VOLUME

23

NUMBER

JANUARY

20

2005

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Advanced-Stage Large-Cell Lymphoma in Children and

Adolescents: Results of a Randomized Trial Incorporating
Intermediate-Dose Methotrexate and High-Dose
Cytarabine in the Maintenance Phase of the APO Regimen:
A Pediatric Oncology Group Phase III Trial
Joseph H. Laver, Jacqueline M. Kraveka, Robert E. Hutchison, Myron Chang, James Kepner,
Molly Schwenn, Nancy Tarbell, Sunil Desai, Sheila Weitzman, Howard J. Weinstein,
and Sharon B. Murphy
From the Medical College of Virginia,
Richmond, VA; Medical University of
South Carolina, Charleston, SC; State
University of New York, Syracuse;
Roswell Park Memorial Institute,
Buffalo, NY; Childrens Oncology Group
Statistical Office, Gainesville, FL; Maine
Bureau of Health, Augusta, ME;
Harvard Medical School; Massachusetts
General Hospital, Boston, MA;
University of Alberta, Edmonton,
Alberta; Hospital for Sick Children,
Toronto, Ontario, Canada; The
University of Texas Health Science
Center at San Antonio, TX.
Submitted November 13, 2003; accepted
October 5, 2004.
Authors disclosures of potential conflicts of interest are found at the end of
this article.
Address reprint requests to Joseph H.
Laver, MD, Department of Pediatrics,
Medical College of Virginia, PO Box
980646, Richmond, VA 23298-0646;
e-mail: jhlaver@hsc.vcu.edu CC:
pubs@childrensoncologygroup.org.
2005 by American Society of Clinical
Oncology
0732-183X/05/2303-541/$20.00

Purpose
The Pediatric Oncology Group adopted a histology-based approach to non-Hodgkins
lymphoma and treated patients with advanced large-cell lymphoma on a separate protocol
(doxorubicin, vincristine, prednisone, 6-mercaptopurin, and methotrexate; APO regimen). In
this study, we assessed the effects of an intense antimetabolite therapy alternating with
APO on overall survival (OS) and event-free survival (EFS) and looked into biologic correlates.
Patients and Methods
From December 1994 to April 2000, we enrolled 180 eligible pediatric patients with stage
III/IV large-cell lymphoma (LCL); 90 patients were randomly assigned to the intermediatedose methotrexate (IDM) and high-dose cytarabine (HiDAC) arm, 85 patients to the APO arm,
and five patients directly to the APO arm by study design due to CNS involvement. Planned
therapy duration was 12 months.
Results
The 4-year EFS for all patients was 67.4% (SE, 4.2%), and OS was 80.1% (SE, 3.6%) without
any significant difference between the two arms. The 4-year EFS and OS were 71.8% (SE,
6.1%) and 88.1% (SE, 4.4%), respectively, for patients with anaplastic large-cell lymphoma,
and 63.8% (SE, 10.3%) and 70.3% (SE, 9.0%), respectively, for patients with diffuse large
B-cell lymphoma. Only 11 patients required radiation (due to unresponsive bulky disease or
CNS involvement). The IDM/HiDAC arm was associated with more toxicity.
Conclusion
The efficacy of incorporating IDM/HiDAC in the treatment plan of pediatric and adolescent
patients with advanced-stage LCL was inconclusive as to its effect on EFS, regardless of the
lymphoma phenotype. It cannot be excluded that with a higher number of patients, one
treatment could prove superior and future studies will build on these data.

DOI: 10.1200/JCO.2005.11.075

J Clin Oncol 23:541-547. 2005 by American Society of Clinical Oncology

INTRODUCTION

Diffuse large-cell lymphoma (LCL) in children and adolescents constitutes 15% to

20% of all pediatric non-Hodgkins lymphoma (NHL).1,2 The Pediatric Oncology
Group (POG) showed different outcomes

and patterns of failure for LCL and small

noncleaved-cell lymphoma and concluded
that it was important to distinguish nonlymphoblastic lymphomas histologically.3
Therefore, the POG adopted a histologybased approach to management of pediatric
NHL using the National Cancer Institute
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Laver et al

Working Formulation.4 Patients with advanced-stage diffuse LCL were treated on a protocol separate from small
noncleaved-cell (Burkitt; BL) or lymphoblastic lymphomas. All the therapeutic programs for LCL were based on a
modified APO regimen (doxorubicin, vincristine, prednisone, 6-mercaptopurine, and methotrexate).5
With the POG data and a modified APO regimen (POG
#8615), we found an event-free survival (EFS) of 70% and
concluded that the addition of cyclophosphamide did not
improve outcome.6 In the current successor study (POG
#9315), we used random assignment to assess effects of
incorporating into the APO backbone, eight courses of
intense antimetabolite therapy (intermediate-dose methotrexate [IDM] given over 24 hours, followed by high-dose
cytarabine [HiDAC] by continuous infusion for 48 hours)
on overall survival (OS) and EFS.

Table 1. Patient Characteristics

APO
IDM/HiDAC
(n 85)
(n 90)
Male-female ratio (No.)
Murphy stage III/IV (No. of patients)
Age, years
Median
Range
B symptoms (%)
High LDH (%)
Mediastinal involvement (%)
Extranodal involvement (%)
Bone
Liver/spleen
Skin

CNS
(n 5)

42/43
75/10

46/44
72/18

4/1
5

13.7
1.2-19.4
34
62
55

13.5
0.60-19.6
48
65
55

10.1
5.2-15.2
40
60
60

27
18
10

20
23
3

60
20
20

Abbreviations: APO, protocol with doxorubicin, vincristine, prednisone,

6-mercaptopurin, and methotrexate; IDM/HiDAC, intermediate-dose
methotrexate/high-dose cytarabine; LDH, lactate dehydrogenase.

Patients with CNS involvement were assigned to the APO arm.

B symptoms: fever 101F or weight loss 10%.

PATIENTS AND METHODS

Patients
Eligible patients had to be younger than 22.0 years at diagnosis of Murphy stage III or IV7 diffuse LCL (confirmed by central
pathology review); have had no treatment; and provide written
informed consent according to federal and local institutional review board guidelines and the Declaration of Helsinki. Because
multiple terminologies were used between centers, patients were
accepted on study with any of the following pathologic categories
of lymphoma: (1) diffuse histiocytic or mixed lymphocytichistiocytic (Rappaport); (2) diffuse large-cell (cleaved or noncleaved); immunoblastic; or diffuse, mixed, small-, and large-cell
(Working Formulation); (3) diffuse large cleaved, large noncleaved, immunoblastic B, immunoblastic T, or true histiocytic
(Lukes-Collins); and (4) centroblastic, centroblastic-centrocytic,
T-zone, lymphoepithelioid cell (Lennerts lymphoma), immunoblastic T or immunoblastic B, anaplastic LCL (ALCL), pleomorphic, or centroblastic-centrocytic-diffuse (updated Kiel). Patients
were enrolled onto the study between December 1994 and April
2000, and their characteristics are shown in Table 1. Initially, cases
were classified in central pathology review using the Working
Formulation and the Real Classification.4,8 For the purpose of this
report, they were reclassified using the current WHO nomenclature9; those cases that could not be reclassified due to lack of
immunophenotype available are referred to as LCL, unclassified.
CNS disease was defined as the presence of positive CSF cytology
and/or the presence of an intracranial mass.

hours followed by cytarabine 500 mg/m2 bolus, and continuous

infusion of cytarabine 60 mg/m2 over 48 hours) every 21 days.
Both maintenance arms included intrathecal methotrexate on day
one of maintenance cycles 1, 3, and 5, and doxorubicin was substituted with methotrexate after a cumulative dose of 300 mg/m2
was reached (after cycle 5 of the APO arm and cycle 10 of the
IDM/HiDAC regimen); the dose of methotrexate was 60 mg/m2
per cycle. Patients with bulky disease at the end of induction (not
achieving complete response [CR]; response criteria listed below)
were eligible for radiation therapy after biopsy proved viable disease. The total dose to the prescription point was 4,140 cGy in 23
daily fractions (180 cGy/d). For patients in partial remission, most
investigators chose to treat them with two cycles of maintenance
therapy before performing a biopsy. CNS diseasepositive patients
were not randomly assigned and were assigned directly to the APO
arm. During induction, CNS diseasepositive patients received
additional intrathecal methotrexate on days 15, 29, and 36, for a
total of six intrathecal methotrexate doses during induction.
Whole-brain irradiation was started during the first week of maintenance. The total radiation dose was 2,400 cGy in 16 daily fractions (150 cGy/d). These patients also received two additional
doses of intrathecal methotrexate on day 1 of maintenance cycles 2
and 4, for a total of five intrathecal methotrexate doses during
maintenance. Methotrexate was substituted for doxorubicin at a
33% dose reduction for patients who received cranial irradiation;
the dose for these patients was 40 mg/m2 per cycle.

Treatment Program
The program consisted of a similar induction and two different maintenance treatment plans and lasted for 12 months for
both arms. Patients were randomly assigned upfront to one of the
two maintenance arms presented in Figure 1. After the induction
phase (doxorubicin 75 mg/m2 day 1 and 22, vincristine 1.5 mg/m2
day 1 and 22, prednisone 40 mg/m2 daily for 28 days, and ageadjusted intrathecal methotrexate on days 1, 8, and 22), patients
were treated every 21 days with APO maintenance (doxorubicin
30 mg/m2 and vincristine 1.5 mg/m2 on day 1, prednisone 120
mg/m2 and 6-mercaptopurine 225/mg/m2 days 1 to 5) or APO
maintenance alternating with IDM/HiDAC (IDM 1 g/m2 over 24

Immunohistochemistry
Immunohistochemistry analysis was performed with a panel
of antibodies directed against lymphoid-associated antigens, effective in paraffin sections, and intended to identify lineage:
B-lineage antibody L26 (CD20; Dako, Carpinteria, CA); T-lineage
antibodies UCHL-1 (CD45Ro), CD3 (Dako), and MT1 (CD43;
Biotest, Denville, NJ); Hodgkins and ALCL antibody Ber-H2
(CD30; Biotest), ALCL-associated antibody ALK-1 (Dako), and
histiocyte/macrophageassociated antibody KP1 (CD68; Dako).
Antibodies were applied in this order when available material
consisted of limited numbers of unstained slides. For cases in
which unstained slides were not available, antibody results from

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Pediatric Large-Cell Lymphoma

Fig 1. Pediatric Oncology Group Study

9315 Treatment Program. APO, protocol
with doxorubicin (DOX), vincristine (VCR),
prednisone (PDN), 6-mercaptopurin (6MP),
and methotrexate (MTX); IT, intrathecal;
IDM/HiDAC, intermediate-dose methotrexate/
high-dose cytarabine.

treating institutions or reference laboratories of primary diagnosis

were accepted if reviewers determined that they were appropriate.
Response Criteria
CR was defined as the disappearance of all evidence of disease
from all sites. This was determined by physical examination and
appropriate laboratory and imaging studies. Partial response (PR)
was determined by at least a 50% decrease in tumor mass by
comparing postinduction imaging to imaging at diagnosis. No
response was defined as failure to achieve PR. The need for
radiation therapy was determined at the end of induction (day 42);
it could be used earlier only as an emergency intervention due to
mediastinal disease with respiratory symptoms.
Statistical Methods
EFS, time from registration to earliest evidence of relapse,
progressive disease, second cancer, or death from any cause (treatment failures) were the major end points of the study. The logrank test was used in comparative analyses. We originally planned
to accrue 237 patients. Assuming proportional hazards, the study
had 80% power to detect a 2-year EFS rate of 0.87 compared
with a 2-year EFS rate of 0.75 in controls, with a significance
level of .05. Planned analyses included two interim analyses and
one final analysis. EFS and OS curves were constructed by
the Kaplan-Meier method with SEs of Peto et al.10,11 Due to the

orphan nature of this disease, with relatively few patients, the

reader should judge nonsignificant differences as inconclusive.
All reported P values are two-sided.

RESULTS

After entering 180 patients from December 1994 to April

2000, a scheduled interim analysis was performed. With 18
and 19 failures on APO and on the IDM/HiDAC arm,
respectively, the difference between the two arms was insignificant (2-sided P .89 by log-rank test). The futility
analysis was not planned, but was requested by the Data
Monitoring Committee (DMC) of POG. Further analysis
indicated that to obtain a significant result at the planned 52
failures, all 15 additional failures would need to be on the
APO arm. The upper limit of the one-sided 99% CI for the
hazard rate was 2.43. Even at that value, the probability that
all the 15 new failures would be on the APO arm is 0.006.
Based on this information, the DMC voted unanimously to
close the study to further accrual.
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Laver et al

Of 180 eligible patients enrolled, 90 were on the APO

arm, including five with CNS involvement who were assigned to the arm by study design, and 90 patients were on
the IDM/HiDAC arm (Table 1). There were two patients
who had induction failures and two who died early, with a
CR/PR rate of 98% on each arm (response rates are depicted
in Table 2). Fifty-nine percent of patients presented with
peripheral lymphadenopathy (cervical, supraclavicular, axillary, inguinal, or other site), 21% had hepatosplenomegaly, and 55% had mediastinal involvement (61% and 54%
of ALCL and B-cell LCL patients, respectively, had mediastinal involvement). Seven percent of patients had skin involvement (10 of 12 had ALCL), and 24% had bone
involvement (one-third had primary bone involvement).
Forty-one percent of the whole group presented with B
symptoms (fever 101F or weight loss 10%), in 47% of
ALCL patients and 36% of B-cell LCL patients, respectively.
Sixty-three percent had elevated lactate dehydrogenase
(76% and 45% of B-cell LCL and ALCL patients, respectively, had increased lactate dehydrogenase).
Phenotype distribution is depicted in Table 3. There
were eighty-six cases with ALCL (58 T-cell and 28 null cell
phenotype), with 98% CD30 and 89% ALK; only 83
patients were randomly assigned, as three patients with
CNS involvement were assigned to the APO arm. There
were seventy-five cases were B-cell LCL, and 73 were randomized because of two patients having CNS involvement,
who were assigned to the APO arm. There was one case of
follicular lymphoma, and one of low-grade lymphoma of
mucosa-associated tissue (MALT) with increased large cells
(the remaining 71 being diffuse large B-cell lymphoma).
Ten cases were classified as peripheral T-cell lymphoma,
unspecified; none of these expressed CD 30 or ALK, but two
expressed CD68. Nine cases did not have immunophenotyping and were categorized as LCL, unclassified.
The 4-year EFS for all patients was 67.4% (SE, 4.2%),
and OS was 80.1% (SE, 3.6%; Fig 2). The EFS for IDM/
HiDAC was almost identical to that of the APO arm
(Fig 3; P .96).

Table 3. Patient Immunophenotype

Type

No.

% CD30

% ALK

ALCL
T-cell
Null cell
PTCL
B-cell LCL
Diffuse large B-cell
FL
MALT
LCL, unclassified

86
58
28
10
75
73
1
1
9

98
96
100
0
18
19
0
0
NA

89
89
89
0
3
3
0
0
NA

Abbreviations: ALCL, anaplastic large cell lymphoma; PTCL, peripheral

T-cell lymphoma, unspecified; LCL, large-cell lymphoma; FL, follicular
lymphoma; MALT, low-grade lymphoma of mucosal associated tissue
with increased large cell.

There were no significant differences in EFS between

arms (P .69, Fig 4) among the randomized diffuse large
B-cell lymphoma patients (37 on IDM/HiDAC and 34 on
APO); 4-year EFS for APO and IDM/HiDAC patients was
63.8% (SE, 10.3%) and 70.3% (SE, 9.0%), respectively. For
randomized T-cell LCL patients (31 on the APO arm and 34
on the IDM/HiDAC arm), the 4-year EFS was 66.1% (SE,
7.3%), and OS was 85.2% (SE, 5.5%), respectively, without
significant difference in EFS between the two treatments
(P .31). The 4-year EFS and OS for all ALCL patients
(N 86) were 71.8% (SE 6.1%) and 88.1% (SE 4.4%),
respectively (Fig 5). For the randomly assigned ALCL patients (38 on APO and 45 on IDM/HiDAC), no significant
difference in EFS between the two treatments (P .70) was
found. There was no statistically significant difference in
EFS for patients with B-cell versus ALCL (P .31). Furthermore, there were no differences in EFS for patients with
mediastinal (P .51) or bone involvement (P .29). Also,
patients in PR at the end of induction (n 49) had EFS
similar to those in CR (n 120; P .39). There were no
significant differences in EFS between patients with stage 3

Table 2. Response Data

No. of Patients

APO
IDM/HiDAC
CNS

CR

PR

58
61
1

23
22
4

No Response/
Increased
Early
Disease
Death
1
1
0

1
1
0

Not
Assessable

Total

2
5
0

85
90
5

NOTE. Response rate: 98% on both arms (81/83 and 83/85, respectively).
Abbreviations: CR, complete response; PR, partial response; APO,
protocol with doxorubicin, vincristine, prednisone, 6-mercaptopurin,
and methotrexate; IDM/HiDAC, intermediate-dose methotrexate/highdose cytarabine.
*Not assessable for response.

Fig 2. The 4-year event-free survival (EFS) for all patients was 67.4% (SE,
4.2%), and overall survival was 80.1% (SE, 3.6%).

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Pediatric Large-Cell Lymphoma

Fig 3. There was no statistical significant difference in event-free survival

(EFS) between the 85 patients on the APO (protocol with doxorubicin,
vincristine, prednisone, 6-mercaptopurin, and methotrexate) arm versus the
90 patients on the IDM/HiDAC (intermediate-dose methotrexate/high-dose
cytarabine) arm (P .96).

or stage 4 disease or age younger than 14 years compared

with age 14 (below or above the median); the P values
were 0.19 and 0.64, respectively. The distribution of the 59
events (induction failure, relapse, or death) according to
treatment arm/histology group is presented in Table 4.
However, the data should be viewed as inconclusive for all
subgroups, and a larger number of patients could result in
statistical significances.
Only 11 of 180 patients received radiation after induction therapy (including patients with CNS disease who were
assigned to the APO arm with radiation). Four of the nonCNS patients had biopsy-proven viable disease; the rest of
them received radiation based on imaging alone. Five of the
11 were alive and well in continuous complete remission at
this writing (one CNS patient and four non-CNS patients).
Most toxicities were hematologic or gastrointestinal.
The percent of a particular reported toxicity in an arm was
the ratio of the number of patients who experienced the

Fig 4. There were no significant differences in event-free survival (EFS)

between the two arms among the 71 diffuse large B-cell patients (37 on
intermediate-dose methotrexate/high-dose cytarabine [IDM/HiDAC] and 34
B-cell patients on APO [protocol with doxorubicin, vincristine, prednisone,
6-mercaptopurin, and methotrexate]; P .69); 4-year EFS for APO and
IDM/HiDAC was 63.8% (SE, 10.3%) and 70.3% (SE, 9.0%), respectively.

Fig 5. For the 86 patients with anaplastic large cell lymphoma (41 on APO
[protocol with doxorubicin, vincristine, prednisone, 6-mercaptopurin, and
methotrexate] and 45 on intermediate-dose methotrexate/high-dose cytarabine [IDM/HiDAC]), the event-free survival (EFS) and overall survival were
71.8% (SE, 6.1%) and 88.1% (SE, 4.4%), respectively; no significant
difference in EFS between the two treatments were depicted.

worst toxicity with a grade 3 or higher during the protocol

treatment over the total number of patients assessable for
toxicity in the arm. The Common Toxicity Criteria defined
by the National Cancer Institute were used for grading.
Seventy percent of the patients on the IDM/HiDAC arm,
compared with 35% on the APO arm, had severe neutropenia and thrombocytopenia. There were 13 documented
bacterial infections on the IDM/HiDAC arm, compared
with 1% on the APO arm. Nausea and vomiting were reported in 15% and 3%, and mucositis, in 15% and 7.5% on
the IDM/HiDAC and APO arms, respectively. During the
study, there were no reports of cardiotoxicity or second
malignant neoplasms.
DISCUSSION

Building on experience, the Group had adopted a histologybased approach to the management of pediatric NHL and
had treated patients with advanced-stage diffuse LCL, regardless of their immunophenotype, on a separate protocol
from small noncleaved or lymphoblastic lymphomas.6 This
is in contrast to other pediatric cooperative groups in Germany (Berlin-Frankfurt-Munster Group [BFM]) and
France (LMB) that treat LCL patients based on the Kiel
classification, which separates LCL into groups according to
morphology and immunophenotype12,13; for instance,
B-cell LCL patients were treated on the BL protocols.14
Comparison of outcomes is quite problematic for protocols
that use treatment based on histology versus those that are
selected by other more complex criteria. Our strategy of
treating patients based on histology while investigating the
phenotype allowed us to compare outcomes of different
types of LCL that were treated uniformly.
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Laver et al

Table 4. Distribution of 59 Events (induction failure, relapse, or death) According to Treatment Arm/Histology Group

APO
IDM/HiDAC
CNS
Total

ALCL
(n 86)

Histology PTCL
(n 10)

Diffuse Large B-cell

(n 73)

LCL, Unclassified/MALT/FL
(n 11)

Total

9/38
12/45
3/3
24/86

2/4
4/6
0/0
6/10

12/34
12/37
1/2
25/73

4/9
0/2
0/0
4/11

27/85
28/90
4/5
59/180

Abbreviations: ALCL, anaplastic large-cell lymphoma; PTCL, peripheral T-cell lymphoma; LCL, large-cell lymphoma; MALT, mucosa-associated tissue; FL,
follicular lymphoma; APO, protocol with doxorubicin, vincristine, prednisone, 6-mercaptopurin, and methotrexate; IDM/HiDAC, intermediate-dose
methotrexate/high-dose cytarabine.

Previous results of the POG showed that cyclophosphamide was not an essential agent in the treatment
program of advanced stage LCL.6 To further improve
outcome, an intense antimetabolite therapy was added.
Methotrexate and cytarabine have a long track record in
lymphoid malignancies15,16, and the POG accumulated
experience combining them at these doses.17 Furthermore, use of cranial and local radiation was eliminated,
except for a few patients with CNS disease or residual
progressive disease after induction.
To date, our study is the only one on which all young
patients with advanced-stage diffuse LCL subtypes were
treated uniformly. Our data showed that seven cycles of
APO alternating with eight cycles of intense antimetabolite
therapy did not improve OS or EFS in advanced-stage pediatric LCL, regardless of phenotype (B-cell, T-cell,
CD30, or ALK). Our preliminary results in smaller
subgroups suggested that phenotype-directed therapy
might be important in the context of our treatment programs.18,19 However, this analysis, with a longer follow-up,
indicates that the intense antimetabolite therapy did not
improve EFS for the whole group, and that there were no
differences in outcome between the different phenotypes.
Comparing our B-cell LCL data with data of other
reports proves difficult because of different inclusion criteria. In French-American-British LMB 1996, the B-cell LCL
patients were treated on the same protocol as patients with
BL and had a similar outcome of 90% EFS.20 However, the
patients staged as Group B on these studies (which would
comprise most of our advanced-stage patients) might have
also included patients with nonadvanced-stage LCL (ie,
unresected stage I) who have an excellent prognosis, making any comparison problematic. The BFM group also
lumps the B-cell LCL with BL.21 Reiter et al reported their
data in patients with diffuse large B-cell lymphomas, showing an EFS of approximately 90%, but again, their stratification in the therapeutic groups was different.13 Although
the histology, biology, and clinical course of B-cell LCL
differs from BL,22 the current trend is to treat advancedstage B-cell LCL along with BL. The risk of CNS involvement is significantly different for B-cell LCL, and at this

time, it is unclear whether these patients need such aggressive

CNS therapy. In our study, less than 3% had CNS involvement
at diagnosis, and we did not encounter primary CNS failures,
despite relatively modest CNS prophylaxis. These patients
might not need intensive administration of alkylating agents,
which did not improve outcome.6
Our data show that the distribution of subtypes of LCL
in children differs from that seen in adults. In adults, most
LCLs are diffuse large B-cell lymphoma,23 whereas in pediatric populations, T-cell lymphomas (consisting mostly of
ALCL) are more frequent.24,25 In the pediatric age range,
most cases with ALCL are associated with the t(2;5) or a
variant translocation and NPM-ALK fusion product.26
Among our cases with ALCL, the proportion of null-cell to
T-cell was comparable to others.27 Our data, although
they showed no improvement with the investigative arm,
compared favorably with ALCL data published by others.
Brugieres et al and Reiter et al reported the Societe Francaise
dOncologie Pediatrique and BFM results, which ranged
between 54% and 76% EFS.27,28 Data from United Kingdom Childrens Cancer Study Group and Massimino et al
showed similar outcomes.29,30
The higher OS compared with EFS for both ALCL and
B-cell LCL might represent successful salvage therapy with
stem-cell transplantation or vinblastine.31
In our previous study, approximately 40% of the relapses
occurred in the first 12 months of therapy, and another 45%, in
the second year.6 The current study added IDM/HiDAC in an
attempt to improve EFS, and the relapse pattern showed that
the majority of them occurred in the first year on both arms.
Thus, it seems that therapy could be intensified, and other
agents may be tested in the context of the APO backbone (ie,
the incorporation of vinblastine in the new ALCL study).
The APO regimen is well tolerated and for the most
part, does not require hospitalization. It also does not
include alkylating agents or epipodophyllotoxins, thus
sparing long-term survivors some adverse sequelae.
There were no reports of cardiotoxicity (cumulative dose
of doxorubicin 300 mg/m2), though it might occur later,
especially in female patients.32 Instead of substituting for
doxorubicin other drugs that carry their own toxicity,

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Pediatric Large-Cell Lymphoma

our current data support the use of this backbone regimen for future clinical trials for LCL.
Future studies should focus on molecular heterogeneity of these lymphomas in the pediatric population and
compare results to adults with similar pathologic diagnoses.

Acknowledgment
We thank Katalin Banki, MD, and Clara Finch, MD, for
participating in the pathology review, and Rachel Stroman,
CRA, for data collection.
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3. Hvizdala EV, Berard C, Callihan T, et al:
Nonlymphoblastic lymphoma in children histology and stage-related response to therapy: A
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9:1189-1195, 1991
4. Writing Committee: National Cancer Institute sponsored study of classifications of nonHodgkins lymphomas: Summary and description
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Authors Disclosures of Potential

Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for
drugs or devices used in a study if they are not being evaluated
as part of the investigation. Honoraria: Sunil Desai, Amgen.
For a detailed description of this category, or for more information about ASCOs conflict of interest policy, please refer to
the Author Disclosure Declaration form and the Disclosures
of Potential Conflicts of Interest section of Information for
Contributors found in the front of every issue.

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