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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 72-77
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Effect of time to complete remission on subsequent survival and
disease-free survival time in AML, RAEB-t, and RAEB
Elihu H. Estey,
Yu Shen, and
Peter F. Thall
From the Departments of Leukemia and Biomathematics, University of
Texas M. D. Anderson Cancer Center, Houston, TX.
 |
Abstract |
The authors examined the relationship between the time required to
enter complete remission (CR) after a first course of chemotherapy for
newly diagnosed acute myeloid leukemia (AML), refractory
anemia with excess blasts in transformation (RAEB-t), or refractory
anemia with excess blasts (RAEB). They also examined subsequent
survival time and disease-free survival time after accounting for
cytogenetic status, age, and treatment. The data set consisted of 1101 patients with these diagnoses treated at the M. D. Anderson
Cancer Center between 1980 and 1996 for whom outcomes were established
after first-course therapy. Of the 1101 patients, 740 (67%) were in CR
after this time; 508 of these 740 (69%) have died (80% had disease
recurrence before death). The authors used the parametric model of Shen
and Thall to estimate, in particular, TC (time to CR),
TC,D (time from CR to death = residual survival after
CR), and TC,R (residual disease-free survival [DFS] after
CR) as functions of the covariates noted above and to estimate the
dependence of TC,D and TC,R on TC.
There was a strong inverse association between TC and both
TC,D and TC,R (P < .001 for both)
that was independent of cytogenetic status, age, or treatment. The
residual survival time of patients who required >50 days to enter CR
was closer to the residual survival time of resistant patients than to
that of patients known to be in CR within approximately 30 days of the
start of treatment. Time to CR is an independent predictor of residual
survival and disease-free survival in patients with newly diagnosed AML
who achieve CR after 1 course of chemotherapy. (Blood.
2000;95:72-77)
© 2000 by The American Society of Hematology.
| |
Introduction |
Reports of clinical trials of patients with acute
myeloid leukemia (AML) universally note whether a given treatment
produces "complete remission" (CR), defined according to standard
criteria.1 This focus on CR as a clinical endpoint stems
from data published in the 1960s indicating that prolonged survival
time in patients with AML is impossible if CR is not
achieved.2 The number of courses required to produce CR is
also frequently reported, reflecting the knowledge that CR occurring
only after more than 1 course of induction therapy is generally shorter
than that observed after the first course.3 However, this
qualification aside, CR is generally viewed as a binary outcome, ie, it
either does or does not occur.
Nonetheless, it appears plausible that events transpiring during a
first, successful course of remission induction therapy may influence
the subsequent outcome. Based on our observations of the brevity of
remission in some patients in whom the criteria for CR particularly a
platelet count >100,000were met only many weeks after beginning
treatment, we have been interested in the relationship between the time
required to enter CR after a first course of chemotherapy and
subsequent disease-free and overall survival times. In this article we
examine these relationships after accounting for treatment and for
factors known to influence these times, specifically age and
cytogenetic status. In addition to providing an overall analysis, we
report separate analyses for patients with de novo AML and for patients
with either AML arising after a history of abnormal blood counts or
with myelodysplastic syndromes (MDS). To examine whether CR remains a
precondition for lengthy survival in the 1980s and 1990s, we also
compared survival times from the response dates for patients meeting
the criteria for CR after the first course of therapy with survival times from response dates for patients who, considered resistant to
this initial course, were taken off-study on this date.
| |
Patients and methods |
Between 1980 and 1996, 1498 patients with newly diagnosed
AML (acute promyelocytic leukemia excluded), refractory anemia with excess blasts in transition (RAEB-t), or refractory anemia with excess
blasts (RAEB) came to the M. D. Anderson Cancer Center for
treatment. Our analysis considered 1101 of 1498 (73%) patients in whom
response (CR, death, or "resistance") was established after the
first course of induction therapy. Criteria for CR were those we have
used previously: a marrow with <5% blasts concomitant with a
neutrophil count of >1000/µL and a platelet count of
>100 000/µL. Of the 1101 patients, 740 (67%) were in CR after 1 course, 290 (26%) were dead, and the remaining 71 (6%) were removed
from their initial treatment protocol because they were considered resistant. Of these 71, 25 (35%) received no additional therapy, and
40 (56%) underwent an alternative treatment protocol (chemotherapy 35, allogeneic transplant 5) that produced CR in 6 patients. In the final 6 of the 71 resistant patients, no information about subsequent therapy
is available. Among the 397 patients in whom a response was not
established after the first course of induction therapy but who
continued to be treated on their initial protocol, 175 (44%) achieved
CR, 88 (22%) died, and 132 (33%) were eventually removed from the
protocol because of resistance. Thus, 81% of the 915 instances of CR
that occurred with the initial treatment protocol were observed after
the first course of therapy, as were 77% of the deaths. This
observation was made after the first course of therapy, however, in
only 35% of the patients considered resistant to the initial protocol.
Figure 1 depicts outcomes in the 1101 patients in whom responses were established after the first course
alone. Of the 740 patients in CR after this course, 508 (69%) have
subsequently died, as have 65 of the 71 (92%) patients called
resistant. Of the 508 patients who died after entering CR, 407 (80%)
experienced disease recurrence before death. To assess the effects of
the time required to achieve CR on subsequent survival time, the
following times are considered: TC is the time from start
of treatment to CR date, TC,D is the time from CR date to
death (ie, the "residual" survival time after CR), TR
is the time from the start of treatment to the date the patient was
considered resistant, TR,D is the residual survival time
from date of resistance, and TD is the time from start of
treatment to death in patients who died before CR occurred or
resistance was observed. We wanted to examine the distributions of each
of the 5 times TC, TC,D, TR,
TR,D, and TD as functions of several baseline
variables (covariates) and, in the cases of the residual survival times
TC,D and TR,D, also as a function of,
respectively, TC and TR. The main question was whether, after accounting for patient covariates, residual survival time after CR, TC,D, was influenced by the time
required to achieve CR, TC. The covariates that we included
in the analysis were patient age, cytogenetic status, and treatment.
Based on previous results,4,5 age was considered as a
numerical (ie, continuous) variable, whereas 3 cytogenetic groups
were distinguished: 1) normal karyotype (considered the baseline or
reference group), 2) inv(16) or t(8;21) and 3) all other karyotypes,
including patients with insufficient metaphases for cytogenetic
analysis, with these categories as previously defined.4,5
The median age of the 1101 patients was 57 years; 43% had normal
karyotypes, 11% had inv(16) or t(8;21) and 46% had other abnormal
karyotypes or insufficient metaphases. Numerous treatment regimens were
investigated during the 1980 to 1996 period, and results with many have
been reported.6-9 Eleven regimens each accrued >25
patients. The most commonly used regimens were idarubicin + high-dose
ara-C (IA, 127 patients), IA + G-CSF (126 patients), and fludarabine + ara-C + G-CSF (FLAG, 111 patients). For this analysis we grouped the
treatment regimens as follows: 1) anthracycline (or
amsacrine) ± conventional dose ara-C (each dose <0.5
g/m2), 2) "high-dose" ara-C (each dose
 0.5g/m2) ± anthracycline (or amsacrine)
but without fludarabine, and 3) high-dose ara-C + fludarabine ± idarubicin. Patients in these 3 treatment groups numbered,
respectively, 186, 549, and 366.
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| Fig 1.
Therapy outcome.
Outcome of therapy in the 1101 patients whose outcomes (complete
remission [CR], death, or resistance) were established after the
first course of chemotherapy. TC = time from start of
treatment to CR; TC,D = time from CR date to death;
TR = time from start of treatment to "resistance";
TR,D = time from resistance date to death; and
TD = time to death in patients dying before considered to
be in CR or to be resistant.
|
|
To estimate each of TC, TC,D, TR,
TR,D, and TD as a function of the covariates
noted above, and of the dependence of the residual survival times
TC,D on TC and TR,D on
TR, we used the general parametric model described by Shen
and Thall10 for multiple nonfatal competing events (here,
CR and resistance) and death. In this formulation, death censors all
nonfatal events that have not occurred, the time to a nonfatal event
and subsequent residual survival time may be either positively or
negatively associated, and the overall survival distribution is a
mixture of 3 different distributions corresponding to death after CR,
death after resistance, and death without an antecedent nonfatal event.
The distribution of each event time is specified marginally by a
parametric model that accommodates covariates and the usual
administrative censoring. One may wonder whether it would not be
simpler to perform the usual Cox regressions for each of
TC, TC,D, TR, TR,D, and
TD while using the time to each nonfatal event (CR or
resistance) as a covariate possibly influencing subsequent residual
survival time after these events. This approach, however, requires the
unrealistic assumption that the underlying death rates for patients who
do or do not experience nonfatal events are the same and that,
moreover, achieving CR or being declared resistant does not alter the
subsequent risk for death. These assumptions are not made under the
model of Shen and Thall, which distinguishes between survival time for patients who achieve CR, TC + TC,D, patients
who are declared resistant, TR + TR,D, and
patients who die without a nonfatal event, TD. The Cox
model, as usually applied, makes no such distinction. Figure
2, which compares the estimated survival
curve of the 1101 patients as derived from the parametric model to the
corresponding Kaplan-Meier curve, illustrates that the parametric model
provides an excellent fit to the data.
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| Fig 2.
Estimated survival time.
Estimated survival time curve of the 1101 patients as derived from the
parametric model compared to the Kaplan-Meier survival curve for the
same patients.
|
|
The Shen-Thall model was also used to estimateas functions of
TC, age, cytogenetics, and treatment classified as
described abovethe time from CR to disease recurrence or to death in
CR, whichever came first, and the time from CR to disease recurrence. We denote the first of these times, corresponding to disease-free survival among patients achieving CR, as TC,R, and the
second time, corresponding to remission duration, as
TC,REL. Among the 740 patients who achieved CR, recurrences
occurred in 472 (64%) patients and death during CR occurred in 101 (14%) patients. One should bear in mind that analyses of remission
duration are confounded because there is no assurance that death in CR
and recurrence are independent events. Without such assurance, the
practice of censoring patients who die in CR, when conducting analyses
of remission duration, is invalid.4 In contrast, no such
problems accompany analyses of disease-free survival time among
patients in CR.
We also conducted separate analyses of patients with de novo AML
(n = 601) and of patients (n = 500) either with AML that arose
after an antecedent hematologic disorder (AHD) or with MDS (RAEB or
RAEB-t). An AHD is defined as a documented abnormality in the blood
count present for at least 1 month before presentation. Of the de novo
group 447 (74%) were in CR after the first course of therapy, 133 (22%) died, and 21 (3%) were resistant. Death occurred in 65% of the
responders and in 90% of the resistant patients. Among the 500 patient
"secondary" group, the CR rate after the first course was 59%,
whereas 31% died and 10% were considered resistant. Seventy-five
percent of the responders and 92% of the resistant patients died.
| |
Results |
Overall results
Table 1 summarizes the estimated effects
of the covariates on TC (time to CR) and TC,D
(residual survival after CR) and also provides the estimated
association parameter describing the relationship between them. For
simplicity, additional parameter estimates specifying each event time
distribution (3 parameters for each event time) are omitted, because
these add no relevant information to the issues under discussion here.
Table 1 demonstrates that the only covariate that had a statistically
significant (P < .05) effect on TC was age
(increasing age associated with longer time to CR). In particular,
neither the presence of an inv(16) or a t(8;21) nor the presence of
other abnormalities had such an effect on TC relative to
what was observed in patients with normal karyotype. There was a trend
however (P = .095) for these other abnormalities to be
associated with a longer TC. Treatment (regimens containing high-dose cytarabine [HDAC] without fludarabine, or
fludarabine + HDAC-containing regimens compared with regimens not
containing HDAC) had statistically insignificant effects on
TC. In contrast, both cytogenetics and age had the expected
highly significant effects on time from CR to death (longer with
inv(16) or t(8;21) shorter with other abnormalities or with increasing
age). Treatment again had no effect. Of greatest interest was the
association parameter describing the relationship between
TC and TC,D. The value for this parameter was
negative ( 0.529, Table 1), indicating that as TC
increased TC,D decreased. The inverse relationship between
these 2 times was highly significant (P < .001), and this was the case regardless of whether the model was fit to include treatment, age, and cytogenetics.
The findings were entirely analogous when TC,R (residual
disease-free survival) was examined in place of TC,D
(residual survival), consistent with the observation that 80% of the
patients who died after achieving CR had a recurrence of disease before
death, as noted above. Specifically, the covariate-adjusted association parameter between TC and TC,R was 0.619
with a standard deviation of .112, indicating that the relationship
between time to CR and subsequent disease-free survival time was
inverse and highly significant (P < .001). As expected, the
multivariate model indicated that inv(16) or t(8;21) was associated
with a longer TC,R (P = .005), whereas other
cytogenetic abnormalities and increasing age were associated with
shorter values for this parameter (P = .002 for both age and
cytogenetics). Like TC,D, TC,R was
unaffected by treatment. Similarly, the covariate-adjusted association
parameter between TC and TREL, the latter
denoting remission duration, was negative (0.580) and highly
significant (P < .001), indicating that longer times to
achieve CR were associated with briefer remissions.
Time to death without achieving CR or being declared resistant
(TD) was shorter with increasing age and cytogenetic
abnormalities other than inv(16) or t(8;21) (P < .0001 for
both), and it was longer with either of the latter 2 abnormalities
(P = .016) and for patients given fludarabine + HDAC regimens
(P = .022). The presence of prognostically unfavorable
cytogenetic abnormalities was strongly associated (P = .009)
with a shorter time from start of treatment to declaration of
resistance (TR), but no other covariate had a statistically
significant effect on this interval. There was the expected inverse
relationship (P = .038) between increasing age and residual
survival time after a patient was declared resistant (TR,D); other covariates had no effect. In contrast to the
inverse relationship between time to CR and residual survival time,
time to resistance and subsequent survival time were positively
associated (association parameter between TR and
TR,D = 0.296), but the relationship was statistically
insignificant (P = .52). One should bear in mind, however,
that only 71 patients were declared resistant and the undoubted
subjectivity associated with the decision to consider patients resistant.
Figure 3 compares median residual survival
times in patients who entered CR at a given time, denoted as t,
with median residual survival times in patients who were declared
resistant at t. The figure includes the 95% confidence
interval for each estimated residual median survival time. The times of
CR are given along the top of the graph, and the times of declaration
of resistance are given along the bottom. Two points should be noted.
First, patients who achieve CR at time t live longer than
patients who are considered resistant at t regardless of the value of
t. Second, reflecting the negative association between
TC and TC,D, there is a sharp decline in
residual survival as time to enter CR increases. In particular, the
residual survival of patients who required more than ~50 days to
enter CR is closer to the residual survival time of resistant patients
than to that of patients known to be in CR within approximately 30 days
of the start of treatment. It is essential to note that the inverse
relationship between TC and TC,D was observed
in patients with inv(16) or t(8;21) (Figure 4A) and in patients with normal or
prognostically poor karyotypes (Figure 4B). However, though median
residual survival time decreased with TC in each of these 2 patient subgroups, this effect was dominated by the effect of
cytogenetics. Specifically, even if remission induction for an inv(16)
or t(8,21) patient took more than 2 months, that patient's estimated
median residual survival time remained longer than that of a patient
with normal or poor cytogenetics who achieved CR more quickly.
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| Fig 3.
Median residual survival.
Median residual survival time after complete remission (CR) or
resistance as functions of the times to these nonfatal events. CR times
are indicated along the top of the graph, and declaration of resistance
times are indicated along the bottom. Of the 740 patients achieving CR,
19 required  20 days, 406 required 21-30 days, 213 required 31-40
days, 65 required 41-50 days, and 37 required >50 days.
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| Fig 4.
Mean residual survival as function of time.
(A) Median residual survival time after complete remission (CR) as a
function of time to CR in patients with inv(16) or t(8;21). (B) Median
residual survival time after CR or resistance as functions of the times
to these events in patients with karyotypes other than inv(16) or
t(8;21).
|
|
Subset analyses
It was possible that the inverse relationship between time to
achieve CR and residual survival time and residual disease-free survival time reflected the presence, in our data set, of a substantial number (500) of patients with AML that developed after AHD or with MDS.
Such patients comprised 45% of all 1101 patients. We addressed this
possibility by conducting separate analyses for the de novo and
secondary groups (Table 2). In both cohorts
the association parameter between TC and TC,D
was negative, indicating an inverse relationship between these 2 times.
This relationship reached statistical significance only in the case of
the de novo cohort (P = .0004). Table 2 also indicates that
the effect of inv(16) or t(8;21) on TC,D was seen only in
the de novo cohort, whereas the effect of other cytogenetic
abnormalities on this parameter was largely a result of its effect on
patients with AML after AHD or with MDS. The effect of age on
TC,D was apparent in both cohorts.
The finding that under the relevant multivariate models TC,
but not treatment, was a predictor of both TC,R
and TC,D strongly suggested that the inverse relationship
between TC and the latter times would be observed in each
of the 3 treatment groups defined in the Patients and Methods section
(no HDAC, HDAC, fludarabine + HDAC). To confirm this suggestion, we
computed the association parameters between TC and
TC,D in each of these 3 treatment groups, numbering 186 (with 120 CR), 549 (with 395 CR), and 366 (with 225 CR) patients,
respectively. In each group, the value for this parameter was negative
(0.248 no HDAC, 0.529 HDAC, 0.922 fludarabine + HDAC), as it had been in the whole data set. The corresponding probability values for the hypothesis that TC and
TC,D were unrelated were P = .376,
P = .002, and P < .001 for no HDAC, HDAC, and
fludarabine + HDAC respectively, recalling that the sample size was
smallest in the no HDAC cohort. Thus, the strong negative association
between TC and TC,D was present in patients
administered HDAC, with or without fludarabine, but the association was
not statistically significant in the patients not administered HDAC.
| |
Discussion |
Most patients with newly diagnosed AML who enter CR do so after the
first course of chemotherapy.11,12 Such patients are considered to constitute a single group regardless of the length of
time needed to achieve CR. Our data, exemplified by Figure 3,
illustrate that this practice is not necessarily justifiable, assuming
that CR is considered a significant outcome at least in part because of
its relationship with subsequent survival and disease-free survival
times. In particular, the data suggest that time to CR (TC)
provides important prognostic information about subsequent survival
(TC,D) and subsequent disease-free survival (TC,R) and that this information cannot be supplanted by
knowledge of the patient's age, cytogenetic status, or treatment.
Indeed, if CR is only achieved after, for example, >50 days, the time to reach CR has more prognostic significance than the fact that CR was
actually achieved. Thus, CR attained only after these lengths of time
is cosmetic. Our findings are similar for patients with de novo AML and
patients with AML arising after AHD or for patients with RAEB/RAEB-t,
and are in fact, the inverse relationship between TC and
subsequent survival time was more striking in the de novo group
(P = .0004). One possible explanation is that the MDS group, to which we added those patients who probably had undocumented MDS
based on AHD before AML was diagnosed, consistently had very short
remissions. Given this relative homogeneity in outcomes after CR,
correlations between the outcome and other parameters would be more
difficult to demonstrate than in the de novo group in which outcomes
after CR are not as homogeneous. Our findings are also, at least
qualitatively, the same for patients who received or did not receive
HDAC. The failure to demonstrate a statistically significant
association between TC and TC,D in the no HDAC
group may reflect the relatively small number of patients achieving CR
after the first course of therapy in this group. Specifically, 86%
of patients achieving CR in the HDAC groups did so after the first
course, whereas in the no HDAC group 61% achieved CR
(P < .001).
There are several potential flaws in our analysis. First, blood counts
were not performed daily in many patients. At least once, 21 days had
elapsed after the start of treatment. Nor were bone marrows necessarily
performed on the first date that blood counts met the criteria for CR.
Hence, the date on which CR was observed was not necessarily the same
as the date on which CR occurred. We are nonetheless unaware of any
bias such that the frequency with which blood counts and bone marrows
were examined was related to patients' perceived prognoses. Second,
there are no objective criteria for declaring a patient resistant to
therapy, and so we cannot retrospectively establish why a given patient was considered resistant at a given time after 1 course of therapy. Nor
can we ascertain why some patients were considered resistant after 1 course (and therefore included in this analysis) and why some were
considered resistant only later (and so not included in the analysis).
Indeed, though the 1101 patients whose records we analyzed included
81% of all CRs eventually observed with protocols for newly diagnosed
AML, only 35% of the resistant patients (only 71 patients) were
included. Hence, it is possible that the resistant patients whom we
analyzed were not those that would have been analyzed at another
hospital. We obviously could have minimized this difficulty by
including all patients resistant after 2 courses of induction therapy,
thereby including > 90% of the "resistant" population. Then,
however, the comparison (eg, as in Fig. 3) would have to be with
patients who were in CR also after 2 courses, if only to find patients
who entered CR relatively late so as to compare with patients who were
declared resistant relatively late, ie, after 2 courses. In turn,
however, this would introduce a new variable, number of courses to CR,
which would be strongly confounded with TC and, hence,
invalidate the analytical model.
Some of our other findings are also noteworthy. In particular, we are
unaware of other studies examining covariates independently related to
the time needed to reach CR achieved after 1 course (TC),
as opposed to analyses exploring covariates related to achieving CR per
se or how many courses are required for this purpose. The observation
that TC was unrelated to treatment regimen may reflect a
balance between the greater suppression of normal hematopoiesis produced by HDAC-containing regimens and the more rapid anti-AML effect
produced by these regimens as opposed to regimens using lower doses of
ara-C. Although the general experience is that use of HDAC results in a
greater proportion of CR achieved after 1 course, this may reflect a
greater reluctance to administer a second course of HDAC than a second
course of lower-dose ara-C. Focusing on those CRs achieved after the
first course, as we do, eliminates this type of bias. The implication
of the relationship between TC and age is discussed below.
There are 2 potential explanations for the effect of TC on
TC,D, and TC,R. The first is that time to CR is
not only related to intensity of the induction therapy but to the
presence of residual AML. Under this hypothesis, recovery of normal
hematopoiesis after induction therapy is slow because of residual AML.
Thus time to CR is an important clinical marker of "minimal residual
disease." The second explanation, equally plausible, is that a
longer time to CR reflects a reduced number, or poorer quality, of
residual normal stem cells. Such quantitative or qualitative defects in normal stem cells lead to more rapid disease recurrence or to earlier
recognition of it. The association between longer TC and increasing age (Table 1) is consistent with this hypothesis because it
is generally accepted that a reduction in stem cell number, function,
or both accompanies aging. The clinical implications of these
explanations are seemingly different. If TC and
TC,D or TC,R are related because TC
reflects residual disease, an intensification of induction therapy
becomes a therapeutic option in patients with long TC. In
contrast, if the relationship between these parameters is a commentary
on the status of normal stem cells, this option is less attractive
because intensification would be expected to continue to reduce stem
cell number or function. One possible approach to this problem would be
to recommend allogeneic stem cell transplantation for patients with
long TC. Transplantation would in theory provide more
effective anti-AML therapy and a new source of stem cells. More
generally, a change in therapy, rather than a change in the dose of
that therapy given during induction, appears indicated in patients with
long TC.
In conclusion, time to CR is an independent predictor of residual
survival and disease-free survival times for patients with newly
diagnosed AML, RAEB-t, or RAEB who achieve CR after 1 course of
chemotherapy. Patients achieving CR only after a lengthy time, eg >50
days, should be considered to have cosmetic CR and should undergo new
therapy. Given our data, we believe that time to CR should be reported
in detail in chemotherapy studies in these diseases and that CR should
no longer be considered an all-or-none phenomenon.
| |
Acknowledgments |
The authors thank Sherry Pierce for help with database management,
Tania Petts for expert secretarial assistance, and the physicians in
the Leukemia Department for providing patient care.
| |
Footnotes |
Submitted February 1, 1999; accepted August 26, 1999.
Reprints: Elihu H. Estey, Department of Leukemia, Box 61, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; e-mail: eestey{at}odin.mdacc.tmc.edu.
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