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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1226-1236
Intensive Treatment of Children With Acute Lymphoblastic Leukemia
According to ALL-BFM-86 Without Cranial Radiotherapy: Results of Dutch
Childhood Leukemia Study Group Protocol ALL-7 (1988-1991)
By
W.A. Kamps,
J.P.M. Bökkerink,
K. Hählen,
J. Hermans,
H. Riehm,
H. Gadner,
M. Schrappe,
R. Slater,
E. van den Berg-de Ruiter,
L.A. Smets,
G.A.M. de Vaan,
R.S. Weening,
J.F. van Weerden,
E.R. van Wering, and
A. van der Does-van den Berg
From the Dutch Childhood Leukemia Study Group (DCLSG), The Hague, The
Netherlands; Beatrix Children's Hospital, University Hospital,
Groningen, The Netherlands; the Department of Pediatrics, University
Hospital, Nijmegen, The Netherlands; Sophia Children's Hospital,
University Hospital, Rotterdam, The Netherlands; the Department of
Medical Statistics, University of Leiden, Leiden, The Netherlands; Emma
Kinderziekenhuis Academic Medical Center, Amsterdam, The Netherlands;
the Department of Clinical Genetics/Department of Cell Biology and
Genetics, Erasmus University, Rotterdam, The Netherlands; the Division
of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam,
The Netherlands; the Berlin-Frankfurt-Münster (BFM) Group,
Hannover, Germany; the Dutch Workgroup on Cancer Genetics and
Cytogenetics (NWKGC); the Department of Pediatric
Hematology and Oncology, Medizinische Hochschule, Hannover, Germany; St
Anna Kinderspital, Vienna, Austria; and the Department of Medical
Genetics, University of Groningen, Groningen, The Netherlands.
 |
ABSTRACT |
In The Netherlands from July 1988 to October 1991, children (0 to 16 years of age) with de novo acute lymphoblastic leukemia (ALL)
were treated according to protocol ALL-7 of the Dutch Childhood Leukemia Study Group (DCLSG). In this protocol, chemotherapy and treatment stratification were identical to the ALL-BFM-86
protocol (Reiter et al, Blood 84:3122, 1994), but
cranial irradiation was restricted to patients with initial central
nervous system (CNS) involvement. Patients were stratified
into 3 risk groups, based on leukemia cell mass and response to initial
treatment: standard-risk group (SRG), risk group (RG), and experimental
group (EG). As in ALL-BFM-86, a randomized study on late
intensification (protocol S) was performed in RG patients, and during
the study (since October 1990), early reinduction treatment (protocol
II) was introduced for SRG patients. Treatment duration for all
patients was 18 months. Two hundred eighteen children entered the
study: 74 SRG, 127 RG, and 17 EG patients. The overall complete
remission (CR) rate was 98%. The 5-year event-free survival (EFS) for
all DCLSG ALL-7 patients was 65.3% (standard error [SE]
3.2%), which was significantly different from the 73% (SE 1%) 5-year
EFS achieved in the ALL-BFM-86 study (P = .02, Z-test).
However, restricting the analysis to SRG patients receiving protocol II
with a total duration of treatment of 18 months, the 5-year EFS rates
were 64.6% (SE 4.0%) and 67% (SE 4%), respectively, and no
significant difference could be established (P = .67, Z-test). The 5-year EFS rates for SRG, RG, and EG patients were 63.5%
(SE 5.6%), 66.6% (SE 4.2%), and 63.3% (SE 12.0%), respectively.
SRG patients receiving protocol II fared better than patients not
receiving protocol II (5-year EFS 76.7% [SE 7.7] and 54.5% [SE
7.5], respectively). No difference in 5-year EFS was observed in RG
patients randomized to receive or not to receive late
intensification with protocol S. The overall CNS relapse rate at 5 years was 5.5%. The incidence rate at 5 years was 11.4% in SRG
patients not receiving protocol II, whereas no CNS relapses occurred in
SRG patients receiving protocol II. Six children died in first complete
remission and 2 children developed a second malignancy (thyroid
carcinoma and acute nonlymphoblastic leukemia). Systemic high-dose
methotrexate (MTX) and intrathecal chemotherapy is a safe
and effective method of CNS prophylaxis in the context of BFM-oriented
treatment for all children with ALL, regardless of the risk group (with
the possible exception of T-ALL patients with high white blood cell
counts). The results of the DCLSG ALL-7 study confirm those of the
ALL-BFM-86 study showing that early reinduction with protocol II is
essential in the treatment of SRG patients and that late
intensification with protocol S does not improve the prognosis for RG patients.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
FROM 1988 TO 1991, CHILDREN with newly
diagnosed acute lymphoblastic leukemia (ALL) in The Netherlands were
treated using the Dutch Childhood Leukemia Study Group (DCLSG) ALL-7
protocol. This protocol was similar to the ALL-BFM-86
protocol,1 with the exception that no prophylactic cranial
radiation was applied. Before 1988, non-high-risk (NHR) ALL patients
were entered into the nationwide DCLSG-ALL-6 protocol that also did not
include prophylactic cranial radiotherapy; children with high-risk (HR) ALL were treated according to institutional guidelines. In 1988, when
the results of DCLSG-ALL-62 were still unknown, cooperation
was sought with the Berlin-Frankfurt-Münster (BFM) group to adopt
their very effective treatment strategy3-5 to further
improve the treatment results of NHR-ALL patients achieved with the
preceding DCLSG ALL-5 study.6
The data presented here represent the treatment results for children
with ALL in The Netherlands diagnosed in the period from 1988 to 1991.
| |
PATIENTS AND METHODS |
Patients.
The population-based DCLSG protocol ALL-7 was open to children (0 through 15 years of age) with de novo ALL diagnosed from July 1988 through September 1991. Patients with mature B-cell ALL, either
morphologic (French-American-British [FAB] type L3) or
immunophenotypic (surface IgM positive), were excluded as well as
patients treated with corticosteroids and/or cytostatic drugs less than
4 weeks before diagnosis. Informed consent was obtained according to
institutional guidelines before treatment and before randomization for
late intensification with protocol S in risk group (RG) patients (see below).
Diagnosis.
The diagnosis of ALL was made by cytomorphological and cytochemical
examination of blood and bone marrow smears at the local institution,
followed by confirmation and classification according to FAB
criteria7,8 by the DCLSG laboratory. For the diagnosis of
ALL,  25% blasts in the bone marrow was mandatory. A sample of
cerebrospinal fluid (CSF), mixed 1:1 with a transport medium, was sent
to the DCLSG laboratory at diagnosis and when a relapse was
suspected.9,10 Central nervous system (CNS) involvement was
defined as the presence of 5/µL cells in the CSF with leukemic blasts (cytomorphological) without major blood contamination (<50/3 erythrocytes) or as leukemic infiltration of the brain, assessed by
cranial computed tomography. The leukemic cell mass estimate, the BFM
risk factor RF, was calculated by the equation: RF = 0.2 × log
(number of peripheral blood blasts/µL + 1) + 0.06 × liver centimeters below costal margin + 0.04 × spleen centimeters below costal margin.11,12 Immunophenotyping was performed by the DCLSG laboratory if cytospin bone marrow smears contained 60% blasts.13 Immunological markers were judged positive if
expressed in 20% of the malignant cells. A leukemia was classified
as precursor B-ALL if the malignant cells were positive for TdT, CD19,
and HLA-DR (pro-B ALL); for TdT, CD10, CD19, and HLA-DR (common ALL); or for TdT, CD10, CD19, HLA-DR, and CyIgµ (pre-B-ALL). A T-ALL was
defined by positivity for TdT, CD2, cytoplasmic CD3 (CyCD3), and/or
CD7. Acute undifferentiated leukemia (AUL) was defined if common ALL,
pre-B, T-cell characteristics, and also myeloid markers were negative.
Cytogenetic analysis was performed by members of the Dutch Working
Party on Cancer Genetics and Cytogenetics at the various Clinical
Genetics Centers in The Netherlands.14 All
findings were peer-reviewed before submission to the database. An
abnormal clone was defined as a minimum of 2 metaphases with the same
structural abnormality or same additional chromosome or 3 metaphases
with the same missing chromosome. Cytogenetic analysis was considered a
failure if less than 20 metaphases with an apparently normal karyotype
from an unstimulated or unsynchronized culture had been analyzed.
Chromosome structural abnormality included all structural abnormalities
(not just translocations). Cell ploidy was based on cytogenetic
findings. The DNA index was measured by the Department of Experimental
Therapy of The Netherlands Cancer Institute (Amsterdam, The
Netherlands).15
Treatment and treatment stratification.
The treatment scheme is summarized in Table
1, while details of the protocol ALL-7 are given in Appendix II.
Patients were stratified into 3 groups; standard-risk group (SRG), RG,
and experimental group (EG), which is identical to the protocol
ALL-BFM-86.1
RG patients who were in continuous complete remission (CCR) after 1 year were randomized to receive or not to receive late intensification
with protocol S if informed consent was obtained. EG patients in first
CR with a matched sibling donor were offered allogeneic bone marrow
transplantation (BMT) after protocol E. Following an earlier amendment
of the study ALL-BFM-86, protocol ALL-7 was amended (in October 1990)
with the introduction of protocol II for SRG patients (group SRT). The
total duration of chemotherapy for all patients was 18 months. In
contrast to the ALL-BFM-86 study, in which cranial irradiation (12 to
18 Gy, depending on age) was applied to all RG and EG patients, in
protocol DCLSG ALL-7 cranial radiotherapy (CRT; 12 to 18 Gy for 15 days
after protocol II) was restricted to patients with initial CNS involvement.
Evaluation criteria.
CR was defined as less than 5% blasts in the bone marrow and recovery
of normal hematopoiesis, absence of peripheral blood blasts, and no
evidence of disease at any other site. Relapse was defined as 20%
blasts cells in the bone marrow and/or blasts cells in the peripheral
blood, CNS involvement, and/or leukemic infiltrations elsewhere.
Results of treatment were evaluated by bone marrow examination on day
42, before the start of protocol M, E, II, and S, and every 12 to 14 weeks during maintenance treatment. All smears were examined at the
DCLSG laboratory. Registration forms with data on dosage, toxicity, and
results of treatment for each patient were sent to the DCLSG operations
office after protocol I, M, E, II, and S; every 3 months during
maintenance treatment; and up to 5 years after cessation of treatment.
Statistical methods.
For comparison of patient and disease characteristics, the Student's
t-test, the Mann-Whitney U test, and the  2 test
were applied. Event-free survival (EFS) was defined as the time from
diagnosis to induction failure, relapse, death in remission, or the
occurrence of a second tumor. For patients event-free and alive at
latest follow-up (censored observations), EFS was calculated until this
latest follow-up. Patients who did not achieve remission were included
in the analysis and considered as treatment failures on day 0. The
duration of survival was calculated from diagnosis to time of death;
the time from diagnosis to latest follow-up evaluation was calculated
as survival for patients alive, the so-called censored observations.
All analyses were based on intention to treat and on data for all
patients who entered the study; no patients have been excluded for
whatever reason (treatment refusal, toxicity, etc).
Survival curves and standard errors (SEs) were calculated
according to the Kaplan-Meier method. The statistical significance of
differences between curves was determined by the 2-sided log-rank
test.16,17 Comparison between DCLSG and BFM 5-year EFS
results was performed using a Z-score.
| |
RESULTS |
Patients.
From July 1988 to October 1991, 267 consecutive children with ALL were
diagnosed; 259 of them were eligible for protocol ALL-7. Two hundred
eighteen (84%) were registered onto the ALL-7 study. Forty-one (16%)
did not enter the study because of institutional choice (39 patients),
missing data (1 patient), or patient's refusal (1 patient). Of the 218 patients on the study, 182 (83%) were registered by pediatricians in
university hospitals and 36 (17%) were registered by pediatricians in
general hospitals. The patient and disease characteristics of the 259 eligible patients are summarized in
Table 2. No significant
differences were observed between the 218 protocol and 41 nonprotocol
patients, except for white blood cell counts (WBC), which were lower in
the nonprotocol patients (P = .012). Of the 218 protocol
patients, 74 (34%) were stratified into the SRG, 127 (58%) into the
RG, and 17 (8%) in the EG (Table 3). Of the 74 SRG patients, 30 did receive protocol II
(SRT patients) and 44 did not. Seventeen patients were stratified into
the EG because of an acute undifferentiated leukemia (AUL;
CD10 and TdT; 1 patient), t(9:22)
(1 patient), t(4;11) (1 patient), poor steroid response (12 patients),
no complete remission on day 42 (1 patient), and progressive disease (1 patient).
Treatment results.
Treatment results are updated as of January 1, 1998.
Induction treatment according to protocol I could be evaluated in 217 of 218 patients: 1 RG patient was lost to follow-up shortly after
diagnosis. Two hundred twelve (98%) patients achieved a CR
(Table 4). Two patients died early during
induction treatment: 1 RG patient with hyperleukocytosis died of
cerebrovascular hemorrhage at day 6 and 1 SRG patient with Down's
syndrome died of pseudomonas septicemia and cardiac failure; 3 patients
died of progressive disease. Three EG patients underwent allogeneic BMT
(2 from a related and 1 from an unrelated donor).
In 14 patients, major protocol violations occurred after remission: RG
treatment applied to 1 SRG patient, too early cessation of therapy (1 SRG patient), allogeneic bone marrow transplantation in 1 RG patient,
treatment for relapse ALL not confirmed by DCLSG laboratory (2 RG
patients), discrepancy in steroid response between DCLSG and
institution (1 RG patient), protocol S refused by already randomized RG
patients (4), treatment reduction because of toxicity (1 RG and 1 EG
patient), and protocol E not applied (2 EG patients). One EG patient
was lost for follow-up after CR.
Six patients died in first CR, 2 of them after protocol violation. The
causes of death were septicemia (1 SRG and 1 RG patient), interstitial
pneumonia (1 SRG patient), and complications of bone marrow
transplantation (1 RG and 2 EG patients).
Sixty-three patients relapsed: 20 patients during therapy, 37 patients
after therapy, and 6 patients after major treatment modifications. The
site of relapse is shown in Table 4. Remarkably, no CNS relapses
occurred in the SRT group (SRG patients who had received protocol II).
Two patients developed a second malignancy: 1 RG patient with initial
CNS disease who had received cranial radiotherapy developed thyroid
carcinoma 40 months after diagnosis of ALL; 1 SRG patient developed
acute myeloid leukemia (FAB-type M1) 2 years after treatment of an
isolated CNS relapse with chemotherapy and craniospinal irradiation.
One hundred forty-one patients are in first CCR at last follow-up.
The estimated 5-year survival is 79.7% (SE 2.5%) for the total group
of 259 patients, 78.7% (SE 2.8%) for the 218 protocol patients
(Fig 1), and 84.9% (SE 5.7%) for the
nonprotocol patients. Estimates for a 5-year EFS are 66.4% (SE 3.0%),
65.3% (SE 3.2%; Fig 1), and 72.3% (SE 7.1%), respectively. The
5-year EFS according to treatment group is 63.5% (SE 5.6%) for all 74 SRG patients, 66.6% (SE 4.2%) for RG patients, and 63.3% (SE 12.0%)
for EG patients (Fig 2).
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| Fig 2.
EFS according to risk group. Stratification after
treatment with DCLSG protocol ALL-7. SRT, standard-risk group receiving
protocol II; SRG, standard-risk group not receiving protocol II; RG,
risk group; EG, experimental group.
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The 5-year EFS for SRG patients not receiving protocol II is 54.5% (SE
7.5%) and for SRG patients receiving protocol II is 76.7% (SE 7.7%;
logrank P = .049). The 5-year survival rates are 75.0% (SE
6.5%) and 86.7% (SE 6.2%), respectively (logrank, P = .25;
Table 4).
The overall isolated CNS relapse rate at 5 years was 5.5%. The
incidence was 11.4% in SRG patients not receiving early reinduction with protocol II, whereas no CNS relapses occured in SRG patients receiving protocol II (Table 5).
Randomized study on late intensification with protocol S for RG
patients.
Of 127 RG patients, 117 were eligible for randomization; 10 patients
could not be randomized for the following reasons: death during
induction (1), lost to follow-up (1), relapse (4), death in CR (2), and
major protocol violations (2). Informed consent was obtained from 51 (44%) of 117 eligible patients: 25 were randomized into group 1 (without protocol S) and 26 into group 2 (with protocol S). Patient and
disease characteristics did not significantly differ between randomized
and nonrandomized patients or between RG-1 and RG-2 patients. The
estimated 5-year EFS, based on randomization group, is 76.0% (SE
8.5%) for RG-1 patients and 65.4% (SE 9.3%) for RG-2 patients
(P = .34) and 69.6% (SE 4.8%) for nonrandomized RG patients
(P = .20). Analysis of the results according to whether protocol S was actually applied or not showed no significant difference in 5-year EFS of 64% (SE 10%) for 25 patients receiving protocol S
and 72% (SE 5%) for 92 patients not receiving protocol S.
Prognostic factor analysis.
None of the factors tested proved to be of significant influence on the
outcome of treatment except for chromosomal anomalies, but these
characteristics were determined in only 62% of the patients (Table 6).
Because of the few significant or marginally significant factors in the
univariate analysis, a multivariate Cox's regression analysis is not reported.
Comparison of DCLSG ALL-7 and ALL-BFM-86.
No significant differences between DCLSG ALL-7 and ALL-BFM-86 patients
were found in the distribution of sex, leukemic cell mass (RF), WBC,
DNA index, immunophenotype, prednisone response at day 8, patients with
Down's syndrome, or initial CNS involvement (data not shown). However,
the following differences were observed between the two study populations.
(1) In the BFM study, patients  18 years of age at diagnosis were
eligible, but in DCLSG ALL-7, only patients 15 years of age were
eligible. The proportion of children 14 years of age is higher
(68/998 [7%]) in the BFM study than in the DCLSG study (3/218
[1%]). (2) For SRG patients, the proportion of patients not
receiving protocol II is significantly higher in the DCLSG ALL-7 study
(44/74 [59%]) than in the ALL-BFM-86 study (110/285 [39%]). (3)
During the study ALL-BFM-86, the total treatment duration was changed
from 18 to 24 months, but not so in DCLSG ALL-7. Of 998 patients
entered into ALL-BFM-86, 143 were treated for 18 months and 855 were
treated for 24 months.1 In the DCLSG ALL-7 study, the total
treatment duration was 18 months for all 218 patients. (4) Cranial
irradiation was applied as CNS prophylaxis to all the BFM RG and EG
patients; in the DCLSG study, it was applied only to patients with
initial CNS involvement (n = 5).
Keeping in mind these differences, several comparisons have been
performed. EFS at 5 years was 73% (SE 1%) for the 998 ALL-BFM-86 patients and 65.3% (SE 3.2%) for the 218 DCLSG patients (P = .021, Z-test). After exclusion of SRG patients not receiving protocol II (110 patients in ALL-BFM-86 and 44 patients in DCLSG), the 5-year
EFS is 74% (SE 1.5%) and 68.0% (SE 3.6%), respectively (P = .12, Z-test). The 5-year EFS of 143 consecutive ALL-BFM-86 patients
treated for 18 months was 67% (SE 4%), compared with 64.6% (SE
4.0%) for the first 143 patients treated according to the DCLSG ALL-7
protocol (P = .67, Z-test).
To evaluate the role of cranial irradiation, the treatment results of
the 127 RG and 17 EG patients treated according to the DCLSG protocol
ALL-7 were compared with those of 90 RG and 24 EG patients treated for
18 months according to the ALL-BFM-86 protocol. The 5-year EFS was
66.6% (SE 4.2%) for DCLSG RG patients and 73% (SE 5%) for BFM RG
patients (P = .33), and 63.3% (SE 12.0%) and 50% (SE 10%),
respectively, for EG patients (P = .40, Z-test).
To rule out any influence of the patients 16 years of age and older in
the BFM study, these analyses were also performed excluding this older
age group. No difference was found between the 5-year EFS of 89 DCLSG
RG patients (68.2%, SE 5.0%) and 89 BFM RG patients (72.5%, SE
4.8%; logrank, P = .77) or between the 5-year EFS of 13 DCLSG
(59.8%, SE 14.0%) and 23 BFM EG patients (52.2%, SE 10.4%; logrank,
P = .99; Fig 3).
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| Fig 3.
EFS of patients stratified into RG or EG, 15 years of
age at diagnosis, and treated for 18 months according to protocol
ALL-BFM-86 or DCLSG ALL-7.
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Within this same subgroup the 5-year EFS of T-ALL patients in the
ALL-BFM-86 (n = 17, irradiated) and in the DCLSG ALL-7 (n = 26, nonirradiated) was 65% (±12) and 60% (±10%), respectively (logrank, P = .71). In the DCLSG ALL-7 study, 3 of 6 T-ALL
prednisone good responders (PGR) with WBC counts greater than 100 × 109/L relapsed and 7 of 20 T-ALL-PGR patients with
WBC counts 100 × 109/L relapsed.
| |
DISCUSSION |
The DCLSG ALL-7 study has confirmed the results of the ALL BFM-86 study
and has shown that, in the context of BFM-oriented treatment, (1)
delayed reinduction treatment (protocol II) is required even for
children with low leukemic cell mass at diagnosis and (2) late
intensification (protocol S) does not improve the outcome for children
with high(er) tumor burden (RG patients).
The 5-year EFS of 218 protocol ALL-7-patients significantly differed
from that of 998 ALL BFM-86 protocol patients (65.3% [SE 3.2%] and
73% [SE 1%], respectively; Z-test, P = .02).1 However, restricting the analysis to similar patient groups, no significant differences in 5-year EFS rates could be found: 64.6% (SE
4.0%) and 67% (SE 4%), respectively (P = .67, Z-test).
Cranial irradiation (18-24 Gy) is highly effective in preventing CNS
relapse, but also adds late adverse side effects on intellectual, psychomotor, and neuroendocrine functioning, especially in young children. In addition, there is an enhanced risk for developing a
second tumor.
The results of the ALL BFM-81 study had already demonstrated that
cranial irradiation can safely be substituted by systemic medium-dose
MTX and intrathecal chemotherapy in ALL patients with low leukemic cell
mass at diagnosis.18
The results of the population-based, multicenter DCLSG ALL-7 study show
that cranial radiotherapy is not needed in patients with ALL treated
with BFM-oriented treatment.
Possible exceptions are children with initial CNS involvement and T-ALL
patients with a high leukemic cell mass at diagnosis (WBC 100 × 109/L)19; unfortunately, the number of T-ALL
patients in the ALL-7 study is too small to draw any conclusions on the
latter subject.
Remarkably, no isolated CNS relapse occurred in 30 ALL-7 SRG patients
receiving protocol II, compared with 5 in 44 patients not receiving
protocol II. This difference might be attributed to the administration
of dexamethasone during protocol II, which penetrates well in the CSF
and has a higher antileukemic cell activity.20,21
Cranial irradiation (12 Gy) was still applied in MRG and HRG patients
in protocol ALL-BFM-90 and is still applied in HRG patients in the
current protocol ALL-BFM-95.22
However, other studies using BFM-oriented treatment have spared
children with ALL the exposure to cranial irradiation by applying intermediate- or high-dose MTX infusions and intrathecal chemotherapy (Table 5). The results of the GATLA protocol for medium-risk patients
are consistent with those of the DCLSG ALL-7 study.23 The
results of the Italian AIEOP protocol-8824 and those of the
Israeli ISN-89 study25 suggest that triple intrathecal
chemotherapy extended throughout maintenance treatment, as originally
applied in the POG ALinC 13 study,26 might further reduce
the incidence of CNS relapse in a large proportion of children with
ALL. In the CCG 1882-modified BFM study, no significant difference was observed in the incidence of isolated CNS relapse in children with
high-risk ALL (1 to 9 years of age and with a WBC count 50 × 109/L; or 10 years of age, excluding those
with lymphomatous features) and rapid early response (25% bone
marrow blasts on day 7), randomized to receive either
intrathecal MTX and cranial irradiation or intensive ith
MTX alone.27
Systemic medium- or high-dose MTX and extended intrathecal chemotherapy
are apparently as effective in preventing CNS relapse as cranial
irradiation, but long-term side effects are still to be evaluated.
Statistically significant decreases in overall and verbal intelligence
quotients and in arithmetic achievement were found in 16 (62%) of 26 patients treated with parenteral MTX for CNS prophylaxis
only.28 Abnormal MRI and CCT scans were seen in 15 (38%)
of 39 patients who had received intrathecal MTX and systemic medium- to
high-dose MTX.
In 20% of these 39 patients, widening of sulci or ventricles,
indicating brain atrophy, were observed; no possible signs of leukoencephalopathy or calcifications were observed.29
Currently, late side effects of CNS prophylaxis with chemotherapy only
seem to be less severe than those of cranial irradiation, but long-term
follow-up is needed to establish late sequelae of this treatment modality.
In contrast to the BFM-86 study, sex, WBC, Hb value, FAB type,
immunophenotype, DNA index, and chromosome ploidy (only relevant for
B-progenitor ALL) were not of significant prognostic value in the DCLSG
ALL-7 study, but this may partly be due to the very intensive therapy
for all patients and to small sample size.
Many investigators have found that DNA ploidy and structural
chromosomal abnormalities are independent prognostic factors, but this
significance can be lost if therapy changes.30,31 Also,
when patients with translocation t(9;22) (N = 2) and t(4;11) (N = 4)
were excluded from such analysis, differences in EFS disappeared between patients with and without leukemic cell chromosomal structural abnormalities.32 However, if patients with leukemic
karyotype t(9;22) and t(4;11) are excluded in the DCLSG ALL 7 study,
the significant difference in 5-year EFS rate for patients with (N = 73) and without (N = 45) chromosomal structural abnormalities persists:
61.1% (SE 5.7%) and 79.5% (SE 6.1%), respectively (logrank, P = .037).
The persistence of peripheral blood blasts after 1 week of (multiagent)
chemotherapy was shown to confer a poor prognosis in St Jude Total
Therapy Study XI33 and in study ALL-BFM-86.1 In
DCLSG ALL-7, the persistence of peripheral blood blasts after 7 days of
monotherapy with prednisone and 1 intrathecal dose of MTX and
prednisolone had no prognostic significance (P = .86). However,
the proportions of patients with circulating leukemic blasts in the
peripheral blood at diagnosis and after 1 week of treatment were
substantially different in the St Jude study and the DCLSG study: 84%
versus 97% at diagnosis and 14% versus 73% after 1 week,
respectively. The proportion of prednisone poor responders was not
significantly different in the ALL-BFM-86 and the DCLSG ALL-7 study
(9.5% and 6%, respectively; P = .08).
Drug sensitivity testing using the MTT assay has been performed in a
minority (27%) of the patients; the results have been published
previously.34
The duration of treatment in the DCLSG ALL-7 study (18 months) was
shorter than in most treatment protocols for children with ALL (2 to 5 years).
The optimal length of treatment is not well established. A
meta-analysis of 42 clinical trials, involving 12,000 randomized children, could not show a difference between 5 years and 3 years of
maintenance treatment; also, the risk of relapse by the addition of a
third year of maintenance was counterbalanced by an increase in the
risk of death during remission.35 On the other hand, the
results of the randomized clinical trials ALL-BFM-81 and 83, comparing
18 versus 24 months of total therapy duration, showed an advantage for
a therapy duration of 24 months.18
Therefore, the outcome of the DCLSG-ALL-7 study might have improved if
the total duration of treatment had been 24 months instead of 18 months.
Recently developed, more sensitive PCR-based techniques for the
detection of minimal residual disease (MRD) at several time points
during treatment may contribute to determine the optimal length of
treatment for individual future patients.36
Before the introduction of the BFM-oriented treatment, children with
ALL in The Netherlands were treated according to protocols based on
Pinkel's Total Therapy.37,38 In the DCLSG ALL-6 protocol (accrual period 1984 to 1988) for children with ALL-NHR, defined as age
of 0 to 15 years, an initial WBC count of less than 50 × 109/L, the absence of a mediastinal mass and/or
cerebromeningeal leukemia at diagnosis (comprising 71% of all ALL
patients), the combination of intravenous medium-dose MTX (2 g/m2, 3×), extended triple intrathecal chemotherapy
during the first year of maintenance treatment, the substitution of
prednison by dexamethasone during induction and biweekly
pulses, and a total duration of treatment of 24 months has proved to be
highly effective, especially in preventing CNS relapse (1.1%), with an
8-year EFS rate of 81% ± 3%.2
The 5-year EFS rate of children with ALL-NHR characteristics in the
DCLSG ALL-7 study using DCLSG-ALL-6 criteria (n = 116; excluding SRG
patients not receiving protocol II) was 70.7% ± 4.2%, compared
with 82.6% ± 2.7% after treatment with protocol ALL-6 (P = .023; logrank test).
We conclude that children with newly diagnosed ALL and treated with
BFM-oriented treatment do not need cranial radiotherapy for CNS
prophylaxis, with the possible exception of T-ALL patients with a high
WBC count. Also, children with low leukemic cell mass at diagnosis do
require delayed reinduction with protocol II, including dexamethasone,
and this therapeutic strategy significantly reduces the CNS relapse
rate. The omission of cranial radiotherapy will most likely reduce the
long-term adverse effects of treatment. It is not clear yet if extended
intrathecal treatment during mainenance therapy is necessary when the
described treatment components are being used. Prospective studies of
neuropsychologic and the treatment-related morbidity are needed.
Although different treatment strategies may give excellent outcome, the
results of the protocols DCLSG ALL-6 and ALL-7 have prompted the DCLSG
to reintroduce ALL-6 treatment for children with ALL-NHR in The
Netherlands. For ALL-HR patients (all other patients with ALL), the
ALL-6 backbone has been intensified using the results of a promising
institutional pilot study (1984 to 1988) of the Pediatric Oncology
Center Groningen, but without cranial irradiation (DCLSG protocol
ALL-9).
| |
APPENDIX I |
DCLSG Board Members 1988.
W.A. Kamps, J.A. Rammeloo, K. Hählen, E.F. van Leeuwen, F.A.E.
Nabben, A. Postma, E.J.M. Sjamsoedin-Visser, E.Th. van `t Veer-Korthof, G.A.M. de Vaan, F.C. de Waal, and R.S. Weening.
NWKGC Members 1988.
R. Slater (Amsterdam), A. Hagemeijer (Rotterdam), E. van den Berg-de
Ruiter (Groningen), A. Hamers (Maastricht), C.G. Beverstock (Leiden),
A. Geurts van Kessel (Nijmegen), S.L. Bhola (Utrecht), W. Kroes
(Amsterdam), and M. van den Blij-Philipsen (Veldhoven).
| |
FOOTNOTES |
Submitted September 9, 1998; accepted April 19, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to W.A. Kamps, MD, PhD, Dutch
Childhood Leukemia Study Group, PO Box 43515, 2504 AM The Hague, The
Netherlands; e-mail: snwlk{at}wxs.nl.
| |
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ABSTRACT
INTRODUCTION