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NEOPLASIA
From the Cattedra di Ematologia, Università di
Roma Tor Vergata, Divisione di Ematologia, Rome, Italy.
We used flow cytometry to quantify minimal residual disease (MRD)
in 56 patients with acute myeloid leukemia (AML) expressing a
leukemia-associated phenotype. Thirty-four patients aged 18 to 60 years
were entered into the AML-10 protocol (induction, consolidation, and
autologous stem-cell transplantation [ASCT]), whereas 22 patients
older than 60 years received the AML-13 protocol (induction,
consolidation, and consolidation II). After induction, the level of MRD
that was best associated with treatment outcome was
4.5 × 10 Complete remission (CR) rates as high as 70% to
80% have been reported in adult patients with acute myeloid leukemia
(AML),1-6 but approximately 60% to 70% patients will
eventually have relapse due to the persistence of residual leukemic
cells surviving after chemotherapy. The persistence of residual
malignant cells below the threshold of conventional morphologic
findings Polymerase chain reaction (PCR) and flow cytometry are the most
commonly used techniques for detecting MRD in patients with AML.
Reverse transcriptase-PCR studies of PML/RAR In this study, we used multiparametric flow cytometry to determine the
levels of MRD after induction, consolidation, and autologous stem-cell
transplantation (ASCT) in AML patients in first CR after induction
therapy. Our objective was to determine the effect of MRD on clinical
outcome and correlate MRD with other recognized prognostic factors,
such as multidrug resistance 1 (MDR1) phenotype and cytogenetic
findings.14
Patients and treatments
The EORTC/GIMEMA AML-10 randomized trial included patients aged 18 to
60 years. The induction treatment combined cytarabine (100 mg/m2 of body-surface area given intravenously on days
1-10), etoposide (100 mg/m2 given on days 1-5), and on days
1, 3, and 5, either daunorubicin (50 mg/m2), mitoxantrone
(12 mg/m2), or idarubicin (10 mg/m2), according
to random assignment. As consolidation, patients received cytarabine
(500 mg/m2 every 12 hours on days 1-6) and the same
anthracycline given in the induction (on days 4 to 6). Patients with an
HLA-compatible sibling were given allografts, whereas the others were
randomly assigned to receive peripheral or bone marrow (BM) stem-cell
transplantation15 (Figure 1).
Patients older than 60 years were entered into the EORTC/GIMEMA AML-13
randomized trial. The patients received mitoxantrone (7 mg/m2 on days 1, 3, and 5), etoposide (100 mg/m2 on days 1-3), and cytarabine (100 mg/m2
on days 1-7) as induction therapy. On achievement of CR, patients were
randomly assigned to receive either an intravenous or an oral
consolidation program (2 cycles). Intravenous consolidation treatment
consisted of idarubicin (8 mg/m2 on days 1, 3, and 5),
etoposide (100 mg/m2 on days 1-3), and cytarabine (100 mg/m2 on days 1-5). Oral consolidation therapy consisted of
idarubicin (20 mg/m2 on days 1, 3, and 5), etoposide (100 mg/m2 twice/day on days 1-3), and subcutaneously
administered cytarabine (50 mg/m2 twice/day on days 1-5;
Figure 1).
Immunophenotypic studies and detection of MRD
After the immunophenotype of the leukemic cells was established,
samples from patients with leukemia-associated phenotypes were selected
and reinvestigated by staining them with the (double-triple) relevant
combinations of antibodies. A given combination of markers was regarded
as relevant if it was expressed in more than 50% of the blasts (Table
1). This step served to define a
phenotypic patient profile which was in turn used to track possible
residual leukemic cells during follow-up. At least 2 antibody
combinations for each case were used to minimize problems caused by
phenotypic switches10 that sometimes accompany relapses.
CellQuest software (Becton Dickinson) was used for acquisition of flow
cytometric data, with application of live gates on the
forward-light-orthogonal light scatter (gate 1, blast region) and
fluorescence plots (gates 2 and 3, double and triple positive
events).
Samples were then analyzed by using the Paint-a-GatePro software program (Becton Dickinson), as previously described.11,17-19 Briefly, this program provides multidimensional, multicolor analysis of FACS-acquired list-mode data files. It allows classification of events by painting them different colors and quantifying them as percentages of total events. This allows visualization in different plots of cell populations difficult to see in 2 dimensions. The Paint-a-Gate program is also equipped with a MouseTrax Control option that allows analysis procedures to be repeated automatically. When this option is activated, every step taken during the analysis is recorded, including the moves made with the computer mouse. Paint-a-Gate stores these sequences in a file so that the analysis can be repeated with many different data files. Thus, for each patient expressing a leukemia-associated phenotype, the MouseTrax Control option was used to set up a tailored procedure that exactly defined the phenotypic patient's profile. This procedure was memorized and run automatically to analyze BM when CR was achieved and during subsequent follow-up. MRD studies during remission were performed on erythrocyte-lysed whole BM samples by using the same association of antibodies defining the specific patient's profile. During data acquisition, a live-gate including the lymphomonocytic and granuloblastic region and excluding debris and platelet aggregates was used, with 106 total events acquired for all samples. The acquired events were analyzed with the Paint-a-Gate program by running the MouseTrax Control option as described above. Studies of a series of normal BM samples from healthy donors created an internal standard reference for distinguishing normal from leukemic patterns.10-13 Dilution experiments were also performed to test the sensitivity
of the assessment technique. Thus, leukemic blasts were mixed with
normal BM samples in decreasing concentrations (10 MDR1 expression and cytogenetic studies MDR1 expression was tested in all samples by using Moab MRK16 (Immunotech, Marseille, France), which reacts with an extracellular epitope of the human 170-kd P-glycoprotein, as described previously.20 The procedures for cytogenetic analysis were previously described in detail.21 Karyotypes were classified according to International System for Human Cytogenetic Nomenclature.22Statistical analysis The relation between MRD and patients' characteristics and response to treatment was assessed with use of a 2-sided 2 or Fisher exact test (when either group included fewer
than 20 cases). A P value of .05 or less was considered to
represent significance. The Spearman rank correlation (r)
was used to assess the relation between the level of MRD after
consolidation and time to relapse. The Kaplan-Meier
method23 was used to estimate overall survival (OS) and
relapse-free survival (RFS). For comparisons of survival and remission
duration in 2 or more groups, the log-rank test was applied. CR and
relapse were defined according to standard criteria.24 OS
was calculated from the date of diagnosis to the date of death or last
follow-up evaluation. RFS was measured from achievement of CR until
relapse. To evaluate the simultaneous effect of different variables on
relapse rate and duration of OS and RFS, we performed a multivariate
analysis using a stepwise regression model.
Determination of MRD after induction Clinical characteristics of the 56 patients included in the study are shown in Table 2. At the end of induction therapy, the median level of MRD was 3.5 × 10 4 residual leukemic cells (range,
0-8.1 × 102). The cutoff value that had the best
statistical correlation with outcome was 4.5 × 104:
58% (15/26) of patients with 4.5 × 104 cells or more
(the MRDInd+ group) had relapse, whereas 40% (12/30) of
those with less than 4.5 × 104 cells (the
MRDInd group) did so (P = .097). No
significant correlation was found between MRDInd+ status
and the expression of MDR1 phenotype or the presence of poor- or
intermediate-risk cytogenetic findings. Similarly, no significant
differences in OS or RFS were observed between the MRDInd+
and the MRDInd group.
Determination of MRD after consolidation Five patients with MRDInd+ status had relapse before or during consolidation and died of progressive disease; thus, 51 patients (21 MRDInd+ and 30 MRDInd) could be
evaluated for MRD at the end of consolidation. The median MRD value
after consolidation was 3.1 × 104 residual leukemic
cells (range, 0-6.8 × 102). A level of
3.5 × 104 residual malignant cells divided the 51 evaluated patients into 2 distinct groups: the MRDCons+
group and the MRDCons group, which had relapse rates of
77% (17/22) and 17% (5/29), respectively (P < .001). Of
the 21 patients in the MRDInd+ group, 7 became
MRDCons and are in continuous CR. Ten (71%) of the
remaining 14 patients in the MRDInd+ group who did not
become MRDCons had relapse (P = .001).
Similarly, among the 30 patients in the MRDInd group, 8 had positive findings after consolidation and 7 (87%) of them had
relapse. In contrast, only 5 (23%) of the remaining 22 with
MRDCons status had relapse (P = .007).
Importantly, the presence of a certain number of residual
leukemic cells (
Determination of MRD after consolidation II Of 22 patients entered into the AML-13 protocol (Table 2), 4 with MRDInd+ status had relapse before receiving the first consolidation treatment and 7 with MRDCons+ status had relapse before receiving the second consolidation. Thus, 11 patients were given consolidation II therapy and could be evaluated for MRD. Among these 11 patients, 9 had MRDCons status and the MRD
level remained below 3.5 × 104 residual leukemic
cells, even after consolidation II; all these patients remain in CR.
The remaining 2 patients had MRDCons+ status and did not
benefit from consolidation II therapy in that the level of MRD remained
above the threshold of 3.5 × 104 residual malignant
cells. One of these 2 patients had relapse after 13 months.
Determination of MRD after ASCT Of 34 patients recruited to the AML-10 protocol (Table 2), 6 did not undergo transplantation because of patient refusal (1 patient), medical reasons (3 patients), or relapse (2 patients, 1 with MRDInd+ status before consolidation and 1 with MRDCons+ status before transplantation). The patient who chose not to undergo transplantation was in the MRDCons+ group and had relapse 15 months later, whereas those excluded for medical reasons are in CR (1 has MRDCons+ status). The remaining 28 patients (10 with MRDCons+ status and 18 with MRDCons status) underwent transplantation and subsequent
MRD determinations. Among the 10 patients with MRDCons+
status, 7 (70%) had relapse and, in all but 1 patient, the level of
residual leukemic cells did not fall below 3.5 × 104,
even after ASCT. Conversely, only 5 of the 18 (28%) patients with
MRDCons had relapse and, in 2 of them, disease recurrence
was preceded by a gradual increase in MRD to the level of
1.4 × 102 leukemic cells. The difference in relapse
rate between the MRDCons+ and MRDCons groups
was significant (P = .031).
Prognostic determinants All relevant prognostic variables (age, French-American-British leukemia class, white blood cell count, MDR1 phenotype, cytogenetic findings, MRDInd+ status, and MRDCons+ status) were pooled into a multivariate model to determine to what extent they independently affected outcome. MRDCons+ status emerged as an independent variable that was significantly associated with a high frequency of relapse (P < .001) and a short duration of OS (P = .025) and RFS (P = .007). Cytogenetic findings were found to independently affect duration of OS and RFS (P = .036 and P = .025, respectively), whereas MDR1 phenotype was significantly associated with a high frequency of relapse (P = .03; Table 3).
MRD testing in patients with AML in clinical remission is a
potentially useful tool for assessing the risk of relapse and guiding
therapeutic decisions. We found that the persistence of high levels of
MRD ( Our findings appear to be at variance with those of San Miguel et
al,11 who observed a correlation between level of MRD and
the probability of relapse not only after intensification but also
after induction. The different therapeutic regimens used in the 2 studies may explain this discrepancy. In the study of San Miguel et al,
the remission-induction therapy consisted of 1 or 2 courses of an
anthracycline and cytosine arabinoside (3 + 7 regimen), followed by
an identical consolidation course. This was followed by 1 or 2 intensification courses consisting of intermediate- or high-dose
cytosine arabinoside and either daunorubicin or idarubicin. The AML-10
and AML-13 protocols are 3-drug-based regimens in which an
anthracycline is used in association with cytosine arabinoside and
etoposide. In addition, in the AML-10 protocol, cytosine arabinoside was given for 10 days instead of 7 during the induction phase. Thus, in
the study of San Miguel et al, a milder debulking effect achieved with
a less intensive therapy may account for the higher level of MRD
(5 × 10 Although our patients with MRDCons+ status underwent ASCT,
they had a relapse rate of 70%. These results confirm the highly predictive role of MRD status at the end of consolidation and are in
keeping with those of Lahuerta et al,25 who reported a
poor prognosis for patients with an MRD level of 0.8% or higher immediately before ASCT. Additional cytoreduction before ASCT or
alternative strategies (use of matched, unrelated-donor transplants or
full-haplotype mismatched transplants26) would be
desirable in these patients. In contrast, only 28% of patients with
MRDCons In one case in our series, the relapse was unexpected and not preceded
by an increase in MRD level, nor were phenotypic switches documented at
the time of recurrence. We hypothesize that the amount of MRD had
remained below the threshold of the sensitivity of the assessment
technique used until the morphologic relapse occurred. We believe that
use of more advanced devices, such as a dual-laser-equipped cytometer,
which allows 4 or more antibodies to be combined, would improve the
sensitivity of the method. In 2 patients in our series, relapse
occurred after peripheral ASCT and, once again, neither changes in the
level of MRD nor phenotypic switches were observed before or at
relapse. However, both patients had a high CD34+ cell count
( With regard to the 5 patients who are in continuous CR in spite of detectable disease after consolidation, we hypothesize that they still have AML, as confirmed by a cytometric pattern showing a uniquely identifiable cluster of leukemia cells. Thus, the limited follow-up time may explain why we have not yet observed relapse in these patients. In conclusion, we found that detection of MRD using flow cytometry is a
useful approach for predicting outcome in patients with AML treated
with intensive regimens. If confirmed, our results will indicate that
future clinical trials should take into account this information in
order to verify the applicability of pre-emptive therapeutic
intervention in patients with a high level of MRD after consolidation
therapy. We also believe that MRD monitoring during follow-up after
therapy is clinically useful, providing adequate surveillance in
patients with residual leukemia (
The authors thank Dr Dario Campana for reviewing the manuscript and providing helpful suggestions.
Submitted March 28, 2000; accepted August 15, 2000.
Supported in part by MURST, Programmi di Ricerca di Interesse Nazionale.
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.
Presented in part at the 41st Annual Meeting of the American Society of Hematology, December 3-7, 1999, New Orleans, LA. Reprints: Adriano Venditti, Cattedra di Ematologia, Università di Roma Tor Vergata, Divisione di Ematologia, Osp S Eugenio, P le dell'Umanesimo 10-00144, Rome, Italy; e-mail: adriano.venditti{at}tin.it.
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© 2000 by The American Society of Hematology.
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Top
Abstract
Introduction
minimal residual disease (MRD)
transcripts in acute promyelocytic leukemia (APL)
3.5 × 10
0.62;
P = .000001; Figure 
