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Chronic Myeloid Leukemia: Current Status and Controversies

Chronic Myeloid Leukemia: Current Status and Controversies

ABSTRACT: Until recently, the standard treatment for newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase who were not eligible for allogeneic stem cell transplant was interferon-alfa alone or in combination with low-dose cytarabine. Moreover, about 20% to 25% of patients who were relatively young and had suitable HLA-matched donors have in recent years been offered treatment by allogeneic stem cell transplantation, a procedure that can cure CML but is associated with an appreciable risk of morbidity and mortality. However, following the recognition in the 1980s that the p210 oncoprotein encoded by the BCR-ABL fusion gene on the Philadelphia chromosome had greatly enhanced tyrosine kinase activity and was probably the initiating event in the chronic phase of CML, much effort was directed toward development of drugs that would selectively inhibit this kinase activity. In 1998 these efforts culminated in the first clinical use of imatinib mesylate (Gleevec), which has since been shown to produce impressive results in treatment of patients with CML in chronic phase. In previously untreated patients, the incidence of complete cytogenetic responses exceeds 80%, and the majority of responses appear thus far to be durable. Imatinib also proved active in patients with accelerated phase and blastic phase disease, but in most of these cases, the benefits have been relatively short-lived. The advent of imatinib has thus necessitated a fundamental reappraisal of the approach to the initial management of CML.

From the time chronic myeloid
leukemia (CML) was recognized
as the first form of leukemia
in 1845, it has probably become
one of the best understood human malignancies.
Its pathogenesis began to
unravel in 1960 with the discovery
that CML cells have a consistent cytogenetic
abnormality, later termed the
Philadelphia (Ph) chromosome.[1,2]
In 1986, researchers discovered that
the Ph chromosome carried a BCRABL
fusion gene, and by the early
1990s, the encoded oncoprotein
(P210-Bcr-Abl) was generally accepted
as the initiating event in chronic
phase CML as a consequence of its
enhanced tyrosine kinase activity.[3,4]
Thereafter, much effort was directed
at inhibiting the kinase activity of this
oncoprotein, culminating in the recent
introduction into clinical practice of
imatinib mesylate (Gleevec), a Bcr-Abl
tyrosine kinase inhibitor (Figure 1).[5-7]
Most remarkably, within 3 years of its
introduction, imatinib has proved to be
the drug of choice in the management
of patients with CML.[8]

Prior to this important therapeutic
milestone, other noteworthy advances
had been made. The disease was
generally considered incurable as re-
cently as 25 years ago; since then, the
use of allogeneic stem cell transplant
(allo-SCT) has resulted in long-term
remissions and almost certainly
"cures" in selected patients.[9] However,
it proved impossible to extend
allo-SCT to all CML patients due
largely to a lack of suitable donors
and the increased risk of potentially
lethal graft-vs-host disease (GVHD)
in older recipients. The recent intro-
duction of use of less-intensive transplant
conditioning regimens has facilitated
greater use of allo-SCT, but
its precise role in the therapeutic algorithm
for patients with CML remains
to be defined.[10]

Other important therapeutic advances
have been the introduction of
interferon-alfa in the early 1980s and
the discovery that adoptive immunotherapy
with donor-derived lympho-

cytes could restore durable remissions
in patients who relapsed following
allo-SCT.[11-13] Despite these major
developments, many important issues
remain unresolved. In this paper,
we will briefly address some of these
questions and controversies.

Molecular Biology

The chronic phase of CML appears
to arise as a consequence of a single
pluripotential hematopoietic stem cell
acquiring a BCR-ABL fusion gene
associated with a Ph chromosome,
which somehow confers a proliferative
advantage to this stem cell over
normal hematopoietic stem cells and
thereby allows the BCR-ABL-containing
cells to displace normal hematopoiesis.
The Ph chromosome
results from the reciprocal translocation
of chromosomal material involving
the long arms of chromosome 9
and chromosome 22, referred to as
t(9;22)(q34;q11). Although more than
90% of CML patients have a Ph chromosome
and a BCR-ABL fusion gene,
about 8% of patients with hematologically
"acceptable" CML lack the Ph
chromosome and are described as having
Ph-negative CML. About half of
such patients have a cytogenetically
occult BCR-ABL gene and are thus
Ph-negative, BCR-ABL-positive cases;
the remainder are BCR-ABL-negative;
some of these have mutations
in the RAS gene.[14]

The mRNA molecules transcribed
from the BCR-ABL fusion gene usually
contain one of two possible BCRABL
junctions, designated e13a2 and
e14a2, respectively (Figure 2). Rarely,
CML patients demonstrate an alternative
consistent chromosomal
translocation such as t(5;12)(q33;p11)
and t(8;13)(p11;q12), both of which
are associated with different oncoproteins
with enhanced tyrosine kinase
activity, namely platelet-derived
growth factor receptor B and fibroblast
growth factor receptor 1. Functional
studies performed on cells from
these leukemias suggest that the signal
pathways activated are very similar
to those activated in the
Bcr-Abl-positive leukemias.

It is generally accepted that the
BCR-ABL fusion gene is the initial
molecular abnormality in chronic
phase; somewhat perversely, the successful
application of imatinib is considered
proof of this notion. Notably,
Bcr-Abl transcripts can also be
detected at very low levels in
normal people, and the vast majority
of such individuals do not develop
CML.[15,16] The origin of these specific
transcripts in normal people remains
unclear.

The precise mechanisms underlying
the above observations, notably
the cause of the chromosomal translocation
and the precise nature of the
proliferative advantage it confers, remain
unknown. Interestingly, a 76-kb
"duplicon" (a low copy DNA repeat
sequence) has been found in close
proximity to the ABL, BCR, and other
genes.[17] Exposure to ionizing radiation
increases the risk of developing
CML; in vitro studies assessing the
effects of high-dose irradiation on
myeloid cell lines have demonstrated
the development of Bcr-Abl transcripts
indistinguishable from those
that characterize CML.[18] However,
the possible contribution of cosmic
radiation in "causing" the typical
sporadic case remains unknown.

The Bcr-Abl oncoprotein appears
to confer a number of key cellular
changes including a reduced apoptotic
response in mutated cells, decreased
proteasome-mediated degradation of
ABL-inhibitory proteins,[19] deregulation
of cellular proliferation, and
decreased adherence of CML cells to
the bone marrow stroma and extracellular
matrix. A number of different
signal transduction pathways are
known to be activated in the presence
of a functioning Bcr-Abl oncoprotein,
but precisely how it induces the leukemic
phenotype is still largely a mystery
(Figure 3).

The progression of the chronic
phase to the more advanced phases is
presumably due to acquisition by the
leukemia clone of one, or more probably,
a series, of additional molecular
changes, often in conjunction with recognizable
new cytogenic abnormalities.
In some cases, specific genes have
been implicated in disease progression,
notably p53, p16, RB, EVI-1,
and possibly LYN. The nonrandom
cytogenic changes that occur in advanced
phase disease, principally +8,
+Ph, +19, and iso (17)q, should eventually
help to identify other new molecular
events.[20]

Prognosis

Currently, several available methods
may help predict survival for individual
patients. Some of these
methods, such as the Sokal prognostic
index, are based on criteria definable
at diagnosis and correlated with
duration of survival for subgroups of
patients treated predominantly with
busulfan (Busulfex, Myleran).[21]
This technique was useful during the
busulfan era and may still have value.
The Euro system, introduced by Hasford
and colleagues, is an analogous
system for predicting survival of patients
treated with interferon-alfa and
may more accurately discriminate
prognosis for patients treated with
interferon-containing regimens.[22]
Other possible prognostic factors are
the presence of genomic deletions in
the region of the reciprocal ABL-BCR
on the derivative 9q+ chromosome
and the rate of shortening of telomeres
in the leukemia clone.[23,24] It is
likely that DNA microarray studies
will also play a future role in the staging
of patients with CML.

Treatment

Although allo-SCT is the only
treatment strategy that currently results
in long-term molecular remission
and probable "cure" in CML
patients in chronic phase, this procedure
is only available to less than onethird
of patients.[25] Until recently,
the standard treatment for newly di-
agnosed CML patients in chronic
phase not eligible for an allo-SCT was
interferon-alfa, either alone or in combination
with low-dose cytarabine.[
26] Interferon-alfa largely
replaced hydroxyurea in the mid-
1990s, when it was demonstrated that
it induces major cytogenetic responses
in about one-third of patients and
an overall survival advantage of 1 to
2 years compared to hydroxyurea.[27]

Interferon-alfa treatment was associated
with a wide range of side
effects including flu-like symptoms,
lethargy, depression, and weight loss.
In an attempt to reduce this toxicity,
clinicians have begun using a longacting
form of the drug-pegylated
interferon-alfa. The notion of adding
cytarabine to interferon-alfa appeared
attractive on the basis of a recent study
demonstrating superior survival for
the combination compared to interferon-
alfa alone, but this result has more
recently been called into question.[27]
Today most hematologists would regard
imatinib alone or in combination
with other agents as the treatment of
choice for patients not destined for immediate
allogeneic SCT.[28]

Imatinib Mesylate
Imatinib entered clinical trials for
patients with CML in chronic phase
as well as those in more advanced
phases in 1998.[29] The drug caused
a rapid reversal of clinical and hematologic
abnormalities and major cytogenetic
responses in over 50% of
chronic phase patients. It was administered
orally, and side effects were
relatively minor, with nausea, headache,
rashes, and fluid retention being
the most common; significant
cytopenias and hepatotoxicity were
less frequent. The toxicity, in general,
seems to be appreciably less than that
associated with interferon-alfa.

Current studies confirm the initial
impressive results of imatinib.[8,30,31]
Notably, over 95% of patients in chronic
phase who are refractory or resistant
to interferon-alfa achieved a complete
hematologic response, and 55% of
these patients achieved a major cytogenetic
response, but thus far very
few patients have achieved convincing
molecular remissions.[32,33] To
what extent such patients obtained
survival benefit could not immediately
be ascertained, though it does now
appear that patients who obtained cytogenetic
responses survive longer
than matched controls.[34] A prospective,
randomized phase III trial
designed to answer this question therefore
started in 2000, and the interim
results were published recently[35];
they revealed that 74% of the patients
treated with imatinib achieved a complete
cytogenetic remission (CCR).
Progression-free survival was significantly
better in the imatinib-treated
cohort compared to the interferon-alfa
and cytarabine cohort (97.2% vs
90.3%, P < .001), but it is too early to
expect evidence of prolonged surviv-
al. It is therefore not possible to conclude
that imatinib as a single agent
cures substantial numbers of patients,
but it may well offer the prospect of
"operational cure" to a significant proportion.
Moreover, whether imatinib
is superior to interferon-alfa plus cytarabine
in previously untreated chronic
phase CML patietns remains to be
determined.

In the molecular analysis of the
cohort achieving a CCR, 3.6% of these
patients achieved a complete molecular
remission (defined by a complete
absence of detectable BCR-ABL transcripts
in the blood; the investigators
considered this to represent > 4.5 log
reduction in BCR-ABL/BCR level
when compared to the median pretreatment
level).[36]

Although imatinib appears to be
quite safe, caution must be exercised
in light of several recent reports. Gratwohl
and his colleagues have reported
a potentially fatal side effect-
cerebral edema-soon after the initiation
of imatinib therapy.[37] An interesting
nonsinister effect-hair
repigmentation-has been reported in
a small cohort of responders.[38] The
mechanisms for these unique effects
remain speculative, although the possible
inhibition of the platelet-derived
growth factor receptor has been suggested
for the former effect. Imatinib
is known to be a potent competitive
inhibitor of the tyrosine kinase associated
with the platelet-derived growth
factor receptor, and a recent report
has confirmed its usefulness in patients
with chronic myeloproliferative
disorders with rearrangements of this
receptor.[39]

  • Imatinib in Advanced Phases of
    CML
    -CML-Studies have also confirmed
    impressive (although less durable)
    clinical activity of imatinib in advanced
    phases of CML.[40-42] This
    is remarkable because imatinib targets
    mainly the Abl kinase activity of
    the Bcr-Abl oncoprotein, and as other
    (additional) genetic events underlie
    disease progression, the drug might
    have been expected to have little or
    no activity in the advanced phases. It
    is now likely to be tested in combination
    with various chemotherapeutic
    agents. Notably, some in vitro evi-
    evidence demonstrates that the combination
    of imatinib and agents such as
    interferon-alfa and hydroxyurea may
    result in anatagonism.[43,44]
  • Imatinib-Refractory Patients-Acquired resistance to imatinib among
    patients in chronic phase appears to
    be rare and can often be overcome by
    increasing the dose of the agent.[45]
    In contrast, resistance has been seen
    in up to 70% of those in myeloid blast
    crisis, and all patients in lymphoid
    blast crisis relapse within 6 months of
    responding to imatinib. This reaction
    appears to result from a variety of
    diverse mechanisms, including acquired
    mutations in the Abl kinase
    domain, Bcr-Abl overexpression, Pglycoprotein
    overexpression reducing
    the cellular uptake of imatinib, selection
    of preexisting mutant cells, and
    possibly excessive degradation of the
    Bcr-Abl protein.[46-49] The intrinsic
    production of some proteins, such as
    alpha-1 acid glycoprotein or a P450
    enzyme, may neutralize imatinib and
    render it ineffective.[50]

    Of great interest is the recent finding
    of "acquired" mutations, which
    result in structural changes that prevent
    imatinib binding but do not prevent
    pathologic phosphorylation of
    the relevant substrates by the oncoprotein.
    Currently, at least 18 different
    mutations have been described
    and are associated with some degree
    of resistance to imatinib. Of particular
    interest is the recent report that
    mutations in the P loop of the Abl
    kinase domain predict for disease
    progression, whereas mutations not
    involving the P loop are less ominous.[
    51] Various lines of evidence
    suggest that these "acquired" mutations
    reflect selection by imatinib of
    mutant clones already present at low
    levels before inititation of treatment
    rather than de novo acquisition during
    imatinib therapy.[52-55] These
    observations mean that even when
    multiple additional genetic events predominate
    in the advanced stages of
    CML, the original molecular event
    still appears to play some role in maintaining
    the aggressively transformed
    phenotype, emphasizing the importance
    of BCR-ABL in the pathogenesis
    of CML.[56]

Interferon-Alfa
Interferon-alfa treatment was until
recently the mainstay of treatment for
CML. It is associated with a wide
range of side effects including flulike
symptoms, lethargy, depression,
and weight loss. In an attempt to reduce
this toxicity, clinicians have begun
using a long-acting form of the
drug-pegylated interferon-alfa. The
notion of adding cytarabine to interferon-
alfa appeared attractive on the
basis of a recent study demonstrating
superior survival for the combination
compared to interferon-alfa alone, but
this result has more recently been
called into question.[28]

It is remarkable that despite being
in clinical use for 2 decades, the precise
mechanism of interferon-alfa's
action remains unknown. Although it
was undoubtedly a valuable drug, it
did not appear to produce any durable
molecular responses. If one defines
"cure" as complete eradication of all
leukemia cells (which would require
persisting failure to detect BCR-ABL
transcripts by reverse transcription
polymerase chain reaction), then interferon-
alfa did not result in cure,
but in a small percentage of patients,
an "operational cure"-low numbers
of cells persisted but appeared unable
to reestablish clinical disease.

Allogeneic Stem Cell Transplant
Cure by allo-SCT depends on the
combined effects of chemotherapy or
chemoradiotherapy conditioning before
transfusion and the graft-vs-leukemia
effect mediated by allogeneic
T lymphocytes.[57] Current results
using human leukocyte antigen
(HLA)-identical sibling donors suggest
the probability of event-free survival
at 5 years of about 60%; the
probability of relapse at 5 years is
15%.[58] In contrast, the results of
allo-SCT performed in more advanced
phases of the disease are generally
poor.[59] Because only about
one-third of all patients considered
for an allo-SCT have an HLAmatched
sibling donor, many efforts
have been directed toward the identification
of suitable alternative donors,
ie, either partially matched family
members or unrelated volunteers.
Clinical results with these alternative
donors appear to be slightly inferior
or comparable to HLA-matched sibling
transplants.[60-62]

The major determinants of survival,
other than the phase of the disease,
include the patient's age at transplant,
the duration of disease from diagnosis,
the cytomegalovirus status of the
patient, acute and chronic GVHD, and
the sex of the donor. Thus, survival
appears to be best among patients who
are transplanted within 1 year of diagnosis,
are less than 40 years of age,
and have a male donor, and in cases
where both patient and donor are cytomegalovirus-
seronegative.[63] For
such a cohort, 5-year disease-free survival
is around 70% to 80%, and the
relapse rate, 10% to 20%.[64]

The precise details of the transplant
procedure and the choice of stem
cells (marrow vs peripheral blood)
also influence outcome.[65] Engraftment
appears to be more rapid following
a peripheral blood stem cell
transplant, but the incidence of chronic
GVHD may be increased.[66,67] It
remains unclear whether the risk of
relapse differs significantly following
transplantation of allogeneic blood
cells rather than marrow cells.[68,69]

Acute and chronic GVHD continues
to be a significant cause of transplant-
related mortality. The best
approach to prophylaxis of GVHD, usually
a combination of cyclosporine and
methotrexate, remains controversial.
Over a decade ago, it was demonstrated
that alloreactive T lymphocytes
cause GVHD reactions and that T-cell
depletion of the graft substantially reduces
the incidence of acute and chronic
GVHD but also increases the risk of
relapse.[70] Allo-SCT using T-cell depletion
with the CD52 monoclonal antibody
Campath-1 results in an actuarial
relapse rate (after transplantation in
chronic phase) of 60% to 70%. Other
methods of T-cell depletion, including
use of other antibodies and E-rosette
formation/soybean lectin agglutination,
also reduce the incidence of GVHD
but increase the incidence of relapse to
varying degrees.[71]

Recently, it was shown that transplantation
of highly purified CD34+
peripheral blood stem cells with Tlymphocyte
add-back does not appear
to be associated with an increased risk
of relapse; this strategy is being tested
further.[72] Prior use of interferonalfa
may be associated with an inferior
survival, although reports are
conflicting.[73-75] Preliminary data
from the European Group for Blood
and Marrow Transplantation (EBMT)
suggest that treatment with imatinib
mesylate does not have a deleterious
effect on subsequent allogeneic transplantation,[
76,77] but this will require
further observation.

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