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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1716-1722
TEL-AML1 Fusion Transcript in Relapsed Childhood Acute
Lymphoblastic Leukemia
By
Karlheinz Seeger,
Hans-Peter Adams,
Dirk Buchwald,
Birgit Beyermann,
Bernhard Kremens,
Charlotte Niemeyer,
Jörg Ritter,
Dirk Schwabe,
Dörte Harms,
Martin Schrappe, and
Günter Henze for the Berlin-Frankfurt-Münster Study Group
From the Departments of Pediatric Oncology/Hematology,
Charité-Virchow-Klinikum, Humboldt-University at Berlin, Berlin;
Gesamthochschule Essen, Essen; Albert-Ludwigs-University, Freiburg;
Westfälische-Wilhelms-University, Münster;
Johann-Wolfgang-Goethe-University, Frankfurt; University Hamburg,
Hamburg; and Medizinische Hochschule Hannover, Hannover, Germany.
 |
ABSTRACT |
The cryptic translocation t(12;21)(p13;q22) has been recently
recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an
excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients
with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed
childhood ALL, bone marrow samples of 146 children were analyzed by
reverse-transcriptase (RT)-polymerase chain reaction (PCR). All
children were treated according to Berlin-Frankfurt-Münster (BFM)
ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical
features and outcome were compared with those of 262 patients who could
not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1-positive. Four of the
negative patients had T-lineage and nine Philadelphia chromosome
(Ph1)-positive leukemia. Thus, the incidence of
TEL-AML1 in relapsed Ph1-negative, B-cell precursor
ALL is 32 of 133 (24%). The 32 TEL-AML1-positive and 101 negative patients differed significantly with respect to duration of
last remission (42.5 v 27 months; P = .0001) and age at initial diagnosis (53.5 v 74 months;
P = .0269). At a median follow-up time of 21.5 months,
children positive for TEL-AML1 had a significantly
(P = .0011) higher probability of event-free survival (EFS;
0.79 v 0.33). The predominant majority of patients had been
treated for initial ALL according to German multicenter BFM (108 of
133) or Cooperative ALL study group (CoALL) (19 of 133)
frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference.
TEL-AML1 positivity predicted a favorable short-term outcome;
long-term results are unknown. Screening for TEL-AML1 should
become routine at relapse diagnosis and might be used for therapy
stratification in future trials.
| |
INTRODUCTION |
CURRENT RISK-BASED treatment regimens
apply distinct prognostic factors as criteria when stratifying children
with acute lymphoblastic leukemia (ALL) into particular treatment
protocol arms with either reduced toxicity (low-risk) or a more
intensive approach to disease control (high-risk). In newly diagnosed
ALL, universally accepted stratification criteria are age and WBC count
at diagnosis,1 but risk assessment is modified by response
to therapy2,3 and other predictive factors, such as
cytogenetic or molecular findings [hyperdiploidy/hypodiploidy,
translocation t(9;22); t(1;19); involvement of 11q23 or their
respective molecular products].4-7 In contrast, the main
determinants of outcome at relapse of ALL are duration of first
remission, immunophenotype of leukemic cells, and site of
relapse.8,9 However, also at relapse, genetic features are
evolving as important predictors of outcome. The translocation t(9;22)
or its molecular counterpart, BCR-ABL fusion transcript, is an
independent risk factor at first relapse of childhood ALL associated
with an adverse prognosis.10,11
Recently, screening of leukemic cells by molecular techniques has
demonstrated that 16% to 32% of newly diagnosed B-cell precursor ALL12-18 have a cryptic translocation t(12;21)(p12;q22)
between TEL, a novel member of the ETS-like family of
transcription factors (chromosome 12), and the AML1 gene of the
AML1/CBF (core-binding factor) transcription factor complex
(chromosome 21).19,20 In the larger series, the frequency
of TEL-AML1 fusion was constantly approximately 25%.13,15,17,18,21 Normal function of AML1 is essential for hematopoiesis,22 and the fusion protein interferes
dominantly with AML1-dependent transcription of target genes, thus
influencing the regulatory pathway necessary for normal growth and
differentiation of hematopoietic cells and contributing to the
pathogenesis of leukemia.22-24 TEL and AML1
are independently involved in several other translocations in acute and
chronic leukemias and myelodysplastic syndromes.25-29
Six studies of children with newly diagnosed ALL treated by
risk-directed combination chemotherapy have associated TEL-AML1 expression in ALL with an excellent prognosis and a long-term continuous complete remission (CCR).13-18 We assessed the
incidence of TEL-AML1-positive ALL at relapse and its
prognostic significance.
| |
MATERIALS AND METHODS |
Molecular detection of the TEL-AML1 fusion mRNA.
RNA isolation and reverse transcription (RT) have been described
elsewhere.10 Nested polymerase chain reaction (PCR) of cDNA
of TEL-AML1 fusion14 and c-ABL-cDNA integrity
control10 were performed as published previously, with the
only difference that a duplex-PCR permitting the simultaneous
coamplification of cDNA of TEL-AML1 and c-ABL was
established. Duplex-PCR was performed with a DNA-Engine PTC-200
(MJ-Research, Watertown, MA). Cycle times and temperatures for
denaturation, annealing, and synthesis for external and internal PCRs
were as follows: initial denaturation, 94°C, 6 minutes; 61°C, 30 seconds, 72°C, 45 seconds, and 94°C, 60 seconds, 30 cycles; final
elongation, 72°C, 10 minutes. Each experiment was repeated at least
once and included no template cDNA as a negative control. Positive
results were confirmed by analyzing at least one additional sample
independently and by sequencing of the PCR products by an ABI 377 automated sequencer (Applied Biosystems, Foster City, CA).
Patients and treatment.
Bone marrow samples from 146 unselected children and adolescents were
obtained at ALL relapse diagnosis. All patients were treated according
to the ALL-REZ BFM 90-96 relapse trials of the Berlin-Frankfurt-Münster (BFM) study group.8,30
Written informed consent was obtained from the patients or their
guardians. The ALL-REZ BFM studies were approved by the institutional
review boards of the Freie Universität Berlin and
Humboldt-University at Berlin. To affirm that the tested samples were
representative for relapsed childhood ALL, all patients that had been
treated on the same protocols but were not tested were used as the
control group. The definition of therapy groups for trial ALL-REZ BFM 96 is provided in Table 1.
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Table 1.
Definition of Strategic Therapy Groups S1 to S4 in
ALL-REZ BFM Relapse Trial Based on Time Point of Relapse, Site of
Relapse, and Immunophenotype
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Data analysis.
Statistical analysis was performed using the SAS Software (SAS
Institute, Cary, NC), version 6.11 for Windows (Microsoft, Redwood,
USA). The analysis entailed univariate statistics,
Wilcoxon rank-sum tests, Fisher's exact test,31 and
survival analysis using the Kaplan Meier method.32 The
level of significance was set to .05.
Event-free survival (EFS) was computed from date of remission to the
last date patients were reported in continuous remission or the date of
an adverse event. In case of nonresponse to therapy or death during
induction, EFS was set to 0. EFS was censored at the date of bone
marrow transplantation (BMT) for survival analyses showing results of
chemotherapy only. In cases of autologous BMT, EFS was censored with
the date of BMT for analyses presenting results of chemotherapy and
allogeneic BMT.33
| |
RESULTS |
Molecular detection of the TEL-AML1 fusion mRNA.
Among 146 analyzed samples, 32 were found to be
TEL-AML1-positive. Corresponding to different fusions with the
AML1 gene, two variant TEL-AML1 RT-PCR amplification
products were detected.12,14,34 The longer PCR
amplification product (269 bp), which resulted from fusion of exon 5 of
TEL with exon 2 of AML1, was predominantly detected (29 of 32 TEL-AML1-positive cases). The shorter amplified product
(230 bp), resulting from fusion of TEL exon 5 with exon 3 of
AML1, was observed in the remaining 3 of 32 cases. This shorter PCR product was also simultaneously amplified in the other
TEL-AML1-positive samples, although with lower intensity than
the longer fragment. DNA sequencing of the 230-bp product show that
exon 2 of AML1 (39 bp) was omitted by alternative splicing in
these cases. Bone marrow samples of 114 patients were negative for
TEL-AML1.
Patients and treatment.
TEL-AML1 fusion transcripts were detected in relapsed
Philadelphia chromosome (Ph1)-negative, B-cell precursor
ALL only. Among 114 TEL-AML1-negative patients, there were
nine Ph1-positive patients and four with T-cell
immunophenotype. Since both Ph1 positivity and T-lineage
are known to be independent risk factors in relapsed childhood ALL,
these patients were excluded from further analysis.8,11
Thus, the study population was restricted to 133 patients with relapsed
Ph1-negative, B-cell precursor ALL, and the incidence of
TEL-AML1 was 32 of 133 (24%). Accordingly, the control group
included only patients with Ph1-negative, B-cell precursor
relapsed ALL (N = 262), who could not be tested due to lack of bone
marrow samples. The characteristics of all 395 patients are listed in
Tables 2 and 3 and shown in Fig
1.
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Table 2.
Clinical Features of Children With Relapsed
Ph1-negative B-Cell Precursor ALL Enrolled in ALL-REZ-BFM
Protocols Tested and Not Tested for TEL-AML1 Expression
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| Fig 1.
Boxplots of continuous variables by patients group. Age,
age at initial diagnosis (months); Age(R), age at relapse diagnosis (months); Dur R, duration of remission (months); Log (PBC), logarithm (base 10) of (peripheral blast cell count [1/µL] + 1); Log
(WBC), logarithm (base 10) of (WBC count [1/µL] + 1); OT,
observation time = (today  date of relapse diagnosis) (months);
n, not tested (n = 262); , TEL-AML1-negative
(n = 101); +, TEL-AML1-positive (n = 32). Boxes
represent the first (25%) and third (75%) quartile of the
distribution; cross-line denotes median; lower whisker, the 5th, and
the upper whisker, the 95th percentile.
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The age at initial ALL diagnosis was lower in the
TEL-AML1-positive group (Table 3 and Fig 1); the oldest
positive patient was 10.6 years at initial ALL diagnosis. However, the
age at relapse diagnosis was similar in all groups. Thus, the duration
of remission was significantly higher in the TEL-AML1-positive
group (Fig 1 and Tables 2 and 3). It is noteworthy that all five
TEL-AML1-positive patients who presented with a second ALL
relapse were late relapses (Table 1). Nonetheless, two very early and
four early relapses could be found in the TEL-AML1-positive
group. Initial treatment was similar in the vast majority of
TEL-AML1-tested patients. One hundred eight of 133 children
were treated according to BFM2,35 and 19 of 133 according
to Cooperative ALL study group (CoALL)36 frontline protocols (Table 2). Only one of the
TEL-AML1-positive patients with an early relapse had been
treated according to an East European protocol.
According to their classification as late relapses, most
TEL-AML1-positive patients are currently stratified into
strategic (S) therapy groups S1 and S2 (Tables 1 and 2). The
significant difference of EFS of all patients by therapy group is shown
in Fig 2.
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| Fig 2.
Kaplan-Meier estimates of EFS related to strategic
therapy groups S1 to S4 (for definition, see Table 1) for 395 patients enrolled in the ALL-REZ BFM protocols. (A) Results of chemotherapy only
(BMT censored); (B) chemotherapy and allogeneic BMT included (see
Materials and Methods). CS, chi-square; DF, degrees of freedom.
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The observation time of tested and not-tested patients was
statistically significantly different (Fig 1 and Table 3). The median
observation time of the not-tested group was 48 months, and 50% of all
adverse events occurred within 26 months after relapse diagnosis (Fig
3). Since the median observation time of the tested group was 21.5 months, response to therapy, frequency of
BMT, and frequency of events in remission cannot be regarded as
estimate of the final outcome. However, a clear pattern regarding outcome emerged (Fig 3). TEL-AML1-positive patients had an
excellent prognosis compared with TEL-AML1-negative patients.
Assuming that TEL-AML1-positive and -negative patients were
equally distributed among tested and not-tested patients, there should
be no differences across both groups. In fact, there were no
significant differences between tested and not-tested patients
regarding sex, age, duration of last remission, and time point of
relapse, WBC and peripheral blast cell count, number of relapses, site,
stratification into therapy groups, response to therapy, and frequency
of BMT. Consequently, the EFS of the not-tested group should be between
the EFS of negative and positive patients. Indeed, the probability of
EFS of not-tested patients disjoins the EFS of positive and negative
patients (Fig 3).
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| Fig 3.
Kaplan-Meier estimates of EFS for 133 children with
relapsed ALL tested for expression of TEL-AML1 transcripts and
262 not-tested patients treated according to ALL-REZ BFM protocols. (A)
Results of chemotherapy only (BMT censored); (B) chemotherapy and
allogeneic BMT included (see Materials and Methods).
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There was only one significant difference between tested and not-tested
patients: the frequency of "other" frontline therapy protocols.
Nineteen of these patients had been treated according to other (ie,
non-BFM) West European protocols and 21 according to East European
protocols.
| |
DISCUSSION |
The TEL-AML1 fusion represents the most frequent gene fusion
arising from a cryptic translocation in childhood
ALL.13-15,17,18,21 In the cited studies, the clinical
characteristics of children with a TEL-AML1-positive ALL were
consistent with respect to B-cell precursor immunophenotype, age
between 1 and 10 years, and mostly WBC count less than 50,000/µL,
features which are generally associated with a low risk and good
prognosis.
A significant association between the frequency of relapse and
TEL-AML1 status was found in the studies reported by McLean et
al,15 Rubnitz et al,17 and, recently, Borkhardt
et al.18 In these reports, the probability of EFS at 5 years for TEL-AML1-positive patients was as high as 91% to
100%, whereas the probability of EFS of negative patients ranged from
65% to 79%. A similar trend was observed by Nakao et al14
and Shurtleff et al.13
Given these promising reports, we determined the incidence, clinical
features, and outcome of TEL-AML1-positive patients in childhood relapsed ALL. Unexpectedly, the incidence was 32 of 146 (21.9%) in unselected patients. All positive patients had relapsed
B-cell precursor ALL, and all but one were younger than 10 years at
initial ALL diagnosis. The patients who were positive at the time of
relapse had a significantly longer duration of remission than negative
patients. The duration of remission was the most important independent
risk factor at relapse diagnosis. A very early relapse carried a 5.9 times higher risk ratio, and an early relapse a 3.8 times higher risk
ratio for a subsequent relapse compared with late relapses (for
definition of relapse time points, see Table 1).8,9
Consequently, the majority of TEL-AML1-positive patients were
found in therapy groups with a better prognosis (Tables 1 and 3).
The outcome of TEL-AML1-positive patients was significantly
better than the outcome of negative patients. This is of particular importance for the decision on high-risk BMT procedures. Yet, it
remains to be verified whether TEL-AML1 is an independent risk factor for relapsed childhood ALL.
The similar frequency of TEL-AML1 positivity in relapsed and
newly diagnosed ALL appears to be in contrast with published data
associating the presence of TEL-AML1 fusion in newly diagnosed ALL with a good prognosis, and these findings emphasize the necessity of molecular diagnostics both at initial diagnosis and at relapse of
ALL to clearly evaluate short-term and long-term results of chemotherapeutic regimens. The majority of the tested TEL-AML1 patients with relapsed ALL had initial treatment according to BFM or
the similar CoALL ALL frontline study. The incidence of TEL-AML1 positivity in initial B-cell precursor ALL of children enrolled in the multicenter BFM2,35 or Associazione
Italiana Ematologia Oncologia Pediatrica (AIEOP)37 ALL
frontline trials has been assessed by Borkhardt et al.18 In
this partly prospective, partly retrospective study, the frequency of
TEL-AML1-positive B-cell precursor ALL was 22.5% (63 of 217 children) and 29.4% (99 of 337 children), respectively. The estimated EFS rate of the retrospectively analyzed population was 90.1% and 79%
at 4 years for the TEL-AML1-positive and -negative patients. Although only three of the TEL-AML1-positive have suffered a
relapse, in contrast to 27 of the negative patients, the observation
time is too short to predict long-term outcome.
Two hypotheses might explain the same frequency of TEL-AML1
fusion detected in newly diagnosed and relapsed ALL. TEL-AML1 positivity is associated with prolonged disease-free intervals. In
agreement with the aforementioned BFM and AIEOP data,18
Rubnitz et al17 reported a probability of EFS of 91% at 5 years for TEL-AML1-positive patients. However, the life-table
curves presented show a clear trend for the occurrence of late relapses
in this group.17 Thus, the same incidence of
TEL-AML1 positivity at relapse indicates that relapse is
delayed, but not decreased in these patients. The median duration of
remission of relapsed TEL-AML1-positive patients was 42.5 months (Table 3). Therefore, an observation period of 4 or 5 years may
be too short to assess final outcome. This is different in relapsed
childhood ALL: more then 50% of all events occurred within 26 month
after diagnosis (see the not-tested group in Fig 3).
More speculative is the hypothesis that the high incidence of
TEL-AML1 fusion at relapse might be the consequence of a new genetic alteration, possibly induced by the preceding treatment, and
the "leukemic relapse" may be in fact a second malignancy. AML1 has been reported to be involved in treatment-related
secondary leukemia.38,39 This observation is supported by
the capacity of DNA topoisomerase II inhibitors to induce a
reproducible site-specific double-strand DNA cleavage in susceptible
regions of AML140 or MLL41
genes, thus, possibly producing an initial step in the pathogenesis of
chromosomal translocations and the subsequent development of leukemias.
Prospective molecular analyses of leukemic cells at first presentation
and at relapse will be required to further elucidate this hypothesis.
In any case, TEL-AML1 status identifies a subgroup of children
with B-cell precursor ALL who achieve long-term disease-free intervals
with current therapeutic regimens either after first or second round of
chemotherapy, and also in case of a second relapse. In contrast,
Ph1- or BCR-ABL-positive ALL, which occurs at a frequency
of 12% in relapsed childhood B-cell precursor ALL and now constitutes the second most frequent fusion gene, is associated with a dismal prognosis and outcome.10,11 Although the underlying
biologic mechanisms remain to be resolved, these findings emphasize the importance of molecular screening to identify not only unfavorable, but
also favorable subsets of ALL for stratification of patients to
appropriate treatment arms within risk-adapted clinical trials, and to
tailor therapy accordingly in future therapeutic strategies.
| |
FOOTNOTES |
Submitted August 4, 1997;
accepted October 21, 1997.
Supported by a grant from the Deutsche Leukämie
Forschungshilfe Aktion für krebskranke Kinder e. V., Bonn,
Germany, and by grants from the Deutsche Krebshilfe, Bonn, Germany.
Address reprint requests Karlheinz Seeger, MD, PhD, Department of
Pediatric Oncology/Hematology, Mail drop Forschungshaus 2.0412, Charité-Virchow-Klinikum, Humboldt-University at Berlin, 1 Augustenburger Platz, Berlin, Germany, 13353.
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.
| |
ACKNOWLEDGMENT |
The critical comments of Stephen Sallan, MD, Dana-Farber Cancer
Institute, Boston, MA, are greatly appreciated. Immunophenotyping was
performed by W.-D. Ludwig, MD, PhD, Department of Medical Oncology/Molecular Biology, Max-Delbrück-Center,
Humboldt-University at Berlin, Berlin, Germany. The technical
assistance of Tillmann Taube, Serge Dragon, Claudia Hanel, Gisela
Götze, and Gabriele Schmitt is gratefully acknowledged, as well
as Andrea Kretschmann's help with data preparation of the ALL-REZ BFM
relapse studies. The support of the physician and nursing staffs of the
participating ALL-REZ BFM centers for providing bone marrow samples is
appreciated.
| |
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Abstract
Introduction
Abstract