Acute Leukemias - Republican Scientific Medical Library

a 20.3 · MRD Monitoring in Clinical Trials of ALL 255
In long-term survivors, the incidence of a MRD-positive
result decreased continuously from a high of 36% following
induction therapy to a low of 7% at months
10–24 of treatment. In contrast, 64% and 56% of patients
who relapsed were MRD-positive following induction
and at 10–24 months, respectively. MRD was a
significant predictor of relapse risk at all time points;
however, the predictive value of a positive result appeared
the strongest between 4 and 9 months following
achievement of remission. These investigators found
MRD to be a significant prognostic marker in a multivariate
analysis. Similarly, using flow cytometric MRD
detection, high MRD level (defined as > 10 –3 )atanyof
several postremission treatment time-points was associated
with a high relapse rate of 94% [56].
From these studies, it appears that MRD assessment
at several time-points during treatment might enhance
predictive value in adult ALL. The German Multicenter
ALL study group (GMALL) found that combining the
results of several MRD measurements during the first
year of treatment enhances the predictive value of any
single time-point. In a recent study, they evaluated the
predictive value of quantitative MRD detection in 196
standard-risk ALL patients in first CR treated on a single
German cooperative group study who were monitored
sequentially during the first year of treatment.
They found that combining MRD values from three
time-points during the first 16 weeks of treatment identified
three novel risk groups. Patients with a rapid
MRD decline (< 10 –4 at day 11 and day 24 of remission
induction) had a 3-year relapse rate of 0%. In contrast,
those patients with slow MRD decline (MRD of ³10 –4
through week 16 of therapy) had a relapse rate of 94%
at three years. The remaining patients fell into an intermediate
risk group where the relapse rate was 47%.
Thus, MRD quantification during treatment identified
new prognostic subgroups within an otherwise homogeneous
standard risk subset of ALL who might benefit
from risk-adapted therapeutic approaches [81].
20.3.3 MRD Monitoring in Selected Disease
Subsets: t(4;11) and t(9;22)
Several smaller studies focusing on the impact of MRD
detection in high-risk ALL have been performed using
RT-PCR of the leukemia-specific fusion transcripts,
MLL-AF4 and BCR-ABL. The MLL-AF4 fusion gene re-
sults from the t(4;11) and is found in approximately 3–
6% of adults and children with ALL and is the most
common cytogenetic abnormality in infants with ALL
[82, 83]. The t(4;11) has been associated with a very poor
prognosis when standard chemotherapy is administered,
but improved survival has been reported for patients
receiving an allogeneic transplant in first remission.
A prospective analysis of MRD monitoring in 25
patients with the MLL-AF4 fusion gene is the largest
study of this ALL subset and demonstrated, using a
qualitative RT-PCR assay, that patients who remained
PCR negative 3–6 months following diagnosis enjoyed
prolonged survival [84]. In contrast, this and other
smaller studies showed that patients who remained
PCR-positive or converted from a negative to a positive
test following transplant were destined to relapse [83,
85, 86].
Beginning in the late 1990s, studies to assess MRD
status following allogeneic stem cell transplantation
(allo-SCT) have provided intriguing information about
the risk of relapse in Philadelphia chromosome positive
(Ph+) ALL patients using RT-PCR monitoring of the
BCR-ABL fusion gene transcript [74, 87–93] (Table
20.4). Using qualitative RT-PCR testing with sensitivities
reported in the 1 in 10 5–6 range, all of these studies
found that patients who were consistently PCR negative
following Allo-SCT were unlikely to relapse. Conversely,
patients in whom MRD was detected after
allo-SCT were at very high risk of relapse. In the largest
published series, Radich et al. found that the relative
risk of relapse (RR) was significantly higher for patients
with detectable BCR-ABL fusion gene transcript following
transplantation than for those without detectable
transcript (RR = 5.7, p=0.025) [90]. The prognostic significance
of the PCR assay remained after controlling
for other clinical variables (e.g., stem cell source, presence
of graft-vs.-host disease) that could influence relapse
risk. Interestingly, the genetic context of MRD
may also be of relevance. In their study, Radich noted
that the risk of relapse was greatest for PCR+ patients
with a p190 BCR-ABL transcript in comparison to patients
who had detectable p210 BCR-ABL transcripts
after transplantation. The median time from detection
of a positive PCR result to relapse was 94 days.
MRD detection prior to transplant for Ph+ ALL is
also a good predictor of relapse-free survival after
Allo-SCT [90, 94]. Based on these data, there has been
a concerted effort to eradicate MRD prior to moving
forward with transplant for these high-risk patients.