&amp

Dr James Armitage

V Sneller

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Annals of Oncology 14 (Supplement 1): i1–i3, 2003
Symposium article DOI: 10.1093/annonc/mdg701
© 2003 European Society for Medical Oncology
Current role and future perspectives for ifosfamide in the 
treatment of malignant non-Hodgkin’s lymphoma—results 
from an expert meeting
V. Sneller1 & J. Armitage2*
1Baxter-Oncology GmbH, Frankfurt, Germany; 2University of Nebraska Medical Center, Omaha, NE, USA
*Correspondence to: Dr James Armitage, University of Nembraska 
Medical Center, Omaha, NE, USA. Tel: +1-402-559-7290; 
Fax: +1-402-559-6114; E-mail: joarmita@unmc.edu
In this supplemental issue of Annals of Oncology, leading experts
from Australia, Europe and the USA present results from their
trials using ifosfamide-containing chemotherapy regimens for the
treatment of malignant non-Hodgkin’s lymphoma (NHL) and
Hodgkin’s disease (HD). The relative merits of the established
regimens, achievable treatment results and future perspectives for
ifosfamide regimens were discussed during a workshop, held in
October 2002 at Cap Ferrat, France. The expert faculty discussed
practical issues related to the use of ifosfamide and mesna includ-
ing suggestions for inpatient and outpatient ifosfamide regimens
in combination with rituximab and guidelines for the management
of possible side-effects. The practical guidelines for outpatient
ifosfamide-based regimens, by fractionating the administration of
ifosfamide, infusomates or oral mesna, were discussed as well.
Many patients with aggressive NHL can be cured with anthra-
cycline-containing chemotherapy regimens. The benefit of adding
rituximab to cyclophosphamide, doxorubicin, vincristine and pred-
nisone (CHOP) chemotherapy for non-pretreated elderly patients
with aggressive NHL was demonstrated in a recently published
randomized trial performed by Groupe d’Étude des Lymphomes
de l’Adulte (GELA) [1]. Despite this, more than half of the
patients are primarily refractory or relapse and require salvage
therapy. A certain subset of patients with chemosensitive disease
can be cured with high-dose therapy and stem cell transplantation.
Before high-dose therapy, patients usually receive combination
chemotherapy regimens to establish tumor chemosensitivity and
to reduce tumor bulk. It is critical that a cytoreductive regimen has
a high response rate with minimal organ-related toxicities, while
at the same time providing adequate collection of peripheral blood
stem cells (PBSC).
Zelenetz et al. report an update on their long experience with a
cytoreductive and mobilization regimen consisting of ifosfamide,
carboplatin and etoposide (ICE), previously published by Mosko-
witz et al. [2]. In the Memorial Sloan Kettering Cancer Center,
New York, this regimen has been used in more than 220 patients
so far with relapsed and refractory aggressive NHL and in more
than 100 patients with HD. In order to attain high response rates,
the ICE regimen was administered every 2 weeks with con-
comitant use of growth factors. A similar dose-dense approach
with 2-weekly CHOP-14 as initial therapy for aggressive NHL
was recently reported by the German High-Grade NHL group [3].
The results in elderly patients showed the superiority of 2-weekly
CHOP in terms of event-free and overall survival compared with
standard 3-weekly CHOP. Zelenetz et al. conclude that 2-weekly
ICE has significant antitumor activity, minimal non-hematological
toxicity and results in a high stem cell yield. Primary refractory
patients who responded to second-line chemotherapy and were
able to receive autologous stem cell transplantation (ASCT)
showed a progression-free survival rate as good as that in chemo-
sensitive relapsed patients. Furthermore, the quality of the clinical
response to ICE is predictive of post-transplant outcome.
Hertzberg et al. present their experiences with outpatient ICE
in 38 patients with relapsed and refractory diffuse large B-cell
lymphoma (DLBCL), follicular lymphoma (FL), HD and mantle
cell lymphoma (MCL). Their data confirm the high efficacy and
good tolerability of fractionated ICE as both a salvage and a
mobilization regimen; a finding which was found to be consistent
in the different histological types of lymphoma. This combination
can be safely given on an outpatient basis every 21 days by admin-
istering ifosfamide in short 1-h infusions over 3 consecutive days
and by using mesna tablets. Hertzberg et al. suggest that the few
studies comparing short versus long infusional ifosfamide regi-
mens in cancer patients have failed to show convincing evidence
of a significant difference in either pharmacokinetics, response
rates or hematological toxicity.
As previously shown by Hamlin et al. [4], patients with good-
risk disease [Second-line age-adjusted international prognostic
index (sAAIPI) I/II] are highly curable with an ICE-based high-
dose therapy (HDT) approach. Another important finding was that
patients who achieved complete remission following therapy with
ICE had significantly improved survival compared with patients
achieving partial remission [2]. Outcome for patients with poor-
risk disease (sAAIPI III/IV) was still not satisfactory and they
might therefore benefit from novel treatment strategies, such as
inclusion of new agents with the goal of increasing the complete
remission rate prior to HDT. One of these promising agents is the
monoclonal antibody rituximab, which has been recently intro-
duced for the initial treatment of aggressive lymphomas in
combination with CHOP-like regimens. There are also promising
data in relapsed and refractory disease, as well as in follicular and
mantle cell lymphomas.
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Zelenetz et al., with the aim of increasing response rates, added
rituximab to the ICE regimen in CD20-positive relapsed and
refractory DLBCL patients, as well as in B-cell anaplastic large-
cell lymphoma. Rituximab plus ICE (R-ICE) appears to double
the complete response rate of ICE alone [5]. This was seen in both
relapsed and refractory patients, but is more pronounced in the
former group. Furthermore, R-ICE appears to overcome the differ-
ences among different prognostic groups of patients, defined by
the Second Line International Prognostic Index (sIPI). The addi-
tion of rituximab to ICE is safe without significant additive toxic-
ity. Whether the increased complete response rate will translate
into prolonged survival following HDT/ASCT remains to be
determined.
A similar approach, with the main intention of improving results
with currently available salvage regimens, is presented by Vose.
R-ICE is administered on an outpatient basis, followed by HDT/
ASCT. The University of Nebraska Medical Center strategy is to
proceed with the transplant as soon as responses, either complete
or partial, can be achieved. Vose reports that R-ICE is effective
and well tolerated and can be administered safely in an outpatient
setting.
Joyce et al. report the results of an outpatient regimen consisting
of rituximab, ifosfamide, mitoxantrone and etoposide (R-IME)
for the treatment of B-cell NHL. In this study mitoxantrone was
substituted for carboplatin, in an attempt to enhance activity in the
follicular and mantle cell sub-types and to reduce the stem cell
toxicity. R-IME is effective in mobilizing sufficient yields of stem
cells that demonstrate no evidence of tumor cell contamination in
the majority of patients. R-IME was effective for cytoreduction in
a broad range of B-cell lymphoma, and did not increase HDT/
ASCT morbidity.
As already outlined, besides high efficacy and good tolerability,
the ability to collect a high number of stem cells is an important
feature of an ideal salvage regimen. The number of CD34+ cells
must exceed 2 × 106 cells/kg to allow satisfactory long-term
recovery of hematopoiesis, but recovery is faster and of better
quality if the number is higher. In addition, the data published
earlier by Bociek et al. [6] suggest that patients with >4 × 106
CD34+ cells/kg may have a superior 2-year probability of survival
compared with patients who have cell yields in the range 1.5 × 106
to 4 × 106 cells/kg6.
Nowrousian et al. report various chemotherapy regimens
combined with growth factors to mobilize stem cells in patients
with different types of malignant disease. The data suggest that
ifosfamide/etoposide-based regimens are highly effective cyto-
reductive and mobilization regimens, which seem to be superior to
cyclophosphamide in combination with growth factor.
Several papers report on the use of ifosfamide-based regimens
not only for the treatment of DLBCL, but also for the treatment of
anaplastic lymphoma, mantle cell lymphoma, relapsed follicular
lymphoma and transformed follicular lymphoma. The manage-
ment of relapsed indolent lymphomas represents one of the most
challenging and controversial areas in hematology due to the many
new options available. The use of ASCT in follicular lymphoma is
limited by frequent contamination of blood and marrow with the
pathological cells, and the inability of even high-dose chemo-
radiotherapy to eradicate systemic disease in most patients [7].
However, ASCT represents an option for patients without an
HLA-identical sibling, particularly if autologous stem cells can be
collected that are PCR negative for residual malignant cells. The
optimal salvage and intensification regimens have to be deter-
mined. First experience with in vivo purging with rituximab points
to a decrease in the number of tumor cells in stem cell harvest for
patients with FL and MCL, but no data are as yet available for
relapsed patients.
Of the patients previously reviewed by Zelenetz et al., 17 had
follicular center lymphoma, of whom 16 had either CR or PR to
ICE, and 11 of 17 were event free at 40 months. Herzberg et al.
treated 11 patients with ICE of whom 10 also received rituximab.
Joyce et al. report promising responses and 1-year survival
achieved by using R-IME in follicular and transformed follicular
lymphomas. Similar results for R-ICE are reported by Vose.
Mantle cell lymphoma is usually not curable with currently
available treatment options. The combination of rituximab with
chemotherapy before harvesting PBSC (in vivo purge) and ASCT
with total body irradiation (TBI) gave remarkable results in one
study [8], but this has not been confirmed in two other studies
[9, 10]. Encouraging survival data from using R-IME in com-
bination with rituximab as a post-transplant therapy suggest that
this regimen should be further explored for the treatment of this
unfavorable disease.
In conclusion, the addition of rituximab to well-established
salvage regimens, such as IME or ICE, further improves results in
a broad spectrum of lymphoma. Encouraged by promising data
with ifosfamide in the relapse setting, several clinical investiga-
tors decided to study the utility of intensification with ifosfamide-
based regimens in the first-line setting. One of these trials which
started recently in the Memorial Sloan Kettering Cancer Center is
testing whether intensification with ICE followed by HDT/ASCT
will improve results in patients who are at high risk for relapse
after having received CHOP chemotherapy.
Since there is no widely accepted standard regimen for the treat-
ment of relapsed NHL, the Collaborative Trial in Relapsed
Aggressive Lymphomas (CORAL) study group has proposed a
comparison of rituximab, dexamethasone, cytarabine, cisplatin
(R-DHAP) with R-ICE, followed by ASCT in patients with
relapsed and primary refractory diffuse large B-cell lymphomas in
order to set-up a new standard. This study will address some
important questions: ‘What is the most efficient salvage regimen
associated with rituximab?’ ‘Will rituximab have an effect in
patients previously treated with rituximab?’ and ‘What is the role
of rituximab after transplant?’
The attendant experts agreed that ifosfamide is a valuable drug
for the treatment of several types of malignant lymphoma and
incorporation of ifosfamide in novel treatment strategies should
be explored.
Disclosure
Dr Sneller is an employee of Baxter Oncology GmbH. Professor
Armitage received an honorarium for participation in the work-
shop.
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2. Moskowitz CH, Bertino JR, Glassman JR et al. Ifosfamide, carboplatin,
and etoposide: a highly effective cytoreduction and peripheral-blood
progenitor-cell mobilization regimen for transplant-eligible patients with
non-Hodgkin’s lymphoma. J Clin Oncol 1999; 17: 3776–3785.
3. Pfreundschuh M, Trümper L, Kloess M et al. Two-weekly CHOP
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blood stem cell transplantation in 16 patients with mantle cell lymphoma.
Ann Oncol 1997; 8: 701–704.
10. Freedman AS, Neuberg D, Gribben JG et al. High-dose chemoradio-
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Current role and future perspectives for ifosfamide in the treatment of malignant non-Hodgkin&apos;s lymphoma-results from an expert meeting

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Current role and future perspectives for ifosfamide in the treatment of malignant non-Hodgkin's lymphoma-results from an expert meeting

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Current role and future perspectives for ifosfamide in the treatment of malignant non-Hodgkin&apos;s lymphoma-results from an expert meeting

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Current role and future perspectives for ifosfamide in the treatment of malignant non-Hodgkin's lymphoma-results from an expert meeting