Diagnosis and Treatment of Childhood Non-Hodgkin Lymphoma Alfred Reiter

Transcription

Diagnosis and Treatment of Childhood Non-Hodgkin Lymphoma Alfred Reiter
Diagnosis and Treatment of Childhood
Non-Hodgkin Lymphoma
Alfred Reiter
Children's University Hospital, Giessen, Germany
Major advances have been made in the treatment of
childhood non-Hodgkin lymphoma (NHL). The recognition that different NHL subtypes require different
treatment strategies was fundamental to developing
successful therapy regimens. Currently established
therapy groups are lymphoblastic lymphoma (LBL) of
precursor B- or T-cell type, mature B-cell neoplasms
(B-NHL), and anaplastic large cell lymphoma (ALCL).
Accurate diagnostic classification is crucial for
allocating patients to appropriate treatment groups.
Therapy protocols designed to treat children with
acute lymphoblastic leukemia (ALL) have proven
highly efficacious for treating children with LBL and
are associated with event-free survival (EFS) rates up
to 80%. For children with B-NHL, a strategy of rapidly
repeated short, dose-intense courses proved more
efficacious, with EFS rates up to 90%. In patients with
ALCL, comparable results are achieved with either
strategy, although this group has the highest relapse
rate. The price of these efficacious treatments is
considerable toxicity. On the other hand, the chance to
survive after relapse is still dismal due to the almost
complete lack of established salvage regimen. Thus,
refinement of the balance between treatment burden
and individual patient risk for failure is a major future
task. A variety of new treatment options, some
already established for treating adult NHL, await
evaluation in childhood NHL.
Introduction
Non-Hodgkin lymphoma (NHL) comprises a heterogeneous
group of lymphoid neoplasms. The distribution of subtypes
according to the World Health Organization Classification
of Tumors of Haematopoetic and Lymphoid Tissues (WHOClassification)1 is significantly different in childhood and
adulthood. In children, lymphoblastic lymphoma (LBL) of
the precursor B- or T-cell type, Burkitt lymphoma (BL)/
leukemia (B-ALL), and anaplastic large-cell lymphoma
(ALCL) predominate, while the proportion of diffuse large
B-cell lymphoma (DLBCL) increases with increasing age.
The typical NHL subtypes of childhood exhibit significant differences in terms of their molecular and cellular
biology and their clinical features, which may be crucial
for determining therapeutic strategies. The most important
disparities in NHL subtypes are significantly different cellcycle kinetics and different dispositions for invasion of the
bone marrow (BM) and central nervous system (CNS),
which is much higher in LBL and BL than other subtypes.2
ences in treatment efficacy are more pronounced in patients with LBL (i.e., patients receiving LSA2-L2 had fewer
relapses) and BL (i.e., patients receiving COMP did better),
while event-free survival (EFS) rates were not significantly
different between treatment regimens in patients with large
cell lymphoma.
Until recently, two different methods were pursued to
stratify therapy for childhood NHL: stratification of treatment modality according to histologic subgroups, and adaptation of treatment intensity according to stage and additional criteria. In the second pattern, primary stratification was for localized versus advanced-stage disease, with
uniform treatment for localized disease of any histology,
while subgroup-directed treatment was used in patients with
advanced-stage disease. However, in a Pediatric Oncology
Group trial, it was shown that even in patients with localized disease, different strategies had different effects in histological subgroups.4 A 24-week maintenance therapy in
addition to a 9-week induction had a beneficial impact on
outcome for patients with LBL but not for those with BL
and large-cell lymphoma.
There are currently three major subgroups of childhood NHL that are distinguished with respect to treatment
strategy (Figure 1): LBL of the precursor B- (pB-LBL) and
T-cell types (T-LBL), B-NHL, and ALCL. Therapeutic protocols used for ALL, which are based on the principle of
continual exposure to cytostatics over a long period of
time, are efficacious for treating children with LBL.3,5,6 In
contrast, a strategy of rapidly repeated short, dose-intense
chemotherapy courses have been shown to be more successful for treating patients with BL/B-ALL and proved
also highly efficacious for treating patients with DLBCL.7-10
Although children with ALCL had comparable outcomes
Stratification of Treatment Modality
According to Subgroup
The Children’s Cancer Group randomized trial CCG-551,3
which compared the LSA2-L2 protocol (cyclophosphamide,
vincristine, methotrexate, daunorubicin, prednisone, cytarabine, thioguanine, asparaginase, carmustine, hydroxyurea) with COMP (cyclophosphamide, vincristine, methotrexate, prednisone) was pivotal for stratifying treatment
modalities according to biological subgroups and revealed
three main findings: (1) different chemotherapy regimens
exert different effects in different NHL subtypes; (2) differences in treatment efficacy are seen mainly in advancedstage disease; and (3) in advanced-stage disease, the differ-
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285
Figure 1. Diagnostic work-up, classification, and stratification of childhood non-Hodgkin lymphoma (NHL) subtypes into
treatment groups.
*Growth pattern diffuse in T-cell–rich B-cell lymphoma (TCRB), nodular, or nodular and diffuse in NLPHL. An overlap between TCRB
and NLPHL cannot be excluded at present.
**Rare cases of DLBCL (with immunoblast/plasmoblast-like cytology) express full-length Alk and can have t(2;17)(p23;q23) (Alkclathrin) translocation (Gascoyne RD 2003).
Abbreviations: TRBCL, T-cell rich B-cell lymphoma; PMLBL, primary mediastinal (thymic) large B-cell lymphoma; HL, Hodgkin
lymphoma; NLPHL, nodular lymphocyte predominant Hodgkin lymphoma; NSHL, nodular sclerosis type Hodgkin lymphoma; PTCL/
NK, peripheral T-cell/natural killer-cell lymphoma; FISH, fluorescence in situ hybridization; PCR, polymerase chain reaction.
with either of those treatment strategies, the ALCL subtype
emerged as a separate treatment group.11-14 The main reasons for this were different prognostic parameters with relevance to stratification of treatment intensity and a higher
chance of survival after relapse compared to the other main
NHL subtypes.15 For rarer and currently less accurately defined NHL subtypes in children, including the small but
heterogeneous group of peripheral T-cell/natural killer cell
lymphoma (PTCL/NK), optimal treatment is not yet established. That and other rare NHL subtypes, such as primary
mediastinal (thymic) large B-cell lymphoma (PMLBL) and
(juvenile) follicular lymphoma, are candidates for new subtype-specific treatments.
Diagnostic Evaluation and Classification
Comprehensive diagnostic evaluation and classification
of cases is essential not only for correct allocation of patients to currently established subgroup treatment regimen
but also for further identification of biologically distinct
subtypes requiring different future treatment. Figure 1 depicts a rational diagnostic work-up program for children
with NHL. Regarding the role of initial surgery, see below.
Caution! Any invasive diagnostics may be dangerous and
should, therefore, be postponed in patients with upper vena
cava syndrome and respiratory distress due to a mediasti-
286
nal tumor. In such cases, immediate treatment with corticosteroids, potentially combined with cyclophosphamide,
for up to 48 hours is beneficial and unlikely to obscure
subsequent pathologic diagnosis. Critical pleural or/and
pericardial effusions require drainage and may enable comprehensive diagnostics.
Cytomorphology, histomorphology, and immunophenotyping are basic diagnostic methods. In most cases, they enable correct classification and allocation of patients to appropriate treatment subgroups. However, according to the
WHO classification, cytogenetics is also required for diagnosis in certain cases, such as variant atypical BL/BL-like.1
Many children present with advanced-stage disease,
including advanced BM invasion or/and malignant effusions. In most such cases, correct diagnosis can be made by
cytology, immunophenotyping by flow cytometry, and cytogenetics (Table 1). If this approach is not possible, diagnosis is based on biopsy, and most cases are correctly classified by cytology of tumor touch imprints, histomorphology, and immunohistochemistry with the available wide
range of paraffin-resistant antibodies.
Regarding appropriate allocation of patients to therapy
groups, there are some crucial differential diagnoses that
require additional selected diagnostics. Typical interfaces
are distinguishing LBL of precursor B-cell type from BL/
American Society of Hematology
BL variants or DLBCL; T-cell rich DLBCL from nodular
lymphocyte predominant Hodgkin lymphoma; PMLBL
from nodular sclerosis type Hodgkin lymphoma; and ALCL
from other peripheral T-cell/NK-cell lymphomas, anaplastic variants of DLBCL, or Hodgkin lymphoma. In these
cases, immunohistochemical staining for expression of
genes associated with differentiation compartments such
as terminal deoxynucleotidyl transferase (TdT; positive
only in precursor B- and T-cell neoplasms) and the germinal center cell-associated marker bcl-6 can be helpful.16
Finally, the identification of subtype-specific chromosomal
translocations may be decisive. However, appropriate material for cytogenetic evaluation is not always available in
NHL patients. In such cases, fluorescence in situ hybridization (FISH), which can be performed on tumor touch preparations, or paraffin sections, is a valid method for visualizing most of the currently known subtype-specific chromosomal translocations.17 In many cases, breakpoint-spanning
DNA fragments or subtype-specific fusion gene transcripts
of specific chromosomal translocations can be detected by
polymerase chain reaction (PCR).18 Recently, it was shown
that BL has a reproducible gene expression profile that can
be used to identify and distinguish molecular BL from other
subtypes.19,20
Newer methodologies, such as identification of genetic
changes in tumor cells and genome-wide gene expression
profiling, will become increasing important for identifying biologically distinct subtypes and therapy targets.
Therefore, whenever possible, following proper diagnostic
classification of an individual patient, appropriate material should be preserved for future research (e.g., purified
tumor cells, shock-frozen tumor tissue).
Subgroup-Directed Treatment Protocols
and Achievements
Lymphoblastic lymphoma
In large, multicenter studies, EFS rates of 60% to more than
80% were achieved, even for children with advanced-stage
T-LBL (Table 2).5,6,21-23 Currently, the most frequently used
Table 1. Immunohistochemical, cytomorphological, and cytogenetic findings in tumor cells in childhood non-Hodgkin
lymphoma subtypes.
Marker
T-LBL
PTCL
ALCL
pB-LBL
Burkitt
DLBCL
TdT
+
–
–
+
–
–
CD19
–
–
–
+
+
+
CD20
–
–
–
+/–
+
+
CD79a
–
–
–
+
+
+
Cyµ
–
–
–
–/+
-/+
–/+
SIg*
–
–
–
–
+
+/–
Pax5
–
–
–
+
+
+
Bcl-6
–
–
–
–
+
+/–
CD1a
+/–
–
–
–
–
–
cµCD3
+
–
–/+
–
–
–
sCD3
–/+
+/–
–/+
–
–
–
CD4
–/+
+/–
–/+
–
–
–
CD5
+/–
+/–
–/+
–
–
–/+
CD7
+/–
+/–
–/+
–
–
–
CD8
–/+
–/+
–/+
–
–
–
CD56
–
–/+
–/+
–
–
–
CD10
+/–
–
–
+/–
+
+/–
CD30
–
–/+
+
–
–
–/+
Alk
–
–
80% +
–
–
–†
FAB-cytology
L1/L2
NA
NA
L1/L2
L3
NA
Cytogenetics Translocations
t(2;5)(p23;q35)
No data t(8;14)(q24;q32)
involving
t(1;2)(q25;p23)
t(2;8)(p11;q24)
14q11.252
plus other less
t(8;22)(q24;q11)
Few data on
frequent translocations
T-LBL available
involving 2p23
so far
PMLBL
–
+
+
+
–
–
+
–
–
–
–
–
–
–
–
–
–
+/–
–
NA
Abbreviations : T-LBL, precursor–T-cell lymphoblastic lymphoma; PTCL, peripheral T-cell lymphoma, unspecified; DLBCL, diffuse
large B-cell lymphoma; ALCL, anaplastic large-cell lymphoma; pB-LBL, precursor B-cell lymphoblastic lymphoma; PMLBL, primary
mediastinal (thymic) large B-cell lymphoma; NA, not applicable ; +, positive ; +/–, often positive ; –/+, occasionally positive ; –, negative
*and light chain restriction κ or α
†positive only in the rare plasmablastic variant
Adapted from Jaffe et al.1
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287
treatment regimens are the LSA2-L2 protocol in numerous
modified forms and the Berlin-Frankfurt-Münster (BFM)
group strategy, which was originally designed to treat children with ALL. Both protocols are divided into phases of
induction, consolidation, reintensification, and maintenance, and include corticosteroids, vincristine (VCR),
anthracyclines, L-asparaginase (L-Asp), cyclophosphamide
(CP), methotrexate (MTX), cytarabine, 6-mercaptopurine
(6-MP), and 6-thioguanine. The main differences between
the protocols are earlier application of L-Asp and highdose (HD) MTX (5 g/m² intravenous over 24 hours) in the
BFM regimen. Treatment duration for both regimens was
18 to 24 months. Repeated continuation courses, including CP and anthracycline until the end of therapy, are part
of the LSA2-L2 protocol, while maintenance includes only
oral 6-MP and MTX in the BFM strategy. Most relapses
occur early, and late relapses are rare. In patients with TLBL most relapses occur during the first 12 months after
diagnosis, suggesting that the duration of maintenance can
be reduced.5
The contribution of individual drugs to patient cure is
largely unknown due to the shortness of randomized trials.
For L-Asp, the effect in T-LBL was demonstrated in the
POG-8704 trial when patients did or did not receive weekly
L-Asp × 20 after induction.21 With backbone BFM protocols, no additive effect on outcome was observed for HD
cytarabine in the consolidation phase nor for intensification blocks up-front of the BFM induction protocol.22,24
Currently, randomized BFM-based trials are ongoing to
determine whether dexamethasone instead of prednisone
during induction can further improve outcome of patients
with LBL, as was observed in children with ALL. Results
of a COG trial that examined the impact of HD MTX during
consolidation and up-front intensification with CP and anthracycline are pending.
Stratification of treatment intensity. Treatment intensity is mainly stratified according to stages I and II versus
stages III and IV. Children with stage I/II are rare. Most have
pB-LBL and achieve EFS rates higher than 90% with reduced-intensity (omission of reintensification in the BFM
protocol) and full-length maintenance therapy. Whether
treatment can be reduced further is difficult to determine.
In a POG trial, a 24-week maintenance in addition to a 9week induction was beneficial for patients with LBL, although their EFS rate was only 63%.4 This suggests that
their biological similarity to ALL is more important than
their low tumor burden and that they might, therefore, benefit from an ALL-type treatment, including maintenance.
Extracompartment therapy. For patients with overt
CNS disease, 18 to 24 Gy cranial irradiation (CRT), in addition to LSA2-L2 or BFM chemotherapy, is highly effective in preventing CNS recurrences.2,5,6 For CNS-negative
patients, treatment that includes intrathecal MTX and systemic HD MTX (0.5-5 g/m²) but no CRT is sufficient CNS
protection in children with stage I/II disease.2,4,5 Although
a randomized trial is not available, cumulative evidence
288
suggests that preemptive CRT can also be omitted for CNSnegative patients with advanced-stage disease. In study
NHL-BFM 95, including 4× HD MTX (5 g/m² intravenous
over 24 hours) and 11 doses of intrathecal MTX but no
CRT, disease-free and CNS relapse-free survival of patients
was not significantly inferior to the historic control group
of the preceding trials NHL-BFM 86 and 90, in which patients received prophylactic CRT.23 HD MTX also appears
to be efficacious in preventing testes relapse.5
B-NHL
Chemotherapy strategies for B-NHL are tailored to the
biological and clinical characteristics of BL and are also
efficacious for patients with other B-NHLs, especially
DLBCL. The prototype therapy courses of the currently
most-used treatment regimens were developed in the St.
Jude Total B program, the French LMB, and the GermanAustrian-Switzerland BFM NHL studies. Based on the
extremely high proliferative activity of BL, a basic principle
is to maintain cytotoxically active drug concentrations over
a period that is sufficient to affect as many lymphoma cells
as possible during the vulnerable active cell cycle, using
either fractionated administration or continuous infusion.25
Other principles are combining drugs with different
mechanisms of action and few overlapping toxicities; highdose intensity over time by keeping between-treatment
intervals short; and efficient CNS-directed therapy to
address the strong tendency for invasion of the CNS,
especially that of BL. Therapeutic strategies that adhere to
this principle of rapidly repeated 4- to 7-day courses
composed of corticosteroids, VCR, CP or ifosfamide, HD
MTX, cytarabine, doxorubicin, etoposide, and triple drug
(MTX/cytarabine/corticosteroid) intrathecal therapy
resulted in EFS rates up to 90% in large, multicenter studies
(Table 2).7-9,26 Evidence for the importance of CP, VCR,
and MTX was derived from early studies on BL in Africa.
Although randomized comparisons are lacking, evidence
for the effect of the MTX dose can be derived from the
significant relapse reduction in patients with advancedstage disease and high tumor mass after a multifold increase
in MTX dose from 0.5 g/m² to 3.0, 5.0, and 8.0 g/m².7,8 The
efficacy of HD cytarabine combined with etoposide was
demonstrated by remission induction in patients who failed
conventional therapy.27
The current highly efficacious regimen correlates with
considerable acute toxicity which could not be decreased
by post-chemotherapeutic granulocyte colony-stimulating
factor (G-CSF).28 Patients with advanced-stage disease are
at significant risk of roughly 3% to die from treatmentrelated complications, especially during the first phase of
therapy.7,8,26,29 Severe oro-intestinal mucositis, caused primarily, but not solely, by HD MTX, and severe neutropenia
are the most important acute toxicities, synergistically promoting serious infections. Metabolic disturbances of acute
tumor cell lysis syndrome (ATLS) is another serious threat
in the first days of treatment that decreased, but did not
American Society of Hematology
Period
pEFS at
3-5 y*
I
I+II 28/84%
219/70%
34/46%
Comments
No. patients
(Age in y)
—
NG
Stages (St. Jude staging system)
No. of patients/pEFS
II
III
IV
Table 2. Results of recent multicenter studies on childhood non-Hodgkin lymphoma (NHL).
Study
Lymphoblastic Lymphoma
NG
NG
82 (1-17)
76%
66%
8/100%
—
20/79%
I/II 23/94%
55/74%
—
6/50%
III/IV 59/55%
17/65%
7/71%
ng
See Table 3
Randomized trial
HD-MTX intravenously over 24 h vs 4 h
T-LBL only, BFM-backbone, early intensification day 8
Randomized trial: 20 weekly L-Asp vs no
4-y pCCR 78 vs 64%
Randomized trial
Modified LSA2-L2 vs ADCOMP EFS 74% vs 64%
281 (0.5-19)
NE
10/83-03/90
NE
T-LBL only
CCG-5026
NG
19/95%
180 (1-21 )
82/90%
05/87-01/92
2/100 %
POG 870421
2/100%
90%
Omission of pre-emptive cranial irradiation
105 (0.5-18)
NG
53/77%
59/79%
B-ALL 74/65%
04/90-03/95
NG
123/79%
NE
60% incl B-ALL
NHL-BFM90-LBL5
NG
I+II 22/95%
NG
NE
82%
62/87%,
B-ALL 102/87%
87%
NE
NE
278/91%
24/73%,
B-ALL 56/74%
80%
NG
NE
88/99%
169/88%
33/81%
B-ALL 79/77%
83 (ng)
133 (0-21)
77%
31/93%
115/98%
221/87%
198 (0-18)
10/86-11/91
42 (0-21)
91%
49/97%
119/98%
04/95-03/01
POG Total9
12/91-12/93
561 (0-17)
89%
53/98%
02/97-12/03
CCG-Hybrid 10
07/89-06/96
413 (1-19)
89 %
SFOP-LMT 9622
SFOP/LMB 897
04/90-03/95
505 (0-18)
NHL-BFM95-LBL23
NHL-BFM 908
04/96-03/01
B-NHL
NHL-BFM 9526
FAB/LMB-96
08/88-02/997
89 (0.8-17)
SFOP-HM89/9114
Anaplastic Large Cell Lymphoma
04/90-03/95
NHL-BFM-90 12
10/60%
ng
III/IV 57/58%
0/–
ne
I/II 15/62%
65%
06/90-05/96
59%
01/93-10/97
72 (0-17)
UKCCSG11
34 (4-15)
AIEOP13
86 (0-21)
ne
12/94-04/00
72%
POG-8704-APO33
* Total group.
Abbreviations: pEFS Kaplan-Meier estimate of event-free survival; NG, not given; ADCOMP, L-asparaginase, daunorubicin, cyclophosphamide, vincristine, methotrexate, prednisone; Lasp, L-asparaginase; pCCR, probability of continuous complete remission; NE, not eligible; T-LBL, T-cell lymphoblastic lymphoma; B-ALL, B-cell acute lymphoblastic leukemia; HD-MTX,
high-dose methotrexate
289
Hematology 2007
completely disappear, after the introduction of a cytoreductive pre-phase, usually consisting of corticosteroid
and low-dose cyclophosphamide and urate oxidase to prevent or treat ATLS.30
Risk-adapted stratification of treatment intensity and
duration. In most North American studies, treatment intensity was stratified according to St. Jude stage, while in the
French LMB and BFM studies, additional criteria (e.g., resectability, tumor mass, and CNS involvement) were explored (Table 3). The main goal of the recent multicenter
trials FAB/LMB-96 (based on the French LMB-89 protocol) and NHL-BFM-95 was to reduce treatment burden
(Table 3).26,29,31,32 Patients with localized resected tumors
have nearly 100% EFS with two 5-day therapy courses and
may not need MTX at all. A favorable balance of efficacy
and toxicity was observed with 4 courses of therapy that
included 3 g/m² MTX given intravenously over 3 hours
(FAB/LMB group B) and 1 g/m² MTX given intravenously
over 4 hours (BFM group R2) in patients with unresected
lymphoma of intermediate risk (group B in the FAB/LMB96 trial, group R2 in the NHL-BFM 95 trial; Table 3). In
the FAB/LMB-96 trial, intermediate-risk patients (group
B) with response to the 7-day cytoreductive prophase COP
(cyclophosphamide/vincristine/prednisone) and the first
course COPADM were randomized in a factorial design
into 4 arms, 2 receiving half-dose cyclophosphamide in
the second induction course and 2 with omission of the
maintenance course M. pEFS was equal with reduced-dose
cyclophosphamide and omission of course M. In both trials, attempts to reduce treatment burden in high-risk patients failed, however. Data from the NHL/BFM-95 study
showed that toxicity and antitumor efficacy of MTX depends on duration of exposure to the drug. A 4-hour MTX
infusion is less toxic than a 24-hour infusion but is also
less efficacious.26 The required efficacy of MTX appears to
differ according to the patient risk for failure. For patients
in the low- and intermediate-risk groups R1 and R2, 1 g/m²
MTX over 4 hours was as efficient and less toxic than the
24-hour infusion. Mucositis grades III/IV and infection
grade III were observed after 6% and 2% of the treatment
courses. Patients at high risk for relapse (groups R3+R4)
benefit from higher MTX efficacy grades in terms of dose
and exposure duration. Regarding treatment duration, there
is little rationale for more than 6 (BFM) to 8 (FAB/LMB96) courses, even for high-risk patients, as roughly onethird of relapses occur during therapy.7,8,26,29
Extracompartment therapy. With chemotherapy alone,
including systemic MTX in risk-adapted doses of 0.5 to 8
g/m² combined with triple-drug intrathecal therapy, CNS
relapse is rarely seen in patients without overt CNS disease
at diagnosis.2,7,8,26,29,32 Intrathecal therapy may even be dispensable in patients with resected localized tumors except
those with head and neck tumors.2 Outcomes of patients
with overt CNS involvement are inferior to those of patients who are CNS-negative with advanced-stage disease,
including BM involvement.2,7,8,26,29 There are no random290
ized trials testing the role of cranial irradiation in patients
with CNS-positive B-NHL. In recent studies patients with
CNS-positive B-NHL had EFS rates of 70% with LMB and
BFM protocols that included 3 g/m² HD cytarabine; 8 g/m²
and 5 g/m² HD MTX intravenously over 4 and 24 hours,
respectively; and intensive intrathecal triple-drug therapy
applied via lumbar puncture (LMB) or fractionated intraventricularly (BFM).8,26,29 These results were comparable
with the outcome of CNS-positive patients receiving in
addition cranial irradiation in a previous LMB study.7 Testicular relapse is rare with therapy strategies that include
HD MTX.7,8
ALCL
Chemotherapy. EFS rates of 65-75% were achieved with different therapeutic strategies including LSA2-L2-type protocols and short-pulse B-NHL–type protocols (Table 2).11-14,33
Treatment durations of these regimens varied between 2 and
5 months and 2 years. Most tumor failures occur within the
first 15 months after diagnosis, although late relapse has been
observed with all treatment strategies. Some patients experience progression very early in treatment.
Due to the heterogeneous nature of treatment regimens,
only limited conclusions can be drawn about the roles of
their individual components. Alkylating agents, HD MTX,
and etoposide are main components of most regimens, but
were absent in the 6-drug APO regimen of the POG-8704
trial at the expense of a high cumulative dose of doxorubicin.33 Thus, one might hypothesize that doxorubicin, VCR,
and steroids are key component drugs. An intriguing observation was the efficacy of vinblastine in multiply recurrent ALCL.15 The role of vinblastine in front-line therapy is
currently under investigation.
Stratification of treatment intensity. The criteria for
stratifying treatment intensity for ALCL are less well established than for other NHL subtypes. Patients with complete resected stage I appear to require only short treatment
of three 5-day courses.12 In an ongoing trial, patients were
allocated to the high-risk group based on the presence of at
least 1 risk factor (skin involvement, mediastinal mass, visceral involvement of the lung, liver, or spleen).34
Extracompartment therapy. ALCL has a moderate tendency for CNS invasion. The incidence of CNS relapse was
low without preemptive CRT in all studies.2,11-14 A recent
randomized trial demonstrated that HD MTX (3 g/m² intravenously over 3 hours) was sufficient to protect the CNS in
CNS-negative patients in the absence of additional intrathecal chemotherapy.34 For the rare patients with overt CNS
disease, 18 to 24 Gy CRT may be an option in addition to
HD MTX, HD cytarbine, and intrathecal triple-drug
therapy.12,14 To date, testicular involvement has not been
reported.
Local therapy modalities
Initial surgery is primarily diagnostic to provide sufficient
biopsy material. Patients with completely resected small
American Society of Hematology
Table 3. Treatment stratification and results in two recent multicenter trials on pediatric B-cell non-Hodgkin lymphoma.
0
Cumulative doses
CP
Ifo
Doxo
Eto
g/m²
g/m² mg/m² mg/m²
120
0
MTX
g/m²
0
Chemotherapy courses
3
COPAD-COPAD
0
0
0
0
pEFS
180
120
180
120
N = 1134
FAB/LMB 9629,31,32
Group
Definition
0
0
0
0
2500
R
800
98%
(3 y)
5.8
4.8
4.3
3.3
0
240
R
180
200
12%
×5
×4
×5
×4
0
50
400
Stage I-resected
II-abdominal
3,
3,
3,
3,
6.8
R
5.8
4
100
900
A
8, ×3
(×4 for
CNS+)
1.4
8
100
1400
90%
(4 y)
COP-COPADM1-COPADM2-CYVE1-(CNS+ only: HD-MTX)CYVE2- M1- M2- M3- M4
Randomization for responders after COP-COPADM1+2:
Reduced intensity “mini-CYVE” and omission M2, M3, M4.
Result: inferior outcome
1, ×2
2.4
8
100
67%
79%
(4 y)
Chemotherapy courses
1, ×4
2.4
8
B
pEFS
A- B
Randomization: MTX iv over 24 hr vs 4 hr
Result: 4 hr less toxic, equally efficacious
5, ×4
2.4
COP-COPADM1-*COPADM2‡-CYM-CYM-M1
*COPADM2‡-CYM-CYM
*COPADM1-CYM-CYM-M1
*COPADM1-CYM-CYM†
94%
(3 y)
P-A- B- A- B
Randomization: MTX iv over 24 hr vs 4 hr
Result: 4 hr less toxic, equally efficacious
5, ×4
I-not resected
II-non-abdominal, III, IV
BM-blasts ≤25%
CNS–
94%
(3 y)
P-AA- BB- CC- AA- BB
Randomization: MTX in AA, BB iv over 24 hr vs 4 hr:
Result: 4 hr less toxic, less efficacious
28%
16%
46%
21%
N = 505
85%
(3 y)
P-AA- BB- CC- AA- BB- CC
Randomization: MTX in AA, BB iv over 24 hr vs 4 hr.
Result: 4 hr less toxic, less efficacious
C
10%
81%
(3 y)
>25% BM-blasts
and/or CNS+
III-LDH 500 <999 U/L
BM+ and LDH <1000 U/L
I+II–not resected
III-LDH <500/U/L
Stage I+II–resected
NHL-BFM 9526
Group
Definition
R1
R2
R3
R4
LDH ≥1000 U/L
and/or CNS+
Abbreviations: P, cytoreductive prophase; MTX, methotrexate; CP, cyclophosphamide; Ifo, ifosfamide; Doxo, doxorubicin; Eto, etoposide; R, randomization; y, years; hr, hours; iv,
intravenously; CNS, central nervous system; BM, bone marrow
*Factorial design randomization for responders to COP-COPADM1.
†Equally efficacious.
‡Dose of cyclophosphamide 3 g/m2 in COPADM2 compared with 1.5 g/m2 in COPADM1.
291
Hematology 2007
localized B-NHL and ALCL have an EFS of nearly 100%
after 2 and 3 short chemotherapy courses, respectively. The
impact of resection on outcome of these patients is unknown, however. In advanced stages, gross sectional surgery does not contribute to cure but may delay the onset of
chemotherapy and is, therefore, obsolete.
There is little evidence for a beneficial role of local
irradiation. Across all entities, patients with localized disease have excellent outcomes with chemotherapy alone.
Patients in advanced stages who still experience relapses
often have widespread disease, making application of radiotherapy difficult and toxic. Nevertheless, since local
sites are a frequent site of recurrence, there may be select
patients who would benefit from local irradiation. The question is how those patients can be accurately identified, while
protecting other patients from the late risks of irradiation
(see below).
Refinement of Risk Adaptation
Further refinement of the balance between treatment burden and risk of failure is warranted. However, reduction of
treatment intensity may be dangerous in the absence of a
salvage strategy with proven efficacy. Most relapses occur
early, leaving patients with highly refractory tumors and
pre-existing morbidity that results from ongoing or recently
completed first-line therapy. Early identification of those
patients who will fail current treatment and alteration of
their treatment may enhance their chances of survival. Thus,
identifying the parameters that predict current treatment outcome with high accuracy is a major task. Within the estab-
lished treatment subgroups, the histologic subtype has no
adverse prognostic impact, except for PMLBL35 and, possibly, the lymphohistiocytic variant of ALCL.14,36 Table 4 depicts parameters that have prognostic significance for current
treatments in addition to St. Jude stage. Many of the parameters are too limited in predictive strength to provide the
basis for major alteration of current treatment, however.
The availability of new methodologic tools will
greatly enhance our ability to distinguish additional biologically distinct subtypes beyond histology and can enable application of subtype-specific therapies. However,
the application of such methods (e.g., gene expression profiling) is often impeded by rather trivial causes, including
a lack of appropriately preserved tumor material. A lack of
tumor material is also a major limitation in the availability
of cytogenetic analyses. Preliminary data suggest that secondary chromosomal aberrations in patients with BL are
associated with a high risk of failure (Table 4).37,38
The kinetics of treatment response is a strong prognostic parameter in many malignancies and is underexplored
in childhood NHL. The primary reason for this may be methodological difficulties in reproducibly evaluating the kinetics due to the complexity of lymphoma manifestations.
Incomplete tumor regression during induction is a frequent
observation. Its affect on the subsequent course differs,
however, since the tumor remnant may be a result of resistant lymphoma or persistent fibrous or necrotic tissue. Conventional imaging and second-look surgery have limited
value in distinguishing patients who are prone to subsequent progress and those for whom the tumor remnant rep-
Table 4. Prognostic factors of patient risk for failure to current treatment regimen.
Group-specific adverse prognostic factors in addition to stage
Established
Candidate
LBL-pB
—
—
LBL-T
Female > 10 years53
Del 6q54
EFS 60%
Relapse probability 46%
MRD monitoring55
Burkitt
LDH > 2N >500 >1000 8,32
CNS disease7-9,29
Age > 15 years7
Polymorphism LTα-TNF56
Nonresponse to prophase7,32
Abber 13q37
Abber chrom 22 37
Gain 7 37
Complex secondary aberrations38
LDH > 1000, pEFS 70%
pEFS 65%
MRD monitoring42
Female > 14 years of age53
pEFS 50%
DLBCL
U/L35
PMLBL
LDH > 2N > 500
Tumor size
ALCL
Mediastinal mass visceral involvement, skin57
Lymphohistiocytic variant14,36
Minimal systemic disease in BM, PB:
> 10 copies NPM-ALK/10,000 copies abl41
Survival 37% (n = 8)
Survival 0 (n = 7)
pEFS 40%
Progression-free 61%
EFS 46%
Cumulative incidence of relapse 71%
MRD monitoring41,58
Abbreviations: EFS, event-free survival; MRD, minimal residual disease; CNS, central nervous system; BM, bone marrow; PB,
peripheral blood; see Table 1 for additional abbreviations
292
American Society of Hematology
resents the fibrous-necrotic waste of the initial lymphoma
with no impact on outcome. The only exception is unequivocal viable tumor on second-look OP.7,8,26,29,32 Functional imaging using positron emission tomography with
F18 fluoro-deoxy-D2-glucose (FDG-PET) may provide a
new tool for early assessment of treatment response. In aggressive adult NHL, negative FDG-PET after the first two
courses of chemotherapy was associated with a 2-year EFS
of 82% compared with a EFS of 43% for patients with positive FDG-PET.39 Whether these findings generalize to childhood NHL is unclear, since FDG-PET avidity differs significantly between lymphoma subtypes.40 Furthermore, to
determine treatment guidelines, prospective evaluation of
prognostic accuracy will be necessary in the context of a
given treatment. Monitoring residual clonal lymphoma
cells in the blood and/or BM by means of aberrant immunophenotype- or PCR-based identification of specific fusion gene products may be an alternative tool for evaluating the kinetics of treatment response.41,42
Treatment of Relapse
The chance of patient survival after relapse from current
front-line protocols is poor, although there might be differences according to NHL subtypes. However, prospective
controlled clinical trials on relapsed pediatric NHL are rare.
One of the more frequently used salvage regimen may be
ICE (ifosfamide, carboplatin, etoposide),43 although reports
on results in relapsed pediatric patients with NHL are rare.
With the combination dexamethasone, etoposide, cisplatin,
HD cytarabine, and L-Asp (DECAL), complete remission
was achieved in 40% of patients while EFS at 2 years was
33%.44 Results were not broken down for NHL subtypes,
however. With ALL relapse protocols, survival rates of less
than 30% were achieved for children with relapse of LBL.45,46
Similarly, survival rates of only 10% to 15% were reported
for children with relapsed or refractory BL/B-ALL, with
therapy approaches consisting of dose-intense chemotherapy followed by autologous or allogeneic hematopoietic stem-cell transplantation (HSCT).29,45,47 Prospective studies are needed to determine whether newer therapy options
such as anti–B-cell–specific monoclonal antibodies have
Table 5. New treatment options for childhood non-Hodgkin lymphoma (NHL).
Option
Action
Allogeneic HSCT
Graft-versus-lymphoma? ALCL, T-LBL
NHL subgroup
Allogeneic HSCT
+rituximab
Graft-NK/MNC ADCC
Evidence/status of development*
Efficacious in refractory childhood ALCL, and T-LBL relapse.46,48
CD20+ B-NHL
Increased ADCC of BL cells of donor MNC (Pfeiffer M et al,
Bone Marrow Transplant. 2005;36:91-97; Escalon MP et al,
J Clin Oncol. 2004;22:2419-2423)
Monoclonal antibodies
Rituximab
Anti-CD20
CD20+ NHL
Phase 3 trials adult DLBCL (Coiffier B et al, N Engl J Med.
2002;346:235-242)
Casual observations in childhood BL relapse
Epratuzumab
Anti-CD22
CD22+ NHL
Response in phase 1-2 (Leonard JP et al, Clin Cancer Res.
2004;10:5327-5334)
SGN-30
Anti-CD30
ALCL
CR/Pr in phase 1-2 in adults (Bartlett NL et al, Blood.
2002;100:362a)
Ongoing phase 2 studies
Nelarabin
Nucleoside analog
T-LBL
Response in phase 1-2 studies in T-ALL(Berg SL et al,
J Clin Oncol. 2005;23:3376-3382)
Clofarabin
Deoxyadenosine analog
LBL, pB+ T
Response in phase 1-2 studies in ALL (Jeha S et al,
J Clin Oncol. 2006;24:1917-1923)
Forodesin
Purine nucleoside
phosphorylase inhibitor
T-LBL
Phase 1, T-cell neoplasms (Gandhi V et al, Blood.
2005;106:4253-4260)
Liposomal
cytarabine
Slow released
cytidine analog
CNS+ BL/B-ALL
Phase 1 (Bomgaars L et al, J Clin Oncol. 2004;22:3916-3921)
NVP-TAE684
Alk inhibitor
Alk+ ALCL
Cell lines, animal models (Galkin AV et al, Proc Natl Acad Sci
U S A. 2007;104:270-275)
Bortezomib
NF-κB inhibitor
PMLBL
Phase 1 (Horton TM et al, Clin Cancer Res. 2007;13:1516-1522)
ru-human keratinocyte
growth factor
High-risk B
Significant reduction of mucositis in phase 3 studies
(Spielberger R et al, N Engl J Med 2004; 351:2590-2598*)
Cytostatic drugs
Other
Palifermin
*References given in the Table but not included in Reference list due to space restriction
Abbreviations: HSCT, hematopoietic stem cell transplantation; MNC, mononuclear cells; ADCC, antibody-dependent cellular cytotoxicity; NF-κB, nuclear factor kappa B; NK, natural killer; see Table 1 for additional abbreviations
Hematology 2007
293
a role in the treatment of these patients. A more favorable
survival rate of 69% at 3 years was reported for 41 relapsed
ALCL patients.15 They were treated with courses of CCNU,
vinblastine, bleomycin or cytarabine followed by autologous HSCT in some of the patients. An intriguing observation was that some patients with follow-up relapses achieved
complete remission with weekly vinblastine 6 mg/m² as a
single agent. However, this retrospective study included
patients from as far back as the 1970s. For patients with
ALCL who failed current front-line protocols, less favorable survival rates were reported.11,12 Early occurrence conferred the highest risk for failure to salvage therapy.15 However, even in those high-risk patients, including patients
with follow-up relapse after autologous HSCT, long-term
remissions were observed after allogeneic HSCT.48 Currently,
prospective clinical trials are ongoing to test the feasibility and efficacy of new treatment strategies for children
with recurring ALCL, including monoclonal anti-CD30 antibodies.
New Treatment Options
Table 5 summarizes candidates for new treatment options
for childhood NHL. Allogeneic HSCT was effective in children with recurring ALCL refractory to chemotherapy. In
the BFM series, the only survivors of T-LBL relapse received allogeneic HSCT. Therefore, allogeneic HSCT, as
part of front-line treatment, may be an option for improving outcomes for the highest-risk patients with ALCL and
T-LBL. Monoclonal antibodies are a new category of treatment options, and rituximab (anti-CD20) is established in
the treatment of adult patients with B-NHL. It is not clear,
however, that monoclonal antibodies will have similar beneficial effects in children with B-NHL due to differences in
the baseline treatment outcome and differences in biological features. The addition of rituximab to CHOP chemotherapy was beneficial for bcl-6–negative but not bcl-6–
positive adult patients with DLBCL.49 However, most children with B-NHL, in particular BL and DLBCL, are bcl-6
positive.50 The effects of rituximab in childhood B-NHL is
being investigated in ongoing studies. A new generation
of purine nucleoside analogs and purine nucleoside phosphorylase inhibitors will expand the spectrum of chemotherapy, especially for T-cell neoplasms. More specifically
targeted future treatment options include disease-specific
kinase inhibitors, such as Alk inhibitors, and drugs that
interfere with the constitutive activation of the nuclear factor-kappa B (NF-κB) pathway in distinct subtypes, such as
PMLBL.51 The availability of new drugs to prevent severe
mucositis is a new option to ameliorate the predominant
severe oro-intestinal toxicity of chemotherapy, especially
for patients with advanced-stage B-NHL.
Acknowledgments
The helpful comments of Ian Magrath, MD, FRCP, FRCPath
(Brussels, Belgium), are gratefully acknowledged.
294
Correspondence
Alfred Reiter, MD, Children’s University Hospital,
Feulgenstrasse 12, 35385 Giessen, Germany; phone +49 (641)
9943420; fax +49 (641) 9943429; [email protected]
References
1. Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World
Health Organization Classification of Tumours. Pathology
and Genetics of Tumours of Haematopoetic and Lymphoid
Tissues. International Agency for Research on Cancer
(IARC) Press: Lyon, France; 2001.
2. Salzburg J, Burkhardt B, Zimmermann M, et al. Prevalence,
clinical pattern, and outcome of CNS-involvement in
childhood and adolescent non-Hodgkin lymphoma differ
according to NHL subtype—a BFM group report. J Clin
Oncol. 2007;25:3815-3922.
3. Anderson JR, Jenkin RD, Wilson JF, et al. Long-term followup of patients treated with COMP or LSA2L2 therapy for
childhood non-Hodgkin’s lymphoma: a report of CCG-551
from the Childrens Cancer Group. J Clin Oncol.
1993;11:1024-1032.
4. Link MP, Shuster JJ, Donaldson SS, Berard CW, Murphy SB.
Treatment of children and young adults with early-stage
non-Hodgkin’s lymphoma. N Engl J Med. 1997;337:12591266.
5. Reiter A, Schrappe M, Ludwig WD, et al. Intensive ALL-type
therapy without local radiotherapy provides a 90% eventfree survival for children with T-cell lymphoblastic lymphoma:
a BFM group report. Blood. 2000;95:416-421.
6. Tubergen DG, Krailo MD, Meadows AT, et al. Comparison of
treatment regimens for pediatric lymphoblastic nonHodgkin’s lymphoma: a Childrens Cancer Group study. J.
Clin Oncol. 1995;13:1368-1376.
7. Patte C, Auperin A, Michon J, et al. The Societe Francaise
d’Oncologie Pediatrique LMB89 protocol: highly effective
multiagent chemotherapy tailored to the tumor burden and
initial response in 561 unselected children with B-cell
lymphomas and L3 leukemia. Blood. 2001;97:3370-3379.
8. Reiter A, Schrappe M, Tiemann M, et al. Improved treatment
results in childhood B-cell neoplasms with tailored intensification of therapy: a report of the Berlin-Frankfurt-Munster
Group Trial NHL-BFM 90. Blood. 1999;94:3294-3306.
9. Bowman WP, Shuster JJ, Cook B, et al. Improved survival
for children with B-cell acute lymphoblastic leukemia and
stage IV small noncleaved-cell lymphoma: a pediatric
oncology group study. J Clin Oncol. 1996;14:1252-1261.
10. Cairo MS, Krailo MD, Morse M , et al. Long-term follow-up of
short intensive multiagent chemotherapy without high-dose
methotrexate (‘Orange’) in children with advanced nonlymphoblastic non-Hodgkin’s lymphoma: a children’s cancer
group report. Leukemia. 2002;16:594-600.
11. Williams DM, Hobson R, Imeson J, et al. Anaplastic large cell
lymphoma in childhood: analysis of 72 patients treated on
The United Kingdom Children’s Cancer Study Group
chemotherapy regimens. Br J Haematol. 2002;117:812-820.
12. Seidemann K, Tiemann M, Schrappe M, et al. Short-pulse Bnon-Hodgkin lymphoma-type chemotherapy is efficacious
treatment for pediatric anaplastic large cell lymphoma: a
report of the Berlin-Frankfurt-Munster Group Trial NHL-BFM
90. Blood. 2001;97:3699-3706.
13. Rosolen A, Pillon M, Garaventa A, et al. Anaplastic large cell
lymphoma treated with a leukemia-like therapy: report of the
Italian Association of Pediatric Hematology and Oncology
(AIEOP) LNH-92 protocol. Cancer. 2005;104:2133-2140.
14. Brugieres L, Deley MC, Pacquement H, et al. CD30(+)
anaplastic large-cell lymphoma in children: analysis of 82
patients enrolled in two consecutive studies of the French
American Society of Hematology
Society of Pediatric Oncology. Blood. 1998;92:3591-3598.
15. Brugieres L, Quartier P, Le Deley MC, et al. Relapses of
childhood anaplastic large-cell lymphoma: treatment results
in a series of 41 children—a report from the French Society
of Pediatric Oncology. Ann Oncol. 2000;11:53-58.
16. Cattoretti G, Chang CC, Cechova K, et al. BCL-6 protein is
expressed in germinal-center B cells. Blood. 1995;86:45-53.
17. Siebert R, Matthiesen P, Harder S, et al. Application of
interphase fluorescence in situ Hybridization for the
detection of the Burkitt translocation t(8;14)(q24;q32) in Bcell lymphomas. Blood. 1998;91:984-990.
18. van Krieken JH, Langerak AW, Macintyre EA, et al. Improved reliability of lymphoma diagnostics via PCR-based
clonality testing: report of the BIOMED-2 Concerted Action
BHM4-CT98-3936. Leukemia. 2007;21:201-206.
19. Dave SS, Fu K, Wright GW, et al. Molecular diagnosis of
Burkitt’s lymphoma. N Engl J Med. 2006;354:2431-2442.
20. Hummel M, Bentink S, Berger H, et al. A biologic definition of
Burkitt’s lymphoma from transcriptional and genomic
profiling. N Engl J Med. 2006;354:2419-2430.
21. Amylon MD, Shuster J, Pullen J, et al. Intensive high-dose
asparaginase consolidation improves survival for pediatric
patients with T cell acute lymphoblastic leukemia and
advanced stage lymphoblastic lymphoma: a Pediatric
Oncology Group study. Leukemia. 1999;13:335-342.
22. Bergeron C, Celine S, Pacquement H, et al. Childhood T-cell
lymphoblastic lymphoma (TLL) Results of the SFOP LMT96
strategy. Pediatr Blood Cancer. 2006;46:967.
23. Burkhardt B, Woessmann W, Zimmermann M, et al. Impact
of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous
system-negative stage III or IV lymphoblastic lymphoma. J
Clin Oncol. 2006;24:491-499.
24. Millot F, Suciu S, Philippe N, et al. Value of high-dose
cytarabine during interval therapy of a Berlin-FrankfurtMunster-based protocol in increased-risk children with
acute lymphoblastic leukemia and lymphoblastic lymphoma:
results of the European Organization for Research and
Treatment of Cancer 58881 randomized phase III trial. J Clin
Oncol. 2001;19:1935-1942.
25. Murphy SB, Bowman WP, Abromowitch M, et al. Results of
treatment of advanced-stage Burkitt’s lymphoma and B cell
(SIg+) acute lymphoblastic leukemia with high-dose
fractionated cyclophosphamide and coordinated high-dose
methotrexate and cytarabine. J Clin Oncol. 1986;4:17321739.
26. Woessmann W, Seidemann K, Mann G, et al. The impact of
the methotrexate administration schedule and dose in the
treatment of children and adolescents with B-cell neoplasms:
a report of the BFM Group Study NHL-BFM95. Blood.
2005;105:948-958.
27. Gentet JC, Patte C, Quintana E, et al. Phase II study of
cytarabine and etoposide in children with refractory or
relapsed non-Hodgkin’s lymphoma: a study of the French
Society of Pediatric Oncology. J Clin Oncol. 1990;8:661-665.
28. Patte C, Laplanche A, Bertozzi AI, et al. Granulocyte colonystimulating factor in induction treatment of children with nonHodgkin’s lymphoma: a randomized study of the French
Society of Pediatric Oncology. J Clin Oncol. 2002;20:441448.
29. Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-risk central nervous system
B non-Hodgkin lymphoma and B acute lymphoblastic
leukemia in children and adolescents. Blood. 2007;109:27362743.
30. Patte C, Sakiroglu C, Ansoborlo S, et al. Urate-oxidase in the
prevention and treatment of metabolic complications in
patients with B-cell lymphoma and leukemia, treated in the
Societe Francaise d’Oncologie Pediatrique LMB89 protocol.
Ann Oncol. 2002;13:789-795.
Hematology 2007
31. Gerrard M, Cairo MS, Weston C, et al. Results of the FAB
LMB 96 international study in children and adolescents
(C+A) with localised, resected B cell lymphoma (large cell
[LCL], Burkitt’s [BL] and Burkitt-like [BLL]). J Clin Oncol.
2003;22:795.
32. Patte C, Auperin A, Gerrard M, et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell
non-Hodgkin lymphoma in children and adolescents: it is
possible to reduce treatment for the early responding
patients. Blood. 2007;109:2773-2780.
33. Laver JH, Kraveka JM, Hutchison RE, et al. Advancedstage 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. J Clin Oncol. 2005;23:541-547.
34. Brugieres L, Le Deley MC, Rosolen A, et al. Anaplastic large
cell lympoma (ALCL) in children: equal efficacy but greater
toxicity of chemotherapy including methotrexate (MTX) 1g/
m2 in 24-hour infusion with intrathecal injection (IT) than
chemotherapy with MTX 3g/m2 in 3-hour infusion without IT:
results of the ALCL99-R1 randomized trial [abstract]. Blood.
2006;108:122a.
35. Seidemann K, Tiemann M, Lauterbach I, et al. Primary
mediastinal large B-cell lymphoma with sclerosis in pediatric
and adolescent patients: treatment and results from three
therapeutic studies of the Berlin-Frankfurt-Munster Group. J
Clin Oncol. 2003;21:1782-1789.
36. Schmitt C, Delsol G, Brugieres L, et al. Lymphohistiocytic
variant of anaplastic large cell lymphoma in children and
adolescents: a long-term study by the French society of
pediatric cancer--lymphoma group. Pediatr Blood Cancer.
2006;46:841-842.
37. Onciu M, Schlette E, Zhou Y, et al. Secondary chromosomal
abnormalities predict outcome in pediatric and adult highstage Burkitt lymphoma. Cancer. 2006;107:1084-1092.
38. Poirel HA, Heerema NA, Swansbury J, et al. Cytogenetic
analysis of 238 pediatric mature B-cell non-Hodgkin
lymphoma (NHL) cases from the randomized international
FAB LMB96 trial identities several patterns of chromosomal
abnormality and new prognostic factors. Pediatr Blood
Cancer. 2006;46:835.
39. Haioun C, Itti E, Rahmouni A, et al. [18F]fluoro-2-deoxy-Dglucose positron emission tomography (FDG-PET) in
aggressive lymphoma: an early prognostic tool for predicting
patient outcome. Blood. 2005;106:1376-1381.
40. Elstrom R, Guan L, Baker G, et al. Utility of FDG-PET
scanning in lymphoma by WHO classification. Blood.
2003;101:3875-3876.
41. Damm-Welk C, Busch K, Burkhardt B, et al. Prognostic
significance of circulating tumor cells in bone marrow or
peripheral blood as detected by qualitative and quantitative
PCR in pediatric NPM-ALK-positive anaplastic large-cell
lymphoma. Blood. 2007;110:670-677.
42. Mussolin L, Basso K, Pillon M, et al. Prospective analysis of
minimal bone marrow infiltration in pediatric Burkitt’s
lymphomas by long-distance polymerase chain reaction for
t(8;14)(q24;q32). Leukemia. 2003;17:585-589.
43. Fields KK, Zorsky PE, Hiemenz JW, Kronish LE, Elfenbein
GJ. Ifosfamide, carboplatin, and etoposide: a new regimen
with a broad spectrum of activity. J Clin Oncol. 1994;12:544552.
44. Kobrinsky NL, Sposto R, Shah NR, et al. Outcomes of
treatment of children and adolescents with recurrent nonHodgkin’s lymphoma and Hodgkin’s disease with dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase, maintenance chemotherapy, and transplantation:
Children’s Cancer Group Study CCG-5912. J Clin Oncol.
2001;19:2390-2396.
295
45. Attarbaschi A, Dworzak M, Steiner M, et al. Outcome of
children with primary resistant or relapsed non-Hodgkin
lymphoma and mature B-cell leukemia after intensive firstline treatment: a population-based analysis of the Austrian
Cooperative Study Group. Pediatr Blood Cancer.
2005;44:70-76.
46. Burkhardt B, Reiter A, Lang P, et al. Relapse in pediatric pts
with T-cell lymphoblastic lymphoma: clinical characteristics
and outcome in the BFM group. Pediatr Blood Cancer.
2006;46:842.
47. Atra A, Gerrard M, Hobson R, et al. Outcome of relapsed or
refractory childhood B-cell acute lymphoblastic leukaemia
and B-cell non-Hodgkin’s lymphoma treated with the
UKCCSG 9003/9002 protocols. Br J Haematol.
2001;112:965-968.
48. Woessmann W, Peters C, Lenhard M, et al. Allogeneic
haematopoietic stem cell transplantation in relapsed or
refractory anaplastic large cell lymphoma of children and
adolescents—a Berlin-Frankfurt-Munster group report. Br J
Haematol. 2006;133:176-182.
49. Winter JN, Weller EA, Horning SJ, et al. Prognostic significance of Bcl-6 protein expression in DLBCL treated with
CHOP or R-CHOP: a prospective correlative study. Blood.
2006;107:4207-4213.
50. Oschlies I, Klapper W, Zimmermann M, et al. Diffuse large Bcell lymphoma in pediatric patients belongs predominantly to
the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (BerlinFrankfurt-Munster) Multicenter Trial. Blood. 2006;107:40474052.
296
51. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis
of primary mediastinal B cell lymphoma identifies a clinically
favorable subgroup of diffuse large B cell lymphoma related
to Hodgkin lymphoma. J Exp Med. 2003;198:851-862.
52. Lones MA, Heerema NA, Le Beau MM, et al. Chromosome
abnormalities in advanced stage lymphoblastic lymphoma of
children and adolescents: a report from CCG-E08. Cancer
Genet Cytogenet. 2007;172:1-11.
53. Burkhardt B, Zimmermann M, Oschlies I, et al. The impact of
age and gender on biology, clinical features and treatment
outcome of non-Hodgkin lymphoma in childhood and
adolescence. Br J Haematol. 2005;131:39-49.
54. Burkhardt B, Bruch J, Zimmermann M, et al. Loss of
heterozygosity on chromosome 6q14-q24 is associated with
poor outcome in children and adolescents with T-cell
lymphoblastic lymphoma. Leukemia. 2006;20:1422-1429.
55. Coustan-Smith E, Sancho J, Behm FG, et al. Prognostic
importance of measuring early clearance of leukemic cells
by flow cytometry in childhood acute lymphoblastic
leukemia. Blood. 2002;100:52-58.
56. Seidemann K, Zimmermann M, Book M, et al. Tumor
necrosis factor and lymphotoxin alfa genetic polymorphisms
and outcome in pediatric patients with non-Hodgkin’s
lymphoma: results from Berlin-Frankfurt-Munster Trial NHLBFM 95. J Clin Oncol. 2005;23:8414-8421.
57. Le Deley MC, Brugieres L, Williams DM, Reiter A. Prognostic
factors in childhood anaplastic large cell lymphoma (ALCL):
results of the European Intergroup Study [abstract]. Blood.
2006;108:581a.
58. Mussolin L, Pillon M, d’Amore ES, et al. Prevalence and
clinical implications of bone marrow involvement in pediatric
anaplastic large cell lymphoma. Leukemia. 2005;19:16431647.
American Society of Hematology