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NEOPLASIA
Quantitative analysis of minimal residual disease predicts relapse in children with
B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01
Jianbiao Zhou,1 Meredith A Goldwasser,2 Aihong Li,1 Suzanne E. Dahlberg,2 Donna Neuberg,2 Hongjun Wang,1
Virginia Dalton,3 Kathryn D McBride,3 Stephen E. Sallan,3,4 Lewis B Silverman,3,4 and John G. Gribben,1
for the Dana-Farber Cancer Institute ALL Consortium
1Department
of Medical Oncology, 2Biostatistics and Computational Biology, and 3Pediatric Oncology, Dana-Farber Cancer Institute, and 4Children’s Hospital,
Harvard Medical School, Boston, MA
In a prospective trial in 284 children with
B-lineage acute lymphoblastic leukemia
(ALL), we assessed the clinical utility of
real-time quantitative polymerase chain
reaction analysis of antigen receptor gene
rearrangements for detection of minimal
residual disease (MRD) to identify children at high risk of relapse. At the end of
induction therapy, the 5-year risk of relapse was 5% in 176 children with no
detectable MRD and 44% in 108 children
with detectable MRD (P < .001), with a
linear association of the level of MRD and
subsequent relapse. Recursive partitioning and clinical characteristics identified
that the optimal cutoff level of MRD to
predict outcome was 10ⴚ3. The 5-year risk
of relapse was 12% for children with MRD
less than one leukemia cell per 103 normal cells (low MRD) but 72% for children
with MRD levels greater than this level
(high MRD) (P < .001) and children with
high MRD had a 10.5-fold greater risk of
relapse. Based upon these results we
have altered our treatment regimen for
children with B-lineage ALL and children
with MRD levels greater than or equal to
10ⴚ3 at the end of 4 weeks of multiagent
induction chemotherapy now receive intensified treatment to attempt to decrease
their risk of subsequent relapse. (Blood.
2007;110:1607-1611)
© 2007 by The American Society of Hematology
Introduction
Modern multiagent anticancer drugs and risk-stratification treatment have made childhood acute lymphoblastic leukemia (ALL)
the most successful example of a curable cancer.1-4 In 4 consecutive
clinical trials conducted by Dana-Farber Cancer Institute (DFCI)
ALL Consortium (a complete list of the members of the Dana
Farber Cancer Institute ALL Consortium is provided in Document
S1, available on the Blood website; see the Supplemental Materials
link at the top of the online article). Between 1981 and 1995, the
5-year event-free survival improved from 74% (⫾ 3%) to
83% (⫾ 2%).5,6 Identification of clinical and biologic features
associated with poor outcome allowed introduction of a riskadjusted strategy.7 It remains important to evaluate novel risk
factors to predict outcome so that therapy can be changed for
children at high risk of relapse and potentially to decrease toxicity
for children in whom less intensive therapy might be administered.
Children in complete remission (CR) can have up to 1010
leukemic cells,8-10 and with one exception,11 studies in childhood
ALL have demonstrated the prognostic significance of detection
and quantification of minimal residual disease (MRD).12-19 MRD
assessment from as early as 2 weeks after starting therapy predicts
outcome,20,21 with additional information obtained by multiple time
points analyses.14,22 Three methods are widely used for monitoring
MRD, multiparameter flow cytometric analysis,8,10 and polymerase
chain reaction (PCR) amplification of either fusion transcripts,23 or
of the antigen receptor rearrangements for immunoglobulin (Ig) or
the T-cell receptors (TCR).14,15 PCR amplification of Ig and TCR
rearrangements is limited by oligoclonality and clonal evolu-
tion,24-26 but is widely applicable and has high sensitivity. Difficulties in quantification of MRD reproducibly can be overcome by
real-time quantitative (RQ)-PCR, using consensus probes for
framework27,28 or joining regions.29 The clinical utility of RQ-PCR
has been reported to date in only small numbers of children.25,30-34
In this prospective study, we report on the clinical utility of
RQ-PCR analysis of MRD in a subset of 284 children with
B-lineage ALL on DFCI ALL Consortium Protocol 95-01. Detection of MRD at levels greater than or equal to one leukemia cell in
103 normal cells at the end of induction therapy was associated with
a 10.5-fold greater risk of relapse compared with those with MRD
below this level, after adjusting for risk and treatment group. Based
upon these findings, we have changed our treatment and intensify
therapy for children with B-lineage ALL with high MRD levels at
the end of remission induction therapy.
Submitted September 2, 2006; accepted April 16, 2007. Prepublished online as
Blood First Edition paper, May 7, 2007; DOI 10.1182/blood-2006-09-045369.
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 USC section 1734.
The online version of this article contains a data supplement.
© 2007 by The American Society of Hematology
BLOOD, 1 SEPTEMBER 2007 䡠 VOLUME 110, NUMBER 5
Patients, materials, and methods
Patients and samples
From 1996 to 2000, 498 children with ALL were enrolled consecutively at
8 participating consortium institutions in DFCI ALL Consortium Protocol
95-01.35 Institutional review board approval was received for treatment and
procurement of samples in all cases. Informed consent was obtained in
accordance with the Declaration of Helsinki. Children were classified at
diagnosis as standard risk (SR) or high risk (HR) based upon age, white
blood cell count (WBC) count, immunophenotype, presence or absence of
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BLOOD, 1 SEPTEMBER 2007 䡠 VOLUME 110, NUMBER 5
ZHOU et al
central nervous system leukemia, and presence or absence of anterior
mediastinal mass, and therapy adjusted for risk group.36 All patients
received a 4-week remission induction regimen, including vincristine,
prednisone, doxorubicin, high-dose methotrexate, and intrathecal therapy.
Postremission consolidation included weekly high-dose asparaginase for all
patients, with a randomization to either E coli or Erwinia asparaginase; high
risk patients also received doxorubicin up to a cumulative dose of
300 mg/m2. Total duration of therapy was 25 months. Bone marrow (BM)
and/or peripheral blood (PB) samples were obtained at diagnosis and at the
end of induction (day 30). Among these children, 491 were eligible for
evaluation, 52 had T-cell ALL and 1 had missing immunophenotype, so that
438 eligible children with B-lineage ALL were eligible for evaluation.
Criteria for inclusion in the present study included B-lineage ALL
achieving complete clinical remission (CR) at the end of induction
therapy, the presence of at least one MRD marker with a sensitivity of at
least 10⫺3, and a day-30 BM sample available for analysis. Of the 438
eligible children enrolled, 154 were excluded from this present analysis
because of induction death (4), induction failure (4), unavailable
diagnostic samples (15), unavailable day-30 BM sample (53), no
informative molecular marker (57), or the required level of sensitivity of
10⫺3 by RQ-PCR was not reached (21). Therefore, 284 children (65%)
were included in the final MRD analysis. Date of analysis was March 2007.
Molecular target identification
DNA and RNA were extracted and purified from mononuclear cells, and
IgH, TCR␥, and TCR␦ products PCR amplified and both strands sequenced.25,37 MRD quantification by RQ-PCR was performed for IgH
rearrangements and TCR rearrangements with results reported as the mean
of triplicates of copy numbers of the target gene divided by the mean of
triplicates of copy numbers of glyceraldehydes-3-phosphate dehydrogenase
(GAPDH).27 Unlike chromosomal translocations where primers can be
designed that will produce reproducible levels of sensitivity, primers and
probes that can be used for IG and TCR rearrangements are constrained by
the specific variable and joining genes used and by the length of the
complementarity determining region III (CDRIII).27,28 In cases where the
CDRIII region is short, there is competition between the rearrangement in
the leukemic cells and in healthy lymphocytes. Assays where the level of
detection was not reproducibly higher than 10⫺3 were excluded from
analysis, and this occurred for 21 children.
Statistical analysis
Differences in presenting characteristics were compared using chi-square
tests. All freedom from relapse (FFR) analyses at the end of induction used
the maximum MRD value of any BM sample obtained at day 30 (⫾ 7-day
window) of treatment for any molecular markers identified. MRD was
categorized as undetectable or into 5 ordered groups defined by a 1 log
difference in detectable MRD level (Table 1). FFR is time between date of
CR and date of relapse, censored at date of last contact or remission death.
The Kaplan-Meier method38 was used to estimate the distribution of FFR,
and univariate associations between MRD groups were tested using
log-rank tests. Multivariable regression analysis of FFR was conducted
using Cox proportional hazards models,39 controlling for treatment group,
risk group, and potential interactions of these and other covariates through a
stepwise selection approach. Recursive partitioning was used to explore the
best cut-point for classifying MRD groups using the Rpart function in R.40
Table 1. Distribution of MRD values at day 30 and freedom from
relapse (FFR) outcome
MRD level
Undetectable
Total
Relapsed
5-year FFR
SE
176
11
0.9
0.02
0.09
10⫺6 to less than 10⫺5
17
2
0.87
10⫺5 to less than 10⫺4
24
5
0.78
0.09
10⫺4 to less than 10⫺3
29
11
0.60
0.10
10⫺3 to less than 0.01
28
18
0.31
0.09
0.01 or more
10
9
0.20
0.13
284
56
0.80
0.02
Total
All tests conducted were 2-sided at .05 significance level. There were no
corrections for multiple comparisons.
Results
Study population
The primary goal was to assess the clinical significance of MRD
quantification at the end of induction therapy. Two hundred
eighty-four children with B-lineage ALL fulfilled criteria for
inclusion in this study. The median follow-up was 5.6 years and
5-year overall FFR was 0.80 (⫾ .02; ⫾ SE). Two children died in
remission without relapse and were censored at date of death and
56 had relapsed by the time of analysis. No significant differences
were observed between those included (n ⫽ 284) and not included
(n ⫽ 146) in the end of induction MRD analysis for risk group
(P ⫽ .36), WBC count group (P ⫽ .14), sex (P ⫽ .35), treatment
group (P ⫽ .59), and age group (P ⫽ .0547). Since the P values for
age group were close to the level for significance, we also looked at
association between age combining the HR age categories compared with the SR ages, and the P value was then .46. Those
included had lower 5-year FFR (80%) than those not included
(88%) (P ⫽ .054). No significant differences were observed between the 81 patients with no informative marker and those for
whom a marker was identified for risk group (P ⫽ .50), WBC
count (P ⫽ .16), age group (P ⫽ .19), sex (P ⫽ .21), treatment
group (P ⫽ .99), and FFR (P ⫽ .08).
MRD value at end of induction predicts relapse
We analyzed the impact of the level of MRD at the end of induction
(day 30) in the 284 children, who had at least one BM sample. For
each child, the maximum MRD value for any marker identified25,37
among the day-30 samples was used. Potential sensitivity of
detection of the rearrangement was assessed from the standard
curves of the cloned PCR product27 and was 10⫺6 in 189 (66.6%),
10⫺5 in 49 (7.3%), 10⫺4 in 26 (89.2%), and 10⫺3 in 20 (7.0%) cases.
MRD was undetectable in 176 (62.0%), 11 of whom relapsed, with
5-year FFR of 0.95 (⫾ 0.02). Eight of these 11 cases had evidence
of clonal evolution, with a different sequence at relapse compared
with that observed at presentation.25 MRD was detectable in 108
(38.0%), 45 of whom relapsed, with 5-year FFR of 0.56 (⫾ 0.05;
P ⬍ .001). There was a linear association of MRD with risk of
relapse (P ⬍ .001) based upon ordinal categories of MRD level
(Table 1). When the MRD level is stratified by these levels as
ordinal, the log-rank trend test indicated a significant linear
association of MRD with risk of relapse (P ⬍ .001). A Cox
regression model of FFR estimated a 2-fold (95% CI, 1.8-2.4) risk
of relapse for each 1 log increased level of MRD (Figure 1).
Moreover, results from fitting a Cox regression model of FFR with
MRD detected or not and an interaction term between MRD
detection and the actual MRD value included as predictors
suggested that among those with detectable MRD, the actual MRD
value was associated with increased risk of relapse (P ⫽ .001) after
accounting for MRD detection overall (P ⬍ .001).
Recursive partitioning analysis was used to explore the best
MRD cut-point based on the FFR outcome with the MRD groups
categorized as in Table 1 and treated as nonordinal categories
(results based on ordinal categories and the actual MRD values did
not differ substantially). One primary split and 2 secondary splits
were observed, resulting in 4 distinct MRD groups: undetectable,
MRD of 10⫺6 to ⬍ 10⫺4, 10⫺4 to ⬍ 10⫺3, and 10⫺3 or higher.
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BLOOD, 1 SEPTEMBER 2007 䡠 VOLUME 110, NUMBER 5
RQ-PCR IN CHILDHOOD ALL
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Table 2. Comparison of known risk factors, treatment groups, and
clinical outcome of patients with high versus low MRD at day 30
Low MRD,
< 10ⴚ3 (%)
High MRD,
> 10ⴚ3 (%)
P
246
38
—
160 (65.0)
14 (36.8)
86 (35.0)
24 (63.2)
211 (85.8)
27 (71.1)
35 (14.2)
11 (28.9)
0 to younger than 1
7 (2.9)
4 (10.5)
1 to younger than 10
205 (83.3)
24 (63.2)
34 (13.8)
10 (26.3)
Male
125 (50.8)
21 (55.3)
Female
121 (49.2)
17 (44.7)
82 (33.3)
5 (13.2)
Variables
Total number
Chi-square, ⬍ .001
Risk group
Standard risk
High risk
WBC count, ⴛ 109/L
Lower than 50 000
50 000 or higher
Chi-square, .02
Age, y
10 or older to younger than 18
Chi-square, .007
Sex
Figure 1. Freedom from relapse by MRD level at day 30. Patients are grouped
based on 6 categories of MRD: undetectable or, if detectable, defined by a 1 log
difference in MRD value as shown in Table 1.
Chi-square, .61
Asparaginase treatment
Randomized to E coli
Randomized to Erwinia
Based upon these recursive partitioning analyses, clinical
considerations, the difficulty of accurately quantifying MRD levels
below a level of 10⫺4, and the finding that all sensitivity of
detection values were 10⫺3 or less, the optimal cutoff level of MRD
to predict relapse was chosen as 10⫺3. As shown in Figure 2, among
the 38 children (13%) with MRD greater than or equal to 10⫺3
(high MRD), 27 relapsed and 5-year FFR was 0.28 plus or minus
0.08 compared with 0.88 plus or minus 0.02 for the 246 (87%)
children with MRD less than 10⫺3 (low MRD) (P ⬍ .001). Of note,
low MRD includes those with undetectable levels. The median
FFR was 34 months in the high MRD group but because of the
small number of relapses was undefined in the low MRD group.
Effect of high versus low MRD within risk subgroups
Children with high MRD at end of induction were more likely to be
high risk, have WBC count of 50 000 ⫻ 109/L or higher, less likely
to be age 1 to younger than 10 years, and less likely to be
randomized to E coli asparaginase (Table 2). We therefore further
explored the effect of MRD level on FFR within risk and treatment
groups. The effect of the clinical significance of the MRD level on
FFR did not appear to differ by risk group or asparaginase
treatment group. Among the subset of standard risk patients, 5-year
FFR was 0.88 (⫾ 0.03) among the 160 with low MRD versus
0.43 (⫾ 0.13) among the 14 with high MRD (P ⬍ .001). Among
Chi-square, .04
64 (26.0)
12 (31.6)
100 (40.7)
21 (55.3)
Yes
29 (11.8)
27 (71.0)
No
217 (88.2)
11 (29.0)
Direct assigned E coli
Log rank, ⬍ .001
Relapse
— indicates not applicable.
the subset of high risk patients, 5-year FFR was 0.88 (⫾ 0.04)
among the 86 with low MRD versus 0.19 ⫾ 0.08 among the 24
with high MRD (P ⬍ .001). Similarly, we did not identify clinically meaningful interactions between MRD level and asparaginase
treatment group (Table 2). Therefore, the effect of MRD on FFR
does not appear to differ by risk or treatment group. Although we
now routinely use fluorescent in situ hybridization (FISH) to screen
for known relevant translocations, this assay was not used routinely
until 2000, before the period of diagnosis of the patients examined
here, so information regarding specific translocations is missing
from sufficient number of patients in the present study to make
reporting not meaningful. However, expression of Tel/AML136 was
not associated with level of MRD (P ⫽ .97). However, the effect of
high MRD versus low MRD may be greatest among those who
expressed Tel/AML1 in whom the 5-year FFR was 0.96 (⫾ 0.03;
2 relapses in 56 children) with low MRD versus 0.13 (⫾ 0.12;
7 relapses in 8 children) with high MRD. Among those who are
Tel/AML1 negative, 5-year FFR was 0.85 (⫾ 0.03) with low MRD
(24 relapses in 160 children) versus 0.36 (⫾ 0.10) with high MRD
(16 relapses in 25 children).
Multivariate modeling of FFR with MRD controlling for other factors
Figure 2. Freedom from relapse by MRD level based on high MRD (> 10ⴚ3)
versus low MRD (< 10ⴚ3).
Multivariable analysis of the prognostic value of high versus
low MRD detection for the risk of relapse was performed using
Cox proportional hazards regression models, with predictors
including MRD (high versus low), risk group (high versus
standard risk), asparaginase treatment group (using 2 treatment
indicators: randomized Erwinia versus randomized E coli
asparaginase, and directly assigned versus randomized E coli
asparaginase), sex, and each of their 2-way interactions added
separately. Likelihood ratio tests were used to assess statistical
significance, and interactions with the treatment group variables
were tested jointly. None of the 2-way interactions were
significant at the 5% level of significance, and these were not
included in further models. Sex was also not significant and was
dropped from the modeling. In all models containing risk group
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BLOOD, 1 SEPTEMBER 2007 䡠 VOLUME 110, NUMBER 5
ZHOU et al
Table 3. Estimates from the final Cox model of FFR with high versus
low MRD at end of induction, risk group, and treatment group
included as covariates
Cox model estimates
Predictors
Day 30 MRD (high vs low)
Risk group (high vs standard)
Hazard
ratio
95% hazard
ratio confidence
limits
P
10.60
6.05
18.55
⬍ .001
1.29
0.75
2.21
.36
1.37
0.65
2.87
.40
1.11
0.54
2.28
.79
Randomized Erwinia (vs
randomized E coli)
Direct assigned E coli (vs
randomized E coli)
and asparaginase treatment group, MRD (high versus low)
remained the only significant independent prognostic factor
(P ⬍ .001). When MRD was included in the main effects model,
both risk group and treatment group were no longer independent
predictors of relapse (Table 3). Controlling for risk and treatment
group, children with high MRD following induction had 10-fold (95%
CI, 6.1-18.6) risk of relapse than those with low MRD.
Since presenting WBC count and age were collinear with risk group
they were not included in this modeling. Substituting these variables for
risk group into the main effects model demonstrates that although MRD
remained highly significant, the WBC count at presentation was also an
independent predictor of relapse after adjusting for other variables in the
model (P ⫽ .07). When an interaction term between MRD and WBC
count group was added to this model it was not significant (P ⫽ .41),
suggesting that the effect of MRD does not differ by WBC count group.
This was further explored by examining the effect of MRD within WBC
count subgroups. Among the 238 children with WBC count lower than
50 000 ⫻ 109/L, 211 had low MRD of whom 24 relapsed, with 5-year
FFR of 0.89 (⫾ 0.02), and 27 had high MRD of whom 18 relapsed, with
5-year of FFR 0.35 (⫾ 0.09), P ⬍ .001. Among the 46 patients with
WBC count of 50 000 ⫻ 109/L or higher, 35 had low MRD of whom 5
relapsed, 5-year FFR of 0.85 (⫾ 0.06), and 11 had high MRD of whom
9 relapsed, with 5-year FFR of 0.11 (⫾ 0.10; P ⬍ .001). The effect of
level of MRD did not differ by WBC count group. Another informative
way to look at the subgroups was to compare relapse rates between
WBC count groups within high or low MRD groups. FFR was not
significantly different between WBC count groups among those with
high MRD (P ⫽ .13) or among those with low MRD (P ⫽ .59),
although in both subgroups there was a trend that having WBC count
lower than 50 000 ⫻ 109/L was associated with better FFR. Having
WBC count of 50 000 ⫻ 109/L or higher did not explain the relapses
among the low MRD group, since 5 of 35 patients with WBC count of
50 000 ⫻ 109/L or higher relapsed (5-year FFR of 0.85 ⫾ 0.06) and
24 of 211 with WBC count lower than 50 000 ⫻ 109/L relapsed (5-year
FFR of 0.89 ⫾ 0.02) among the low MRD group. These exploratory
subgroup analyses further suggested no interaction between MRD
group and WBC count group, that is, that the effect of MRD did not
differ between WBC count groups. Although having WBC counts of
50 000 ⫻ 109/L or higher leads to poorer outcome in general, this by
itself did not explain the relapses that occurred in the low MRD group.
Discussion
Previous studies have shown that early response to therapy in childhood
ALL is an important indicator of treatment outcome and that quantitative assessment of MRD by either flow cytometric or PCR-based
analyses can be used to assess the risk of subsequent relapse.12-19 Here,
we report the use of RQ-PCR to determine the prognostic significance of
the detection and quantification of MRD at the end of induction therapy
in B-lineage ALL. We demonstrate that quantitative assessment of
MRD in children with ALL is the most important prognostic factor
determining subsequent relapse. Children with high MRD at the end of
induction had a shorter time to relapse and a 10.5-fold risk of relapse
than those with low MRD levels after controlling for risk and treatment
group. Further illustration of the value of this approach is highlighted by
the finding of a linear relationship of MRD with relapse, as well as the
importance of the actual quantitative MRD value after controlling for
MRD detection.
The difficulty in reproducibly quantifying PCR products can
largely be overcome by the use of RQ-PCR. Although this
approach is being incorporated in ongoing clinical trials, results
have been reported to date in only relatively small numbers of
patients.25,30-34 The sensitivity of flow cytometric detection of MRD
depends on the specificity of the immunophenotype and on the
number of cells available for study. Although the estimated levels
of MRD may vary, flow cytometry and PCR-based detection of
MRD in ALL yields concordant results in the vast majority of
cases, leading some groups to suggest that both types of analyses
should be performed in combination.34,41
Previous studies have demonstrated that antigen receptor rearrangements are not always stable and that that the risk of change
increases with time.24,42 We have demonstrated in this protocol that
up to 10% of relapses occurred with a different antigen receptor
rearrangement than at presentation,25 and of note the majority of
relapses that occurred in children with no detectable MRD at day
30 relapsed with disease bearing a novel rearrangement compared
with that observed at diagnosis. Ideally more than one target should
be followed for MRD assessment in children with ALL as well as a
combined use of flow cytometric and PCR-based analyses.34,41
However, consideration must also be given to the cost of multiple
types of analyses for multiple markers in the assessment of MRD.
In the present report, assessment of the level of MRD at day 30
alone, even when only one MRD target is assessed, was sufficient
to identify patients at sufficiently high risk of relapse to merit
change in therapy. More importantly, assessment of MRD at day 30
is sufficiently early to allow subsequent change of therapy to
attempt to alter the poor prognosis of these patients. In this study,
first pass direct sequencing alone was used to identify suitable
markers since it was an aim of the study to identify in what
proportion of children this approach would be successful. On this
basis, 102 children were excluded from analysis in whom either no
informative rearrangement was detected or the marker could not be
quantified at sufficient sensitivity. This is unacceptably high if
MRD levels are to be used for treatment decisions. In ongoing
studies where clinical decisions are being made based upon the
MRD levels, additional steps are being taken to identify suitable
markers for study in the vast majority of patients. Irrespective of
these limitations, quantification of MRD by RQ-PCR at day 30 by
itself identified patients at sufficiently high risk of relapse and early
enough in their disease course to change therapy to attempt to alter
prognosis. Based upon these results, we have changed our treatment approach and children with B-lineage ALL and high MRD at
the end of induction therapy now receive treatment intensification
to attempt to decrease their risk of subsequent relapse.
Acknowledgment
This work was supported by NIH grant CA68484 (J.G.G. and S.E.S.).
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BLOOD, 1 SEPTEMBER 2007 䡠 VOLUME 110, NUMBER 5
RQ-PCR IN CHILDHOOD ALL
Authorship
Contribution: J.G.G. designed the study and supervised the analyses; J.Z., A.L., and H.W. performed laboratory analysis; M.A.G.,
S.E.D., and D.N. performed statistical analysis; L.B.S. and S.E.S.
designed the clinical study; V.D. and K.D.M. collected and verified
samples and clinical data; J.G.G., M.A.G., and J.Z. wrote the paper;
all authors agree with the final paper.
1611
A complete list of the members of the Dana-Farber Cancer
Institute ALL Corsortium is provided in Document S1.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: John G. Gribben, CRUK Medical Oncology Department, Barts and The London School of Medicine,
Charterhouse Square, London EC1M 6BQ; e-mail:
[email protected].
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From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
2007 110: 1607-1611
doi:10.1182/blood-2006-09-045369 originally published
online May 7, 2007
Quantitative analysis of minimal residual disease predicts relapse in
children with B-lineage acute lymphoblastic leukemia in DFCI ALL
Consortium Protocol 95-01
Jianbiao Zhou, Meredith A Goldwasser, Aihong Li, Suzanne E. Dahlberg, Donna Neuberg, Hongjun
Wang, Virginia Dalton, Kathryn D McBride, Stephen E. Sallan, Lewis B Silverman and John G.
Gribben
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