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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- HDT arms, but neither was powered to show an overall
phoma (HL) are cured with radiation therapy and/or survival advantage. Importantly, in the study by the
combination chemotherapy. However, patients who re- German HL study group there was a superior PFS for the
lapse after attaining a complete remission with a full transplanted patients who had an initial remission dura-
course standard chemotherapy program such as ABVD, tion of either greater than or less than 1 year (Fig 1,
and those with primary refractory disease have a poor reprinted with permission). Based on these two clinical
outcome with standard dose second-line chemotherapy trials nearly all patients with relapsed or refractory
(SDSC) regimens. Two phase III random assignment trials disease should be considered transplant-eligible. De-
comparing SDSC with high-dose therapy (HDT) and au- spite improvements in supportive care, long-term EFS
tologous stem cell transplantation (ASCT) are reported. has improved by at most 10% in recent reports. There-
Each study demonstrated a statistically significant im- fore, disease-related, patient-specific, and treatment-
provement in both event-free survival (EFS) and progres- related prognostic factors must predict outcome and will
sion-free survival (PFS) for the patients treated on the be discussed in this section.

CHEMOSENSITIVE DISEASE IS REQUIRED TO above, of the 161 patients enrolled, 13 patients

ACHIEVE BENEFIT FROM HIGH-DOSE could not be randomly assigned secondary to
THERAPY (HDT)/AUTOLOGOUS STEM CELL dexa-BEAM related mortality (eight patients) or
TRANSPLANTATION (ASCT) severe infection. In relapsed and refractory HL,
ifosfamide-based regimens can achieve the above
High dose therapy and autologous stem cell
stated goals.
transplantation (ASCT) is the best curative op-
Balzarotti et al7 has recently reported the re-
tion for patients with relapsed and primary re-
sults of 62 patients treated with the IGEV regi-
fractory Hodgkin’s lymphoma (HL).1-5 Chemosen-
sitive disease to standard dose second-line men. IGEV consists of ifosfamide 2000 mg/m2
chemotherapy (SDSC) is necessary for transplant intravenously (IV) d 1 to 4; gemcitabine 800
eligibility in the United States. There is limited mg/m2 IV d 1 and 4; vinorelbine 20 mg/m2 IV d 1;
information regarding the optimal SDSC regi- prednisolone 100 mg/m2 IV d 1 to 4, and G-CSF
men. The requirements for an effective SDSC support. The treatment program consisted of
regimen are as follows: demonstration of cytore- four cycles of IGEV administered at 3-week
duction in at least 75% of patients with minimal interval followed by HDT for responding pa-
extramedullary toxicity and without severe bone tients. The response rate to IGEV was 84%. The
marrow suppression compromising the ability to median number of CD34⫹ cells collected was 6.6
collect an adequate number of peripheral-blood ⫻106/kg after a median of two (range 1 to 3)
progenitor cells (PBPCs).6 Specifically, in the apheresis procedures. Extramedullary side ef-
phase III randomized German study described fects were minimal.
We reported the results of a comprehensive
program for the treatment of 82 patients with
uniform cytoreductive chemotherapy with only
From the Lymphoma and Hematology Services, Memorial
two cycles of ifosfamide, carboplatin, and etopo-
Sloan-Kettering Cancer Center, New York, NY.
Author’s disclosure of potential conflicts of interest is found side (ICE) with responders offered HDT and
at the end of this article. ASCT. All patients in this trial had biopsy-proven
Address reprint requests to Craig H. Moskowitz, MD, Assis- relapsed or refractory disease, and our data were
tant Attending Physician, Lymphoma and Hematology Ser- analyzed by intent to treat. ICE chemotherapy was
vices, Memorial Sloan-Kettering Cancer Center, 1275 York
Avenue, New York, NY 10021; email:
a highly effective SDSC regimen in HL. The re-
© 2004 by American Society of Clinical Oncology. sponse rate to ICE was 90% with no ICE-related
1092-9118/04/360-367 extramedullary toxicity. The median number of


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



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-
Fig 1. Freedom from treatment failure for patients in ran- tional imaging pre-ASCT. If one combines the two
domized German Hodgkin’s disease study group (GHSG) study
separated by initial remission duration. Reprinted with permis- programs there is a marked survival advantage
sion.4 for those patients who have normal functional
imaging at the time of transplant. On the basis of
CD34⫹ cells/kg collected was 7.6 ⫻106/kg after a this information more intensive cytoreduction or
median of two apheresis procedures.8 extending standard regimens in patients with
In contrast to diffuse large B cell lymphoma abnormal functional imaging pre-ASCT warrants
(DLBCL), where patients achieving a complete a prospective clinical trial14 (Fig 2).

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 We have recently reported our results on 91

Some reports have suggested that patients with patients with primary refractory HL of which
primary refractory disease do less well than those eight (9%) patients were found to have diffuse
patients who achieved an initial remission to large B cell lymphoma on the repeat biopsy. In
front-line therapy.15,16 Therapy for patients with these cases, the initial diagnosis of HL was con-
primary refractory HL has changed in the past firmed by pathology review. This has both prog-
decade because progression-free survival (PFS) is nostic as well as therapeutic implications while
only 8% to 15% when SDSC is administered. the choice of SDSC in NHL nearly always incor-
Results with HDT indicate an improved PFS of porates rituximab. Our data indicates that HDT/
30% to 40%. A major problem with the published ASCT is standard treatment for patients with
refractory disease series is the lack of a uniform primary refractory HL, if chemosensitivity to
definition of primary refractory disease. Defini- SDSC has been established. Although data from
tions of refractory disease in the literature range the autologous bone marrow transplant registry
from progression of disease on upfront therapy to (ABMTR) found no difference in overall survival
a partial response three months posttreatment. in the patients transplanted with chemorefrac-
Moreover, the inclusion of patients with uncon- tory versus chemosensitive disease; many pa-
firmed pathology may result in the incorporation tients in this series had no available data con-
of patients with aggressive non-Hodgkin’s lym- cerning response to SDSC. Our patients have all
phoma (NHL), with a nonmalignant disorder (in- received SDSC and had repeat imaging studies
fection or sarcoid-like reactions) or patients with before HDT. There is a marked survival advan-
residual radiologic abnormalities but no active tage for patients who have chemosensitive dis-
HL into a HDT program. These other non-HL ease. In fact, survival is identical for patients
entities are often strongly positive on functional with chemosensitive relapsed or primary refrac-
imaging; thereby making histologic confirmation tory disease treated at MSKCC from 1993 to
even more imperative. 200317 (Fig 3).

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.


Table 1. Adverse Prognostic Factors for Treatment
There are some reports suggesting that aug- Outcome After ASCT for Hodgkin’s Disease
menting therapy for patients with refractory HL Vancouver: B symptoms at relapse, extranodal disease at relapse,
is beneficial; but primary refractory disease is but duration of 1st CR ⬍ 12 months
one of many prognostic factors affecting out- Stanford: B symptoms at relapse, pulmonary/bone marrow
come.18 The factors that affect outcome are sum- involvement, more than minimal disease at ASCT
City of Hope: ⬎ 2 prior regimens, extranodal disease at relapse, PSC
marized in Table 1.19-23 Unfortunately, there is
as sole stem cell source
limited information using these prognostic factors
MD Anderson: ⬎ 2 prior regimens, extranodal involvement, abnormal
to change therapy. In our first study of ICE performance status, chemorefractory
followed by HDT and ASCT, Cox regression anal- Boston: ⬎ 1 extranodal site, ECOG classification ⬎ 0,
ysis determined that the factors associated with a progressive disease at ASCT
poor outcome pre-ICE were: extranodal sites of SFGM: Extranodal relapse, duration of CR ⬍ 12 mo
disease (ENS), p ⫽ .001, initial response duration ABMTR: Chemorefractory, abnormal LDH KPS ⬍ 90%
Nebraska: second-line IPI
less than 1 year (p ⫽ .001), and B symptoms (p ⫽
.001). Using this three-factor model, we identified Abbreviations: ASCT, autologous stem cell transplantation;
CR, clinical remission; PSC, peripheral stem cells; SFGM,
three groups of patients with widely disparate
Societe Francaise de Greffe de Moelle; ECOG, Eastern Coop-
outcomes with this treatment approach. Clini- erative Oncology Group; ABMTR, autologous bone marrow
cally however, relapsed and refractory HL can be transplant registry; LDH, lactate dehydrogenase; KPS, Karnof-
divided into two groups: favorable – those with sky performance status; IPI, International Prognostic Index

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 changed. Now cytoreduction was done with trans-
with two or three risk factors. Patients with plant doses of ICE followed by stem cell support;
favorable disease have a PFS of 76% while pa- this is followed by a second autotransplant for
tients with unfavorable disease have a progres- responding patients. This three-arm study, how-
sion-free survival (PFS) of only 26%. (Fig 4)24 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
This three-factor model was the basis of our (30 months) patients with multiple risk factors
third-generation, risk-adapted comprehensive appear to have an improved outcome with a more
study (MSKCC protocol 98 to 71). In this study, intensive risk-adapted approach. (Fig 5)25
patients with zero or one risk factor (extranodal
disease (ENS), initial response duration ⫽ 1 year,
or B symptoms at time of study enrollment), The use of HDT and ASCT is standard therapy
group A, were treated exactly the same as in the for chemosensitive relapsed and primary refrac-
second-generation program; in that study EFS tory HL. The indications for and the use of allo-
was 80%. Patients with two risk factors, group B, geneic stem cell transplantation (AlloSCT) in pa-
received one dose of standard dose ICE followed tients with relapsed or primary refractory HL are
by one dose of augmented ICE second-line ther- poorly defined. The two main reasons to consider
apy as well as a more dose-intense transplant AlloSCT are (1) Infusion of a lymphoma-free stem
conditioning regimen. Finally, for patients with cell product (not a concern in HL), and (2) The
all three risk factors, group C, the program was graft versus lymphoma effect. The major problem

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- include using immunosuppressive chemotherapy
tality compared to ASCT. The European Bone agents, generally fludarabine, in combination
Marrow Transplantation registry recently re- with an alkylating agent.28 Another technique is
ported the results of a matched study of ASCT based on using low-dose, total-body irradiation
versus AlloSCT for lymphoma for patients treated with or without fludarabine.29 Lastly, Mackinnon
between 1982 and 1998. All lymphomas were et al30 have led the effort using a T-cell depleted
included in the analysis, of which 167 patients approach by incorporating the humanized mono-
had HL. Unfortunately, in HL the transplant- clonal antibody alemtuzumab for T-cell depletion
related mortality for AlloSCT was extremely high followed by fludarabine and melphalan; donor
at 51.7%. In addition, HL was the only lymphoma lymphocyte infusions are added for patients with
where relapse-free survival was inferior for residual disease or those not evolving to 100%
AlloSCT as compared to ASCT.26 donor chimerism.30 The RI conditioning regimen
The transplant conditioning regimen in approaches have used standard ASCT condition-
AlloSCT was originally intended to cytoreduce ing regimens, most commonly BEAM (carmus-
lymphoma while providing immunosuppression tine, etoposide, cytarabine, and melphalan).31
to prevent graft rejection. It has become clear in These ASCT regimens cytoreduce lymphoma with
the past decade that the benefit for AlloSCT is low transplant-related toxicity and support allo-
largely related to immune-mediated graft versus geneic engraftment.
lymphoma effect. This premise has led to the use Only general recommendations can be made
of reduced-intensity (RI) or nonmyeloablative using AlloSCT. (1) A conventional AlloSCT should
(NMT) conditioning regimens to achieve engraft- not be administered in patients who have failed
ment and allow for the development of a graft ASCT. (2) NMT is reasonable therapy for patients
versus lymphoma effect as the main form of who have failed ASCT provided that the disease
therapy for the tumor. A few general approaches responds to some form of salvage chemotherapy.
are currently being used.27 The NMT approaches (3) In patients with a human leukocyte antigen-

identical sibling donor who have poor risk disease evaluating anti-CD30 monoclonal antibody ther-
as defined as initial remission duration of less apy. Similar to rituximab therapy in NHL, these
than 1 year with concomitant B symptoms and antibodies may be used post-ASCT to treat mini-
stage IV disease, RI AlloSCT with regimens such mal residual disease. More importantly, one
as BEAM should be considered before ASCT. (4) should not forget that radiotherapy remains a
The use of ASCT for cytoreduction followed by treatment modality that can be exploited as op-
NMT in poor risk patients is a reasonable study posed to eliminated in the management of
alternative to RI AlloSCT in poor risk patients. HL.32,33 The accuracy of the radiation treatment
volume could be improved by incorporating PET
FUTURE STUDIES scan information to help determine the gross
tumor volume. In addition, intensity-modulated
In conclusion, HDT and ASCT are standard ther- radiation therapy broadens the range of radiation
apy for patients with relapsed and primary refrac- treatment options, while minimizing the radia-
tory HL provided chemosensitivity is established. tion dose to normal tissues. This is particularly
Future studies need to evaluate the role of abnor- useful for patients with bulky and/or complex
mal PET scan as part of risk-adapted therapy mediastinal disease or for areas that have been
Great strides made in the management of HL irradiated previously.34
in the past decades stem from carefully done
prospective clinical trials, but despite our best AUTHOR’S DISCLOSURE OF POTENTIAL
therapy, 15% of patients with HL will die of their CONFLICTS OF INTEREST
disease. It is critical that new agents be studied in Research Funding—Bristol-Myers Squibb; IDEC; Ge-
HL. A number of phase I/II studies are under way nentech.

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