Controversies in the Management of
Relapsed and Primary Refractory
Hodgkin’s Lymphoma
By Craig H. Moskowitz, MD
Abstract: The majority of patients with Hodgkin’s lym-
phoma (HL) are cured with radiation therapy and/or
combination chemotherapy. However, patients who re-
lapse after attaining a complete remission with a full
course standard chemotherapy program such as ABVD,
and those with primary refractory disease have a poor
outcome with standard dose second-line chemotherapy
(SDSC) regimens. Two phase III random assignment trials
comparing SDSC with high-dose therapy (HDT) and au-
tologous stem cell transplantation (ASCT) are reported.
Each study demonstrated a statistically significant im-
provement in both event-free survival (EFS) and progres-
sion-free survival (PFS) for the patients treated on the
CHEMOSENSITIVE DISEASE IS REQUIRED TO
ACHIEVE BENEFIT FROM HIGH-DOSE
THERAPY (HDT)/AUTOLOGOUS STEM CELL
TRANSPLANTATION (ASCT)
High dose therapy and autologous stem cell
transplantation (ASCT) is the best curative op-
tion for patients with relapsed and primary re-
fractory Hodgkin’s lymphoma (HL).1-5 Chemosen-
sitive disease to standard dose second-line
chemotherapy (SDSC) is necessary for transplant
eligibility in the United States. There is limited
information regarding the optimal SDSC regi-
men. The requirements for an effective SDSC
regimen are as follows: demonstration of cytore-
duction in at least 75% of patients with minimal
extramedullary toxicity and without severe bone
marrow suppression compromising the ability to
collect an adequate number of peripheral-blood
progenitor cells (PBPCs).6 Specifically, in the
phase III randomized German study described
From the Lymphoma and Hematology Services, Memorial
Sloan-Kettering Cancer Center, New York, NY.
Author’s disclosure of potential conflicts of interest is found
at the end of this article.
Address reprint requests to Craig H. Moskowitz, MD, Assis-
tant Attending Physician, Lymphoma and Hematology Ser-
vices, Memorial Sloan-Kettering Cancer Center, 1275 York
Avenue, New York, NY 10021; email: moskowic@mskcc.org.
© 2004 by American Society of Clinical Oncology.
1092-9118/04/360-367
360
HDT arms, but neither was powered to show an overall
survival advantage. Importantly, in the study by the
German HL study group there was a superior PFS for the
transplanted patients who had an initial remission dura-
tion of either greater than or less than 1 year (Fig 1,
reprinted with permission). Based on these two clinical
trials nearly all patients with relapsed or refractory
disease should be considered transplant-eligible. De-
spite improvements in supportive care, long-term EFS
has improved by at most 10% in recent reports. There-
fore, disease-related, patient-specific, and treatment-
related prognostic factors must predict outcome and will
be discussed in this section.
above, of the 161 patients enrolled, 13 patients
could not be randomly assigned secondary to
dexa-BEAM related mortality (eight patients) or
severe infection. In relapsed and refractory HL,
ifosfamide-based regimens can achieve the above
stated goals.
Balzarotti et al7 has recently reported the re-
sults of 62 patients treated with the IGEV regi-
men. IGEV consists of ifosfamide 2000 mg/m2
intravenously (IV) d 1 to 4; gemcitabine 800
mg/m2 IV d 1 and 4; vinorelbine 20 mg/m2 IV d 1;
prednisolone 100 mg/m2 IV d 1 to 4, and G-CSF
support. The treatment program consisted of
four cycles of IGEV administered at 3-week
interval followed by HDT for responding pa-
tients. The response rate to IGEV was 84%. The
median number of CD34⫹ cells collected was 6.6
⫻106/kg after a median of two (range 1 to 3)
apheresis procedures. Extramedullary side ef-
fects were minimal.
We reported the results of a comprehensive
program for the treatment of 82 patients with
uniform cytoreductive chemotherapy with only
two cycles of ifosfamide, carboplatin, and etopo-
side (ICE) with responders offered HDT and
ASCT. All patients in this trial had biopsy-proven
relapsed or refractory disease, and our data were
analyzed by intent to treat. ICE chemotherapy was
a highly effective SDSC regimen in HL. The re-
sponse rate to ICE was 90% with no ICE-related
extramedullary toxicity. The median number of
HODGKIN⬘S LYMPHOMA MANAGEMENT CONTROVERSIES
Fig 1. Freedom from treatment failure for patients in ran-
domized German Hodgkin’s disease study group (GHSG) study
separated by initial remission duration. Reprinted with permis-
sion.4
CD34⫹ cells/kg collected was 7.6 ⫻106/kg after a
median of two apheresis procedures.8
In contrast to diffuse large B cell lymphoma
(DLBCL), where patients achieving a complete
361
response on the basis of computed tomography
(CT) criteria to SDSC have a survival advantage,9
in HL, response rate is sometimes difficult to
assess because of large residual fibrotic masses.
For example, despite a 90% response rate to two
cycles of ICE chemotherapy in HL, most patients
cannot achieve a true clinical remission (CR) as
defined by Cheson criteria.10
THE ROLE OF FUNCTIONAL IMAGING IN
PATIENTS WITH HL
Functional imaging improves the accuracy of
initial HL staging. For many years gallium scan-
ning has complemented CT for staging and re-
sponse evaluation. Fluorine-18 fluorodeoxyglu-
cose positron emission tomography (PET) has
replaced gallium scanning in the United States as
the functional imaging test of choice for a variety
of reasons that include improved resolution, re-
duced nonspecific abdominal uptake, and ease
of administration.11-13 A critical question facing
physicians regarding PET imaging in HL is the
positive predictive value (PPV) and negative
predictive value (NPV) in the evaluation of a
residual mass.
Since 1994 all patients with HL at Memorial
Sloan-Kettering Cancer Center (MSKCC) were
enrolled on intent to treat trials encompassing
two doses of ICE– based chemotherapy followed
by ASCT for responders. The second study had
more patients with poor prognostic factors (Fig 2).
Functional imaging studies pre- and post-ICE are
available on all 173 patients. After excluding the
22 patients who failed ICE chemotherapy, we
compared the outcome of the 152 patients by
response to ICE (complete or partial response) or
normalization of functional imaging versus ab-
normal functional imaging pre-ASCT. In study
one all patients had gallium imaging and in study
two all patients had PET scans. In both clinical
trials the most important risk factor predicting
outcome in these patients was abnormal func-
tional imaging pre-ASCT. If one combines the two
programs there is a marked survival advantage
for those patients who have normal functional
imaging at the time of transplant. On the basis of
this information more intensive cytoreduction or
extending standard regimens in patients with
abnormal functional imaging pre-ASCT warrants
a prospective clinical trial14 (Fig 2).
362
Fig 2. Event-free survival of patients treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2003 on the basis of the
results of functional imaging (FI) tests pre-autologous stem cell transplantation.
PRIMARY REFRACTORY HL
Some reports have suggested that patients with
primary refractory disease do less well than those
patients who achieved an initial remission to
front-line therapy.15,16 Therapy for patients with
primary refractory HL has changed in the past
decade because progression-free survival (PFS) is
only 8% to 15% when SDSC is administered.
Results with HDT indicate an improved PFS of
30% to 40%. A major problem with the published
refractory disease series is the lack of a uniform
definition of primary refractory disease. Defini-
tions of refractory disease in the literature range
from progression of disease on upfront therapy to
a partial response three months posttreatment.
Moreover, the inclusion of patients with uncon-
firmed pathology may result in the incorporation
of patients with aggressive non-Hodgkin’s lym-
phoma (NHL), with a nonmalignant disorder (in-
fection or sarcoid-like reactions) or patients with
residual radiologic abnormalities but no active
HL into a HDT program. These other non-HL
entities are often strongly positive on functional
imaging; thereby making histologic confirmation
even more imperative.
CRAIG H. MOSKOWITZ
We have recently reported our results on 91
patients with primary refractory HL of which
eight (9%) patients were found to have diffuse
large B cell lymphoma on the repeat biopsy. In
these cases, the initial diagnosis of HL was con-
firmed by pathology review. This has both prog-
nostic as well as therapeutic implications while
the choice of SDSC in NHL nearly always incor-
porates rituximab. Our data indicates that HDT/
ASCT is standard treatment for patients with
primary refractory HL, if chemosensitivity to
SDSC has been established. Although data from
the autologous bone marrow transplant registry
(ABMTR) found no difference in overall survival
in the patients transplanted with chemorefrac-
tory versus chemosensitive disease; many pa-
tients in this series had no available data con-
cerning response to SDSC. Our patients have all
received SDSC and had repeat imaging studies
before HDT. There is a marked survival advan-
tage for patients who have chemosensitive dis-
ease. In fact, survival is identical for patients
with chemosensitive relapsed or primary refrac-
tory disease treated at MSKCC from 1993 to
200317 (Fig 3).
HODGKIN⬘S LYMPHOMA MANAGEMENT CONTROVERSIES
Fig 3. Event-free survival of relapsed versus primary refractory patients treated at Memorial Sloan-Kettering Cancer Center from
1993 to 2003. HL, Hodgkin’s lymphoma.
PROGNOSTIC FACTORS IN RELAPSED AND
REFRACTORY HL
There are some reports suggesting that aug-
menting therapy for patients with refractory HL
is beneficial; but primary refractory disease is but
one of many prognostic factors affecting out-
come.18 The factors that affect outcome are sum-
marized in Table 1.19-23 Unfortunately, there is
limited information using these prognostic factors
to change therapy. In our first study of ICE
followed by HDT and ASCT, Cox regression anal-
ysis determined that the factors associated with a
poor outcome pre-ICE were: extranodal sites of
disease (ENS), p ⫽ .001, initial response duration
less than 1 year (p ⫽ .001), and B symptoms (p ⫽
.001). Using this three-factor model, we identified
three groups of patients with widely disparate
outcomes with this treatment approach. Clini-
cally however, relapsed and refractory HL can be
divided into two groups: favorable – those with
363
Table 1. Adverse Prognostic Factors for Treatment
Outcome After ASCT for Hodgkin’s Disease
Vancouver: B symptoms at relapse, extranodal disease at relapse,
duration of 1st CR ⬍ 12 months
Stanford: B symptoms at relapse, pulmonary/bone marrow
involvement, more than minimal disease at ASCT
City of Hope: ⬎ 2 prior regimens, extranodal disease at relapse, PSC
as sole stem cell source
MD Anderson: ⬎ 2 prior regimens, extranodal involvement, abnormal
performance status, chemorefractory
Boston: ⬎ 1 extranodal site, ECOG classification ⬎ 0,
progressive disease at ASCT
SFGM: Extranodal relapse, duration of CR ⬍ 12 mo
ABMTR: Chemorefractory, abnormal LDH KPS ⬍ 90%
Nebraska: second-line IPI
Abbreviations: ASCT, autologous stem cell transplantation;
CR, clinical remission; PSC, peripheral stem cells; SFGM,
Societe Francaise de Greffe de Moelle; ECOG, Eastern Coop-
erative Oncology Group; ABMTR, autologous bone marrow
transplant registry; LDH, lactate dehydrogenase; KPS, Karnof-
sky performance status; IPI, International Prognostic Index
364
Fig 4. Event-free survival (EFS) of patients treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2003 based on
pretreatment risk factors.
zero or one risk factors and unfavorable – those
with two or three risk factors. Patients with
favorable disease have a PFS of 76% while pa-
tients with unfavorable disease have a progres-
sion-free survival (PFS) of only 26%. (Fig 4)24
CAN RISK-ADAPTED THERAPY IMPROVE EFS
IN PATIENTS WITH RELAPSED/REFRACTORY
HL?
This three-factor model was the basis of our
third-generation, risk-adapted comprehensive
study (MSKCC protocol 98 to 71). In this study,
patients with zero or one risk factor (extranodal
disease (ENS), initial response duration ⫽ 1 year,
or B symptoms at time of study enrollment),
group A, were treated exactly the same as in the
second-generation program; in that study EFS
was 80%. Patients with two risk factors, group B,
received one dose of standard dose ICE followed
by one dose of augmented ICE second-line ther-
apy as well as a more dose-intense transplant
conditioning regimen. Finally, for patients with
all three risk factors, group C, the program was
CRAIG H. MOSKOWITZ
changed. Now cytoreduction was done with trans-
plant doses of ICE followed by stem cell support;
this is followed by a second autotransplant for
responding patients. This three-arm study, how-
ever, uses one universal theme: Patients must
have chemosensitive disease to their “ICE” ther-
apy; group A to standard doses of ICE, group B to
augmented ICE, and group C to transplant doses
of ICE. Although median follow-up is still short
(30 months) patients with multiple risk factors
appear to have an improved outcome with a more
intensive risk-adapted approach. (Fig 5)25
ALLOGENEIC TRANSPLANTATION
The use of HDT and ASCT is standard therapy
for chemosensitive relapsed and primary refrac-
tory HL. The indications for and the use of allo-
geneic stem cell transplantation (AlloSCT) in pa-
tients with relapsed or primary refractory HL are
poorly defined. The two main reasons to consider
AlloSCT are (1) Infusion of a lymphoma-free stem
cell product (not a concern in HL), and (2) The
graft versus lymphoma effect. The major problem
HODGKIN⬘S LYMPHOMA MANAGEMENT CONTROVERSIES
Fig 5. Event-free survival (EFS) of patients treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2003 based on a
risk-adapted approach. RF, regional failure.
with AlloSCT is the high treatment-related mor-
tality compared to ASCT. The European Bone
Marrow Transplantation registry recently re-
ported the results of a matched study of ASCT
versus AlloSCT for lymphoma for patients treated
between 1982 and 1998. All lymphomas were
included in the analysis, of which 167 patients
had HL. Unfortunately, in HL the transplant-
related mortality for AlloSCT was extremely high
at 51.7%. In addition, HL was the only lymphoma
where relapse-free survival was inferior for
AlloSCT as compared to ASCT.26
The transplant conditioning regimen in
AlloSCT was originally intended to cytoreduce
lymphoma while providing immunosuppression
to prevent graft rejection. It has become clear in
the past decade that the benefit for AlloSCT is
largely related to immune-mediated graft versus
lymphoma effect. This premise has led to the use
of reduced-intensity (RI) or nonmyeloablative
(NMT) conditioning regimens to achieve engraft-
ment and allow for the development of a graft
versus lymphoma effect as the main form of
therapy for the tumor. A few general approaches
are currently being used.27 The NMT approaches
365
include using immunosuppressive chemotherapy
agents, generally fludarabine, in combination
with an alkylating agent.28 Another technique is
based on using low-dose, total-body irradiation
with or without fludarabine.29 Lastly, Mackinnon
et al30 have led the effort using a T-cell depleted
approach by incorporating the humanized mono-
clonal antibody alemtuzumab for T-cell depletion
followed by fludarabine and melphalan; donor
lymphocyte infusions are added for patients with
residual disease or those not evolving to 100%
donor chimerism.30 The RI conditioning regimen
approaches have used standard ASCT condition-
ing regimens, most commonly BEAM (carmus-
tine, etoposide, cytarabine, and melphalan).31
These ASCT regimens cytoreduce lymphoma with
low transplant-related toxicity and support allo-
geneic engraftment.
Only general recommendations can be made
using AlloSCT. (1) A conventional AlloSCT should
not be administered in patients who have failed
ASCT. (2) NMT is reasonable therapy for patients
who have failed ASCT provided that the disease
responds to some form of salvage chemotherapy.
(3) In patients with a human leukocyte antigen-
366
identical sibling donor who have poor risk disease
as defined as initial remission duration of less
than 1 year with concomitant B symptoms and
stage IV disease, RI AlloSCT with regimens such
as BEAM should be considered before ASCT. (4)
The use of ASCT for cytoreduction followed by
NMT in poor risk patients is a reasonable study
alternative to RI AlloSCT in poor risk patients.
FUTURE STUDIES
In conclusion, HDT and ASCT are standard ther-
apy for patients with relapsed and primary refrac-
tory HL provided chemosensitivity is established.
Future studies need to evaluate the role of abnor-
mal PET scan as part of risk-adapted therapy
Great strides made in the management of HL
in the past decades stem from carefully done
prospective clinical trials, but despite our best
therapy, 15% of patients with HL will die of their
disease. It is critical that new agents be studied in
HL. A number of phase I/II studies are under way
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