British Journal of Haematology, 2002, 119, 1524

Review
STI-571 IN CHRONIC MYELOGENOUS LEUKAEMIA
STI-571 (imatinib mesylate) is the prototype for signal
transduction inhibitors. It is the model for rational drug
design, in that it targets the genetic mutation of the disease.
STI-571, a 2-phenylaminopyrimidine, is a highly selective
inhibitor of the protein tyrosine kinase family, which
includes BCRABL protein, the platelet-derived growth
factor (PDGF) receptor and the c-kit receptor. Chronic
myelogenous leukaemia (CML) is a stem cell disorder
characterized by the Philadelphia chromosome and is
dependent on the constitutively active tyrosine kinase
protein BCRABL. In the CML model, STI-571 competitively
binds to the ATP-binding site of the BCRABL and inhibits
protein tyrosine phosphorylation. This review begins with a
historical overview of CML therapy, then discusses STI-571
and its impact in the treatment of CML via clinical trials.
The second part of this review addresses the issue of CML
resistance to STI-571. A summary of the currently known
mechanisms of resistance and the available options to
overcome resistant disease is reviewed.
HISTORICAL PERSPECTIVE OF CHRONIC
MYELOGENOUS LEUKAEMIA
Chronic myelogenous leukaemia (CML) has a worldwide
incidence of 12 cases per 100 000 people. CML is a stem
cell disorder in which myeloid lineage cells undergo clonal
expansion. The clinical presentation often includes granulocytosis, marrow hypercellularity and splenomegaly. The
natural course of the disease involves three sequential
phases (chronic, accelerated and blast crises). Chronic phase
can persist for several years but the accelerated and blast
crises phases last only months. Each phase of the disease
becomes more resistant to therapy and, in the past, median
survival was 45 years after diagnosis (Kurzrock et al,
1988; Sawyers, 1999; Kalidas et al, 2001).
The Philadelphia chromosome abnormality, which defines
CML, was discovered in 1960 and was initially described as
a shortened chromosome 22 (Nowell & Hungerford, 1960)
(Table I). It was not until 1973 that the translocation
(9;22) was reported (Rowley, 1973). Ninety-five per cent of
Philadelphia chromosome-positive CML patients have the
traditional t(9;22) abnormality, while the remaining cases
have variant or complex translocations involving the
breakpoint cluster region (bcr) to cellular Abelson protooncogene (c-abl) on chromosome 9. In the Philadelphia

Correspondence: D. M. Talpaz, Department of Bioimmunotherapy,

MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 422,
Houston, TX 77030, USA. E-mail: mtalpaz@mdanderson.org
 2002 Blackwell Publishing Ltd

chromosome, the first exon of the abl product is replaced

with sequences from the bcr gene, resulting in a fusion
protein BCRABL (Bartram et al, 1983; Heisterkamp et al,
1983; Groffen et al, 1984; Shtivelman et al, 1985).
There are three isoforms of the BCRABL fusion protein:
185 190-kDa, 210-kDa and 230-kDa. All the isoforms
encode the same portion of the ABL tyrosine kinase, but
differ in the length of the BCR sequence at the N-terminus
(Sawyers, 1999; Kantarjian & Talpaz, 2001; Verweij et al,
2001). Chronic phase CML cases express the 210-kDa BCR
ABL protein, whereas Philadelphia chromosome-positive
acute lymphoblastic leukaemia (ALL) cases express either
the 210-kDa or 190-kDa BCRABL proteins. The 230-kDa
BCRABL fusion protein has been associated with a
subgroup of CML patients with more indolent disease,
whereas the 190-kDa BCRABL protein has greater tyrosine
kinase activity than the 210-kDa protein. These differences
suggest variability in oncogenic potential between the
isoforms (Faderl et al, 1999; Sawyers, 1999; Verweij et al,
2001).
The BCRABL fusion protein has constitutive tyrosine
kinase activity (Sawyers, 1999; Verweij et al, 2001). The
ABL kinase consists of an activation loop that contains an
ATP binding domain. This domain has a highly conserved
region and is suspected to be critical to the functional
activity of BCRABL tyrosine kinase (Schindler et al, 2000).
Catalytic activity with tyrosine phosphorylation occurs at
the amino-terminal end of the ATP-binding site within the
activation loop (Schindler et al, 2000; von Bubnoff et al,
2002).
Unlike wild-type abelson kinase, which shuttles between
the nucleus and cytoplasm, BCRABL is confined to the
cytoplasm. In this locale, BCRABL undergoes auto-phosphorylation and these tyrosine residues become docking
sites for the SH2 domains of adaptor proteins GRB2 or CRKoncogene-like-protein (CRKL). These adaptor molecules
facilitate activation of downstream signalling proteins.
BCRABL affects oncogenes p21Ras, c-Myc, lipid kinase
PI3K, mitogen-activated protein kinase family, tyrosine
phosphatases, signal transducer and activator of transcription (STAT) factors, and cell-cycle regulatory proteins
p27Kip and cyclins (Okuda et al, 1996; Sawyers, 1999;
Gesbert & Griffin, 2000; Gesbert et al, 2000; Griffin, 2001;
Kantarjian & Talpaz, 2001). The deregulation of normal
signal transduction leads to abnormal cell cycling, antiapoptotic behaviour and increased cell proliferation.
BCRABL is also involved in abnormal cell adhesion and
promotion of genetic instability. It is suspected that phosphorylated CRKL induces aberrant adhesion that benefits
leukaemogenesis. CML cells may then escape the negative

15

16

Review
Table I. Milestones in the history of STI-571 and CML.

Year

Event

1960
1973
1983
1984
1984
1988
1998
2001

Abnormal chromosome 22 (Philadelphia chromosome) identified and associated with CML

Translocation 9;22 defined
Molecular studies define fusion abnormality of breakpoint cluster gene (bcr) with cellular abl gene (c-abl)
Fusion cytoplasmic protein BCRABL found to alter cell proliferation, adhesion and survival
Constitutive abnormal BCRABL tyrosine kinase activity defined
Development of synthetic pharmacologic inhibitors that target tyrosine kinases
Phase I clinical trials using STI-571 initiated
STI571 is approved for treatment of CML that is refractory to IFN-a therapy

Table II. Evolution of therapy and monitoring in CML.

Period of time

Agent

Method of disease monitoring

Survival outcome

19501959

Busulphan

34 years

19601969

Hydrea

19701979
19801989
19902002

Allogeneic bone marrow transplant

Interferon-a
STI-571

WBC count
Spleen size
WBC count
Spleen size
Cytogenetics
Cytogenetics
Cytogenetics
RT-PCR
Quantitative PCR

45 years
5560% long-term survival
67 years
Unknown at this time

WBC, white blood cell count; RT-PCR, reverse transcription polymerase chain reaction.

regulation that stromal cells normally place on haematopoietic cells via direct contact. This thereby enables a
prolonged proliferative phase (Gordon et al, 1987; Dowding
et al, 1991; Raitano et al, 1997; Bhatia & Verfaillie, 1998;
Sawyers, 1999). It is also suspected that BCRABL may play
a role in genomic instability and in transformation of CML
into blastic crises. Over time, the leukaemic clone loses its
ability to differentiate and secondary chromosomal abnormalities inclusive of trisomy 8, duplication of the Philadelphia chromosome, mutations or deletions of p16 and p53
arise which are thought to herald blastic crises (Laneuville
et al, 1992).
CML THERAPY AND MONITORING
Treatment of CML originally focused on the control of
leukaemic cell mass. The first available therapy was ionizing
splenic irradiation, but in 1953 treatment options expanded
to include busulphan (Kurzrock et al, 1988; Sawyers, 1999;
Kalidas et al, 2001). CML disease status was initially
monitored by white blood cell counts and spleen size.
Busulphan demonstrated a 90% haematological response,
but did not alter the progression of the disease. Several years
later, hydroxyurea was introduced. Comparative trials
showed that hydroxyurea had a longer median duration
of survival in chronic phase CML, but progression to blast
crises was not deterred (Hehlmann et al, 1993; Kalidas et al,

2001). The median survival was 45 years, with a 10-year

survival rate of 5% (Baccarani, 2001) (Table II).
In the 1970s, allogeneic bone marrow transplants presented a curative option for CML. Preparative regimens
included high dose chemotherapy with busulphan and
cyclophosphamide or combined chemotherapy with cyclophosphamide and fractionated total body irradiation
(Baccarani, 2001; Kalidas et al, 2001). Ten-year survival
rates of 5060% were reported in these allogeneic bone
marrow transplants (Horowitz et al, 1996). Matched sibling
bone marrow transplants are currently recommended as
treatment for younger patients (age < 3040 years) and
patients with chronic phase CML within 1 year of diagnosis
(Horowitz et al, 1996; Sawyers, 1999; Kalidas et al, 2001).
Despite the curative potential, allogeneic bone marrow
transplants carry high upfront mortality and have limited
availability dependent on donor status. Patients who were
unable to undergo allogeneic transplants had limited
options as autologous bone marrow transplants did not
appear to have any survival benefit in CML (Goldman et al,
1982).
With the evolution of therapy from the control of
haematological symptoms to the treatment of the bone
marrow, cytogenetic responses were introduced for disease
monitoring. Cytogenetic responses are defined as complete or
major karyotype responses. A complete cytogenetic response
is reported as 0% of Philadelphia chromosome-positive

 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 1524

Review
metaphases. A major cytogenetic response, which includes
both complete and partial responses, is defined as 135%
Philadelphia chromosome-positive metaphases. FISH (fluorescence in situ hybridization) is the most common technique
to evaluate for Philadelphia chromosome (Kalidas et al,
2001).
In the mid-1980s a-interferon (IFN-a) was introduced as
a treatment for CML (Talpaz et al, 1983). IFN-a was shown
to induce an 80% complete haematological and 26%
complete cytogenetic remission in chronic phase CML
(Kantarjian et al, 1995). Later, additional clinical trials
showed single-agent IFN-a to be superior to prior therapies,
with prolongation of survival (Talpaz et al, 1983, 1986;
Kloke et al, 1993; Ozer et al, 1993; Kantarjian et al, 1995;
The Italian Cooperative Study Group on Chronic Myeloid
Leukaemia, 1994; Allan et al, 1995; Ohnishi et al, 1995;
Chronic Myeloid Leukaemia Trialists Collaborative Group,
1997; Baccarani, 2001). Single centre data at the MD
Anderson Cancer Center showed a 10-year survival of 40%,
whereas a European collaborative study of 317 patients
who became complete cytogenetics responders had a
projected 10-year survival rate or 72% (Bonifazi et al,
2001).
Clinical trials with combination therapy to improve
survival results were undertaken. The only combination
proven to have efficacy was cytarabine (ara-C) and IFN-a.
Both cytogenetic response and survival were reportedly
improved with this combination in a French clinical trial
(Guilhot et al, 1997). Additional studies later confirmed the
cytogenetic benefit but did not report a survival difference
(Baccarani et al, 2002). In addition to advances in immunotherapy, molecular techniques were introduced as novel
monitors of disease. RT-PCR (reverse transcription polymerase chain reaction) and real-time PCR were the first
examples of molecular monitoring. However, the significance of positive PCR studies in the setting of survival will
need to be determined.
Although improvements in survival and cytogenetic
remissions were seen, IFN-a therapy carried considerable
side-effects. Allogeneic bone marrow transplants were
curative but also had significant morbidity and mortality.
Novel therapies for CML were pursued and included
homoharrington (plant alkaloid), decitabine (hypomethylating agent), troxacitabine (cytosine analogue), various
vaccines, and signal transduction inhibitors (STI).
STI-571
STI-571 (imatinib mesylate, Glivec, Gleevec, CGP 57148B)
is the prototype for signal transduction inhibitors. STI-571,
a 2-phenylaminopyrimidine, is a highly selective inhibitor of
the protein tyrosine kinase family, which includes BCRABL
protein, the platelet-derived growth factor (PDGF) receptor,
and the c-kit receptor (Druker et al, 2001a,b; Verweij et al,
2001; Savage & Antman, 2002). STI-571 competitively
binds to the ATP-binding site of BCRABL and inhibits
protein tyrosine phosphorylation (Schindler et al, 2000; von
Bubnoff et al, 2002). This compound was proven in vitro
to inhibit BCRABL-induced tumour formation in immuno-

17

deficient mice. In vivo studies later confirmed that STI-571

prevented growth of haematopoietic cells that expressed
BCRABL but did not affect normal cell function (Druker
et al, 1996).
CLINICAL ACTIVITY OF STI-571
STI-571 is metabolized via the hepatic CYP3A4 enzyme and
inhibits the CYP2D6 and CYP2C9 pathways. Significant
drug interactions via this hepatic system require careful
monitoring of pharmacological levels (Druker et al, 2001a,b;
Savage & Antman, 2002). STI-571 is rapidly absorbed after
oral administration with 98% bioavailability and a half-life
ranging from 13 to 16 h. In vitro studies have shown that
STI-571 at a concentration of 1 lmol l is sufficient for
cytolysis. This therapeutic level of STI-571 can be obtained
in patients taking a daily dose of 300 mg (Druker et al,
2001a).
The main toxicities encountered from STI-571 include
nausea, musculoskeletal symptoms (muscle cramps, arthralgia, myalgia), oedema (central, truncal, periorbital) and
skin rash and myelosuppression. Diarrhoea is possibly
caused by inhibition of c-kit receptor, which is expressed
on intestinal cells that govern motility. Hepatotoxicity
related to drug hypersensitivity can be seen within 100 d
of drug initiation (Druker et al, 2001a,b). Clinical studies
show that myelosuppression is the dose-limiting toxicity. In
patients with chronic phase CML, 25% developed grade 3
neutropenia (absolute neutrophil count < 1 109 l) and
16% grade 3 thrombocytopenia (platelet count < 50 109 l)
with the daily 400 mg dose. In blast crises and accelerated
phase, close to 50% of the patients experienced grade 4
neutropenia. Patients with more advanced disease, prior
myelosuppression from IFN therapy, or prior busulphan
treatment were more susceptible to myelosuppression
(Druker et al, 2001c).
The maximum tolerated dose of STI-571 was not reached
in phase I trials but efficacy was seen with doses that were
300 mg or higher. Additional phase II clinical trials in
chronic and accelerated phase CML patients led to dose
adjustments. Chronic phase CML is treated at 400 mg daily
and accelerated or blast phase with 600 mg daily (Druker
et al, 2001a).
STI-571 AND CML CLINICAL TRIALS
Phase I trials included both chronic and blast phase patients
with CML. In the chronic phase subgroup, 83 patients who
failed prior IFN therapy were treated with STI-571 at doses
ranging from 25 mg to 1000 mg. Of 54 patients who
received 300 mg or higher as a daily dose, 98% (n 53) of
the patients achieved complete haematological response
(CHR) and 31% (n 17) a major cytogenetic response.
Seven out of the 17 cytogenetic responders had complete
cytogenetic remissions. The haematological responses all
occurred within 4 weeks of therapy (Druker et al, 2001a).
In the blast crises subgroup, 58 patients with blast crises
CML or Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL) were treated with daily doses

 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 1524

18

Review

ranging from 300 to 1000 mg. A complete haematological

remission was seen in 55% (21 38) of CML blast crises and
70% (14 20) of Philadelphia chromosome-positive ALL
patients. Nearly all the lymphoid patients relapsed within
23 months and 60% of the blast crises patients relapsed
within 6 months (Druker et al, 2001b).
A phase II trial conducted with 454 evaluable chronic
phase CML patients refractory to IFN-a showed a 95% CHR
at 400 mg or greater and 60% had a major cytogenetic
response (complete and partial). Forty-one per cent of the
total number of patients experienced complete cytogenetic
response. Progression-free survival was 89% at 18 months
(Kantarjian et al, 2002a). Recent phase II studies in newly
diagnosed chronic phase patients suggested that a very high
and perhaps dose-dependent cytogenetic response rate was
seen with STI-571 when compared to IFN-a (Kantarjian
et al, 2002b).
In accelerated phase CML, phase II trials showed that
patients taking 600 mg d STI-571 had longer time to
progression and superior survival when compared to
400 mg d. In a multicentre clinical trial, 235 CML patients
enrolled in a phase II trial, 181 had confirmed accelerated
phase CML. Overall haematological response was 82% with
34% CHR. Major cytogenetic response was 24% with 17%
complete cytogenetic response. With the two different
dosage regimens, the results indicated that 600 mg d led
to greater cytogenetic response (28% vs 16%) and a higher
survival at 12 months (78% vs 65%). There was no
reported higher toxicity with the 600 mg oral dose (Talpaz
et al, 2002).
In CML blast crises, two recently published studies
showed benefit in using STI-571 over standard cytotoxic
therapies. Seventy-five CML blast crises patients were
treated with STI-571 in a dose escalation (300 mg to
1000 mg) trial. In 47 of these patients, this was the first
salvage chemotherapy. Fifty-two per cent (39 of 75) had a
haematological response and 16% cytogenetic response.
Median survival was 65 months and estimated 1-year
survival was 22%. When compared to traditional cytarabine-based therapy, STI-571 as first salvage was shown to
prolong survival (Kantarjian et al, 2002c). In a separate
multicentre phase II trial, 260 patients were enrolled. CML
blast crises were confirmed in 229 of the patients, of which
148 (65%) were newly diagnosed CML and 81 (35%) had
received prior therapy. Multivariate analysis demonstrated
that the initial dose of STI-571 (600 mg), haemoglobin
value (at least 10 g dl), platelet count (at least 100 109 l)
and blood blast level (below 50%) were independent
predictors for a sustained CHR. In 36% of previously
untreated patients a sustained haematological response
was noted with 9% achieving a sustained CHR. Sixteen per
cent established a major cytogenetic response and 7%
achieved complete cytogenetic response (Sawyers et al,
2002).
Phase III clinical trials are currently ongoing, although a
landmark trial has already demonstrated the efficacy of STI571 as a single-agent for front-line CML therapy. The
combined therapy of IFN (5 MIU m2 d) and low dose ara-C
(20 mg m2 d for 10 d month) was compared to 400 mg d

STI-571. One thousand one hundred and six patients were

randomized to the two arms. STI-571 was found to have
longer time to progression and higher cytogenetic response.
Complete cytogenetic response was 40% [American Society
for Clinical Oncology (ASCO) oral presentation 2002
reported 68%, unpublished data] and major cytogenetic
response was 63% in the STI571 arm. This was significantly
higher than the interferon-a arm in which complete
cytogenetic response was 2% and major cytogenetic
response 10%. The results of this study suggested that
STI-571 should be utilized as front-line therapy in CML
(Druker et al, 2002). In addition, several other trials are
underway to evaluate STI-571 in combination with cytotoxic agents. In vitro studies suggest synergistic antiproliferative properties between STI-571 and IFN, ara-C and
daunorubicin. Additional clinical trials will review the role
of STI-571 after bone marrow transplant (Druker et al,
2001a).
CML RESISTANCE TO STI-571 THERAPY
There appear to be two types of resistance to STI-571,
upfront non-responders (primary resistance) or initial
responders who later relapse with disease (acquired resistance). All three CML phases have primary resistance. In late
chronic phase CML, less than 10% are haematological nonresponders and 4550% will have cytogenetic resistance.
Eighteen per cent of accelerated phase and 48% of blast
phase CML patients have primary resistance. In primary
resistance, it is suspected that BCRABL is not inhibited
effectively or that secondary mutations cause BCRABLindependent cell proliferation. Acquired resistance that
occurs after an initial response is more complicated and
may involve other mechanisms (Druker et al, 2001a). In
patients who relapse with disease after an initial response to
therapy, several molecular mechanisms of resistance have
been suggested (Table III).
In vitro studies
Gene amplification has been reported as an evolutionary
adaptive mechanism to avoid growth inhibition (Hastings
et al, 2000). In CML, gene amplification has been seen as
the mechanism of transformation from chronic to blastic
phase. Duplication of the Philadelphia chromosome or
isolated gene amplification was the most common mutation
(Collins, 1986; Collins & Groudine, 1987). Gene amplification has also been described as a common mechanism of
drug resistance. This has been explored in vitro with human
CML (BCRABL) cell lines with acquired STI-571 resistance
and in BCRABL cDNA transfected murine cell lines (Wu
et al, 1995; Weisberg & Griffin, 2000; Gorre et al, 2001).
Several human cell lines with the BCRABL mutation have
been co-cultured with increasing concentrations of STI-571
in order to generate resistant cell lines. One such cell line,
LAMA84-R, originated from a patient in CML blast crisis
and showed that the likely mechanism of resistance to STI571 was elevated levels of BCRABL protein from gene
amplification of bcrabl (le Coutre et al, 2000). Mahon et al
(2000) studied four human cell lines with induced STI-571

 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 1524

1) gene amplification

Mahon et al (2000)

 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 1524

1) a1-Acid glycoprotein (AGP) does not
cause resistance to STI-571
1) Src-related kinase (Lyn) induced proliferation
independent of BCRABL
1) a1-Acid glycoprotein (AGP) causes resistance
to STI-571
1) Point mutations in BCRABL kinase domain
2) Gene amplification
1) Point mutation
1) Point mutations in ATP-binding site and
activation loop BCRABL
1) Overexpression of Brutons tyrosine kinase
and ATP synthestases
1) Src-related kinase (Lyn) overexpression and
BCRABL independent cell proliferation

Jorgensen et al (2002)

Donato et al (2002)

Donato et al (2002)

Hofmann et al (2002b)

Hofmann et al (2002a)
von Bubnoff et al (2002)

Gorre et al (2001)

Gambacorti-Passerini et al (2000)

1) Cytoplasmic sequestration

2) BCRABL protein overexpression

1) Gene amplification

3) P-glycoprotein overexpession

Vigneri et al (2001)

Weisberg & Griffin (2000)

1) Gene amplification

le Coutre et al (2000)

2) BCRABL protein overexpression

Mechanism of resistance resistance to STI-571

Reference

Table III. Mechanisms of resistance to STI-571.

Four patients (CML or ALLPh+)

with advanced disease

19 patients with ALL Ph+

Patient with ALL Ph+

Eight patients (CML or ALL Ph+)

Nine patients with advanced stage CML

Human cell line

LAMA 84- R
Human cell line
LAMA 84-R
K562-R
AR 230-R
KCL 22-R
Murine cell line
BaF 3
Human cell line
K562
Murine cell line
Ba F3
Human cell line
K562
Human cell line
K562
Human AGP from CML patients
Human cell line
K562-R
Patients with BCRABL positive leukaemia

Study Material and origin

Native resistance

Native resistance

Native resistance
Native resistance

Native resistance

Co-cultured in increasing
concentrations STI-571
Native resistance

Co-cultured in increasing
concentrations STI-571
BaF 3 transformed with
human BCRABL clone

BaF 3 transformed with

human BCRABL clone

Co-cultured in increasing
concentrations STI-571
Co-cultured in increasing
concentrations STI-571
KCL 22-R native resistance

Method of generated
resistance to STI-571

In vivo

In vivo

In vivo
In vivo

In vivo

In vivo

In vitro

In vitro

In vitro

In vitro

In vitro

In vitro

Data

Review
19

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Review

resistance (including LAMA84-R) and confirmed that gene

amplification was a likely modality of resistance.
Weisberg & Griffin (2000) also demonstrated gene
amplification in resistant cell lines but suggested that
elevated BCRABL protein levels can occur without gene
amplification. In a study that generated resistant clones
from a human CML (K562) and transformed murine
(Ba F3) cell line, the murine model demonstrated gene
amplification and elevated BCRABL protein expression.
However, the K562 resistant line did not have detectable
amplification of the bcrabl gene but still expressed high
levels of the p210 BCRABL protein. This result suggested
that elevated protein levels without gene amplification can
lead to clinical drug resistance (Weisberg & Griffin, 2000).
In contrast to the above studies, Mahon et al (2000)
reported the absence of both gene amplification and
elevated BCRABL levels in a K562 resistant cell line
called K562-R. This resistant cell line was developed by
co-culturing K562 in increasing doses of STI-571 (Mahon
et al, 2000).
Mahon et al (2000) suggests that several mechanisms
beyond gene amplification and mutation can generate STI571 resistance. In the LAMA84R cell line, overexpression of
P-glycoprotein (P-gp) was seen in addition to the gene
amplification. P-gp is a multidrug resistance protein encoded by the multidrug resistance gene (MDR-1) and alters
target drug uptake into the cell. P-gp specifically causes
drug efflux out of the cell through the plasma membrane
and prevent its activity (Mahon et al, 2000).
Other mechanisms of resistance focus on BCRABL
protein activity. Wild-type Albelson kinase can induce
apoptosis when present in the nucleus of the cell. BCR
ABL, which also has this capability, usually localizes to the
cytoplasm where it promotes leukaemogenesis. Vigneri &
Wang (2001) showed that STI-571 forces BCRABL into
the cell nucleus where it activates apoptosis. One proposed
mechanism of resistance is cytoplasmic re-entry of BCR
ABL after STI-571 therapy. This cytoplasmic sequestration
prevents BCRABL nuclear activation of the apoptotic
pathway.
Donato et al (2001a) have shown that BCRABL
independent signalling pathways can induce resistance
to STI-571. K562 cell lines were cultured in STI-571 and
a resistant cell line (K562-R) was created (Donato et al,
2001a). In K562-R, a src-related kinase, LYN was found
to mediate cell proliferation independent of BCRABL (Wu
et al, 2002). Interestingly, PD 180970 (a kinase inhibitor
that targets both the src-family and c-abl) was shown to
induce apoptosis in K562 and K562R cell lines (Donato
et al, 2001b). In cell lines established from patients in
blast crisis with acquired STI-571 resistance, Donato et al
(2001a) also showed that these cell lines retained BCR
ABL gene expression but had upregulation of src family
kinases (HCK or LYN). Src family kinase inhibitors (PP2,
CalBiochem, CGP-76030, Novartis) led to apoptosis in
four out of five cell lines. Additional studies provided
confirmatory evidence that BCRABL independent pathways could lead to STI-571 resistance. Cell lines from
CML patients in blast crisis showed low BCRABL protein

expression and high levels of src-related kinase (Donato

et al, 2002).
In vivo studies
Point mutations are another proposed mechanism of
resistance to STI-571. Several point mutations in the
BCRABL gene have been identified (Barthe et al, 2001;
Gorre et al, 2001; Hochhaus et al, 2001; von Bubnoff et al,
2002; Hofmann et al, 2002b). In the review by Gorre et al
(2001), the most common mutation in six patients was a
single nucleotide change that caused an amino acid
substitution (isoleucine for threonine at position 315) in
the activation loop of c-Abl. This alteration prevented STI571 binding to BCRABL. Pre- and post-STI-571 exposure
studies determined that the point mutations occurred after
therapy (Gorre et al, 2001). von Bubnoff et al (2002)
analysed the BCRABL product in eight CML and ALL
Philadelphia chromosome-positive patients with clinical
STI-571 resistance. Five of the patients had distinct point
mutations at positions 255 (Glutamic acid to Lysine,
Valine), 253 (Tyrosine to histadine) and 396 (histadine to
proline). These mutations conferred conformational changes that affected the activation loop of BCRABL, specifically
at the ATP binding site (von Bubnoff et al, 2002). It appears
that substitutions of one amino acid at position 255 and
315 in the ABL kinase domain can cause enough of a
conformational change to prevent STI-571 binding and
clinical resistance results (Barthe et al, 2001; Gorre et al,
2001; Hochhaus et al, 2001; Hofmann et al, 2002b).
Other extracellular mechanisms such as drug sequestration have also been suggested to serve as accessory roles
in STI-571 resistance a-1-acid glycoprotein (AGP), a
plasma protein with drug-binding capability, is highly
expressed in the blood of CML patients (Jorgensen et al,
2002). Prior studies have reported the importance of AGP
in STI-571 resistance (Gambacorti-Passerini et al, 2000).
However, Jorgensen et al (2002) evaluated 99 Philadelphia
chromosome-positive CML cases and reported that,
although often elevated in CML, AGP did not cause
resistance to STI-571. In vitro cell proliferation assays
were performed with the K562 CML cell line and showed
that even supraphysiological levels of AGP did not inhibit
STI-571 activity.
Hofmann et al (2002b) performed gene expression studies
on bone marrow samples from 19 patients with Philadelphia-positive ALL patients in an attempt to predict resistance to STI-571. Reduced levels of proapoptotic gene BAK1
and cell cycle control gene p15 INK4b were seen. Elevated
levels of Brutons tyrosine kinase (BTK) and two ATP
synthetases (ATP5A1 and ATP5C1) were also noted. BTK is
expressed in B cells and is involved in phospholipasedependent signalling. STI-571 binding to the BCRABL,
resuts in the overexpression of BTK and possibly leads
to a bypass mechanism and continued cell proliferation.
In addition, ATP synthetases are also overexpressed in
response to STI-571 and lead to increased cellular levels of
ATP. Competitive inhibition for the catalytic domain of
BCRABL then occurs, with clinical resistance to STI-571
(Hofmann et al, 2002b).

 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 1524

Review
OVERCOMING MECHANISMS OF RESISTANCE
Treatment of STI-571-resistant CML is challenging. In
addition to the traditional cytotoxic chemotherapies, several modalities have been proposed including drug withdrawal, adjustment of drug dosing and novel agents.
Tipping et al (2001) have performed in vitro studies of STI571 withdrawal in resistant cell lines. In one out of four
cell lines, withdrawal of STI-571 for 2 months led to
reacquired sensitivity to STI-571. This cell line (LAMA84-R)
has two defined mechanisms of resistance, gene amplification and overexpression of P-glycoprotein. This evidence
suggests that drug holidays may re-establish sensitivity to
STI-571.
Therapies that target the possible mechanism of resistance have been proposed. Verapamil is a potent inhibitor of
P-glycoprotein and has been shown, by in vitro studies, to
improve cell sensitivity to STI-571 (Mahon et al, 2000). In
the setting of BCRABL cytoplasmic sequestration, the use
of leptomycin B (LMB) in combination with STI-571 has
been suggested. LMB blocks protein exportation from the
nucleus, and when given in combination with STI-571 can
trap BCRABL in the nucleus. Vigneri & Wang (2001)
showed in vitro that 2025% of BCRABL proteins were
sequestered in treated K562 cells. In theory, combination
STI571 and leptomycin can lead to irreversible apoptosis
when single agent therapy is not sufficient. Unfortunately,
LMB has limited clinical use due to significant neuronal
toxicity. Suggestions have been made, however, of using
this drug combination to purge autologous bone marrow for
transplant patients with refractory disease (Vigneri & Wang
2001).
Novel agents that can treat STI-571-resistant disease are
the most promising therapies. WP744, an anthracycline,
was cultured with K562R (a resistant STI-571 cell line) and
induced apoptosis with 10-fold greater ability than doxorubicin (Priebe et al, 2002). Src-family kinase inhibitors have
been suggested as single agents or in combination with
other tyrosine kinase inhibitors (Donato et al, 2002).
Current in vitro data indicates that this may be a new
target for therapy.
Griffin (2002) recommended adopting a preventative
approach to resistance and suggested that, eventually,
combination signal-transduction inhibitors will need to be
given in a manner similar to current human immunodeficiency virus antiretroviral therapy. Prevention of resistance will also require early elimination of leukaemic clones
(Griffin, 2002). This suggests an aggressive induction
therapy approach with combined standard chemotherapy
and signal-transduction inhibitors.
CONCLUSION
STI-571 is the culmination of more than 40 years of
research in CML. The treatment of CML began with
palliation of symptoms and then moved towards therapy
that had an impact on survival, such as allogeneic bone
marrow transplant and interferon-a. This evolutionary
process is highly illuminating because of the rational

21

transition from the discovery of the abnormal chromosome

to abnormal gene to abnormal protein activity to a specific
inhibitor. STI-571 is the rational prototype for future
treatment design, in that it targets the genetic mutation of
the disease. Although a remarkable break-through, there
are still numerous issues that remain unresolved. STI-571
may not be a curative therapy and combination modalities
(immunotherapeutic) and resistance escape pathways will
need to be addressed by an upfront approach or in secondline agents.
Department of Bioimmunotherapy,
M D Anderson Cancer Center,
Houston, TX, USA

Anne S. Tsao
Hagop Kantarjian
Moshe Talpaz

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Keywords: CML, imatinib mesylate, resistance, BCRABL,

clinical trials.

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