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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Immunology and of Epidemiology and
Biostatistics, University Hospital Rotterdam/Erasmus University
Rotterdam; Dutch Childhood Leukemia Study Group, The Hague; Department
of Pediatrics, University Hospital Groningen, The Netherlands;
Institute of Human Genetics, University of Heidelberg; Department of
Pediatrics, Medizinische Hochschule Hannover, Germany; Children's
Cancer Research Institute, St Anna Kinderspital, Vienna, Austria; and
Department of Pediatrics, University of Milano, Ospedale S. Gerardo,
Monza, Italy.
We performed sensitive polymerase chain reaction-based minimal
residual disease (MRD) analyses on bone marrow samples at 9 follow-up
time points in 71 children with T-lineage acute lymphoblastic leukemia
(T-ALL) and compared the results with the precursor B-lineage ALL
(B-ALL) results (n = 210) of our previous study. At the first 5 follow-up time points, the frequency of MRD-positive patients and the
MRD levels were higher in T-ALL than in precursor-B-ALL, reflecting the
more frequent occurrence of resistant disease in T-ALL. Subsequently,
patients were classified according to their MRD level at time point 1 (TP1), taken at the end of induction treatment (5 weeks), and at TP2
just before the start of consolidation treatment (3 months). Patients
were considered at low risk if TP1 and TP2 were MRD negative and at
high risk if MRD levels at TP1 and TP2 were 10 Childhood acute lymphoblastic leukemia (ALL) has a
B-lineage origin in approximately 85% of patients and a T-lineage
origin in the remaining approximately 15% of patients.1
Typical T-lineage ALL (T-ALL) is diagnosed in male adolescents and is
frequently characterized by hyperleukocytosis, mediastinal mass, and
central nervous system involvement.2,3 Children with T-ALL
generally have a poorer prognosis than those with precursor B-lineage
ALL (B-ALL).1,4 In T-ALL, the following
characteristics were shown to have a negative effect on treatment
outcome: patient age 15 years or older, L2 blast morphology, karyotype
other than hyperdiploidy, and CD3+.2,3
The most immature T-ALLs (CD1 Individualization of ALL treatment might further improve outcome and
long-term quality of life. This may be achieved through minimal
residual disease (MRD) studies that allow the sensitive detection of
leukemic cells undetectable by normal cytomorphologic examination,
thereby providing accurate information about the in vivo efficacy of
cytotoxic treatment.18,19 The most broadly applicable MRD
technique in ALL is polymerase chain reaction (PCR) analysis of
clone-specific immunoglobulin and T-cell receptor (TCR) gene
rearrangements, which are easily identified in most pediatric and adult
patients with ALL.19-21 Based on the sequences of the
patient-specific junctional regions, sensitivities of 10 Several large-scale studies in childhood ALL have shown that MRD
analysis can predict outcome by determining the reduction of the
leukemic cell burden during the first months of
therapy.23-27 Multivariate analysis showed that MRD
information is an important prognostic factor at all
follow-up time points taken during and after treatment and that this
MRD information is independent of the classical clinical parameters at
diagnosis such as age, sex, white blood cell count (WBC),
immunophenotype, chromosome aberrations, and prednisone
response.25-27 For example, prognostically relevant subgroups such as T-ALL or ALL characterized by t(9;22), t(12,21), or
t(4;11) are still heterogeneous in treatment
response,2,28-31 but MRD information during treatment of
these leukemia subtypes is more discriminative in predicting treatment
outcome.26,32,33
The impact of MRD information in childhood ALL appeared to be superior
to classical treatment group classification at diagnosis, as was
demonstrated by the study of the International BFM Study Group
(I-BFM-SG). In this study, a precise risk group classification was
achieved by combining sensitive (10 The aim of the present MRD study was to identify the different response
groups within T-ALL and to elucidate the differences in overall
treatment response between T-ALL and precursor B-ALL. From the cohort
of patients included in the I-BFM-SG study, we were able to analyze 71 patients with T-ALL for their MRD pattern using one or 2 TCR gene
rearrangements as PCR targets. These data were used to compare the
presenting features and outcomes of the 71 patients with T-ALL with
those of the previously reported 210 precursor B-ALL
cases.27
Patients and cell samples
All children were treated according to protocols of the Austrian BFM
Group (protocol ALL-BFM 90), the German BFM Group (protocol ALL-BFM
90), the AIEOP-ALL-91 protocol, or the Dutch Childhood Leukemia Study
Group (DCLSG, protocol ALL-8).12,34,35 The 3 treatment
protocols all had the same I-BFM-SG backbone. Patients with T-ALL were
stratified into 2 treatment groups, medium-risk group (MRG) and
high-risk group (HRG), according to the presenting features such as
leukemic cell mass and prednisone response.12,34,35 All
patient samples were obtained according to the informed consent guidelines of the local or national medical ethics committees.
The cohort of childhood ALL included in the I-BFM-SG MRD study from
March 1991 to May 1995 (n = 625) contained 74 patients with T-ALL
(12%); 30 had been previously analyzed.27 In the present
study, 41 of the 44 remaining patients with T-ALL could be analyzed
according to the same criteria The earlier analyzed group of precursor B-ALL was sufficiently large
(n = 210) for the comparative T-ALL versus precursor B-ALL study and
did not require the inclusion of extra patients. Five-year RFS rates of
the analyzed T-ALL group (n = 71) were 60% (±6% SE) compared with
76% (±3%) in the precursor B-ALL group (Figure 1B). Survival of the
T-ALL group studied is comparable to that of the total group of
patients with T-ALL treated according to the same
protocol.12,34,35 Patient characteristics of the 71 T-ALL
and the 210 precursor B-ALL patients are given in Table 1.
Identification of PCR targets at diagnosis
PCR-based MRD detection during follow-up The MRD-PCR analyses of BM samples during follow-up of the patients with T-ALL were performed as described in the earlier BIOMED-1 report.22 Briefly, single PCR amplification with the standardized primer sets of the clone-specific rearrangement using 1 µg DNA (equivalent to 105-106 cells) was followed by dot blotting and hybridization with the corresponding 32P-labeled, patient-specific junctional region probe. Radioactive signals were evaluated using phosphor imaging. The sensitivity of each identified MRD-PCR target was established by use of a dilution experiment, in which DNA from the leukemic cells at diagnosis was diluted in 10-fold dilution steps into control DNA from a mixture of blood MNCs of 10 different healthy donors. Preferably, 2 independent PCR targets were used per patient, of which at least one reached a sensitivity of at least 10 4.
When MRD-PCR analysis of BM follow-up samples resulted in a
hybridization signal, this time point was considered to be MRD positive. Consequently, if no signal was obtained, this time point was
considered MRD negative, irrespective of the PCR target sensitivity. The frequency of leukemic cells in the BM samples during follow-up was
estimated by comparison of the signals with those of the 10-fold dilution samples of DNA at diagnosis. This resulted in reproducible semiquantitative estimations of MRD-PCR results of 10 Statistical analyses Relative frequencies were compared between groups using the 2 of Fisher exact test. Between- and within-group
comparisons of MRD levels were made using the Mann-Whitney U
and the Wilcoxon test, respectively. RFS according to the MRD results
at the various time points was determined using Kaplan-Meier plots.
Comparison of groups was performed using the log rank test or the log
rank trend test for ordered groups (eg, MRD levels). Multivariate
analysis of the predictive value of MRD at the various time points,
allowing for different other variables (treatment group, age, sex, WBC on a continuous scale, and prednisone response) was performed using Cox
regression analysis. It was further analyzed whether the prognostic
effects of MRD levels differed between T-ALL and precursor B-ALL by
investigating appropriate interaction terms in the regression models.
P  .05 was considered significant.
Number of MRD-PCR targets In 66% (47 of 71) of the patients with T-ALL, 2 PCR targets (42 patients) or 3 PCR targets (5 patients) were used for MRD detection. The remaining 34% of patients with T-ALL were analyzed by one MRD-PCR target. The 123 PCR targets used in the patients with T-ALL comprised 89 TCRG gene rearrangements, 10 incomplete TCRD gene rearrangements, 20 complete TCRD gene rearrangements, and 4 TAL1 deletions. In 76% (93 of 123) of these targets, sensitivities of at least 104 were reached: 58 targets
had a sensitivity of 104, 28 targets had
105, and 7 targets had 106.
In the precursor B-ALL group, 40% (84 of 210) of patients were monitored with one MRD-PCR target and 60% (126 of 210) were monitored with 2 targets (113 patients) or 3 targets (13 patients). Use of 1, 2, or 3 MRD-PCR targets did not significantly differ between T-ALL and precursor B-ALL (P = .4). MRD in T-ALL is distinct from precursor B-ALL At the time of morphologic remission (TP1), that is, at 5 weeks of treatment, 80% (43 of 54) of patients with T-ALL were still MRD positive in contrast to 54% (78 of 144) patients with precursor B-ALL. In both groups the frequency of positive patients at TP2 (just before consolidation treatment) had approximately halved compared with the frequency found at TP1: 45% (25 of 55) in the T-ALL group and 26% (40 of 156) in the precursor B-ALL group. A further decrease at later time points was similar in both groups, but the frequency of MRD-positive patients remained higher in patients with T-ALL compared with patients with precursor B-ALL until halfway through maintenance treatment (mean difference, 14% ± 13%) (Figure 2).
Not only the frequency of MRD-positive patients but also the
level of MRD at the first 3 time points was significantly higher in
T-ALL than in precursor B-ALL (all P MRD levels did not differ significantly between patients analyzed with one MRD-PCR target and patients with 2 or 3 MRD-PCR targets. This applied to all time points in T-ALL and precursor B-ALL. Prognostic value of MRD in T-ALL is higher than in precursor B-ALL At each follow-up time point, MRD levels were highly associated with subsequent relapse rates: the higher the MRD level, the worse the prognosis (P[trend] < .001). Patients with T-ALL (n = 15) who were MRD negative or who had low MRD levels (104 or lower) at TP1 had a 5-year RFS rate of 100%. The
5-year RFS rates of patients with MRD-negative precursor B-ALL at TP1
were 96% (±2%) and 74% (±8%) for patients with low MRD levels
(Figure 3). High MRD levels
(102 or more) at TP1 resulted in a significantly lower
5-year RFS rates in T-ALL patients than in patients with precursor
B-ALL 14% (±8%) and 35% (±11%), respectively
(P = .04). This difference in RFS between precursor B-ALL
and T-ALL was also found at TP2 for high MRD levels
(P = .01) and intermediate MRD levels (103)
(P = .05). At TP3, patients with MRD-negative T-ALL had a
5-year RFS rate of 97% (±3%) compared with 86% (±3%) in precursor
B-ALL (not significant), and patients with MRD-positive T-ALL had a 5-year RFS rate of 22% (±8%) compared with 30% (±8%) in precursor B-ALL (not significant). From TP2 onward, the discrimination
between survival of MRD-positive and MRD-negative patients was always better in patients with T-ALL than in patients with precursor B-ALL.
Although apparent, these differences between T-ALL and precursor B-ALL
were not always significant.
The prognostic value of MRD level differed significantly between T-ALL
and precursor B-ALL at TP1 and TP2 (P = .03 and
P < .01, respectively). Using Cox regression analysis, it
was found that with each 10-fold decrease in MRD level at TP1 (from
10 MRD-based risk group classification The previously defined MRD-based risk group classification requires MRD information of TP1 and TP2. Patients at low risk were MRD negative at both time points, patients at high risk had MRD levels of 103 or higher at both time points, and the remaining
patients formed the intermediate-risk group.27 Forty-three
patients with T-ALL and 109 patients with precursor B-ALL could be
analyzed at TP1 and TP2 and could consequently be classified. These
patient subgroups did not differ significantly from the groups that
lacked one or both time points with respect to distribution of age,
sex, treatment group, and survival.
More than twice as many patients with T-ALL were classified in the
MRD-based high-risk group than patients with precursor B-ALL
The distribution of 1 versus 2 or 3 MRD-PCR targets did not significantly differ between the MRD-based risk groups of patients with T-ALL (P = .28) and patients with precursor B-ALL (P = .27), though the numbers of patients in some subgroups were low. Further classification of MRD-based intermediate-risk patients Later time points may have additional value for recognizing patients at good and poor risk in the MRD-based intermediate-risk group. MRD information of the BM sample taken just before reinduction treatment (TP3) did not have a significant additional value for patients with intermediate-risk precursor B-ALL (P = .08). On the other hand, for patients with intermediate-risk T-ALL, at TP3 a significant difference in outcome was found between MRD-negative patients (n = 10, 5-year RFS of 100%) and MRD-positive patients (n = 8, 5-year RFS of 38%) (P = .004). TP4 (start of maintenance treatment) also seemed to be of additional value for the intermediate-risk T-ALL group in contrast to precursor B-ALL; MRD-negative patients with T-ALL (n = 11) had a 5-year RFS of 82%, and MRD-positive patients (n = 3) had a 5-year RFS of 0% (P = .002). As found previously, TP5 at 1 year is an interesting time point for further monitoring patients with ALL initially classified as at intermediate risk. This holds true for precursor B-ALL and for T-ALL. We found significant differences between MRD-positive and MRD-negative patients, despite low patient numbers (P < .001 for T-ALL and P = .004 for precursor B-ALL).Because of the larger gradient of RFS according to MRD levels at TP1
and TP2 in T-ALL and the consistently lower relapse rates in the
patients with MRD-negative T-ALL compared with patients with precursor
B-ALL (Figure 3), one would expect it to be easier to discriminate
between good and poor treatment responses in patients with T-ALL in the
MRD-based intermediate-risk group. Indeed, the 10 T-ALL patients with
seemingly moderate treatment responses at TP1, as defined by low or
intermediate MRD levels ( Association between MRD-based risk group classification and T-ALL maturational stage Based on immunophenotype, patients with T-ALL could be categorized as having immature CD1/CD3 T-ALL
(n = 17), CD1+ T-ALL (n = 37), and mature
CD1/CD3+ T-ALL (n = 17) with 5-year RFS
rates of 47%, 72%, and 41%, respectively. The 43 patients with T-ALL
of the MRD-based risk group classification comprised 12 immature T-ALL,
25 CD1+ T-ALL, and 6 mature T-ALL. The 25 CD1+
T-ALL patients were not randomly distributed over the MRD-based risk
groups. In line with the relatively good prognosis of CD1+
T-ALL, they represented 90% (9 of 10) of the MRD-based low-risk group
and 57% (12 of 21) of the MRD-based intermediate risk group but only
33% (4 of 12) of the MRD-based high-risk group (P = .01). In addition, the 12 immature CD1/CD3 T-ALL
were not randomly distributed over the MRD-based risk groups: no
immature patients with T-ALL were classified as low risk, whereas 5 were classified as MRD-based high risk and the remaining 7 were classified as intermediate risk. Despite the low patient numbers, these
findings were in line with the difference in 5-year RFS between these 2 immunophenotypic subgroups. For the small group of mature
CD3+ T-ALL patients (n = 6), no association with
MRD-based risk groups was detected.
Prognostic value of MRD in the T-ALL patient group Multivariate analysis was performed for the 71 patients with T-ALL. Simultaneous evaluation of MRD-based risk group and treatment group showed that both factors were significantly related to RFS (P < .001 and P = .03, respectively). No additional prognostic value was found for age, sex, prednisone response, and WBC count on a continuous scale, although the latter weakly correlated with the MRD-based risk group classification.
T-lineage ALL is associated with more high-risk features than
precursor B-ALL.2,4 Despite the improvement in outcome by
intensive chemotherapy, patients with T-ALL generally have a
significantly worse RFS than patients with precursor
B-ALL.1,4,12,34 This difference in outcome was reflected
by the MRD pattern when studying 9 follow-up time points taken during
and after treatment by sensitive PCR techniques (detection limit
10 Recently, MRD was proven to be the most important prognostic parameter in several large prospective studies.25-27 Now we confirm that also within the relatively small subgroup of T-ALL patients, MRD is a highly relevant prognostic factor. The impact of MRD level information differed significantly between T-ALL and precursor B-ALL at early time points, TP1 and TP2. For each 10-fold decrease in MRD level, approximately 80% fewer relapses were found in T-ALL compared with approximately 60% fewer relapses in precursor B-ALL. Our results are consistent with those of previous MRD studies in T-ALL, which showed that MRD correlated with outcome.40,41 Dibenedetto et al41 found that the presence of MRD at the beginning of maintenance treatment was the strongest predictor of poor outcome. In our study MRD information at this relatively late time point was predictive. However, our semiquantitative MRD technique allowed us to discriminate between patients with good and poor prognoses at earlier time points, which is essential for early treatment stratification. The currently applied MRD-based risk group classification in childhood ALL, which is based on the kinetics of tumor reduction during the first 3 months of treatment, was found to be valid for T-ALL as well. All patients with T-ALL who were classified in the MRD-based high-risk group subsequently relapsed. Half of the patients with T-ALL were classified as at intermediate risk with a 5-year RFS rate of 76%, and 23% of the patients with T-ALL were classified as at low risk with a 100% RFS rate. Survival in the intermediate-risk and low-risk groups was similar to that in precursor B-ALL; only survival in the high-risk group was different in T-ALL than in precursor B-ALL (0% vs 25%). The distribution of T-ALL over the MRD-based risk groups was distinct from that of precursor B-ALL (Figure 4). More than twice as many patients with T-ALL were classified in the high-risk group (28% vs 11%), but the T-ALL low-risk group was half the size of the precursor B-ALL low-risk group (23% vs 46%). Consequently, approximately half of the patients with T-ALL belonged in the intermediate-risk group. MRD monitoring at later time points (TP3, TP4, TP5) gave additional prognostic value for the patients with intermediate-risk T-ALL who were classified as good and poor risk based on the absence and presence of MRD at each time point, respectively. Further monitoring of intermediate-risk precursor B-ALL was less valuable (only TP5 gave a significant difference), probably reflecting the larger heterogeneity in this ALL subgroup. Several BFM studies have shown the power of the initial prednisone response for recognition of many patients at high risk.8,9,12,29,42,43 However, our previous MRD study demonstrated that the prednisone response had no additional value on top of the MRD-based risk group classification.27 In addition, in this study, MRD information was a stronger prognostic factor than the prednisone response. Only 3 of 12 MRD-based high-risk precursor B-ALL patients and only 8 of 12 MRD-based high-risk T-ALL patients were predicted by poor prednisone response; all 11 patients had relapses. The other patients with poor prednisone response (n = 8) all belonged to the MRD-based intermediate-risk group, and half of them (4 of 8) had relapses. The distribution of patients with T-ALL over the MRD-based high-risk
and low-risk groups seemed straightforward, showing either a resistant
MRD pattern with 100% relapses or MRD negativity at TP1 and TP2 with
0% relapses, respectively. However, 10 intermediate-risk T-ALL
patients with moderate MRD levels (10 When the 10 intermediate-risk T-ALL patients with moderate MRD
levels at TP1 and MRD negativity at TP2 were shifted to the MRD-based
low-risk group, the MRD-based risk group classification further
improved Our MRD study shows that the MRD-based risk-group classification is
highly valuable for T-ALL. Within 3 months of diagnosis, MRD analysis
allowed the recognition of therapy-resistant T-ALL patients (28%) with
poor outcomes and a substantial group of T-ALL patients (23% or even
47%) with excellent prognoses. This implies that up to 75% of
patients with T-ALL might be classified as either low-risk or high-risk
patients. Although the overall survival rate of T-ALL is lower than
that of precursor B-ALL, still 60% to 70% of patients with T-ALL are
long-term survivors.15-17 Many of these survivors can now
probably be recognized as low-risk T-ALL patients. These data further
support the application of MRD kinetic information for treatment
stratification in childhood ALL. It should be emphasized that for this
purpose the MRD techniques should reach sensitivities of at least
10 Independent from prognostic parameters at diagnosis, MRD analysis provides direct insight into the in vivo drug sensitivity of ALL cells. Our study shows that this type of information allows a highly accurate prediction of outcome within the 2 major immunophenotypic ALL categories, particularly in T-ALL. It can be anticipated that sensitive MRD analysis comprises a tool to define distinct risk groups within other seemingly homogeneous prognostic categories, such as leukemias with a particular chromosomal aberration.
We thank Annemarie Wijkhuijs and Daniëlle Jacobs (Rotterdam,
Netherlands), Dorothee Erz, Yvonne Stark, and Simone Busenbender (Heidelberg, Germany), and Susanna Fischer and Marianne Konrad (Vienna,
Austria) for their expert technical assistance. We thank the
participants of the International BFM Study Group for their close
collaboration in performing the MRD study, namely the Dutch Childhood
Leukemia Study Group (P.J. van Dijken, K. Hählen, W.A. Kamps,
E.F. van Leeuwen, F.A.E. Nabben, A. Postma, J.A. Rammeloo, G.A.M. de
Vaan, A.J.P. Veerman, E.Th. van 't Veer-Korthof, and R.S. Weening),
the German BFM Group (W. Dörffel, C. Niemeyer, F. Berthold, M. Rister, A. Jobke, M. Domula, H. Wehinger, K. Hofmann, F.J. Göbel,
P. Heidemann, J.D. Beck, N. Graf, U. Mittler, A. Reiter, J.D. Thaben,
G. Henze, R. Dickerhoff, J. Treuner, R. Geib, P. Exadactylos, U Bode,
G. Eggers, W. Schröter, and C. Tautz), the Austrian BFM Group (B. Ausserer, F.M. Fink, R. Jones, G. Mann, G. Müller, I. Mutz, R. Ploier, W. Pobegen, K. Schmitt, and O. Stöllinger), and the
Italian AIEOP Group (G. Masera, V. Conter, M.G. Valsecchi, M. Aricò, E. Madon, G. Basso, E. Barisone, L. Zanesco, M.C. Putti,
M.T. Di Tullio, A. Murano, P.A. Macchia, and C. Favre). We thank Dr T. Szczepa
Submitted December 27, 2000; accepted February 20, 2002.
Supported by the BIOMED-1 program of the European Commission (grant BMH-CMT 94-1675), Dutch Cancer Society/Koningin Wilhelmina Fonds (grants EUR 94-852 and SNWLK 97-1567), Ank Van Vlissingen Foundation (M.J.W., J.J.M.v.D.), Deutsche Krebshilfe (C.R.B.), M. Tettamanti Foundation (A.B., G.M., E.D.), Associazione Italiana per la Ricerca sul Cancro, Minestero Università e Ricerca Scientifica e Technologica, Österreichische Kinderkrebshilfe (E.R.P.-G., K.H.), and FWF P-13575-MED (E.R.P.-G.).
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.
Reprints: J. J. M. van Dongen, Department of Immunology, Erasmus University Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands; e-mail: vandongen{at}immu.fgg.eur.nl.
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Top
Abstract
Introduction
70°C for DNA extraction.
ski, Dr K. Hählen, and Dr T. Révèsz for critical reading of the manuscript.
gene rearrangements in acute lymphoblastic leukemia.
Blood.
1993;82:3063-3074