Annals of Oncology 14 (Supplement 1): i5–i10, 2003

Symposium article DOI: 10.1093/annonc/mdg702

Ifosfamide, carboplatin, etoposide (ICE)-based second-line

chemotherapy for the management of relapsed and refractory
aggressive non-Hodgkin’s lymphoma
A. D. Zelenetz*, P. Hamlin, T. Kewalramani, J. Yahalom, S. Nimer & C. H. Moskowitz

Lymphoma and Hematology Disease Management Teams, Memorial Sloan-Kettering Cancer Center, New York, USA

Despite advances in the management of aggressive non-Hodgkin’s lymphoma, the treatment of relapsed and
primary refractory disease remains a major challenge. High-dose chemotherapy or radio-chemotherapy followed
by autologous or allogeneic stem cell transplantation (SCT) is a potentially curative treatment approach; how-
ever, the applicability of this approach is restricted to patients responding to second-line chemotherapy. Thus,

Downloaded from annonc.oxfordjournals.org by guest on November 24, 2010

second-line therapy must be both efficacious and without stem cell or organ toxicity that would compromise
the ability to proceed to SCT. The ifosfamide, carboplatin and etoposide (ICE) regimen was developed to
address these challenges. In a series of prospective clinical trials, 222 patients were treated with the ICE regi-
men, with an overall response rate of 72%. The mobilization of stem cells with this regimen was excellent,
with 86% of patients mobilizing at least 2.0 × 106 CD34+ cells/kg. The incidence of treatment-related toxicity
precluding SCT after ICE is very low. Herein, we report the clinical results of this treatment program for 222
patients with 5-year median follow-up for surviving patients. Rituximab was subsequently added to the ICE
regimen for patients with diffuse large B-cell lymphoma (DLBCL) to improve upon these favorable results.
This resulted in an increased complete remission rate. Additional follow-up is necessary to determine if this
improvement in the complete remission rate will confer an increase in the overall survival following SCT.

Introduction low incidence of non-hematological toxicity and a brief duration

Aggressive non-Hodgkin’s lymphoma is potentially curable,
with doxorubicin-based chemotherapy resulting in long-term
failure-free survival rates of 40–45%, as demonstrated by the
National High-Priority Lymphoma study [1]. Recent advances,
such as the addition of rituximab to CHOP for diffuse large B-cell
lymphoma (DLBCL) or the use of an accelerated dosing regimen,
may increase the overall survival (OS) by an additional 10–15%,
although the follow-up is relatively short [2]. Unfortunately,
despite these advances about half of all diffuse large-cell lymph-
oma (DLCL) patients will have either persistence of tumor
following initial therapy (primary refractory disease) or a relapse
after a complete remission. For these patients, stem cell trans-
plantation (SCT) has been demonstrated to have the greatest
potential for a curative outcome [3]. However, this treatment
approach has typically been restricted to patients with disease
sensitive to second-line chemotherapy (Figure 1). Consequently,
the effectiveness of the second-line regimen is of paramount
importance.
To be suitable as pre-transplant therapy, a second-line regimen
should have the following features: effective cytoreduction, a
*Correspondence to: Dr A. D. Zelenetz, Memorial Sloan-Kettering Cancer
Center, 1275 York Avenue, New York, NY 10021, USA.
Tel: +1-212-639-2656; Fax: +1-212-717-3036;
E-mail: a-zelenetz@ski.mskcc.org
of therapy [4–7]. Some of the most commonly used regimens,
etoposide/high-dose cytarabine/cisplatinum (ESHAP), dexa-
methasone/cisplatin/cytarabine (DHAP) and BCNU (bis-chloro-
ethylnitrosourea)/etoposide/cytarabine/melphalan (mini-BEAM),
have inherent limitations which may preclude SCT, including
poor stem cell mobilization and non-hematological toxicities
such as nephrotoxicity (DHAP and ESHAP) and pulmonary tox-
icity (mini-BEAM). To address these limitations, we developed
the ifosfamide, carboplatin and etoposide (ICE) regimen as a
short-course, dose-intensive regimen for cytoreduction and stem
cell mobilization [8]. Though the results with the ICE regimen
were good, only 45% of patients with chemosensitive disease are
cured with SCT; therefore, to improve these results, combination
of ICE with immunotherapy was studied.
Among the evolving therapies for NHL, anti-CD20 mono-
clonal antibodies (mAb) have shown significant promise [9, 10].
CD20 is a membrane-bound phosphoprotein with expression
restricted to B-cell precursors and mature B-cells; it is not
expressed on plasma cells or stem cells [11]. Approximately 93%
of B-cell lymphomas express CD20, which has many features
(e.g. it is not rapidly internalized, nor is it shed) that make it an
attractive target for immunotherapy. Rituximab is a chimeric
anti-CD20 IgG1κ mAb, which is comprised of murine variable
regions and human constant regions. In vitro studies show that
rituximab can lyse human B-cells via antibody-dependent cellu-

© 2003 European Society for Medical Oncology

i6
Figure 1. Flow of patients undergoing treatment for aggressive non-
Hodgkin’s lymphoma (NHL). Initial treatment consists of doxorubicin-
based chemotherapy such as cyclophosphamide, doxorubicin, vincristine
and prednisone (CHOP) [with the addition of rituximab for diffuse large
B-cell lymphoma (DLBCL)]. Patients with either primary refractory disease
or recurrence are candidates for second-line chemotherapy. Patients
responding to second-line chemotherapy proceed to high-dose therapy and
autologous or allogeneic stem cell transplantation. BSC, best supportive
care.
lar cytotoxicity (ADCC) and complement mediated lysis [12].
We have sought to improve on the ICE regimen by the addition of
rituximab (R-ICE).
In the following update, the results of the ICE regimen for 222
patients treated over 7 years, now with 5 years median follow-up
for surviving patients, are presented. The ICE regimen remains
an excellent second-line chemotherapy approach, with short-
duration, dose-intense chemotherapy capable of highly effective
cytoreduction and peripheral blood progenitor cell (PBPC)
mobilization. Given the importance of stem cell mobilization to
proceed with the potentially curative high-dose therapy (HDT)/
autologous stem cell transplantation (ASCT), we propose a new
method of evaluating second-line chemotherapy programs which
accounts for mobilization failures in the response rate—the
mobilization-adjusted response rate (MARR). This will facilitate
future comparisons of new and existing second-line regimens.
Finally, we report preliminary results from the R-ICE regimen,
demonstrating an improvement in complete response rates.
Patients and methods
Patients
Two hundred and twenty-two patients were enrolled on consecutive Insti-
tutional Review Board (IRB) approved protocols for relapsed and primary
refractory NHL lymphoma at Memorial Sloan-Kettering Cancer Center
(MSKCC) from 28 January 1993 to 1 August 2000. An additional 31 patients
were treated on the R-ICE chemotherapy regimen and a preliminary report of
these results was presented at the Annual Meeting of the American Society of
Hematology in December 2001. The results of these two populations (ICE
and R-ICE) are reported separately. Those study patients receiving protocol-
directed investigational cytokines for the mobilization of stem cells were excluded
from the analysis of PBPC mobilization—for this analysis the granulocyte
colony-stimulating factor (G-CSF) mobilization data from the 163 patients
reported in the initial ICE paper are utilized [8].
Eligibility for second-line therapy and HDT/ASCT
All patients were staged according to the Cotswold modification of the Ann
Arbor system [13]. Hematopathologists at MSKCC performed histological
reviews of the original and pre-ICE biopsy specimens. Histopathology,
initially classified according to the International Working Formulation [14],
was retrospectively reclassified according to the World Health Organization
(WHO) classification scheme [15]. In general, patients with aggressive histo-
logy (DLBCL, mantle cell lymphoma, transformed indolent lymphoma,
peripheral T-cell lymphoma and anaplastic large-cell lymphoma) were
eligible, although depending on protocol availability other histologies may
have been allowed. All patients had biopsy confirmation of relapsed or pri-
mary refractory disease prior to the initiation of ICE-based chemotherapy
and had previously received only one doxorubicin-based chemotherapy pro-
gram. Patients were required to have a corrected carbon monoxide diffusion
capacity >50% of predicted and serum creatinine ≤1.5 mg/dl (or creatinine
Downloaded from annonc.oxfordjournals.org by guest on November 24, 2010
clearance ≥60 ml/min). Patients achieving a complete or partial response (CR
or PR) to (R)-ICE were eligible for HDT with ASCT, provided a bone marrow
biopsy revealed adequate cellularity and no involvement with large-cell
lymphoma at the conclusion of ICE-based chemotherapy. Patients with small
cleaved cells in the bone marrow were eligible. Finally, all patients had to
have collected a minimum of 2 × 106 CD34+ cells/kg.
Modified International Working Group response criteria
The International Working Group response criteria [16] were modified to
include the results of functional imaging with Gallium or 2-[fluorine-18]
fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan.
A complete response was defined as no evidence of disease by computed
tomography (CT) scan and a normal functional imaging study (Gallium or
PET) as documented by restaging ∼2 weeks after completion of ICE. A con-
ditional complete response was defined as no clinical signs or symptoms of
lymphoma, but residual radiographical abnormalities <2 cm which were
inaccessible to biopsy, and showed at least a 75% regression in size from the
original radiographical study with negative functional imaging (gallium or
PET). A partial response was defined as a >50% decrease in the sum of the
products of the diameters of each measurable lesion with or without a positive
functional imaging result.
ICE second-line chemotherapy treatment program
Three cycles of ICE chemotherapy were planned to be administered at 2 week
intervals, as previously reported [8]. A brief summary of the treatment pro-
gram is as follows: patients were treated as inpatients. On admission, a 12-h
creatinine clearance was measured for subsequent carboplatin dosing. Chemo-
therapy was administered as follows: etoposide 100 mg/m2 by intravenous
bolus on days 1–3; carboplatin area under the curve (AUC) 5 (5 × [25 + CrCl],
maximum dose 800 mg) by intravenous bolus on day 2; and ifosfamide
admixed with mesna both at a dose of 5 g/m2 by 24-h continuous infusion
beginning on day 2. Patients were treated with filgrastim 5 mcg/kg/day on days
5–12 for cycles 1 and 2. Filgrastim was increased to 10 mcg/kg/day following
the third cycle until the completion of peripheral blood stem cell collection.
Chemotherapy was ideally repeated every 14 days or when the absolute neu-
trophil count was ≥1000 cells/mcl and the platelet count was ≥50 000/mcl.
Patients receiving R-ICE chemotherapy had rituximab 375 mg/m2 adminis-
tered as an intravenous bolus on day 1 and commenced ICE on day 3. The first
cycle of R-ICE was preceded by an additional dose of rituximab 375 mg/m2 on
day –2.
Peripheral blood progenitor cells were collected as previously described
[8] following the third cycle of R-ICE when the total white blood cell count
 i7

(WBC) had risen to ≥5000 cells/mcl (most commonly on days 11 or 12 post Table 1. Patient characteristics for ICE (n = 222)
day 1 of ICE). Collection continued until >6 × 106 CD34+ cells/kg body wt had
been collected or for a maximum of five apheresis procedures. During apher- Characteristic No. of patients (%)
esis 10 l of whole blood was processed over 2.5–3 h. A minimum of 2.0 × 106 Median age 46
CD34+ cells/kg body wt was considered a successful collection.
14–59 186 (84)

Transplant conditioning regimens 60–71 36 (16)

Status
One hundred and fifty-three patients underwent ASCT. Conditioning regi-
Relapsed 124 (56)
mens were determined based on prior radiotherapy and protocol availability
at the time of transplantation. Eighty-two patients (54%) received a chemo- Refractory 98 (44)
therapy only conditioning regimen, while 71 patients (46%) received a total Sex
body irradiation (TBI)-based conditioning regimen. Male 146 (66)
Involved field radiotherapy (boost radiotherapy) was administered to 87 Female 76 (34)
patients prior to the high-dose conditioning regimen in patients whose resi-
PS
dual disease after ICE-based therapy was limited to less than or equal to two
0–1 156 (70)
anatomical regions. Boost radiotherapy was delivered at 150 cGy twice daily
fractions administered over 6 days in patients who received TBI to a total 2–4 66 (30)
dose of 1800 cGy, or 3000 cGy given over 10 days in patients receiving high- Stage (Ann Arbor)

Downloaded from annonc.oxfordjournals.org by guest on November 24, 2010

dose chemotherapy alone. I/II 47 (21)
III 37 (17)
Mobilization-adjusted response rate IV 138 (62)
The mobilization-adjusted response rate (MARR) was defined as the [overall LDH
response rate (ORR) (%) minus mobilization failure rate (%)]. This response WNL 105 (47)
rate was calculated for the 163 patients included in the original ICE database,
Elevated 117 (53)
who received G-CSF mobilization as noted above. Additionally, this response
BM
rate was calculated for the R-ICE patients, who also received uniform G-CSF
mobilization. Patients enrolled on protocols investigating novel cytokines Negative 164 (74)
were excluded from this analysis. Positive 58 (26)
Extra-nodal sites
Statistics 0 58 (26)
Progression-free survival (PFS) and OS were assessed from the first day of 1 68 (31)
(R)-ICE chemotherapy. Progression-free survival events were defined as ≥2 96 (43)
disease progression or death from NHL. Survival analyses were performed to B- or T-cell
obtain estimates of median survival for the various second-line age-adjusted
B-cell 194 (87)
International Prognostic Index (sAAIPI) groups using the methods of Kaplan
and Meier [17]. The log-rank test [18] was used to compare survival distribu- T-cell 28 (13)
tions for the sAAIPI groups. Histology
DLCL 176 (79)
ALCL 17 (8)
Results
MCL 11 (5)
Patients FL 1–2 9 (4)
The characteristics of 222 patients treated with ICE are described FL 3 3 (1)
in Table 1. The characteristics of 31 patients treated with R-ICE LPHD 4 (2)
are summarized below (see ‘Improving the outcome of ICE with SLL 2 (1)
Rituximab’). The median age of the population was 46 years AAIPI risk group
(range 14–71), reflecting the patient population referred to Low 30 (13)
MSKCC for treatment of relapsed and refractory disease. Unfavor- Low–intermediate 68 (31)
able characteristics including elevated lactate dehydrogenase High–intermediate 82 (37)
(LDH), poor performance status (ECOG <2 or Karnofsky ≤70%) High 42 (19)
and advanced stage were seen in 53%, 30% and 79% of patients,
respectively. AAIPI, age-adjusted International Prognostic
Index; ALCL, anaplastic large cell lymphoma;
BM, bone marrow; ICE, ifosfamide, carboplatin,
Response to ICE
etoposide; DLCL, diffuse large-cell lymphoma;
One hundred and fifty-nine patients responded to ICE for an FL, follicular non-Hodgkin’s lymphoma; LPHD,
ORR of 71.6%, with 63 patients achieving a CR (28.4%) and 96 lymphocyte predominant Hodgkin’s disease;
patients achieving a PR (43.2%) (Table 2). DLBCL comprised MCL, mantle cell lymphoma; PS, performance
the majority of these patients (79%) with 28% achieving a status; SLL, small lymphocytic lymphoma;
WNL, within normal limits.
CR and 41% a PR. Neither peripheral T-cell lymphoma (PTCL)
i8

Table 2. Response to ICE chemotherapy by histology

Histology No. of CR PR F
patients
n % n % n %
Overall 222 63 28.4 96 43.2 63 28.4
DLCL 176 50 28.4 72 40.9 54 30.7
B-cell 150 42 28 66 44 42 28
T-cell 26 8 30.8 6 23 12 46.2
ALCL 17 4 23.5 9 53 4 23.5
MCL 11 0 0 7 63 4 37
FCL 1–3 12 5 41.7 6 50 1 8.3
Othera 6 4 67 2 33 0 0

a
LPHD = 4 and SLL = 2.
ALCL, anaplastic large cell lymphoma; DLCL, diffuse large-cell
lymphoma; FCL, follicular cell lymphoma; ICE, ifosfamide, carboplatin,

Downloaded from annonc.oxfordjournals.org by guest on November 24, 2010

etoposide; LPHD, lymphocyte predominant Hodgkin’s disease; MCL,
mantle cell lymphoma; SLL, small lymphocytic lymphoma.

(PR 23%, CR 31%) nor mantle cell lymphoma (MCL) (PR 63%,
CR 0) responded particularly well.

Stem cell mobilization

One hundred of the 163 patients who received standard G-CSF
mobilization as described above underwent leukapheresis. Ninety-
one per cent began stem cell collection on day 11 or day 12
following day 1 of ICE. The median stem cell collection was
8.4 × 106 CD34+ cells/kg body wt in a median of three apheresis
procedures (range 1–5). Fourteen per cent of patients failed to
mobilize the minimum of 2 × 106 CD34+ cells/kg body wt.
In the initial 31 patients treated with R-ICE, a median of
6.3 × 106 CD34+ cells/kg body wt were harvested (range 0.3–
15.6) in a median of three aphereses (range 1–5). Less than
2 × 106 CD34+ cells/kg body wt were collected in five patients
(16%).

Mobilization-adjusted response rate

For the 163 patients evaluable for stem cell mobilization treated
with ICE and G-CSF mobilization and for the 31 patients treated
with R-ICE, MARR was calculated as described in the Patients
and methods section. The MARR for the ICE regimen was 52%
by intention-to-treat analysis. For the R-ICE regimen, MARR in
evaluable patients reported at ASH 2001 was 61% by intention-
to-treat.

Autologous stem cell transplantation

One hundred and forty-six of 159 patients responding to ICE
underwent ASCT. The 13 patients who did not proceed to stem
cell transplantation refused ASCT, failed to mobilize adequate
numbers of stem cells or had rapid disease progression prior to
the initiation of stem cell transplantation. Seven patients who
failed ICE chemotherapy received additional treatment and went
on to receive ASCT, these patients were considered ICE failures.
A total of 153 patients received ASCT.
Figure 2. Results of the overall experience with ifosfamide, carboplatin and
etoposide (ICE). (A and B) Progression-free survival and overall survival
for 222 patients treated with ICE as cytoreduction with intent to proceed to
autologous stem cell transplantation (ASCT). (C) Progression-free survival
of patients stratified by response to ICE (excluding treatment failures).
There is a significant difference in progression-free survival between
patients achieving a complete response (CR) versus partial response (PR) to
the ICE cytoreduction.
 i9

Table 3. Mobilization adjusted-response rate for ICE, R-ICE and other regimens

Regimen Disease n ORR CR PR Aphereses Median CD34+ % Failed mobilization MARR Refs
[median (range)] (× 106 cells/kg) (<2 × 106 cells/kg)
ICE NHL 163 66.3 24 42 3 (1–5) 8.4 14 52 [8]
R-ICE NHL 31 81 55 26 6.3 17 64 [19]
Mini-BEAM HD 55 84 51 33 (1–7) 2.7 43 41 [20]
a
Ifos/Vino NHL, HD 10 40 0 40 10.9 <11 29–40 [21]
MINE NHL, HD 27 67 38 29 3 13.3 8 59 [22]
VIM NHL, HD 46 56 39 17 3 10.6 8 48 [22]
ESHAP HD, NHL 84 64a 37a 27a (1–4) 4.9 15 ∼49 [23]
2
CY (1.5 g/m ) HD, NHL 78 64 a
37 a
27 a
(1–4) 3.3 29 ∼35 [23]
DHAP NHL 38 63.9 25 38.9 2 (1–3) 5.9 14.7 49.2 [24]
CY NHL 34 63.9 25 38.9 2 (1–3) 7.1 10.5 53.4 [24]

a
ESHAP response rate is base on their historic data.

Downloaded from annonc.oxfordjournals.org by guest on November 24, 2010

CR, complete response; CY, cyclophosphamide; DHAP, dexamethasone/cisplatin/cytarabine; ESHAP, etoposide/high-dose cytarabine/cisplatinum;
ICE, ifosfamide, carboplatin, etoposide; mini-BEAM, BCNU (bis-chloro-ethyl nitrosourea)/etoposide/cytarabine/melphalan; Ifos/Vino, ifosfamide and
mitoxantrone; MARR, mobilization-adjusted response rate; MINE, ifosfamide, mesna, mitoxantrone and etoposide; ORR, overall response rate; PR,
partial response; R-ICE, ICE plus rituximab; VIM, etoposide, ifosfamide and mitoxantrone.

Progression-free and overall survival
At a median follow-up of 5 years (64.6 months) for surviving
patients, the PFS and OS are 29.2% and 38.4% by intention-to-
treat analysis and 38.9% and 48.6% for chemosensitive patients
(Figure 2A and B). Chemosensitive patients in a CR had a
superior 5-year survival compared with those transplanted in a
PR for both PFS (52.2% versus 30.1%; P = 0.012) (Figure 2C)
and OS (59.3% versus 41.7%; P = 0.03) (data not shown).
Patients who did not respond to ICE had a median survival of
only 4.8 months.
Improving the outcome of ICE with rituximab (R-ICE)
Attempts were made to improve the pretransplant cytoreduction
by increasing the CR rate with the addition of rituximab to ICE
(the goal was an increase from 24% to 45%). Preliminary results
of our trial of rituximab combined with ICE chemotherapy have
been reported [19]. Briefly, at the time of the initial report 31
patients with relapsed or refractory DLBCL were evaluable.
Rituximab 375 mg/m2 was administered on day 1 of each cycle
with ICE administered starting on day 3. In cycle 1 an additional
dose of rituximab was administered on day –2. Addition of rituxi-
mab increased the incidence of neutropenia and prolonged the
median time between treatments to 19 days.
Addition of rituximab did not significantly impact on mobiliza-
tion failures (17%) and the median number of stem cell collected
was 6.3 × 106 CD34+ cells/kg body wt. Though the ORR com-
pared to historical controls was not significantly improved (81%
versus 73%), the CR rate was (55% versus 28%). Further analysis
of this trial is pending and will be reported separately.
Discussion
The role of high-dose therapy and ASCT in the treatment of
recurrent aggressive lymphoma has been well described, includ-
ing the randomized Parma trial [3]. However, the Parma trial was
limited by the fact that it only included patients with chemosensi-
tive, relapsed disease. Thus, the critical role of cytoreductive
therapy for primary refractory patients was not addressed.
Numerous regimens have been used for cytoreduction prior to
ASCT including DHAP, ESHAP, mini-BEAM and dexa-BEAM
(with high-dose dexamethasone) [5–7, 25]. While these regimens
have been effective, they were not specifically designed for pre-
ASCT cytoreduction. We developed the ICE regimen specifically
for pre-ASCT cytoreduction with the following goals: effective
cytoreduction; minimal non-hematological toxicity; and ability
to mobilize adequate numbers of peripheral progenitor stem
cells. Based on intention-to-treat, slightly more than half of the
patients with relapsed or refractory aggressive NHL will proceed
to ASCT with ICE-based cytoreduction.
In the data reviewed above, ICE achieves these goals with a
high ORR in patients with relapsed and refractory disease (72%)
as well as a low rate of failure to mobilize stem cells (14%). We
feel that these are the two most significant parameters in evalu-
ating the effectiveness of a pre-transplant cytoreductive regimen.
These parameters can be incorporated into a single value, the
mobilization-adjusted response rate [MARR = ORR (%)—
mobilization failures (%)] to evaluate the effectiveness of a
cytoreductive regimen. In the data reviewed above for ICE,
MARR is 52%. The MARR for R-ICE is 64%. Table 3 illustrates
the potential utility of MARR. For example, ORR for HD with
mini-BEAM for HD is 84% which would appear to be an excel-
lent regimen. However, with a 43% rate of mobilization failure,
MARR is only 41%. In contrast, ESHAP for HD and NHL has an
ORR of 64%, but because of the much lower mobilization failure
rate of 15%, it has a similar MARR despite the inferior ORR. We
propose using the MARR parameter as a primary end point in
comparative studies of cytoreductive regimens.
It is clear from this result that there is substantial room for
improvement in the cytoreductive regimens. Clearly, efforts to
i10
improve the quality of response to second-line chemotherapy
may be warranted, given the improvement in PFS and OS with
complete responses compared with partial responses. Further-
more, we are currently investigating the utility of prognostic
models capable of distinguishing distinct risk groups for whom
new therapeutic approaches are necessary.
One novel approach to enhancing ICE chemotherapy is to add
the chimeric monoclonal antibody rituximab to the regimen. Pre-
clinical data suggests that the combination of rituximab with
certain agents, including platinum derivatives, enhances cell kill
compared with chemotherapy alone. Clinical trials have demon-
strated that addition of rituximab to conventional chemotherapy
results in little additional toxicity. A large randomized trial of
rituximab combined with CHOP chemotherapy for elderly
patients with DLBCL has shown statistically and clinically
meaningful improvements in event-free survival and OS com-
pared to CHOP alone. We have added rituximab to the ICE
regimen. Though the combination is well tolerated with no
impact on stem cell mobilization, we did see an increase in the
myelotoxicity. Preliminary results demonstrate that the CR rate
in the patients treated with R-ICE were significantly higher com-
pared with the historical controls but we await further follow-up
to determine if this will translate into an improvement in overall
outcome.
Disclosure
The authors do not have any financial relationships with com-
panies whose products are mentioned in the text.
References
1. Fisher RI, Gaynor ER, Dahlberg S et al. A phase III comparison of CHOP
versus m-BACOD versus ProMACE-CytaBOM versus MACOP-B in
patients with intermediate- or high-grade non-Hodgkin’s lymphoma:
results of SWOG-8516 (Intergroup 0067), the National High-Priority
Lymphoma Study. Ann Oncol 1994; 5: 91–95.
2. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab
compared with CHOP alone in elderly patients with diffuse large-B-cell
lymphoma. N Engl J Med 2002; 346: 235–242.
3. Philip T, Chauvin F, Armitage J et al. Parma international protocol: pilot
study of DHAP followed by involved-field radiotherapy and BEAC with
autologous bone marrow transplantation. Blood 1991; 77: 1587–1592.
4. Velasquez WS, Cabanillas F, Salvador P et al. Effective salvage therapy
for lymphoma with cisplatin in combination with high-dose Ara-C and
dexamethasone (DHAP). Blood 1988; 71: 117–122.
5. Velasquez WS, McLaughlin P, Tucker S et al. ESHAP—an effective
chemotherapy regimen in refractory and relapsing lymphoma: a 4-year
follow-up study. J Clin Oncol 1994; 12: 1169–1176.
6. Colwill R, Crump M, Couture F et al. Mini-BEAM as salvage therapy
for relapsed or refractory Hodgkin’s disease before intensive therapy
and autologous bone marrow transplantation. J Clin Oncol 1995; 13:
396–402.
7. Girouard C, Dufresne J, Imrie K et al. Salvage chemotherapy with mini-
BEAM for relapsed or refractory non-Hodgkin’s lymphoma prior to
autologous bone marrow transplantation. Ann Oncol 1997; 8: 675–680.
8. 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.
9. Maloney DG, Grillo-Lopez AJ, White CA et al. IDEC-C2B8 (Rituxi-
mab) anti-CD20 monoclonal antibody therapy in patients with relapsed
low-grade non-Hodgkin’s lymphoma. Blood 1997; 90: 2188–2195.
10. McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-
CD20 monoclonal antibody therapy for relapsed indolent lymphoma:
half of patients respond to a four-dose treatment program. J Clin Oncol
1998; 16: 2825–2833.
11. Nadler LM, Ritz J, Hardy R et al. A unique cell surface antigen identify-
ing lymphoid malignancies of B cell origin. J Clin Invest 1981; 67: 134–
140.
12. Reff ME, Carner K, Chambers KS et al. Depletion of B cells in vivo by a
chimeric mouse human monoclonal antibody to CD20. Blood 1994; 83:
435–445.
13. Lister TA, Crowther D, Sutcliffe SB et al. Report of a committee con-
vened to discuss the evaluation and staging of patients with Hodgkin’s
disease: Cotswolds meeting. J Clin Oncol 1989; 7: 1630–1636.
Downloaded from annonc.oxfordjournals.org by guest on November 24, 2010
14. National Cancer Institute sponsored study of classifications of non-
Hodgkin’s lymphomas: summary and description of a working formu-
lation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic
Classification Project. Cancer 1982; 49: 2112–2135.
15. Harris NL, Jaffe ES, Diebold J et al. The World Health Organization
classification of neoplastic diseases of the haematopoietic and lymphoid
tissues: Report of the Clinical Advisory Committee Meeting, Airlie
House, Virginia, November 1997. Histopathology 2000; 36: 69–86.
16. Cheson BD, Horning SJ, Coiffier B et al. Report of an international
workshop to standardize response criteria for non-Hodgkin’s lympho-
mas. NCI Sponsored International Working Group. J Clin Oncol 1999;
17: 1244.
17. Kaplan E, Meier P. Nonparametric estimation from incomplete observa-
tions. J Am Stat Assoc 1958; 53: 457–481.
18. Azen SP, Roy S, Pike MC et al. A new procedure for the statistical
evaluation of intrauterine contraception. Am J Obstet Gynecol 1977;
128: 329–335.
19. Kewalramani T, Zelenetz A, Bertino J et al. Rituximab significantly
increases the complete response rate in patients with relapsed or primary
refractory DLBCL receiving ICE as second-line therapy (SLT). Orlando,
Fl, USA: American Society of Hematology 2001.
20. Dreger P, Marquardt P, Haferlach T et al. Effective mobilisation of
peripheral blood progenitor cells with ‘Dexa-BEAM’ and G-CSF: timing
of harvesting and composition of the leukapheresis product. Br J Cancer
1993; 68: 950–957.
21. Magagnoli M, Sarina B, Balzarotti M et al. Mobilizing potential of
ifosfamide/vinorelbine-based chemotherapy in pretreated malignant
lymphoma. Bone Marrow Transplant 2001; 28: 923–927.
22. Mayer J, Vasova I, Koristek Z et al. Ifosfamide- and etoposide-based
chemotherapy as salvage and mobilizing regimens for poor prognosis
lymphoma. Eur J Haematol Suppl 2001; 64: 21–27.
23. Watts MJ, Ings SJ, Leverett D et al. ESHAP and G-CSF is a superior
blood stem cell mobilizing regimen compared to cyclophosphamide
1.5 g/m2 and G-CSF for pre-treated lymphoma patients: a matched pairs
analysis of 78 patients. Br J Cancer 2000; 82: 278–282.
24. Pavone V, Gaudio F, Guarini A et al. Mobilization of peripheral blood
stem cells with high-dose cyclophosphamide or the DHAP regimen plus
G-CSF in non-Hodgkin’s lymphoma. Bone Marrow Transplant 2002;
29: 285–290.
25. McLaughlin P, Velasquez WS, Redman JR et al. Chemotherapy with
dexamethasone, high-dose cytarabine, and cisplatin for parenchymal
brain lymphoma. J Natl Cancer Inst 1988; 80: 1408–1412.