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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1094-1099
NEOPLASIA
TEL/AML1 gene fusion is related to in vitro drug sensitivity for
L-asparaginase in childhood acute lymphoblastic
leukemia
Nicole L. Ramakers-van Woerden,
Rob Pieters,
Annemarie H. Loonen,
Isabelle Hubeek,
Ellen van Drunen,
H. Berna Beverloo,
Rosalyn M. Slater,
Jochen Harbott,
Jeanette Seyfarth,
Elisabeth R. van Wering,
Karel Hählen,
Kjeld Schmiegelow,
Gritta E. Janka-Schaub, and
Anjo J. P. Veerman
From the Department of Pediatric Hematology/Oncology, University
Hospital Vrije Universiteit, Amsterdam; the Division of
Oncology/Hematology, Sophia Children's Hospital, Erasmus University,
Rotterdam; the Department of Cell Biology and Genetics and the
Department of Clinical Genetics, Erasmus University, Rotterdam; the
Dutch Childhood Leukemia Study Group, The Hague, The Netherlands;
Oncogenetic Laboratory, Children's Hospital, University of Giessen;
the COALL Study Group, Hamburg, Germany; Tissue Typing Laboratory and
the Department of Pediatric Hematology/Oncology, Rigshospitalet,
Copenhagen, Denmark.
 |
Abstract |
The t(12;21) translocation resulting in TEL/AML1 gene fusion is
present in approximately 25% of patients with precursor B-lineage pediatric acute lymphoblastic leukemia (ALL). Studies suggest an
association with a good prognosis; however, relapse can occur. We
studied the relation between t(12;21), determined by fluorescence in
situ hybridization or polymerase chain reaction, and in vitro drug
resistance, measured by the MTT assay, in childhood B-lineage ALL at
diagnosis. A total of 180 ALL samples were tested, 51 (28%) of which
were positive for t(12;21). The median LC50 values did not
differ significantly between TEL/AML1-positive and -negative samples
for prednisolone, dexamethasone, daunorubicin, thiopurines, epipodophyllotoxins, and 4-HOO-ifosfamide. However, the
TEL/AML1-positive patients were relatively more sensitive to
L-asparaginase (ASP; 5.9-fold; P = .029) and
slightly but significantly more resistant to vincristine (1.5-fold;
P = .011) and cytarabine (1.5-fold; P = .014).
After matching for unevenly distributed patient characteristics that is, excluding patients younger than 12 months, patients with
CD10-negative immature B-lineage ALL, patients with Philadelphia
chromosome, and patients who were hyperdiploid (more than 50 chromosomes) from the TEL/AML1 negative groupthe only remaining
difference was a relative sensitivity for ASP in the TEL/AML1-positive
samples (10.8-fold; P = .012). In conclusion, the presence of
TEL/AML1 gene fusion in childhood precursor B-lineage ALL does not seem to be associated with a high in vitro drug sensitivity, except for ASP,
indicating that these patients could benefit from treatment schedules with significant use of this drug.
(Blood. 2000;96:1094-1099)
© 2000 by The American Society of Hematology.
| |
Introduction |
The prognosis of children with leukemia has improved
dramatically in the past decades because of the development of
effective combination chemotherapy. Nevertheless, approximately 25% of
children with acute lymphoblastic leukemia (ALL) die of resistant or
relapsed disease. Moreover, patients who may be cured with relatively
mild chemotherapy might nowadays be overtreated and experience
unnecessary side effects. It is, therefore, of great importance to
identify children with highly sensitive leukemia who can be cured with minimal therapy and children who need specifically intensified therapy.
Hence, clinical and biologic features of prognostic importance are
sought to tailor therapy according to risk.1
Cytogenetic abnormalities of leukemic cells have proven to be valuable
independent prognostic factors. For example, hyperdiploidy (more than
50 chromosomes) correlates with a favorable outcome, whereas
translocations such as t(9;22) and t(4;11) are associated with a poor
survival rate.1-6 It is thought that these aberrations reflect or cause differences in drug sensitivity. Since the improvement of in vitro drug sensitivity assays, the in vitro cellular drug resistance profile has itself also proven to be a strong independent prognostic factor.7-10
Recently, molecular techniques have identified the t(12;21)(p13;q22)
translocation, occurring in approximately 25% of newly diagnosed
precursor B-lineage childhood ALL,11-19 resulting in the
fusion of TEL to the transactivation domain of AML1. The TEL gene is a
member of the ETS-family of transcription factors.20,21 AML1 knockout mice provide evidence that this gene is essential for
hematopoiesis (for review, see Lococo et al22). The
expression of the TEL/AML1 fusion gene appears to interfere with
AML1-dependent gene regulation in a dominant-negative
manner.23
In childhood ALL, patients with TEL/AML1 display a favorable phenotype,
precursor B cell (CD10+, CD19+, HLA DR+), and a favorable age
distribution, often between 2 and 10 years. Some studies have shown
that patients with TEL/AML1 have excellent prognoses, ranging from 90%
to 100% event-free survival rates.13,15,16,19,24,25 However, Takahashi et al26 report that in the 8511/8610
Japanese TPOSG protocols, there is no significant difference in
disease-free survival between TEL/AML1-positive and -negative
B-precursor ALL. Furthermore, the frequency of TEL/AML1 gene fusion in
relapsed Philadelphia (Ph1) chromosome-negative, precursor B-cell ALL
has been reported to be 24% in patients treated with the
Berlin-Frankfurt-Münster (BFM) group
protocols.27,28 The latter study indicates that TEL/AML1-positive patients have relapses later and might only display
better short-term outcomes. These results are in conflict with those of
Loh et al,29 who report a very low incidence of TEL/AML1
gene fusion in relapsed patients treated with Dana-Farber Cancer
Institute (DFCI) protocols, indicating that the prognostic impact of
TEL/AML1 gene fusion might well be therapy dependent. Hence, the
independent prognostic value of TEL/AML1 has to be further evaluated in
large, prospective studies with sufficient lengths of follow-up. The
question also arises whether this gene fusion leads to a specific in
vitro drug resistance profile or phenotype and whether a more specific
treatment can then be devised.
In this study using the MTT assay, we have investigated whether
TEL/AML1 positive patients differ from other cases of B-lineage ALL in
in vitro drug resistance profile, and compared to a matched precursor
B-cell lineage TEL/AML1 negative group excluding Ph1 chromosome, infant
and hyperdiploid (> 50) cases.
| |
Materials and methods |
Patients and leukemic cell samples
Freshly obtained cells from bone marrow or peripheral blood of 192 children with newly diagnosed, untreated ALL from the Dutch Childhood
Leukemia Study Group, the German Co-operative ALL (COALL) study group,
the Rigshospitalet in Copenhagen, Sophia Children's Hospital in
Rotterdam, and the University Hospital Vrije Universiteit were used for
this study.
Immunophenotyping and DNA index flow cytometry were performed at
reference laboratories of the participating groups; patient characteristics (gender, age, white blood cell count at diagnosis) were
collected by study centers. Karyotyping of the Dutch patients was
performed by members of the Netherlands Working Party on Cancer Genetics and Cytogenetics at regional cytogenetics centers. Karyotyping of Danish patients was performed at the Rigshospitalet. B-lineage immunophenotype was defined as HLA-DR+/terminal
deoxynucleotidyl transferase (TdT)+/CD19+ ALL
and further differentiated as follows: proB-ALL
(CD10 /cytoplasmic µ chain
(cµ)/surface immunoglobulin
(sIg)), common (c)-ALL
(CD10+/cµ/sIg) and
preB-ALL (CD10+ or
CD10/cµ+/sIg). No
B-ALL samples
(CD10/cµ/sIg+) were
present in this study.
Leukemic blast cells were isolated within 48 hours of sampling by
density-gradient centrifugation (Lymphoprep, 1.077 g/mL; Nycomed
Pharma, Oslo, Norway; at 480g for 15 minutes). After washing, the cells were resuspended in RPMI 1640 (Dutch modification; Gibco BRL,
Breda, The Netherlands) containing 20% fetal calf serum (Gibco BRL)
and other supplements.30 When necessary, contaminating normal cells were removed by monoclonal antibodies linked to magnetic beads, as described previously.31 All samples contained
more than 80% leukemic cells, as determined by cytospin preparations stained with May-Grünwald-Giemsa (Merck, Darmstadt, Germany).
Reverse transcription-polymerase chain reaction assay
RNA isolation and reverse transcription (RT) were performed as
described elsewhere.27 Amplification of the TEL/AML1 fusion gene was performed as published previously, using the following primers: TEL external sense,
5'-AGCCCCATCATGCACCCTCTGATCC-3'; TEL internal sense,
5'-GCAGAATTCCACTCCGTGGATTTCAAACAGTCC-3'; AML1 external
antisense, 5'-GTGGTCGGCCAGCACCTCCACC-3'; AML1 internal antisense,
5'-AACGCCTCGCTCATCTTGCCTGGGCTC-3'.17,27 The
ubiquitously expressed ABL gene was amplified in a separate polymerase
chain reaction (PCR) as a control for the RNA isolation and subsequent cDNA synthesis.27
Fluorescence in situ hybridization
Dual-colored fluorescence in situ hybridization (FISH) experiments
for the t(12;21) were performed with the cosmid probe 50F4 for the exon
2 of TEL32 and cosmid 664 containing the first 5 exons of
the AML1 gene.33 Nick translation was used to label cosmid
probe 664 with biotin-16-dUTP (Boehringer Mannheim, Amsterdam, The
Netherlands) and cosmid probe 50F4 with digoxygenin-11-dUTP (Boehringer
Mannheim).34
FISH analysis was performed on cytospins stored at  20°C as
described previously.35 Briefly, slides were pretreated
with RNase and pepsin solutions, followed by postfixation with
acid-free formaldehyde and denaturation. Probes were denatured (4 minutes at 72°C in 70% formamide) in the presence of a 100-fold
excess of Human-COT-1 DNA (Life Technologies, Breda, The
Netherlands), and preannealed for 60 minutes at 37°C. Hybridization
of the probes to the slides was allowed to proceed overnight at
37°C. The biotin hybridization signal (cosmid 664) was visualized
using fluorescein avidin (Vector Laboratories, Burlingame,
VT) and biotinylated anti-avidin D sandwich detection
(affinity purified; Vector Laboratories). The digoxigenin hybridization
signal (cosmid 50F4) was detected using anti-digoxigenin-rhodamine
(Boehringer Mannheim) and donkey anti-sheep-Texas red (Jackson
ImmunoResearch Laboratories, Westgrove, PA). Cells
were counterstained with DAPI/Vectashield mounting medium (Vector
Laboratories). Fluorescence signals were visualized on an Axioskope
fluorescence microscope (Zeiss, Weesp, The Netherlands) with an Atto Arc 100-W lamp (Zeiss) equipped with double
and triple bandpass filters for simultaneous visualization of
rhodamine-TR/fluorescein isothiocyanate/DAPI. At least 200 nuclei were
blindly scored by 2 independent observers. In t(12;21)-positive
patients, the 2 probes coalesced to form a fusion spot (Slater et al,
manuscript in preparation).
In vitro drug resistance assay
In vitro drug cytotoxicity was determined in the MTT
(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide) assay as described previously.30,36 Briefly, 100 µL cell
suspension was cultured for 4 days in the absence (ie, control) or
presence of 6 duplicate concentrations of each drug. During a final
6-hour incubation, the yellow MTT tetrazolium salt was reduced to
formazan (purple-blue) crystals by the living cells only, resulting in an optical density linearly related to the number of viable
cells.36,37 Drug sensitivity was assessed by the
LC50, the drug concentration lethal to 50% of the cells.
The assay was deemed evaluable when a minimum of 70% leukemic cells
were present in the control wells after 4 days of incubation and when
the control optical density was higher than 0.050.30,31
Drug concentration ranges were based on earlier studies and were aimed
at obtaining LC50 values for highly sensitive and for resistant cases. The following drugs and concentration ranges were
used: prednisolone disodium phosphate (PRED; 0.06-250 µg/mL; Bufa
Pharmaceutical Products, Uitgeest, The Netherlands), dexamethasone sodium phosphate (DEX; 0.0002-6.0 µg/mL; Brocacef, Almere, The Netherlands), vincristine (VCR; 0.05-50 µg/mL; Oncovin; Eli Lilly, Amsterdam, The Netherlands), L-asparaginase (ASP;
0.003-10 IU/mL; Medac, Hamburg, Germany), daunorubicin hydrochloride
(0.002-2.0 µg/mL; Cerubidine; Rhône-Poulenc Rorer, Amstelveen,
The Netherlands), doxorubicin hydrochloride (0.008-8.0 µg/mL;
Adriblastina; Pharmacia, Woerden, The Netherlands), mitoxantrone
(0.001-1.0 µg/mL; Novantrone; Lederle, Etten-Leur, The Netherlands),
6-mercaptopurine (15.6-500 µg/mL; Sigma, St. Louis, MO),
6-thioguanine (1.6-50 µg/mL; Sigma), cytarabine (Ara-C; 0.002-2.5 µg/mL; Cytosar; Upjohn, Ede, The Netherlands), teniposide (0.003-8.0 µg/mL; Vumon; Bristol-Myers, Weesp, The Netherlands), etoposide
(0.05-50 µg/mL; etoposide-TEVA; TEVA-Pharma, Mijdrecht, The
Netherlands), and 4-hydroperoxy-ifosfamide (0.10-100 µg/mL; kindly
provided by Asta Medica, Frankfurt am Main, Germany).
It has been shown that the source of the leukemic cells (bone marrow or
peripheral blood) does not affect the drug resistance measured.36 Eleven of 180 samples were tested after
cryopreservation (3 of 51 TEL/AML1-positive and 8 of 129 TEL/AML1-negative samples), which has been shown not to affect the drug
resistance measured.37
Statistics
Distributions of clinical and biologic variables for patients with
and without TEL/AML1 gene fusion were compared by the Mann-Whitney U or  2 test. LC50 values for the
drugs tested were compared between TEL/AML1 gene fusion-positive and
-negative samples by Mann-Whitney U test.
| |
Results |
For 192 patients in this study, the presence of TEL/AML1 gene fusion
was successfully determined either by FISH (Dutch patients, n = 95) or
by RT-PCR (Danish and German patients, n = 97). For the Dutch patients,
whose diagnoses were made between November 1988 and June 1997, the FISH
studies were carried out on cryopreserved cytospins. Some of these
patients were selected because they had karyotypic abnormalities of
chromosome 12p. Of the 95 patients with successful FISH results, 31 (32.6%) were positive for TEL/AML1. Using the TEL probe cos 50F4, 15 of 23 (65.2%) displayed loss of heterozygosity. The 97 German COALL
study group and Danish patients with successful RT-PCR results received
their diagnoses between April 1993 and April 1997 and were tested on a
prospective basis. Twenty-one (21.6%) of these patients were positive
for TEL/AML1 fusion (11 of 42, 26.2%, COALL samples; 10 of 55, 18.2%, Danish samples). In total, 52 TEL/AML1-positive patients and 140 TEL/AML1-negative patients were identified, yielding an overall prevalence of TEL/AML1 in the samples received for in vitro drug resistance testing of 27.1%.
All TEL/AML1-positive patients were older than 2 years of age and
expressed the B-lineage common/precursor B (c/preB) immunophenotype. Patients whose DNA index or karyotype was available were not
hyperdiploid (unknown, n = 12). Only 11.5% of the TEL/AML1-positive
patients were older than 10 years of age, whereas 17.9% of the
TEL/AML1-negative group were. In contrast, patients in the
TEL/AML1-negative group had various immunophenotypes and displayed
other high-risk parameters. For example, 6 patients were infants and 5 were positive for the Ph1 chromosome, as shown by cytogenetic analysis
or PCR. The distribution of initial white blood cell count did not
differ significantly between the 2 groups. Twenty-seven percent of
the TEL/AML1-negative patients were hyperdiploid (more than 50 chromosomes).
Karyotypes were available for 29 (55.8%) TEL/AML1-positive patients
and 89 (63.6%) TEL/AML1-negative patients; Table
1 contains a summary for the positive
patients. Seven of the TEL/AML1-positive samples had an apparently
normal karyotype, no patient had hyperdiploidy, and no other specific
translocations were identified in this group. Of the TEL/AML1-negative
patients, 28 of 89 had a normal karyotype, and specific translocations
included 2 t(9;22)(q34;q11), 2 involved 11q23 (t(6;11)(q27;q23) and
t(1;11)(p32;q23), and 3 t(1;19)(q23;p13).
Of the 52 TEL/AML1-positive samples, 1 could not be used in the MTT
assay because of a low percentage of blasts; of the remainder, 49 (96%) were successfully cultured in vitro. Of the 140 TEL/AML1-negative samples, 11 were not tested for in vitro drug
sensitivity because of a low number of cells received or a low
percentage of blasts in the sample. Of the remainder, only 70% (90 of
129) were successful. Most of the culture failures in the
TEL/AML1-negative group resulted because of less than 70% leukemic
blast cells in the control wells (n = 31); other causes of
failure were insufficient cell survival (n = 4), contamination
(n = 1), and technical reasons (n = 3). The failure rate was
significantly higher in the TEL/AML1-negative group than in the
positive group (P 2 < .001).
Control cell survival, expressed as the average optical density of the
control wells, was higher in the TEL/AML1-positive samples than in the TEL/AML1-negative samples (1.7-fold difference between averages; Pt test < .001). Because it has been
described that hyperdiploid c/preB samples have a lower success rate in
the MTT assay,38 only those known to be non-hyperdiploid
were also compared. The success rate for the TEL/AML1-positive patients
remained significantly higher (36 of 37, 97%) than the
non-hyperdiploid TEL/AML1-negative patients (53 of 70, 76%;
P = .005). The TEL/AML1-negative patients with
successful MTT results did not differ significantly in presenting features from those with failed MTT assay results, except for age
distribution (median age, 58 and 43 months, respectively; P =
.048). The distribution of important clinical and biologic parameters
within the TEL/AML1-positive and -negative groups with a successful MTT
assay is summarized in Table 2. The
event-free survival rate of the total group at the median follow-up
time of 38 months was 81.9% ± 3.8%.
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Table 2.
Clinical and biologic characteristics of 139 patients
with TEL/AML1 gene fusion-negative and -positive B-lineage ALL with in
vitro resistance data
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For most of the 8 classes of drugs tested, there was a complete overlap
of individual LC50 values between TEL/AML1-positive and
-negative samples (Table 3). The only drug
for which the TEL/AML1-positive group was significantly more sensitive
was ASP (median, 5.9-fold; P = .029). The median
LC50 values for the glucocorticoids PRED and DEX were,
respectively, 4.5- and 1.3-fold lower in the TEL/AML1-positive group;
however, this difference was not statistically significant (P =
.297 and P= .324, respectively). The TEL/AML1-positive group
was slightly but significantly more resistant to VCR (1.5-fold; P
= .011) and Ara-C (1.5-fold; P = .014). Other analogues of
anthracyclines, epipodophyllotoxins, and thiopurines showed similar
results.
After comparing TEL/AML1-positive and -negative samples within the
cohort of patients with CD10+ B-lineage phenotype, age older than 12 months, non-hyperdiploidy, and absence of the Ph1 translocation, the
only remaining significant difference between the 2 groups was a
relative sensitivity to ASP (10.8-fold; P = .012) in
the TEL/AML1-positive patients (see Table 4
for a summary of the drugs tested; Figure
1). Sensitivity for ASP in the
TEL/AML1-positive patients remained evident on removal of all patients
older than 10 years from both groups (9.7-fold; P = .036).
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Table 4.
Relation between TEL/AML1 and in vitro drug resistance
in a cohort of 80 patients with childhood ALL with comparable risk
factors
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| Fig 1.
TEL/AML1 and in vitro drug resistance for ASP,
PRED, and VCR.
Relation between TEL/AML1 and in vitro drug resistance for ASP (A),
PRED (B), and VCR (C) in childhood c/preB ALL. LC50 values
for c/preB, older than 12 months, non-hyperdiploid (> 50 chromosomes), non-Philadelphia translocation TEL/AML1-negative versus
TEL/AML1-positive patients. Boxes represent the 25th to the 75th
percentiles with the median, shown as a horizontal bar. Whiskers give
the minimum and maximum values. LC50 values are expressed
as µg/mL; those for ASP are expressed as IU/mL. P values were
determined by the Mann-Whitney U test.
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Hyperdiploid patients with childhood ALL also have high in vitro
sensitivity to L-asparaginase and other
antimetabolites.38 Hence, the TEL/AML1-positive patients
(with known DNA index; n = 36) were compared to the hyperdiploid
TEL/AML1-negative patients (defined by DNA index 1.16-1.35; n = 18).
Hyperdiploid patients were a median 3.5 times more sensitive to ASP
(P = .057).
Within the TEL/AML1-positive group, the in vitro resistance profile was
compared between the 7 patients with apparently normal karyotype versus
the 22 patients with additional karyotypic abnormalities; there were no
significant differences for any of the drugs tested.
| |
Discussion |
In the present study we have examined the relation between TEL/AML1
gene fusion and in vitro drug resistance. The prevalence of TEL/AML1 in
this group of 192 children with B-lineage ALL was 27.1%. Clinical and
biologic features of the TEL/AML1-positive patients agree with those of
other reports in the literature in that they form a distinct group of
exclusively c/preB phenotype, are mostly between 2 and 10 years of age,
have non-hyperdiploid ALL, and are Ph1 chromosome negative.
We show that TEL/AML1 gene fusion in untreated childhood
c/preB ALL is associated with relative sensitivity to ASP. For all other drugs tested, the TEL/AML1-positive patients did not differ from
the TEL/AML1-negative patients except regarding VCR and Ara-C. When the
overall group of TEL/AML1-negative patients was considered, including
those with other immunophenotypes (proB), those with different ages
(younger than 12 months; relatively more patients older than 10 years),
and those with Ph1 positivity, the TEL/AML1-positive patients were
unexpectedly resistant to VCR and Ara-C. However, the degree of
relative resistance was small, with only a 1.5-fold difference in
median LC50 for VCR and Ara-C.
In vitro drug resistance profiles have been shown to be
related to immunophenotype, age, and hyperdiploidy in childhood
ALL.38-41 Hence, to determine the effect of the t(12;21) on
in vitro drug resistance, we compared the sensitivity profiles between
TEL/AML1-positive and -negative patients in the cohort with CD10+
B-lineage phenotype, older than 12 months, no hyperdiploidy, and
absence of high-risk t(9;22). Here again the TEL/AML1-positive patients
were more sensitive to ASP, whereas the relative resistance to VCR and
Ara-C disappeared. The degree of relative sensitivity to ASP is
considerable; the TEL/AML1-positive patients were a median 10.8 times
more sensitive. Because patients with hyperdiploid B-lineage childhood
ALL have increased sensitivity to ASP,38 when this group
was removed from the TEL/AML1-negative population the sensitivity of
the TEL/AML1-positive patients to this drug became even more apparent.
In this study, the hyperdiploid TEL/AML1-negative patients had even
more in vitro sensitivity to ASP than the TEL/AML1-positive
(non-hyperdiploid) patients did.
It is surprising that we find such a marked difference in
culture success rates between the TEL/AML1-positive (96%) and
TEL/AML1-negative (70%) patients. The average success rate of the MTT
assay at our laboratory is approximately 76% to 80% for fresh ALL
samples taken at diagnosis. Most of the failures in the present study
resulted from low leukemic cell survival in the control wells, that is, non-drug-induced "spontaneous" cell death. We have no
explanation for this higher proportion of autonomous cell survival in
the TEL/AML1-positive patients.
After the first reports on the exceptionally good prognoses of
TEL/AML1-positive patients,13,15,16,19,24,25 it has been
questioned whether this could be partially dependent on the treatment
protocol used. Lanza et al42 of the BFM-based Italian AIEOP
study report that 2 of 11 TEL/AML1-positive ALL patients without any
apparent poor-risk factors died after relapse (22 and 31 months after
diagnosis). Takahashi et al26 report that 5 of 21 (24%)
TEL/AML1-positive patients had relapses. Moreover, Harbott et
al27 and Seeger et al28 of the BFM study group have found that the prevalence of TEL/AML1 gene fusion in c/preB non-Ph1+ ALL patients at relapse is, unexpectedly, equivalent to that
at diagnosis (24%). In contrast to these reports, the incidence of
TEL/AML1 in relapsed patients on DFCI protocols has been reported to be
very low (1 of 32).29 Hence, the prognostic value of the
TEL/AML1 gene fusion may not be as clear-cut as originally proposed.
In the present study, we show that the TEL/AML1-positive patients do
not display an overall profile of relative in vitro drug sensitivity.
It is interesting to note that the only drug for which
TEL/AML1-positive patient samples are relatively sensitive is ASP. This
may explain the remarkably good long-term prognosis of
TEL/AML1-positive patients at St. Jude Children's Research Hospital
and the DFCI,13,15,29 where the treatment protocols include
a relatively intensive ASP-regimen, particularly when compared with the
BFM-based protocols.43-46 As an example of the latter
protocols, the DCSLG ALL-VII study prescribe 8 to 12× 10 000
IU/m2 Erwinia ASP intravenously at 3- to 4-day
intervals, depending on the risk group.47 In comparison,
DFCI protocols 81-01 and 85-01 prescribe 20 to 28×
Escherichia coli ASP 25 000 IU/m2 intramuscularly,
depending on the risk group.43
It has been shown by 3 independent groups that in vitro
L-ASP sensitivity is of prognostic value in patients with
childhood ALL.7,9,48 It would be of great interest to study
prospectively whether in vitro L-ASP sensitivity is
predictive of outcome in TEL/AML1-positive patients in a group
undergoing uniform treatment. The treatment received by the patients in
the present study differed, and the follow-up was too short to address
this or to analyze the event-free survival of the TEL/AML1-positive and
the TEL-AML1-negative patients.
In conclusion, TEL/AML1-positive ALL patients are in vitro highly
sensitive for ASP only. Our findings suggest that TEL/AML1-positive patients might benefit from treatment schedules with significant use of
L-ASP at doses that secure complete asparagine
depletion.29
| |
Acknowledgments |
We thank the pediatric oncology centers participating in the DCLSG, the
Netherlands, the German COALL study group, and the Rigshospitalet,
Denmark. Board members of the DCLSG are H. van den Berg, M. V. A. Bruin, J. P. M. Bökkerink, P. J. van Dijken, K. Hählen, W. A. Kamps, F. A. E. Nabben, A. Postma, J. A. Rammeloo, I. M. Risseeuw-Appel, A. Y. N. Schouten-van Meeteren, G. A. M. de Vaan, E. T. van `t Veer-Korthof, A. J. P. Veerman, M. van Weel-Sipman, and R. S. Weening. Board members of the COALL-92/97 study group are U. Göbel, U. Graubner, R. J. Haas, G. E. Janka-Schaub, N. Jorch, H. Jürgens, H. J. Spaar, and K. Winkler. The cosmid probe 50F4 was
developed by Dr M. Baens (Human Genome Laboratory, University of
Leuven, Belgium), and the cosmid probe 664 was developed by Dr N. Sacchi (Medical School, University of Milan, Italy). Both probes were
kindly provided by Prof A. Hagemeijer (European Concerted Action
Coordinator, University of Leuven, Belgium). We also thank C. G. Beverstock, H. de France, A. Geurts van Kessel, A. Hagemeijer-Hausman, A. Hamers, B. de Jong, and R. M. Slater of the Netherlands Working Party on Cancer Genetics and Cytogenetics.
| |
Footnotes |
Submitted September 23, 1999; accepted March 30, 2000.
Supported by the Dutch Cancer Society grants IKA 89-06 and VU95-021;
the Danish Cancer League and the Danish Cancer Society grant 96 144 10 9132.
Reprints: N. L. Ramakers-van Woerden, Department of Pediatric
Hematology/Oncology, University Hospital Vrije Universiteit, PO Box
7057, 1007 MB Amsterdam, The Netherlands; e-mail:
ramakersvanwoerden{at}azvu.nl.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction