SEMINAR

Seminar

Hodgkins lymphoma

Lynny Yung, David Linch

Hodgkins lymphoma was first described in 1832, but the nature of the pathognomic Reed-Sternberg cell, on which
diagnosis of the disease is based, has only been elucidated in the past few years. Radiotherapy has been used to treat
localised disease since the 1940s, and in the 1960s, effective combination chemotherapy regimens were introduced
for anatomically advanced disease. The past three decades have witnessed continued improvement in outcome to
such an extent that Hodgkins lymphoma is now one of the most curable of all non-cutaneous malignancies. With
improved survival and extended follow-up, relevance of treatment-induced late effects has become apparent, and
modern therapeutic strategies must fully account for these effects. We review the pathology of Hodgkins lymphoma,
and its clinical presentation, investigation, present management, and natural history, including late effects of
treatment.
Hodgkins lymphoma is a rare malignancy, with an
incidence of about 24 per 100 000 per year.1 Prevalence
in women peaks in the third decade and then falls, but in
men it remains fairly constant after this time.1 Diagnosis
of Hodgkins lymphoma is based on the finding of
Hodgkin/Reed-Sternberg cells in an appropriate cellular
background of reactive leucocytes and, in some cases,
fibrosis. The disorder is classified into two distinct
entities: nodular lymphocyte-predominant Hodgkins
lymphoma; and classical Hodgkins lymphoma.2
Nodular lymphocyte-predominant Hodgkins lymphoma represents about 5% of all cases of the disease. It is
most common in males, and typically presents with
limited nodal disease of the neck without constitutional
symptoms.3
Classical Hodgkins lymphoma is divided into four
subtypes (panel 1). In the developed world, nodular
sclerosing classical Hodgkins lymphoma accounts for
over two-thirds of all cases. Lymphocyte-rich classical
Hodgkins lymphoma is a newly defined entity, and is
closely similar to the disorder previously classified as
diffuse lymphocyte-predominant Hodgkins disease.
Lymphocyte-depleted Hodgkins lymphoma is now rarely
diagnosed; most patients diagnosed with this entity would
now be classified as having nodular sclerosing disease or
anaplastic large-cell lymphomas. All subtypes of classical
Hodgkins lymphoma are at present treated in the same
way.

Pathogenesis
In nodular and classical lymphocyte-predominant
subtypes of Hodgkins lymphoma, the malignant cell
is derived from a B lymphocyte, with clonal immunoglobulin gene rearrangements in most patients.46
Malignant cells in nodular lymphocyte-predominant
Hodgkins lymphoma have the immunophenotype and
Lancet 2003; 361: 94351
Royal Free and University College Medical School, London
WC1E 6HX, UK (L Yung MRCP, Prof D Linch FRCP)
Correspondence to: Prof D Linch, Department of Haematology, Royal
Free and University College Medical School, University College
London, 98 Chenies Mews, London, WC1E 6HX, UK
(e-mail: d.linch@ucl.ac.uk)

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Panel 1: WHO classification of Hodgkins lymphoma

Nodular lymphocyte-predominant Hodgkins lymphoma

Classical Hodgkins lymphoma
Nodular sclerosis classical Hodgkins lymphoma
Mixed cellularity classical Hodgkins lymphoma
Lymphocyte-rich classical Hodgkins lymphoma
Lymphocyte-depleted classical Hodgkins lymphoma

genotype of post-germinal-centre B cells, whereas in

classical Hodgkins lymphoma, mature B-cell antigen
expression can be low or absent, and no immunoglobulin
is produced despite immunoglobulin gene rearrangements
and subsequent somatic mutations (panel 2). In some
cases of the disease, absence of immunoglobulin
production is attributable to mutations in the
immunoglobulin gene (eg, creation of stop codons),7,8 but
in others, dysregulation of transcriptional machinery
entailed in immunoglobulin gene expression takes place.8
The immunoglobulin receptor complex provides
important survival signals to developing B cells, and
absence of immunoglobulin expression could put
Hodgkin/Reed-Sternberg cells at a survival disadvantage
unless other antiapoptotic events had happened.
Epstein-Barr virus infection is one such possible
event.911 Nuclear proteins of this virus, such as EBNA and
LMP1 (latent membrane protein 1), have been detected
in about 40% of cases of classical Hodgkins lymphoma,
with the highest frequency in mixed cellularity disease.12
LMP1 is known to have oncogenic potential by triggering
BCL2 expression and acting via the CD40 cell-signalling
pathway, allowing cells to evade cellular apoptotic
mechanisms.13 Association with Epstein-Barr virus varies
with age; childhood Hodgkins lymphoma is almost
invariably associated, as are most cases in elderly people.
The lowest rates of Epstein-Barr virus-associated
Hodgkins lymphoma are reported in young adults (age

Search strategy and selection criteria

We systematically searched Medline with terminology relating
to the aspects of Hodgkins lymphoma discussed in this
Seminar. Articles were retrieved up to October, 2002, and
studies reported in full and abstract form have been included.

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Panel 2: Comparison of phenotypes of classical and

lymphocyte-predominant Hodgkins lymphoma

Panel 3: Ann Arbor staging system with Cotswold

modifications for Hodgkins lymphoma

Antigen

Stage
1 Involvement of one lymph-node region or lymphoid
structure (eg, spleen, thymus, Waldeyers ring)
2 Two or more lymph-node regions on the same side of the
diaphragm
3 Lymph nodes on both sides of the diaphragm
31: with splenic hilar, coeliac, or portal nodes
32: with para-aortic, iliac, or mesenteric nodes
4 Involvement of extranodal site(s) beyond that
designated E
Modifying features
A No symptoms
B Fever, drenching night sweats, weight loss greater than
10% in 6 months
X Bulky disease: greater than a third widening of
mediastinum
greater than 10 cm maximum diameter of
nodal mass
E Involvement of single, contiguous, or proximal extranodal
site
CS Clinical stage
PS Pathological stage

Classical Hodgkins
lymphoma
(Reed-Sternberg
cells)
Occasionally positive
Usually negative

CD20
Other B-cell
antigens
CD30
Positive
CD15
Usually positive
Immunoglobulin Absent
expression

Nodular lymphocytepredominant Hodgkins

lymphoma (L&H
cells)
Usually positive
Usually positive
Negative
Negative
Present

L&H=atypical and lymphocytic and histiocytic.

1534 years),9 raising the possibility that alternative

lymphotropic viruses are implicated in the pathogenesis of
cases negative for Epstein-Barr virus.13 Hodgkins
lymphoma associated with immunosuppressed states such
as HIV-1 infection, post-solid organ and bone-marrow
transplantation, and congenital immunodeficiency states
is also usually associated with this virus.14
A further mechanism by which Hodgkin/ReedSternberg cells might escape apoptosis is via the NFB
pathway (figure 1).1518 NFB belongs to a family of
transcription factors implicated in regulation of many
processes, including apoptosis and oncogenesis. It is
upregulated in Reed-Sternberg cells in most patients with
classical Hodgkins lymphoma, and is regulated by several
upstream elements, including CD40 ligand and tumour
necrosis factor-receptor-associated factors, though the
exact mechanism is still unclear.17 NFB is present in the
cytosol of the resting cell attached to its inhibitor IB.
Activation of the cell by various routes, such as via CD40
ligand or LMP1, leads to activation of Ikinase (IKK) and
phosphorylation of IB and subsequent ubiquitination
with degradation by the 26S proteasome.16 Liberated
NFB is then able to move into the nucleus in which it
activates transcription of several target genes implicated in
prevention of apoptosis. Furthermore, the C-FLIP
protein, which inhibits apoptosis and has been implicated
in germinal-centre cell survival, was expressed in
malignant cells of 18 of 19 patients with Hodgkins
lymphoma.19

Cytokines, eg,
TNF

LMP

IB

IB

p50

p65

IB
Proteasomal
degradation

p50 p65

p50

p65
Target gene
transcription

Figure 1: NFB activation

TNF=tumour necrosis factor; P=phosphate. p50 and p65 are
heterodimers of NFB.

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The presenting features of Hodgkins lymphoma are

many. Most patients present with an enlarged but
otherwise asymptomatic lump, typically in the lower neck
or supraclavicular region. Mediastinal masses are frequent
and are sometimes discovered after routine chest
radiography. Patients might complain of chest discomfort
with a cough or dyspnoea. About 25% of patients will have
systemic symptoms at presentation, typically fatigue, fever,
weight loss, and night sweats. Pruritus and intermittent
fevers usually associated with night sweats are classic
symptoms of Hodgkins lymphoma.

Staging
The Ann Arbor staging system was developed more than
30 years ago to define patients who could be treated by
radiotherapy, and it is still valuable in defining treatment
even though radiation alone is not generally used. The
system was modified in 1989 (Cotswold modifications;
panel 3),20 taking into account the importance of bulky
disease and the fact that laparotomy and splenectomy
were no longer recommended as staging procedures,
because they have no effect on overall survival and are

Panel 4: EORTC risk factors in localised disease25

CD40

Ikinase
P

Clinical presentation

Favourable
Patients must have all features:
Clinical stage 1 and 2
Maximum of three nodal areas involved
Age younger than 50 years
Erythrocyte sedimentation rate (ESR) less than 50 mm/h
without B symptoms or ESR less than 30 mm/h with B
symptoms
Mediastinal/thoracic ratio less than 035
Unfavourable
Patients have any features:
Clinical stage 2 with involvement of at least four nodal areas
Age older than 50 years
ESR greater than 50 mm/h if asymptomatic or ESR
greater than 30 mm/h if B symptoms
Mediastinal/thoracic ratio greater than 035

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1
2
3
4
5
6
7

Age older than 45 years

Male sex
Serum albumin less than 40 g/L
Haemoglobin concentration less than 105 g/dL
Stage 4 disease
Leucocytosis (white-cell count greater than or equal to
15109/L
Lymphopenia (less than 06109/L or less than 8% of the
total white-cell count)

100

Cumulative proportion surviving

(%)

Panel 5: Hasenclever index26

1990s
(n=1177)

80
60
40

1980s
(n=1755)

20

p<0001

0
0

associated with significant morbidity and occasionally

mortality.21
Lymphangiography is also now rarely done, and CT is
the major means of staging intrathoracic and intraabdominal disease. MRI is largely restricted to assessment
of specific situations such as bony involvement and
spinal-cord compression. Fluorodeoxyglucose-positron
emission tomography (FDG-PET), relying on the uptake
of 2-fluoro-2-deoxy-D-glucose by metabolically active
tissues, might provide more accurate staging information
than CT,2224 but is not yet standard practice.

Prognostic factors
The British National Lymphoma Investigation (BNLI)
published a prognostic index in localised Hodgkins
lymphoma in 1985 based on analysis of more than
2000 patients.21 This index was complex and not widely
adopted, though the principle of determining treatment
on the basis of risk factors has become well established.
The EORTC (European Organisation for the Research
and Treatment of Cancer) have identified several features
indicative of a worse prognosis in stage 1 and 2 disease
and have used them to stratify treatment (panel 4).25 In
advanced disease, the international prognostic score (or
Hasenclever index) was developed (panel 5)26 on the basis
of analysis of 5141 patients treated initially with an
anthracycline-containing chemotherapy regimen. Seven
factors were identified, which individually reduced
predicted 5-year freedom from progression rate by
around 8%.

Response assessment
Residual masses after treatment are very frequent in
Hodgkins lymphoma, creating problems in establishing
which patients have had a complete response. The entity
of unconfirmed or uncertain complete response has been
introduced,27 which refers to patients in whom there is
uncertainty about remission status because of persistent
radiological abnormalities, especially in the mediastinum.
Planar and single-photon emission CT (SPECT) gallium
scanning have been used to assess residual masses.28
Gallium is predominantly excreted via the gastrointestinal
tract, which could limit its use in assessment of
abdominal disease.29 Comparative studies between
gallium scanning and PET are underway.30
PET scanning is likely to have an important role in
clarification of remission status in patients with an
uncertain or unconfirmed complete response since
2-fluoro-2-deoxyglucose is taken up by residual
metabolically active tumour cells and not fibrotic tissue.31
FDG-PET has been shown to have significantly higher
sensitivity, specificity, and positive and negative
predictive values for disease-free survival than CT.31,32
Our practice is to do PET no earlier than 3 weeks after
completion of treatment in patients who have suspicious
symptoms or a residual mass on end-of-treatment CT.

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1970s
(n=1540)

10

15
20
Time (years)

25

30

35

Figure 2: Survival in Hodgkins lymphoma

Data of 4472 patients recorded on the BNLI (British National Lymphoma
Investigation) database with all stages of Hodgkins lymphoma treated
with radiotherapy, chemotherapy, or combined therapy.

On the basis of clinical findings and results of PET,

patients can be closely monitored with repeat PET if
necessary, or might be offered further treatment.
However, PET cannot reliably assess extranodal or
inflammatory disease well,32 and at present, biopsy of
unusual lesions is recommended.

Treatment
Both localised and advanced Hodgkins lymphoma can be
cured in most patients, and outcome has improved over
the past three decades (figure 2). Unlike many other
forms of cancer, it is often possible to cure Hodgkins
lymphoma even if first-line treatment fails. This fact
creates the dilemma of whether it is better to use a more
extensive treatment initially, to cure as many individuals
as possible, or whether a less intensive treatment should
be used first, followed by aggressive salvage therapy in
more patients.
Nodular lymphocyte-predominant Hodgkins lymphoma
No prospective randomised trials have been undertaken
specifically in patients with nodular lymphocytepredominant Hodgkins lymphoma. Disease is usually
localised, and is often treated with surgical excision and
involved-field radiotherapy, though if excision is
complete then radiotherapy might be unnecessary. The
European Task Force on Lymphoma reported a 96%
complete response rate to primary treatment, with a 99%
and 94% 8-year disease-specific survival for stage 1 and
2 disease, respectively.3 Patients with advanced-stage or
relapsed disease are generally treated in the same way as
patients with classical Hodgkins lymphoma (see below).
Researchers from Germany and Stanford, USA, have
reported use of the CD20 monoclonal antibody
rituximab in patients with nodular lymphocytepredominant Hodgkins lymphoma. Treatment is welltolerated, and results have been encouraging, with a very
high response rate.33,34 These data are preliminary, and
need longer follow-up, but rituximab should certainly be
considered in patients failing combination chemotherapy.
Classical Hodgkins lymphoma
All forms of classical Hodgkins lymphoma are usually
treated in the same way, although in some centres
specific histological subtypes are used as prognostic
factors, and could therefore modify the risk group and
treatment prescribed. Therapy is mainly based on
anatomical stage.

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Localised disease
Many trials have been done in localised Hodgkins
lymphoma, but to directly compare results from different
trials is difficult. Entry criteria vary, and some groups
stratify localised disease into several different risk groups.
The EORTC, for instance, has divided localised disease
into two risk groups (panel 4). In the UK, usual practice
has been to have only one category of localised disease,
and patients with stage 2B or 3A disease are automatically
regarded as advanced disease.
Traditionally, treatment for localised disease was
radiotherapy alone. Complete remission rates were very
high, but relapse was frequent. The more extensive the
radiation fields, the lower the relapse rate, and in a
randomised trial done by the BNLI, mantle or inverted-Y
fields resulted in a roughly 11% higher time-to-treatmentfailure value than involved-field radiotherapy.35 In Europe,
even more extended radiation fields have been used
routinely, but even so, 2030% of patients still relapse.
More extensive radiation fields have not translated into
improved survival, attesting to the success of
chemotherapy in radiation failures.36 Nonetheless, such
high relapse rates are now deemed unacceptable.
Relapse risk can be reduced by use of combined
treatment with chemotherapy and radiotherapy. Little
evidence exists that this combined modality treatment
improves survival;36 however, with this therapy, shorter
courses of chemotherapy than are used in advanced
disease and more restricted radiation fields can be used.
In the EORTC H7 combined modality treatment trial
for unfavourable-risk disease, four cycles of chemotherapy
were as effective as six, and involved-field radiation was as
effective as subtotal nodal irradiation.37 Even in this poorrisk group of patients, failure-free survival and overall
survival at 6 years were 89% and 90%, respectively. By
contrast, in patients with better-risk disease, shorter
courses of chemotherapy are adequate. For example, in
the EORTC/GELA H8 trial for favourable-risk disease,
three cycles of a MOPP (chlormethine, vincristine,
procarbazine, and prednisolone)/ABV (doxorubicin,
bleomycin, and vinblastine) hybrid regimen plus involvedfield radiotherapy were more effective than subtotal nodal
irradiation, and gave a 4-year event-free survival of 99%.38
Three cycles of combination chemotherapy (usually
ABVD [doxorubicin, bleomycin, vinblastine, and
dacarbazine]) plus involved-field radiotherapy should thus
be judged the standard for treatment in favourable-risk
localised disease. Various even shorter chemotherapy
regimens have been combined with involved-field
radiotherapy,39 and although they might be less efficacious
than three cycles of ABVD or equivalent, they probably
have fewer short-term and long-term toxic effects.
As well as reducing the amount of chemotherapy, it
might also be possible to reduce the radiation field and
dose in combined modality treatment. In the German
HD8 trial, patients with stage 1 or 2 disease and at least
one risk factor were treated with four courses of
alternating COPP (cyclophosphamide, vincristine,
procarbazine, and prednisone) and ABVD. Rates of
survival or freedom from treatment failure did not differ
between patients receiving consolidation involved-field
radiotherapy and those receiving extended-field
radiation.40 The present HD10 trial is designed to
investigate use of reduced doses of radiation and restricted
fields.41
Concern over radiation-induced second malignancies
has raised the issue of whether localised disease should be
treated with chemotherapy alone, and this issue is the
subject of ongoing trials.

946

Trial
name

Disease
stage

CALGB48

3, 4

INT Milan49 1A4

NCIC50

CALGB
895251

3B4 or
after wide
field radiotherapy

Number
of
patients
361

427
(415
evaluable)

301

34 or after 856
radiotherapy
failure

Treatment

FFS
(%)

OS
(%)

Time
(years)

MOPP
50*
MOPP/ABVD
65*
ABVD
61*

MOPP/ABVD
67
alternating
MOPP/ABV
69
hybrid (radiotherapy to initial
bulk in both
arms)

MOPP/ABV
71
hybrid
MOPP/ABVD
67
alternating

MOPP/ABV
67
ABVD
65

66
75
76

74

10

72

81

83

85
87

CALGB=Cancer and Leukaemia Group B; NCIC=National Cancer Institute of

Canada; FFS=failure-free survival; OS=overall survival. *p<005. This trial was
closed early due to an excess of treatment-related deaths and second
malignancies in the hybrid arm.

Selected randomised trials of chemotherapy alone or with

radiotherapy in advanced disease

Advanced disease
Introduction of the MOPP chemotherapy regimen in the
1960s was a major landmark in treatment of advanced
Hodgkins lymphoma.42 Over the next few years, several
modifications to this regimen were made, which
maintained efficacy but reduced associated toxic
effects.4346 The ABVD regimen was introduced in the
1970s as non-crossresistant salvage for patients failing
MOPP,4347 and was later used as first-line treatment,
particularly because the drugs in ABVD were far less likely
to induce infertility and secondary leukaemia than were
those in MOPP. ABVD was also combined with MOPP or
MOPP-like therapy in either an alternating or hybrid
regimen to introduce many drugs over a short period in the
hope of reducing development of tumour resistance. A
series of randomised trials4851 subsequently established
ABVD as the gold standard (table) on the basis of its
efficacy and reduced long-term toxic effects.
Encouraging results have been reported with some
alternative regimens. The Stanford V regimen is a
12-week course of seven active drugs with radiotherapy to
sites of initial bulk disease. Data for 142 patients showed a
5-year failure-free survival of 89% and a 5-year overall
survival of 96%.52 A small randomised Italian study,
however, noted the Stanford V regimen to be inferior to
ABVD;53 randomised trials of Stanford V versus ABVD are
continuing in several countries.
The German Hodgkin Study Group54 compared their
standard alternating regimen (COPP and ABVD) with a
hybrid regimen (BEACOPP [bleomycin, etoposide,
doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone]) and a dose-intensified version of
this regimen (escalated BEACOPP). Escalated BEACOPP
needs routine administration of granulocyte-colony
stimulating factor. Results of the final analysis showed
significant improvement in freedom from treatment failure
at 5 years in the BEACOPP arm compared with the COPP
and ABVD arm (76% vs 69%); a further substantial
improvement was seen in the escalated BEACOPP arm, in
which freedom from treatment failure at 5 years was
87%.54 Both BEACOPP arms showed an advantage in
overall survival at 5 years over the standard COPP and

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ABVD arm; however, no significant difference between

baseline BEACOPP and escalated BEACOPP was noted.
Nine cases of acute myeloid leukaemia/myelodysplastic
syndrome were reported in the escalated dose arm
compared with four in the baseline BEACOPP arm and
one in the COPP and ABVD arm.54 This finding
emphasises the fact that longer follow-up will be needed
before final conclusions can be drawn. Furthermore,
patients have considerably more chance of infertility with a
procarbazine-containing regimen than with ABVD.55 At
the very least, results of this study show there is a clear
dose-response relation within the dose range possible
without haemopoietic stem-cell support.
A further issue is whether intensive regimens, such as
escalated BEACOPP, should be reserved for high-risk
patients. In the UK, the ChlVPP alternating with
PABLOE regimen56 has been widely used, and analysis of
326 patients showed not only a reduced failure-free
survival in poor-risk patients (IPS 47) but also a reduced
salvage rate with alternative therapies.57 Thus, regimens
such as escalated BEACOPP might be most beneficial in
high-risk patients. Researchers have suggested that highrisk patients might benefit from high-dose therapy and
stem-cell transplantation in first remission,58 but results of
a randomised trial did not substantiate this.59 It is
noteworthy in this trial that patients receiving continued
conventional dose therapy had good 5-year failure-free
survival of 83%, showing the difficulty in defining a poorprognosis group once a good response to initial therapy has
been obtained.
Radiotherapy in advanced Hodgkins lymphoma
Consolidation radiotherapy has frequently been used in
patients with advanced Hodgkins lymphoma, especially in
patients achieving an unconfirmed or uncertain complete
response or in those with bulky disease at presentation.
Evidence for this practice is not strong. The Groupe
dEtude des Lymphomes de LAdulte H89 trial indicated
no benefit to radiotherapy consolidation compared with
two extra cycles of a doxorubicin-containing regimen.60
Results of the EORTC 20884 trial similarly showed no
advantage of consolidation radiotherapy in remission after
MOPP/ABV hybrid therapy.61 Furthermore, a metaanalysis comparing chemotherapy with combined modality
therapy suggested that the addition of radiotherapy might
be associated with a reduced survival attributable to longterm effects of treatment.62 Despite these negative
conclusions about consolidation radiotherapy, two
regimens with good results both use radiotherapy
consolidation in most patients. In Stanford V,52 85% of
patients received radiotherapy, and in escalated
BEACOPP,54 radiotherapy was given to most patients.
Treatment of childhood Hodgkins lymphoma
Hodgkins lymphoma in children and adolescents is
curable in over 90% of cases.63 Several specific childhood
treatment regimens have been developed, which
encompass the same general principles, namely, avoidance
of laparotomy staging, risk-adjusted therapy, combined
modality treatment at all stages of disease, avoidance of
procarbazine in boys to protect future fertility, and keeping
radiation dose and field and anthracycline dose to a
minimum.64 Many of these same principles are now being
applied in adults with Hodgkins lymphoma.
Relapsed disease
Some patients receiving chemotherapyeither de novo or
after radiation failurewill have refractory disease or will
relapse. Occasionally, patients can be cured by

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radiotherapy if persistent or relapsed disease is localised,

but most patients will need systemic treatment. Many
patients with long first remissions can be cured by further
standard dose chemotherapy, but results of such
approaches are poor if remission has been short or disease
was refractory to initial chemotherapy.65,66
High-dose chemotherapy and autologous stem-cell
transplantation was pioneered in patients with relapsed
Hodgkins lymphoma more than 40 years ago, but it has
only become an established modality of treatment in the
past two decades.67 Procedure-related mortality has fallen
over recent years because of better selection of patients
and improved supportive care68 and more rapid
engraftment associated with peripheral-blood stem cells,
which have now largely replaced bone marrow as the
source of haemopoietic stem cells.69 In large single-centre
series,68 and in Registry reviews,70 about 4050% of
transplanted patients with relapsed or resistant disease are
alive after 5 years. Several different conditioning regimens
have been used, and high-dose chemotherapy is generally
preferred to total-body irradiation. This preference is
because chemotherapy is logistically easier to administer,
is as effective as total body irradiation, and might be
associated with less pneumonitis, although high-dose
chemotherapy is undoubtedly also associated with
pneumonitis, especially in patients who have received
mediastinal radiation in the preceding year.71,72 After highdose therapy, irradiation of persistent masses or sites of
previous large volume disease is common practice,
although no trial data to substantiate this practice are
available.
Before high-dose therapy, standard-dose chemotherapy
is usually given to reduce disease bulk and determine
chemosensitivity. In patients who have disease that
progresses through standard-dose salvage therapy, or have
persistent B symptoms or a raised concentration of lactate
dehydrogenase, results of high-dose therapy are probably
too poor to justify proceeding to this course of action.
However, in some cases, a mass will not immediately
reduce in size, and failure to achieve a formal response
(complete or partial remission) should not exclude a
patient from receiving an autograft.
The BNLI did a small randomised trial of BEAM
(carmustine, etoposide, cytarabine, and melphalan)
followed by autologous stem-cell transplantation or miniBEAM (the same drugs at reduced doses) in patients with
refractory or relapsed disease. A highly significant
progression-free survival advantage was noted in the highdose treatment arm,73 and similar results have
subsequently been reported from a larger German study.74
Neither study showed an overall survival benefit, which
might, in part, be attributable to the small size of these
trials, or might be because some patients failing standarddose salvage therapy can still be rescued by high-dose
therapy at a later time. When therefore is the optimum
time to consider an autograft procedure? This procedure
is widely recommended for all patients younger than age
65 years who fail first-line chemotherapy, although this
treatment might not be appropriate if first complete
remission lasted more than 3 years.
The value of allogeneic transplantation in patients with
Hodgkins lymphoma is unclear. In large published series,
high rates of transplant-related mortality have been
reported.7578 Nonetheless, patients surviving an allogeneic
transplant may have a reduced relapse rate,7779 suggesting
a graft-versus-lymphoma effect. There is interest in use of
less toxic non-myeloablative allogeneic transplants in
Hodgkins lymphoma, especially in patients who have
failed a previous autograft. In a UK study of 24 patients

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Panel 6: Late effects of Hodgkins lymphoma and

its treatment

Second malignancies
Cardiac disease
Endocrine dysfunction
Psychological trauma
Lung damage (usually subclinical)
Hyposplenism (after splenectomy or splenic irradiation)
Dental caries

with relapsed or refractory disease, only two procedurerelated deaths were reported. Several patients who
subsequently relapsed responded to donor lymphocyte
infusions. Further follow-up and larger trials will be
needed to ascertain the role of this modality of
treatment.80

Late effects of Hodgkins lymphoma and its

treatment
Because the cure rate for Hodgkins lymphoma has risen,
and longer-term follow-up data have become available,
the importance of late effects of treatment have become
more apparent (panel 6). In a study of young adult
patients aged younger than 29 years at diagnosis, who
achieved continuing complete remission after first-line
or second-line treatment, actuarial overall survival at
20 years was 93% and 85%, respectively, compared wth
985% in the age-matched general population.81 Further
review of patients treated for favourable-risk disease
indicated that treatment-related mortality exceeded that
from Hodgkins lymphoma by 1215 years after initial
therapy.82 The two most frequent causes of excess deaths
are second malignancies and ischaemic heart disease.
The most common second malignancy in patients with
Hodgkins lymphoma is lung cancer. This disease is
mainly
attributable
to
radiotherapy,
although
chemotherapy also contributes to the risk.83,84 It is
imperative that all patients who have had thoracic
radiation are strongly encouraged never to smoke. Risk of
developing secondary myeloid leukaemia is related to the
cumulative dose of alkylating agents received, and
therefore, arises predominantly in patients who have had
remitting and relapsing disease. Secondary breast cancer
mainly occurs after irradiation to the mediastinum or
axillae, especially when given to adolescent females or
young women. A dose-response relation exists, which
underscores use of the minimum radiation dose needed
for tumour control.85 Risk in such patients of ever
developing breast cancer is about 2050%,86 and patients
at such high risk need to be aware of this fact and offered a
screening programme. Other malignancies that arise in
excess in patients treated for Hodgkins lymphoma
include non-Hodgkin lymphomas, head and neck
tumours, cancers of the colon, stomach, and thyroid, and
malignant melanoma.84,86,87 Patients should be advised to
consult their doctor if they have any suspicious symptoms,
and they should be strongly advised to use effective
measures to avoid sunburn.
The Stanford group reported about a three-fold
increase in relative risk of cardiac death in patients who
did not die from Hodgkins lymphoma,88 which is a major
risk because prevalence of cardiac disease in the general
population is so high. The major contributing factor is
mediastinal irradiation when a dose in excess of 30 Gy is
used.88 Whether or not the increasing use of
anthracyclines will have a long-term effect on cardiac
disease is not yet clear.

948

The most common endocrine disorders are

hypothyroidism after radiation to the lower neck and
infertility. Around 50% of patients receiving neck
irradiation will develop hypothyroidism, and these
individuals should have their thyroid function assessed
every year.89 Recipients of neck irradiation are also at
higher risk of development of dental caries and other oral
diseases.90 The importance of regular dental attention
should be emphasised to patients.
Infertility arises after irradiation of the gonads and after
use of drugs such as procarbazine and alkylating agents.
Repeated use is most damaging, and young female
patients receiving an autologous transplant will often
remain fertile if they are still menstruating before receiving
high-dose therapy.68 Sperm cryopreservation before
chemotherapy is standard practice for men who have not
completed their families. Artificial insemination has a low
success rate per cycle; however, intracytoplasmic sperm
injection may improve the success rate.91 Hodgkins
lymphoma can typically be slow-growing, which might
permit harvesting of eggs, in-vitro fertilisation, and
embryo storage in those young women who have an
established partner.92 Oocyte cryopreservation and ovarian
tissue banking are presently in development.93
Psychological trauma associated with contracting a
malignant
disease,
receiving
radiotherapy
and
chemotherapy, and coping with risk or eventuality of
relapse is great. In one survey,94 many patients reported a
lower perceived level of overall health and dissatisfaction
in their personal relationships as a result of disease, its
treatment, or both. Many also had difficulties in obtaining
life assurance and financial loans.
Present treatment strategies must therefore aim to give
minimum therapy without jeopardising the high rates of
cure that are now possible with front-line therapy.

Novel treatments
Cytotoxic drugs
Gemcitabine, an analogue of cytarabine, has antitumour
activity in Hodgkins lymphoma.95 It is well tolerated with
a favourable toxicity profile, and given at a dose of
1250 mg/m2, it has been reported to have a response rate
in excess of 35% in heavily pretreated patients.96
In view of the fact that NFB is frequently activated in
Hodgkin/Reed-Sternberg cells, this pathway is an
important target for new drug development. Particular
attention is focused on proteasome inhibitors, which
prevent degradation of IB and thus keep the liberation of
active NFB to a minimum.17,97
Immunotherapy
Ex-vivo generation of Epstein-Barr virus-specific cytotoxic
T lymphocytes for reinfusion into patients with Hodgkins
lymphoma has had limited success.98 However, strategies
aimed at generation of LMP-selective cytotoxic T lymphocytes with autologous dendritic cells could prove more
efficacious.99
One of the most promising antigens for targeted
immunotherapy is the CD30 antigen, which is highly
expressed on Hodgkin/Reed-Sternberg cells. Several
groups of researchers have shown that antiCD30
monoclonal antibodies chemically linked to active toxins
have antitumour activity in Hodgkin cell lines and also
in SCID mice inoculated with tumour.100103 Studies
investigating radioimmunotherapy with 131I-labelled
antiCD30 are also underway.104
Internalisation of an antibody-conjugated toxin can be
amplified by use of antibodies with specificity for both a
tumour-associated antigen and a cell-surface antigen,

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SEMINAR

which facilitates internalisation of the formed complex.

CD25 is the interleukin 2 receptor. An antiCD30 and
CD25 immunotoxin was tested in SCID mice inoculated
with Hodgkins lymphoma and achieved a substantially
higher cure rate than that achieved with single agent
alone.105 Phase 1 and 2 trials have been done in patients
with refractory disease, and moderate responses have been
reported.106
An alternative use of bispecific antibodies is to augment
cell-mediated tumour killing by target-killer cell
interaction. Bispecific antibodies recognising CD30 and
CD3 or CD28 on T cells have been developed and are
active in animals.107,108 Bispecific antibodies recognising
CD30 and either CD16, which is expressed on natural
killer cells, granulocytes, and macrophages, or CD64,
which is expressed on monocytes, macrophages, and
activated neutrophils, have also been developed.109,110

Conclusion
The nature of the malignant cell in Hodgkins lymphoma
is now understood, but the mechanism of tumorigenesis
has not been fully elucidated. Results of treatment
continue to improve, and with such high cure rates, late
effects become more important. In many situations, the
same ultimate survival can be achieved with different
therapeutic approaches. Less intensive initial therapy
cures fewer patients, but many failures can be rescued by
subsequent more intensive treatment. Choice of approach
is thus dependent on an appreciation of short-term and
long-term side-effects, and increasingly the patient must
be involved in an informed decision-making process.
Conflict of interest statement
None declared.

Acknowledgments
LY is funded by the Lymphoma Research Trust and DL receives funding
from the Medical Research Council, Cancer Research UK, the Leukaemia
Research Fund, and the Lymphoma Research Trust. DL sits on the
Roche Oncology Advisory Board. The funding sources had no role in the
writing of this Seminar.

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