secondary cancer in a more recent analysis [5 ].

&&

Early-stage classical Hodgkin lymphoma is defined
as clinical stage I/II disease according to the
Ann-Arbor classification (Table 1). Apart from nod-
ular lymphocyte predominant Hodgkin lymphoma,
Across all patients, causes of death other than Hodg-
kin lymphoma are more common after a few years
and the cumulative incidence of deaths from other
causes is higher than that of Hodgkin lymphoma
&

all other subtypes are considered classical Hodgkin
lymphoma. Advances in the past decades have
turned Hodgkin lymphoma from a deadly disease
into one of the best curable malignancies. With the
currently used combined modality treatment, over
90% of early-stage patients achieve long-term remis-
sion and can be considered cured [1,2]. However,
this success in tumor control is associated with long-
term toxicity. Potential severe side-effects include
cardiac toxicity and secondary malignancies. Media-
stinal radiotherapy in large-field technique and
anthracycline-based chemotherapy have shown to
be associated with an increased cardiovascular risk
& &
[3 ,4 ]. Higher doses of procarbazine and radio-
therapy were associated with an increased risk of
after 20 years [6 ]. This underscores the need for
further treatment reduction without jeopardizing
tumor control in early-stage Hodgkin lymphoma.
This call for maintaining optimal tumor control is
further underlined by a recent patient preference
German Hodgkin Study Group (GHSG), Department I of Internal Medi-
cine, University Hospital Cologne, Cologne, Germany
Correspondence to Dr Andreas Engert, MD, Chairman, German Hodgkin
Study Group, Professor for Internal Medicine, Hematology and Oncol-
ogy, University Hospital of Cologne, Department I of Internal Medicine,
Kerpener Str. 62, D-50924 Köln, Germany. Tel: +49 221 478 5933/
5966; fax: +49 221 478 3778; e-mail: andreas.engert@uk-koeln.de
Curr Opin Oncol 2016, 28:377–383
DOI:10.1097/CCO.0000000000000314

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Lymphoma

Early favorable Hodgkin lymphoma

KEY POINTS
 De-escalation strategies in patients with early-stage
Hodgkin lymphoma on the basis of an early interim
negative PET-scan so far have not been successful.
 New drugs such as brentuximab vedotin and
antibodies directed against PD1 have shown promising
results in relapsed and refractory Hodgkin lymphoma
and will likely also play a key role in the treatment of
newly diagnosed patients in the future.
 Treatment protocols employing new technologies, for
example, MRD measurement, are likely to complement
or substitute PET-adapted treatment in the future and will
lead to further individualization of treatment.
The GHSG HD10 trial demonstrated that two cycles
of doxorubicine, bleomycin, vinblastine, dacarba-
zine (ABVD) are as effective as four cycles of ABVD,
and 20 Gy of involved field-radiotherapy (IF-RT) is as
effective as 30 Gy of IF-RT regarding freedom from
treatment failure (FFTF) [2]. Even when comparing
the most intensive regime, four cycles of ABVD
followed by 30 Gy IF-RT, with the least intensive
combination, two cycles of ABVD followed by 20 Gy
IF-RT, no difference in FFTF could be detected [2].
Therefore, two cycles of ABVD followed by 20 Gy IF-
RT is the currently recommended GHSG standard in
adult early favorable Hodgkin lymphoma.

Early unfavorable Hodgkin lymphoma

questionnaire undertaken by the German Hodgkin
&
Study Group (GHSG) [7 ]. In this survey, patients
clearly expressed that undergoing a second course of
treatment for relapsed disease was one of their main
worries. This indicates that cure with first-line treat-
ment is of utmost importance from the patient’s
perspective.
CURRENT TREATMENT
RECOMMENDATIONS
Early-stage Hodgkin lymphoma is commonly div-
ided into early favorable disease and early unfavor-
able disease according to predefined risk factors.
Table 1 illustrates the most widely used risk factor
systems. In general, the absence of risk factors in
combination with clinical stage I or II according to
the Ann-Arbor classification defines early favorable
Hodgkin lymphoma. The presence of at least one
risk factor usually leads to a classification of early
unfavorable Hodgkin lymphoma. Current GHSG
treatment recommendations are summarized in
Table 2.
In the GHSG HD14 trial, two cycles of BEACOPPes-
calated followed by two cycles of ABVD (‘2þ2’) were
superior to four cycles of ABVD with regard to FFTF
[1]. Both regimens were followed by 30 Gy IF-RT.
Substituting the first two cycles of ABVD with BEA-
COPPescalated led to increased acute toxicity,
though this difference did not translate into
increased treatment-related mortality [1]. Therefore,
the ‘2þ2’ regimen has become the currently recom-
mended GHSG standard for treating early unfavor-
able Hodgkin lymphoma in adult patients less than
60 years of age. In a different interpretation of the
HD14 results, the trial failed to show improved
overall survival (OS) with ‘2þ2’ compared to four
cycles of ABVD while clearly adding acute toxicity
by introducing BEACOPPescalated [1]. Favoring this
interpretation, four cycles of ABVD chemotherapy
followed by 30 Gy of IF-RT is widely used.
REVIEW OF CURRENT CLINICAL TRIALS
Early results have shown that a negative fluoro-
deoxy-glucose-positron emission tomography

Table 1. Risk factor systems in early-stage Hodgkin lymphoma

GHSG EORTC NCIC/ECOG

Definition of risk (a) Large mediastinal mass; (b)
factors extranodal disease; (c) ESR 50
without B-symptoms or 30 with B-
symptoms; (d) 3 nodal areas
Definition of Favorable: clinical stage I/II without risk
favorable/ factors; unfavorable: clinical stage IA/
unfavorable IB/IIA with at least one risk factor or
disease clinical stage IIB with risk factor (c)
and/or (d) but without (a) or (b)
(a) Large mediastinal mass; (b)
age 50 years; (c) ESR 50
without B-symptoms or 30
with B-symptoms; (d) 4 nodal
areas
Favorable: clinical stage I/II
(above diaphragm) without risk
factors; unfavorable: clinical
stage I/II (above diaphragm)
with at least one risk factor
(a) Histology other than LP/NS; (b)
age 40 years; (c) ESR 50; (d)
4 nodal areas
Favorable: clinical stage I/II without
risk factors; unfavorable: clinical
stage I/II with at least one risk
factor

ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment of Cancer; ESR, erythrocyte sedimentation rate;
GHSG, German Hodgkin Study Group; LP, lymphocyte predominant subtype; NCIC, National Cancer Institute of Canada; NS, nodular sclerosis subtype.

378 www.co-oncology.com Volume 28  Number 5  September 2016

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 Treatment of early-stage Hodgkin lymphoma Borchmann et al.

Table 2. Current GHSG treatment recommendations for Hodgkin lymphoma

Young patients (18–59 years old) Elderly patients (60 years old)

Early favorable 2  ABVD þ 20 Gy IF-RT 2  ABVD þ 20 Gy IF-RT or 2  AVD þ 20 Gy IF-RTa

Hodgkin lymphoma
Early unfavorable 2  BEACOPPescalated 2  ABVD þ 2  AVD þ 30 Gy IF-RTa or
Hodgkin lymphoma þ 2  ABVD þ 30 Gy IF-RT or 4  AVD þ 30 Gy IF-RTa
4  ABVD þ 30 Gy IF-RT

ABVD, doxorubicine/bleomycin/vinblastine/dacarbazine; GHSG, German Hodgkin Study Group; IF-RT, involved field-radiotherapy.
a
In elderly patients (60 years old) it is not recommended to use BEACOPPescalated at all and bleomycin for more than two cycles owing to concerns about
&
increased toxicity [8,9 ,10].

(PET) scan after two cycles of chemotherapy has
an excellent negative predictive value for disease
progression [11], especially in early-stage Hodgkin
lymphoma [12]. This motivated various clinical
trials to attempt omission of radiotherapy after a
negative postchemotherapy interim PET.
The UK RAPID trial included patients (n ¼ 602)
from both favorable and unfavorable risk groups
according to the GHSG and European Organisation
for Research and Treatment of Cancer (EORTC)
criteria (Table 1). However, most patients had favor-
able early-stage Hodgkin lymphoma according to
&
both sets of criteria [13 ]. After three cycles of ABVD
chemotherapy, patients received an interim
PET-scan. All patients with a Deauville-score [14]
3 were classified as PET-positive. Patients who were
interim PET-negative were randomized into two
groups, receiving either IF-RT or no further treat-
ment [13 ]. Importantly, 87.6% (n ¼ 127) of patients
&
in the PET-positive group (n ¼ 145) were alive with-
out disease progression after a median follow-up of
&
62 months [13 ], underscoring the poor positive
predictive value of an interim PET-scan for disease
progression. In the per-protocol analysis of 392
patients having negative interim PET-scans after
a median follow-up of 60 months, the 3-year
progression-free survival (PFS) rate was 97.1% in
the radiotherapy group and 90.8% in the group with
no further treatment (P ¼ 0.02). OS was similar in an
intention-to-treat analysis, with a 3-year OS rate of
97.1% in the radiotherapy group and 99.0% in the
&
group with no further treatment [13 ]. Despite
the clear difference in the PFS rate, the authors
conclude that ‘[. . .] patients with negative PET find-
The EORTC/LYSA/FIL H10 (Fig. 1) trial tested
treatment stratification after an interim PET-scan in
both early favorable and early unfavorable Hodgkin
lymphoma patients according to the EORTC criteria
(Table 1) [15]. A Deauville-score [14] of 3 was
classified as PET-positive. Early favorable patients
were randomized into a standard arm, in which
patients received three cycles of ABVD followed
by 30 Gy (þ6 Gy) of involved node-RT (IN-RT).
In the experimental arm, patients with a negative
PET-scan after two cycles of ABVD received two
additional cycles of ABVD, whereas treatment
for patients with a positive PET-scan was intensified
to two additional cycles of BEACOPPescalated
followed by 30 Gy (þ6 Gy) of IN-RT. A total of 381
early favorable patients were PET-negative after two
cycles of ABVD. Out of the 188 PET-negative
patients in the standard arm, only one patient
experienced disease progression. In contrast, nine
out of 193 PET-negative patients in the experimen-
tal arm experienced disease progression. Con-
sequently, the independent data monitoring
committee (IDMC) concluded that noninferiority
of the experimental arm is unlikely to be shown
and recommended stopping the experimental treat-
ment strategy for PET-negative patients [15].
H10
F 2 ABVD PET 1 ABVD + INRT 30 Gy (+ 6 Gy)
R
2 ABVD P – 2 ABVD
E
T 2 BEACOPPesc + INRT 30 Gy
+
(+ 6 Gy)

ings after three cycles of ABVD have a very good H10

prognosis either with or without consolidation 2 ABVD PET 2 ABVD + INRT 30 Gy (+ 6 Gy)
U
radiotherapy. Although the noninferiority margin R
was exceeded in this study, the results suggest that 2 ABVD P – 4 ABVD
E
radiotherapy can be avoided for patients with nega- T 2 BEACOPPesc + INRT 30 Gy
+
(+ 6 Gy)
&
tive PET findings.’ [13 ]. We disagree with the
author’s conclusion. In our view this is a negative
study, which suggests that radiotherapy is still FIGURE 1. Flowchart of the EORTC/LYSA/FIL H10 trial.
necessary in the RAPID trial setting. Reproduced with permission from Raemaekers et al. [15].

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Lymphoma
In the unfavorable part of the EORTC/LYSA/FIL
H10 trial (H10U), patients were randomized into
two arms. In the standard arm, patients received
four cycles of ABVD followed by 30 Gy (þ6 Gy) of
IN-RT [15]. In the experimental arm, PET-negative
patients after two cycles of ABVD received four
additional cycles of ABVD. Treatment in patients
with a positive interim PET was intensified with two
additional cycles of BEACOPPescalated followed by
30 Gy (þ6 Gy) of IN-RT. The IDMC concluded after
interim analyses that noninferiority of the exper-
imental treatment strategy for early unfavorable
PET-negative patients is very unlikely to be shown.
A total of 519 patients were evaluated. Out of
251 patients in the standard arm, seven patients
experienced an event. In contrast to that, 16 events
occurred among the 268 patients in the experimen-
tal arm [15].
The results of the treatment intensification
strategy for the interim PET-positive patients
of the EORTC/LYSA/FIL H10 trial (Fig. 1) were
presented at the 2015 International Conference
&
on Malignant Lymphoma (ICML) meeting [16 ].
Analysis was performed taking together early favor-
able and unfavorable patients as the treatment
intensification strategy was the same. Out of
192 PET-positive patients in the standard arm,
41 patients experienced death or relapse, whereas
only 16 out of 169 did so in the intensified exper-
imental arm. PFS and OS for the treatment intensi-
fication strategy versus the standard arm were 91
versus 77% and 96 versus 89%, respectively. The
difference in PFS was highly significant (P ¼ 0.002)
&
[16 ]. This part of the EORTC/LYSA/FIL H10 trial
clearly showed that treatment escalation to BEA-
COPPescalated for interim PET-positive patients
after two cycles of ABVD is feasible in early-stage
Hodgkin lymphoma patients. This approach
challenges the results of the GHSG HD14 trial [1]
in early unfavorable Hodgkin lymphoma as it saves
the majority of patients from receiving BEACOPPes-
calated without worsening their chances of a cure.
Results of a multicenter phase II trial, which
included 34 patients evaluating brentuximab
vedotin combined with AVD (brentuximab
vedotin þ AVD) in nonbulky Hodgkin lymphoma,
were presented at the 2015 American Society of
Clinical Oncology (ASCO) meeting [17]. A lead-in
cycle of brentuximab vedotin monotherapy on days
1 and 15 was followed by four to six cycles of
brentuximab vedotin þ AVD. Patients had mainly
early favorable Hodgkin lymphoma (62%). Com-
plete response (CR) was achieved by 53% of patients
after brentuximab vedotin monotherapy, and in
97% of patients after two cycles of brentuximab
vedotin þ AVD. A total of 88% overall had
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responded at end of treatment. Two patients had
progressive disease (PD), and two other patients
experienced intolerable toxicity leading to treat-
ment termination including one death [17]. In
our opinion, this trial shows the potential of com-
bination regimens including new drugs such as
brentuximab vedotin and conventional chemother-
apy. The brentuximab vedotin þ AVD combination
tested might provide a blueprint for further develop-
ment of combination regimens that are more effec-
tive than conventional chemotherapy and might
thus allow omission of radiotherapy in early-stage
Hodgkin lymphoma.
Preliminary results of a phase II trial in early
unfavorable Hodgkin lymphoma were reported at
the 2015 ICML meeting. Twenty-five patients were
treated with four cycles of brentuximab vedo-
tin þ AVD followed by 30 Gy of involved site-RT
(IS-RT) [18]. A positive PET-scan was defined by a
Deauville-score [14] of 4. Eighty-eight and 90% of
patients achieved a negative PET-scan after two and
four cycles of brentuximab vedotin þ AVD, respect-
ively. Two patients had refractory disease confirmed
by histology. Of note, nine of the 25 patients were
advanced stage patients according to GHSG criteria
(Table 1) [18]. In our view, remission rates in this
trial were encouraging, considering the unfavorable
patient characteristics.
At the 2015 American Society of Hematology
meeting, results of a US Intergroup trial in nonbulky
early-stage Hodgkin lymphoma were presented [19].
This study also attempted to stratify treatment by
a PET-scan performed after two cycles of ABVD.
PET-negative patients received two additional cycles
of ABVD, whereas PET-positive patients underwent
treatment escalation with two cycles of BEACOP-
Pescalated followed by 30 Gy of IF-RT. A positive
PET-scan was defined by a Deauville-score [14] of
4. After a median follow-up of 2 years, eight out of
131 PET-negative patients relapsed, whereas three
out of 13 PET-positive patients relapsed, resulting in
estimated 3-year PFS rates of 92 and 66%, respect-
ively [19]. This trial largely resembled the strategy of
the EORTC/LYSA/FIL H10 [15] trial, but had no
standard arm for direct comparison of PET-adapted
treatment within the trial. However, the relapse rate
of the PET-negative patients within this trial was
comparable to the experimental arm of the EORTC/
LYSA/FIL H10 [15] trial, which we consider unac-
ceptably high in early-stage Hodgkin lymphoma
patients. Therefore, this trial provides further
evidence that interim PET-scan-based omission of
radiotherapy in early-stage Hodgkin lymphoma
patients is currently not justified.
A small pilot phase II trial investigated
two cycles of brentuximab vedotin monotherapy
Volume 28  Number 5  September 2016

followed by three or six cycles of ABVD in 12 patients
with stage IA, IIA, or IIIA Hodgkin lymphoma [20].
A Deauville-score [14] of 4 was defined as a positive
PET-scan. The overall response rate (ORR) was
92% and the complete response rate was 83% after
brentuximab vedotin monotherapy lead-in and
improved to 100% at the end of treatment [20]. In
our view, the main finding of this trial is the high
response rate after only short brentuximab vedotin
treatment in treatment naive, mostly early-stage
Hodgkin lymphoma patients, which is significantly
higher than that after brentuximab vedotin use
in the refractory or relapsed (r/r) setting [21].
Additionally, it shows that first-line brentuximab
vedotin alone can be curative in a subset of patients,
which was recently also shown in an analysis of r/r
&
patients [22 ].
The GHSG HD16 trial, which finished patient
recruitment in early 2016, randomized patients with
GHSG early favorable Hodgkin lymphoma into two
treatment arms. In the standard arm, patients were
treated with two cycles of ABVD followed by 20 Gy
of IF-RT, irrespective of a PET-scan performed after
chemotherapy. In the experimental arm, all patients
also received two cycles of ABVD. Subsequently,
PET-positive patients received 20 Gy of IF-RT, and
PET-negative patients were just followed up without
Table 3. Currently recruiting clinical trials in early-stage adult Hodgkin lymphoma
Estimated Patient
Phase enrollment population
II 123 18–60 y/o patients with bulky clinical
stage I–II
II 34 Patients 18 y/o with nonbulky clinical
stage IA, IB or IIA
II 86 18–70 y/o patients with early unfavorable
nonbulky disease according to EORTC
criteria
II 200 Patients 18 y/o with bulky clinical stages
I–II
III 170 18–60 y/o patients with early unfavorable
nonbulky disease according to EORTC
criteria
II 59 18–60 y/o patients with early unfavorable
or subdiaphragmatic disease
II 40 18–60 y/o patients with
supradiaphragmatic clinical stage I/II PET-
positive disease after two cycles of ABVD
ABVD, doxorubicine/bleomycin/vinblastine/dacarbazine; CR, complete response; EORTC, European Organisation for Research and Treatment of Cancer; G-CSF,
granulocyte colony-stimulating factor; IF-RT, involved field-radiotherapy; IN-RT, involved node-radiotherapy; IS-RT, involved site-radiotherapy; PR, partial response;
SD, stable disease; y/o, years old.
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Treatment of early-stage Hodgkin lymphoma Borchmann et al.
further treatment [23]. Results of this trial will pro-
vide further evidence on the usefulness of interim
PET-scans for treatment de-escalation in early-stage
favorable Hodgkin lymphoma and are eagerly
awaited.
The GHSG HD17 trial, which is still recruiting
patients as of the publication of this article, random-
izes patients with GHSG early unfavorable Hodgkin
lymphoma into two treatment strategies. In the
standard arm, patients receive the GHSG standard
of two cycles of BEACOPPescalated followed by two
cycles of ABVD followed by 30 Gy of IF-RT. Patients
in the experimental arm are stratified according
to the results of an interim PET-scan after chemo-
therapy. PET-positive patients receive 30 Gy of
IN-RT, whereas PET-negative patients are just fol-
lowed up without any radiotherapy [24]. Results of
this trial will help to answer the question of feasi-
bility of radiotherapy omission in early unfavorable
PET-negative patients after chemotherapy. Omis-
sion of radiotherapy for PET-negative patients might
be feasible within this trial’s setting, in which all
patients receive more aggressive chemotherapy than
&
in the RAPID [13 ] or EORTC/LYSA/FIL H10
[15] trial.
A selection of ongoing clinical trials in early-
stage adult Hodgkin lymphoma is given in Table 3.
Treatment Identifier [reference]
Two cycles of ABVD followed by four more cycles NCT01118026 [25]
of ABVD for interim PET-negative patients or two
cycles of BEACOPPescalated þ radiotherapy for
PET-interim positive patients
Two cycles of brentuximab vedotin þ AVD followed NCT02505269 [26]
by four more cycles for interim PR/SD and two
more cycles for interim CR patients
Dose dense ABVD (d1 þ d8 of a 21-day cycle) with NCT02247869 [27]
mandatory G-CSF support for four cycles
Two cycles of ABVD followed by four more cycles NCT01390584 [28]
of ABVD þ IN-RT for interim PET-negative patients
or four cycles of BEACOPPescalated þ IN-RT for
interim PET-positive patients
Standard arm: four cycles of ABVD; experimental NCT02292979 [29]
arm: four cycles of brentuximab vedotin þ AVD
Four cycles of brentuximab vedotin þ AVD followed NCT01868451 [30]
by 20–30 Gy of IS-RT
Two cycles of BEACOPPescalated followed by NCT02298283 [31]
30 Gy (þ6 Gy) IF-RT followed by eight cycles of
brentuximab vedotin consolidation
www.co-oncology.com 381
Lymphoma
CONCLUSION
In this article, we outlined the challenges for further
clinical research in early-stage Hodgkin lymphoma:
trying to cure the vast majority of all patients with
first-line treatment thereby reducing long-term
toxicity. This review on current clinical trials has
shown two main strategies, which are pursued in
order to achieve that goal. One approach emerging
before the advent of targeted drugs such as brentux-
imab vedotin was to use PET-stratification after
chemotherapy to spare at least some patients from
&
radiotherapy. Both the UK RAPID [13 ] and the
EORTC/LYSA/FIL H10 [15] trial demonstrated that
this is not possible without accepting a lower cure
rate in first-line treatment. Many smaller studies
discussed within this review used brentuximab
vedotin in various combinations with conventional
chemotherapy to increase efficacy of first-line che-
motherapy and reduce either the total amount of
chemotherapy or omit radiotherapy altogether.
These trials are mostly preliminary but promising
and further development of brentuximab vedotin in
first-line treatment after its success in r/r Hodgkin
&&
lymphoma [21,32 ] is a promising route for future
clinical research. We believe that the integration of
brentuximab vedotin into first-line treatment for
early-stage Hodgkin lymphoma could further
improve efficacy of chemotherapy so that omission
of radiotherapy might become possible for the
majority of patients.
Recently, immune checkpoint inhibitors target-
ing the interaction between programmed cell death
protein 1 and programmed death-ligand 1 have
shown very encouraging activity in r/r Hodgkin
lymphoma patients. Long-term remissions were
observed in classical Hodgkin lymphoma patients
having received a plethora of prior therapies, with
& &&
very few other treatment options, if any [33 ,34 ].
The role of this new class of drugs in first-line treat-
ment of Hodgkin lymphoma is not yet defined. The
integration of these very active substances into the
first-line treatment will have to be explored and
results of early clinical trials are eagerly awaited.
Biomarker-based treatment stratification
approaches for early-stage Hodgkin lymphoma
patients could become another option for guided
reduction of therapeutic intensity. Various DNA and
protein-based biomarkers have emerged more
& In this abstract, data from a large patient questionnaire is presented. It shows what
recently [35 ,36,37]. These markers might allow
assessment of minimal residual disease (MRD) in
patients leading to a stratification of treatment in
accordance with the presence or absence of MRD.
Additionally, biomarkers are needed to predict
response to both brentuximab vedotin and immune
checkpoint inhibitors as both induce long-term
remissions and are potentially even curative in a
382 www.co-oncology.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
&
minority of patients [22 ,38 ]. Identifying these
&
patients before initiation of treatment might spare
some patients both from chemotherapy and
radiotherapy.
Acknowledgements
The authors would like to acknowledge all patients
participating in its trials on behalf of the GHSG.
Financial support and sponsorship
None.
Conflicts of interest
SB has no conflicts of interest to disclose. BvT has
performed consultancy work for and received payments
for lectures, payments for the development of educational
presentations and travel expenses from Takeda. AE has
performed consultancy work for, received grant support,
consulting fees and fees for review activities and has
grants pending from both Takeda and BMS.
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& of special interest
&& of outstanding interest
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patients themselves think about their treatment and what was important for them
retrospectively.
8. Wongso D, Fuchs M, Plutschow A, et al. Treatment-related mortality in
patients with advanced-stage Hodgkin lymphoma: an analysis of the German
Hodgkin Study Group. J Clin Oncol 2013; 31:2819–2824.
9. Böll B, Goergen H, Behringer K, et al. Bleomycin in older early-stage favorable
& Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group
(GHSG) HD10 and HD13 trials. Blood 2016; 127:2189–2192.
This paper presents a retrospective analysis of the use of bleomycin in Hodgkin
lymphoma in patients older than 60 years and recommends not using bleomycin for
more than two cycles because of increased and potentially deadly toxicity.
Volume 28  Number 5  September 2016

10. Böll B, Görgen H, Fuchs M, et al. ABVD in older patients with early-stage
Hodgkin lymphoma treated within the German Hodgkin Study Group HD10
and HD11 trials. J Clin Oncol 2013; 31:1522–1529.
11. Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of che-
motherapy predicts treatment failure and progression-free survival in Hodgkin
lymphoma. Blood 2006; 107:52–59.
12. Evens AM, Kostakoglu L. The role of FDG-PET in defining prognosis of
Hodgkin lymphoma for early-stage disease. Blood 2014; 124:3356–3364.
13. Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-directed therapy
& for early-stage Hodgkin’s lymphoma. N Engl J Med 2015; 372:1598–1607.
This large phase III trial attempted treatment de-escalation after an interim PET in
early-stage Hodgkin lymphoma. The main finding is a higher relapse rate after
omission of radiotherapy in interim PET-negative patients.
14. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin
lymphoma: The Lugano Classification. J Clin Oncol 2014; 32:3059–3067.
15. Raemaekers JMM, André MPE, Federico M, et al. Omitting radiotherapy in
early positron emission tomography-negative stage I/II Hodgkin lymphoma is
associated with an increased risk of early relapse: clinical results of the
preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J
Clin Oncol 2014; 32:1188–1194.
16. Raemaekers JMM. Early FDG-PET adapted treatment improves the outcome
& of early FDG-PET-positive patients with stages I/II Hodgkin lymphoma (HL):
final results of the randomized intergroup EORTC/LYSA/FIL H10 trial. Palazzo
dei Congressi, Lugano (Switzerland), 17–20 June 2015: 13th International
Conference on Malignant Lymphoma; 2015.
This important presentation together with abstract includes the final results of the
EORTC/LYSA/FIL H10 trial. The most interesting finding with the potential to
change future treatment recommendations is a fantastic outcome for early un-
favorable patients with a strategy of starting with ABVD and intensifying treatment
in interim PET-positive patients to BEACOPPescalated after two cycles of
chemotherapy.
17. Abramson JS, Arnason JE, LaCasce AS, et al. Brentuximab vedotin plus AVD
for non-bulky limited stage classical Hodgkin lymphoma: a phase 2 trial. J Clin
Oncol 2015; 33(Suppl 15):8505.
18. Kumar A, Yahalom J, Schoder H, et al. Preliminary efficacy and safety of
brentuximab vedotin and AVD chemotherapy followed by involved-site radio-
therapy in early stage, unfavourable risk Hodgkin lymphoma. Hemotol Oncol
2015; 33 (Suppl.):100–180.
19. Straus DJ, Pitcher B, Kostakoglu L, et al. Initial results of US Intergroup trial of
response-adapted chemotherapy or chemotherapy/radiation therapy based
on PET for non-bulky stage I and II Hodgkin lymphoma (HL) (CALGB/Alliance
50604). Blood 2015; 126:578.
20. Federico M, Luminari S, Pellegrini C, et al. Brentuximab vedotin followed by
ABVDþ/ radiotherapy in patients with previously untreated Hodgkin lym-
phoma: final results of a pilot phase II study. Haematologica 2016;
101:e139–e141.
21. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of
brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lym-
phoma. J Clin Oncol 2012; 30:2183–2189.
22. Gopal AK, Chen R, Smith SE, et al. Durable remissions in a pivotal phase 2
& study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma.
Blood 2015; 125:1236–1243.
This publication presents long-term follow up data of brentuximab vedotin in
relapsed or refractory Hodgkin lymphoma. Interestingly, some heavily pretreated
patients achieve durable long-term remissions with this new substance.
23. HD16 for early stage Hodgkin lymphoma. ClinicalTrials.gov Identifier:
NCT00736320.
24. HD17 for intermediate stage Hodgkin lymphoma. ClinicalTrials.gov Identifier:
NCT01356680.
25. Response-based therapy assessed by PET scan in treating patients with
bulky stage I and stage II classical Hodgkin lymphoma. ClinicalTrials.gov
Identifier: NCT01118026.
1040-8746 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Treatment of early-stage Hodgkin lymphoma Borchmann et al.
26. Brentuximab vedotin plus AD in non-bulky limited stage Hodgkin lymphoma.
ClinicalTrials.gov Identifier: NCT02505269.
27. Dose-dense ABVD first line therapy in early stage unfavorable Hodgkin’s
lymphoma. ClinicalTrials.gov Identifier: NCT02247869.
28. Chemotherapy based on PET scan in treating patients with stage I or stage II
Hodgkin lymphoma. ClinicalTrials.gov Identifier: NCT01390584.
29. Brentuximab vedotin associated with chemotherapy in untreated patients with
Hodgkin lymphoma. ClinicalTrials.gov Identifier: NCT02292979.
30. Brentuximab vedotin combined with AVD chemotherapy and involved-site
radiotherapy in patients with newly diagnosed early stage, unfavorable risk
Hodgkin lymphoma. ClinicalTrials.gov Identifier: NCT01868451.
31. Brentuximab vedotin as consolidation treatment in patients with stage I/II HL
and PET positivity after 2 cycles of ABVD. ClinicalTrials.gov Identifier:
NCT02298283.
32. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as
&& consolidation therapy after autologous stem-cell transplantation in patients
with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a
randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015;
385:1853–1862.
Final results of the AETHERA trial are presented in this major publication. The
brentuximab vedotin arm had superior PFS compared with the placebo arm.
Therefore, maintenance treatment with brentuximab vedotin after autologous
stem-cell transplantation will probably be widely used in the future.
33. Armand P, Shipp MA, Ribrag V, et al. PD-1 blockade with pembrolizumab in
& patients with classical Hodgkin lymphoma after brentuximab vedotin failure:
safety, efficacy, and biomarker assessment. Blood 2015; 126:584.
This study presents data of a trial of the anti-PD1 antibody pembrolizumab in
relapsed or refractory Hodgkin lymphoma. The results largely resemble those of a
similar trial published shortly before this one and using nivolumab as the anti-PD1
antibody. There is no evidence so far, that a specific antibody interfering with the
programmed cell death protein 1 (PD1)–programmed death-ligand 1 (PD-L1)
interaction is better than another in Hodgkin lymphoma.
34. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in
&& relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 2015; 372:311–
319.
This study presents the results of the first trial of an antibody directed against PD1
in relapsed or refractory Hodgkin lymphoma. Nivolumab showed impressive
activity in heavily pretreated patients. Consequently, many trials employing a
strategy of interfering with the PD1–PD-L1 interaction are currently underway
or planned and results of these are eagerly awaited.
35. Vandenberghe P, Wlodarska I, Tousseyn T, et al. Non-invasive detection of
& genomic imbalances in Hodgkin/Reed-Sternberg cells in early and advanced
stage Hodgkin’s lymphoma by sequencing of circulating cell-free DNA: a
technical proof-of-principle study. Lancet Haematol 2015; 2:e55–e65.
Data on genomic imbalances in cell-free DNA of Hodgkin lymphoma patients are
presented in this publication. The importance of this study lies in the fact that it
provides clear evidence that Hodgkin lymphoma patients have cell-free DNA
derived from their malignancy in their peripheral blood, which can be used, for
example, to evaluate MRD.
36. Oki Y, Neelapu SS, Fanale M, et al. Detection of classical Hodgkin lymphoma
specific sequence in peripheral blood using a next-generation sequencing
approach. Br J Haematol 2015; 169:689–693.
37. Farina L, Rezzonico F, Spina F, et al. Serum thymus and activation-regulated
chemokine level monitoring may predict disease relapse detected by PET scan
after reduced-intensity allogeneic stem cell transplantation in patients with
Hodgkin lymphoma. Biol Blood Marrow Transplant 2014; 20:1982–1988.
38. Ansell S, Armand P, Timmerman JM, et al. Nivolumab in patients (Pts) with
& relapsed or refractory classical Hodgkin lymphoma (R/R cHL): clinical out-
comes from extended follow-up of a phase 1 study (CA209-039). Blood
2015; 126:583.
This abstract and presentation gives an update on already published data of a trial
employing the anti-PD1 antibody nivolumab in relapsed or refractory Hodgkin
lymphoma, confirming both efficacy and safety with longer follow-up.
www.co-oncology.com 383