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Next Article 
Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2755-2759
Should Polymerase Chain Reaction Analysis to Detect Minimal
Residual Disease in Patients With Chronic Myelogenous Leukemia Be
Used in Clinical Decision Making?
By
Stefan Faderl,
Moshe Talpaz,
Hagop M. Kantarjian, and
Zeev Estrov
From the Departments of Leukemia and Bioimmunotherapy, The University
of Texas M.D. Anderson Cancer Center, Houston, TX.
 |
ARTICLE |
CHRONIC MYELOGENOUS leukemia (CML) is a
unique myeloproliferative disorder usually associated with a
distinctive cytogenetic abnormality the Philadelphia chromosome
(Ph)that leads to leukemogenesis.1 Ph is a shortened
chromosome 22 resulting from a reciprocal translocation of the long
arms of chromosomes 9 and 22 that transposes the 3' segment of the
ABL gene from 9q34 to the 5' segment of the BCR gene on
22q11. The resulting BCR-ABL gene is transcribed into a
chimeric mRNA and then translated into fusion proteins of varying size
(p190bcr-abl, p210bcr-abl, and
p230bcr-abl) according to the breakpoint location of the
genes involved.2 Ph is observed by cytogenetic analysis in
more than 90% of patients with CML, almost all of whom express the
chimeric protein p210 bcr-abl, but much less
frequently in patients with other leukemias in which expression of the
smaller fusion protein p190bcr-abl occurs more
frequently.2,3 Preclinical in vitro and in vivo models of
tumor development suggest a crucial role for Ph
translocation-associated molecular events to initiate and perpetuate
CML disease.4,5 Thus, the fusion products of the
BCR-ABL gene are thought to play a central role in CML as
mediators of myeloid proliferation and transformation.
The availability of information from cytogenetic and molecular studies
lent itself to a more precise assessment of low volumes of residual
disease in CML. It has become apparent that conventional therapy with
hydroxyurea and busulfan produces hematologic remissions (ie,
normalization of peripheral blood counts and absence of signs and
symptoms of disease) in 50% to 80% of patients but only rare and
short-lived cytogenetic remissions (ie, suppression of the Ph+ clone). As a result, patients will invariably progress
to a blastic phase and die from its complications.6
Two treatment modalities introduced in the 1980s have become especially
useful tools for inducing cytogenetic remissions in CML patients.
Allogeneic matched sibling stem cell transplantation (SCT) in CML has a
curative potential arising from the elimination of Ph+
hematopoietic progenitors and allows disease-free survival (DFS) rates
of 30% to 70%.7,8 Interferon- (IFN-) was identified as the first biological agent capable of inducing cytogenetic remission
in patients with CML.9 Over the past decade, numerous studies of IFN- as treatment for CML have shown complete hematologic remissions (CHR) in 80% to 90% of patients and major cytogenetic remissions (ie, suppression of Ph+ cells below 35% in
metaphase spreads) in 30% to 40%, some of which are
durable.10,11 The significance of achieving a cytogenetic response as an independent variable for survival prolongation was
confirmed by multivariate analysis, further supporting the therapeutic
efforts aimed at suppressing Ph+ clones.10
Therefore, detection of the Ph translocation is not only a diagnostic
tool but also at the core of a strategy to assess the response of
individual patients to therapeutic interventions, namely SCT and
IFN-, and evaluate treatment efficacy by monitoring residual
disease. Indeed, arguments in favor of monitoring residual disease are,
at first sight, compelling. Typically, cytogenetic relapse precedes
hematological relapse and, provided disease recurrence is detected
early enough, effective salvage therapy (such as donor lymphocyte
infusions) can produce a response in up to 80% of patients whose
disease relapses after allogeneic SCT.12 For
IFN--treated patients who attain a complete cytogenetic remission,
the duration of treatment can be individually tailored according to the
presence or absence of the BCR-ABL transcription product in
blood or bone marrow samples.
Cytogenetic analysis is essential to diagnose and follow the course of
CML and for identifying karyotypic changes in addition to the Ph
chromosome. However, its sensitivity is low (1% to 5%) due to the
limited number of adequate metaphases examined (usually 20 to
25).13 By the time disease is detectable by cytogenetic studies, clinical relapse may be inevitable. It may also miss some
cases of BCR-ABL+ CML in which Ph is not
detected.14 Therefore, more sensitive methods for the
molecular diagnosis and follow-up of residual disease are now being
used. Fluorescence in situ hybridization (FISH) and its variants,
interphase (i-FISH) and hypermetaphase FISH (h-FISH), allow analysis of
a larger number of cells (>500) in a timely and efficient manner,
with the added benefit that some (i-FISH) can be applied to nondividing
cells, a fraction of cells with a low proliferative rate
(as may be the case in residual disease).15 However, in
many centers, polymerase chain reaction (PCR) assays are becoming the
techniques of choice for detecting residual disease on a molecular
level. PCR allows identification of a single Ph-bearing cell among
104 to 108 normal cells, a sensitivity
unparalleled by any other available method.16
In applying PCR techniques clinically, what might be learned about the
kinetics of the disappearance and reappearance of residual disease and
the significance of detecting residual disease in CML patients treated
with either allogeneic SCT or IFN-?
Many investigators have reported, with varying results, on the
detection of minimal residual disease in patients with CML who have
undergone allogeneic SCT (Table
1).17-22 Using nested PCR, Roth
et al20 analyzed 64 CML patients after allogeneic SCT and
detected BCR-ABL transcripts at one time point in 37 of the
patients. Of those 37, 13 eventually had a disease relapse, with a
median time to relapse of 5 months. No relapses were observed in
patients with negative PCR results. Roth et al thus concluded that
nested PCR could define subgroups of patients in apparent clinical
remission but with an increased risk of disease recurrence. In
contrast, Miyamura et al,19 also using nested PCR, detected no association between PCR positivity and subsequent relapse in their
series of 64 patients with CML in remission after allogeneic SCT. In
five cases, the persistence of detectable BCR-ABL transcript for up to 2 years postremission did not result in disease recurrence. Hughes et al,17 on the basis of nested PCR results in 37 CML patients in remission after allogeneic SCT, concluded that PCR positivity within 6 months after transplantation did not predict a
worse outcome, whereas PCR positivity later than 6 months after transplantation did. Radich et al18 presented a
comprehensive multivariate analysis of 346 patients who had undergone
allogeneic transplants for CML and then been analyzed by PCR for the
presence of BCR-ABL transcripts. The multivariate analysis
identified PCR-positivity at 6 to 12 months posttransplantation as one
independent variable for influencing subsequent relapse. The
significance of the presence of BCR-ABL transcripts in
predicting disease recurrence was, however, lost in patients who tested
positive more than 36 months post-SCT. A different approach was chosen
by Lin et al,22 who used a competitive PCR method to
quantify BCR-ABL transcripts rather than analyzing qualitative
PCR data. In 98 patients with CML post-SCT, the probability of relapse
was significantly increased in patients with higher versus lower levels
of BCR-ABL. Gaiger et al21 reported that only
serial PCR measurements identified patients at high risk (ie,
BCR-ABL positivity in serial samples) and low risk of relapse (ie, transient positivity). Different techniques, various levels of PCR
sensitivity, and short follow-up durations make it difficult to
interpret these studies.
The discordance among these studies raises two key questions: (1) Why
are some results so discordant and how can they be interpreted? (2) Is
persistent residual disease predictive of relapse?
First, data from molecular studies, especially those involving PCR,
should be appraised critically. PCR is a powerful tool, but has a
number of shortcomings that can lead to both false-negative and
false-positive results. Technical pitfalls such as sample contamination, inadequate sample volume, inappropriate sample source,
loss of sensitivity of junctional probes, and degradation of target
molecules are a major cause of inaccurate results. Furthermore, shifts
in disease markers as reflected in the findings of oligoclonality, subclone formation, clonal evolution, and incomplete target sequence rearrangements in the neoplastic cell population must be considered if
one intends to correlate PCR negativity with absence of
disease.13 In CML in particular, attention should be paid
to rare molecular fusions (such as e6a2, e19a2, fusions lacking exon
a2) and evolution of subclones expressing different fusion products
than the original clone.3,23-25 This biologic diversity may
give rise to false-negative results and pose problems in diagnosis and
monitoring of residual disease in CML. A major drawback of current PCR
studies is the lack of quantification of PCR data. A mere positive or
negative PCR result is not enough information to draw meaningful
conclusions. Given the degree of variability in the sensitivity of the
PCR assays used in the studies cited (Table 1), it is difficult to interpret and compare results reported by different investigators. What
has also become apparent from these studies is the shift in the
population of patients with the increasing sensitivity of PCR assays.
Only a few patients are left that qualify as PCR , thus
rendering PCR "too sensitive" to serve a prognostic purpose. But
even if quantitative PCR is used and the amount of residual disease
monitored, can data from such studies be informative? If a threshold of
residual disease above which a patient is likely to relapse or,
conversely, below which remission is sustained is found, then residual
disease monitoring using quantitative PCR may be useful. Hochhaus et
al26 compared cytogenetic responses to treatment with
IFN- to molecular responses and defined cut-off points for the ratio
of BCR-ABL to ABL in four response groups. However, the
cut-off points do not establish a threshold for relapse versus
remission, and no other study to date has provided convincing evidence
of one. In fact, the behavior of residual disease may be just as
individual as the patients treated, with different kinetics, distinct
host-disease interactions, and varying responses to diverse treatment regimens.
Taking these considerations into account, what conclusions can be drawn
from identifying persistent residual disease by a positive PCR
reaction? The BCR-ABL rearrangement may be neither the only nor
the first molecular abnormality pathogenetically linked to the leukemic
process in CML, even though BCR-ABL may be considered a
"window" though which antecedent clonal cells must progress to
result in CML. However, secondary or epigenetic events may be required
for full leukemogenesis. Fialkow et al27 and later Raskind
et al28 were the first to show, by using
glucose-6-phosphate dehydrogenase as a marker for clonality, that some
hematopoietic cells of the neoplastic clone were Ph. PCR
primers can only detect a sequence that one is looking for, and cannot
be used as a screening tool for other unknown but nevertheless equally
important sequences. By the same token, it is well documented that
patients can express the BCR-ABL transcripts and stay in clinical remission for many years.29 Are the residual cells detected in these patients indeed leukemic or just
"BCR-ABL+" and lacking some major attributes
of truly leukemic cells? Using a highly sensitive reverse transcriptase
(RT)-PCR assay capable of detecting one BCR-ABL mRNA-expressing
cell among 108 white blood cells, Biernaux et
al30 found BCR-ABL transcripts in healthy
individuals in an age-dependent manner. The transcripts were detected
most often in adults (22 of 73), much less often in children (1 of 22),
and not at all in umbilical cord blood (0 of 22). This observation has
been confirmed by Bose et al,31 who found p210 and p190
BCR-ABL transcripts in 4 of 16 and 11 of 16 normal individuals,
respectively, using a similar RT-PCR approach. Although further
validation of these findings is needed, they indicate the presence of
leukemia-specific fusion genes in some hematopoietic cells without the
accompanying clinical syndrome of leukemia. Such genes may constitute
abnormalities that by themselves are not able to generate the leukemic
phenotype without the interaction with as yet unidentified leukemogenic
events. Alternatively, leukemic fusion genes may be expressed in
hematopoietic cells that have entered an apoptotic pathway before
acquiring a characteristic leukemic karyotype that may already have
lost its relevance. Similarly, clinically nonrelevant
clonal disease has been observed in otherwise cured
tumors.32,33 Two questions then follow: What does a
positive PCR reaction mean in a patient who is in clinical and
cytogenetic remission? Does it justify a therapeutic intervention using
chemotherapy or allogeneic SCT?
Finally, consideration should be given to some important host factors.
BCR-ABL+ cells in patients with CML who maintain
long-term remission may be dormant. A tumor is considered dormant if
the malignant cells present in an organism are kept under growth
control by certain mechanisms for a prolonged period but retain their
neoplastic potential.34
For example, in patients with CML who are in cytogenetic remission
after treatment with IFN-, PCR techniques can still commonly identify BCR-ABL transcripts up to a median of 22+ months
postremission (Table 2).35,36
Hochhaus et al37 measured levels of BCR-ABL expression in 20 such patients using a quantitative PCR method. In all
of them, a median of 750 transcripts/µg RNA was found. They suggested
that treatment with IFN- was not capable of eradicating residual
disease, thus establishing an impediment to a cure with IFN-
therapy, unlike with allogeneic SCT. Recently Kurzrock et al38 showed that patients in complete cytogenetic response
after IFN- treatment may become PCR for
BCR-ABL if followed long enough. In particular, 10 of 18 patients in complete cytogenetic response tested negative for BCR-ABL by PCR; the median duration of cytogenetic responses
was longer in patients who were PCR than in those who
were PCR+ (42 v 12 months; P < .01).
However, the association of PCR negativity with long-term event-free
survival was not clear because dormant progenitor cells below the
threshold of PCR detection may still have been present. Using RT-PCR,
Talpaz et al39 analyzed seven patients who attained
complete cytogenetic remission after IFN- treatment and who were
also PCR for BCR-ABL, and found that myeloid and
erythroid colonies from blood and marrow samples in these patients
still expressed BCR-ABL transcripts. In addition, one patient
in this study group has been in a complete cytogenetic remission for
3.5 years without relapse. Furthermore, no cytogenetic relapse was
observed in two patients with positive colonies in the subsequent 4.5 years of a maintained remission after this publication (M. Talpaz,
personal communication, December 1998). These results were
confirmed by a study by Pasternak and Pasternak,40 who
showed the persistence of BCR-ABL mRNA-expressing cells in
Dexter-type long-term cultures derived from bone marrow and blood
samples from CML patients in cytogenetic remission.
That the immune system plays an important role in keeping the malignant
cell population in CML dormant is confirmed by several other
observations: (1) 60% to 80% of patients whose disease relapses after
allogeneic SCT attain cytogenetic remissions with donor lymphocyte
infusions12; (2) there is a positive correlation between
the presence of graft-versus-host disease and a reduced risk of relapse
after SCT and, conversely, an increased risk of relapse after the
transplantation of T-cell-depleted donor marrows41; (3)
there is a positive correlation between cytogenetic response and grade
of IFN--associated autoimmune phenomena42; and (4) BCR-ABL transcripts can be present in healthy individuals in
the absence of CML.30,31
As the findings discussed demonstrate, sensitive techniques such as PCR
can detect evidence of residual disease in many patients with CML who
have achieved complete cytogenetic responses with either allogeneic SCT
or IFN- therapy. A positive PCR reaction does not always equal
relapse, and a negative PCR reaction does not equal cure. Therefore,
"cure" should be understood as a functional process
("functional cure") rather than the absence of all evidence of
disease ("molecular cure"), which is probably not possible, or
even relevant, in any case. This concept has important implications in
understanding residual disease, its kinetics, tumor dormancy, and the
role of immunomodulation in residual disease. With increasing sensitivity of PCR assays, most patients will test positive, making qualitative PCR results less useful and raising the issue of a quantitative threshold of residual disease as prognostic marker. However, no such threshold has been established in the studies to date
that would be clinically useful.
PCR has provided us with a wealth of exciting and interesting data that
has already contributed significantly to our understanding of residual
disease in CML and other leukemias. However, to conclude that
"molecular cures" are the only possible pathways to long-term event-free survival is premature. The PCR technique, although considered a valid clinical testing procedure, should be used cautiously as a laboratory test until sufficient data are available to
show that it meets acceptable criteria of sensitivity, specificity, and
positive and negative predictive values. How new PCR technologies such
as "real-time" PCR quantification will solve these concerns and
become a reliable tool for the clinician merits further investigation. Until then, clinicians should exercise caution in basing clinical decision making on such studies, given the significant morbidity and
mortality associated with aggressive therapeutic interventions aimed at
molecular disease eradication in patients who might just do as well without.
| |
FOOTNOTES |
Submitted October 26, 1998; accepted January 11, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Zeev Estrov, MD, The University of Texas,
M.D. Anderson Cancer Center, Department of Bioimmunotherapy, Box 302, 1515 Holcombe Blvd, Houston, TX.
| |
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ARTICLE
REFERENCES
-Treated CML Patients in Cytogenetic Remission