Acute Leukemias - Republican Scientific Medical Library

a 20.3 · MRD Monitoring in Clinical Trials of ALL 251
rangements can be relatively costly and time-consuming.
In the latter case, to reduce the costs associated with
designing fluorescent probes that match patient-specific
sequences, “consensus” probes matching recurring
germ line segments, such as V [47], J [48], and Kde
regions [49] that are applicable to multiple patients
can be used. Another concern is clonal evolution, secondary
rearrangements that can occur during the disease
course which may result in the loss of the specific
junctional region identified at diagnosis, thereby producing
false-negative MRD results. Therefore, it has
been recommended that two or more independent
PCR targets for each patient are used to monitor MRD
[22, 23, 50].
20.3 MRD Monitoring in Clinical Trials of ALL
20.3.1 MRD Studies in Pediatric ALL
Measurements of MRD during therapy of pediatric ALL
have demonstrated the ability to provide crucial information
about the response to treatment and the risk
of relapse. A number of large-scale prospective trials
have been performed that illustrate the prognostic value
of MRD measurements during the first weeks of therapy.
The group at St. Jude Children’s Hospital evaluated
MRD on day 19 of remission induction therapy in a
large cohort of 110 children treated at their center using
flow cytometric techniques [51]. They found unique
phenotypic markers for MRD monitoring in 90% of
the children using their panel of antibodies. Interestingly,
51 of 110 patients studied achieved a profound remission
by day 19 of induction therapy, defined as a
MRD level of < 0.01%. The treatment outcome for this
group of patients was outstanding, with a 3-year cumulative
incidence of relapse of 1.9 ± 1.9% for this group as
compared to 28.4 ± 6.4% for patients with MRD levels
³0.01% (p < 0.001). The independent prognostic value
of MRD quantification has also been observed when
FC MRD monitoring is performed during the first
weeks of remission induction therapy (Table 20.2)
[52–58]. These studies emphasize the point that this
technology is feasible and useful as a prognostic marker
and can provide quantitative MRD information, even
when samples are sent from participating clinical centers
to a central referral laboratory for analysis. However,
since a standardized quantitative FC protocol has
not yet been developed and accepted, a careful compar-
ison of results from different centers is difficult to accomplish.
In contrast, during the last several years, the European
pediatric centers have begun to adopt a standardized
protocol for PCR-based MRD quantification of IgH and
TCR gene rearrangements [24, 46]. In a landmark paper,
Cave and colleagues [59] demonstrated that measurement
of MRD level in early remission was the most important
predictor of clinical outcome in 178 children
treated in a large French cooperative group study. These
investigators, using a semiquantitative technique,
showed that detection of high MRD levels (defined as
>10 –2 ) after achievement of morphologic remission
were strongly predictive of relapse; whereas, patients
with very low levels of MRD had similarly good outcomes
as those patients in whom no MRD was detected.
Indeed, other investigators have also suggested that it
may not be essential to eradicate all MRD in order to
achieve prolonged DFS [60]. The precise nature of these
residual clonal cells that do not appear to give rise to relapse
remains to be defined, but may highlight the multistep
pathogenesis that is presumed to be responsible
for the development of acute leukemia. These studies
also suggest that MRD measurement at a single treatment
time-point may not provide sufficient clinical
prognostic information and that serial MRD measurements
augment the predictive capacity of the test. In another
large study of MRD involving 240 children with
ALL, van Dongen et al. [61] found that combining semiquantitative
MRD information from several time-points
during treatment identified three risk groups. Fortythree
percent of patients were in a low-risk group with
a 3-year relapse rate of only 2%; 43% were in an intermediate-risk
group with a relapse rate of 23%; and
15% were in a high-risk group with a 75% relapse rate.
Other studies confirm the significance of serial, quantitative
measurements of MRD [41, 62–67]. These and
other PCR-based MRD studies are summarized in Table
20.3.
Investigators have also compared MRD results in
blood and marrow to determine whether monitoring
using blood samples, which is far more accessible and
tolerable for patients, yields similar results to bone marrow
MRD monitoring [51, 68–75]. To date, the data suggest
that blood monitoring may yield comparable results
to marrow MRD levels for patients with T-lineage
ALL using both flow cytometric and PCR-based methods
[51, 71]. The results of blood MRD detection with
precursor-B ALL, however, do not seem to be as