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683

Review Article

Drug Therapy

I

MATINIB

M

ESYLATE

A N

EW

O

RAL


T

ARGETED

T

HERAPY

D

AVID

G. S

AVAGE

, M.D.,

AND

K

AREN

H. A

NTMAN

, M.D.

From the Herbert Irving Comprehensive Cancer Center, Columbia Uni-
versity College of Physicians and Surgeons, New York.

MATINIB (Gleevec, Novartis, Basel, Switzer-
land), formerly referred to as STI571, is an inhib-
itor of specific protein tyrosine kinases that was
targeted to the platelet-derived growth factor (PDGF)
receptor (Fig. 1). It was found to inhibit the consti-
tutively active fusion product arising from the Phil-
adelphia (Ph) chromosome of chronic myelogenous
leukemia (CML) and c-kit (CD117), which is overex-
pressed in gastrointestinal stromal tumors. Studies of
imatinib in other tumors that express c-kit or the
PDGF receptor are under way. Imatinib was approved
by the Food and Drug Administration in May 2001
for the treatment of CML that is refractory to inter-
feron therapy and in February 2002 for the treatment
of gastrointestinal stromal tumors.

PROTEIN KINASES AS THERAPEUTIC
TARGETS

Protein kinases are enzymes that transfer phosphate
from adenosine triphosphate to specific amino acids on
substrate proteins (Fig. 2). The phosphorylation of
these proteins leads to the activation of signal-trans-
duction pathways, which have a critical role in a variety
of biologic processes, including cell growth, differen-
tiation, and death.

2,3

Protein kinases are composed of
two subfamilies, the protein serinethreonine kinases
and the protein tyrosine kinases. Several protein kinas-
es are deregulated and overexpressed in human can-
cers and are thus attractive targets for selective phar-
macologic inhibitors. The most extensively studied is
the BCR-ABL tyrosine kinase of CML.

1,4-9

Imatinib
impairs BCR-ABLmediated transfer of phosphate
to its substrates (Fig. 2). In early trials, imatinib has
had extraordinary activity against CML and gastro-
intestinal stromal tumors.

1,10-14
I

CHRONIC MYELOGENOUS LEUKEMIA

Clinical Features

CML arises as the result of a mutation in a plu-
ripotent stem cell and is characterized by progressive
granulocytosis, marrow hypercellularity, and spleno-
megaly.

4-6,15-18

The diagnostic hallmark is the Ph chro-
mosome (Fig. 3),

19,20

which is present in all dividing
cells of hematopoietic lineage, as well as in B and
T cells in some patients, but is absent in all other cells.
Although hematopoiesis is overwhelmed by the Ph-
chromosomepositive clone, a normal Ph-chromo-
somenegative pool of stem cells persists.

5,16,17

The
goal of treatment is the suppression or elimination of
the Ph-chromosomepositive clone and the restora-
tion of Ph-chromosomenegative hematopoiesis.
CML has a biphasic or triphasic course but is usu-
ally diagnosed during the initial, or chronic, phase, in
which the granulocytic population expands but re-
mains able to differentiate. The chronic phase is rel-
atively stable and responds to therapy, but it eventu-
ally evolves into an intermediate, accelerated phase,
in which increasing doses of hydroxyurea are needed
to control disease, followed by a blast phase. Blast-
phase disease resembles acute leukemia. Its phenotype
is myeloblastic in 70 to 80 percent of patients and lym-
phoblastic in 20 to 30 percent.
With conventional treatment the median survival
among patients with CML is about five years, but the
range is very broad. Some patients with an aggressive
form of chronic-phase disease survive only months,
whereas others, who have indolent, chemoresponsive
CML, live 10 years or longer.

Figure 1.

Imatinib Mesylate.
Molecular weight, 589.7
Formula, C
30
H
35
N
7
SO
4
N N
H
N
O CH
3
SO
3
H
N
N
N
N
H
Imatinib mesylate

684

N Engl J Med, Vol. 346, No. 9

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The New Engl and Jour nal of Medi ci ne

Pathogenesis

The Ph chromosome is a truncated chromosome
22 that results from a reciprocal exchange of genetic
material between the long arms of chromosomes 9
and 22 (Fig. 3). The translocation t(9;22) results
in the juxtaposition of 3' DNA sequences derived from
the Abelson (

ABL

) proto-oncogene normally located
on chromosome 9 with 5' sequences of the breakpoint
cluster region (

BCR

) gene on chromosome 22.

21-24

The

ABL

proto-oncogene is homologous with the
transforming gene present in the Abelson leukemia
virus, which causes leukemia in mice.

4-6



ABL

encodes
a tyrosine kinase that is tightly regulated, whereas
the activity of BCR-ABL is autonomous and mark-
edly increased relative to that of normal ABL.
The Ph chromosome is present in approximately 95
percent of patients with classic CML. About half of the
remaining 5 percent of patients have been found to
have the

BCR-ABL

gene when the polymerase chain
reaction (PCR) is used for identification and are
classified as being Ph-chromosomenegative,

BCR-
ABL

positive. Although the precise oncogenic mech-
anism of BCR-ABL is unknown,

4-7

its tyrosine kinase
activity leads to the chronic phase of CML.

25

Trans-
plantation of hematopoietic stem cells containing a

BCR-ABL

gene construct into mice results in a dis-
ease resembling CML.

26,27

The Ph chromosome is
also detected in about 25 percent of adults and
5 percent of children with acute lymphoblastic leu-
kemia (ALL) and is associated with an aggressive
course and poor survival.

28-30

Only about one third of
patients with Ph-chromosomepositive ALL have the

Figure 2.

Mechanism of Action of BCR-ABL and of Its Inhibition by Imatinib.
Panel A shows the BCR-ABL oncoprotein with a molecule of adenosine triphosphate (ATP) in the kinase pocket. The substrate is
activated by the phosphorylation of one of its tyrosine residues. It can then activate other downstream effector molecules. When
imatinib occupies the kinase pocket (Panel B), the action of BCR-ABL is inhibited, preventing phosphorylation of its substrate. ADP
denotes adenosine diphosphate. Adapted from Goldman and Melo

1

with the permission of the publisher.
BCR-ABL
ATP
Phosphate
Tyrosine
Substrate
Effector Substrate
ADP
Chronic myelogenous
leukemia
Tyrosine
Phosphate
A B
BCR-ABL
Imatinib
Tyrosine
Substrate
Effector Substrate
Chronic myelogenous
leukemia
Tyrosine
X

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685

Figure 3.

Translocation Leading to the Philadelphia (Ph) Chromosome and the Role of BCR-ABL in the Pathogenesis of CML (Panel A)
and the Effect of Normal (Panel B) and Abnormal (Panel C) c-kit Function on Platelet-Derived Growth Factor and Gastrointestinal
Stromal Tumors.
The Ph chromosome is a foreshortened chromosome 22 resulting from an exchange between the long arms of chromosomes 9 and
22 (Panel A). The translocation t(9;22) results in the juxtaposition of 3' DNA sequences derived from the

ABL

proto-oncogene
on chromosome 9 with 5' sequences of the breakpoint cluster region

(BCR)

gene on chromosome 22, forming a fusion gene,

BCR-
ABL.

(The reciprocal formation of the

ABL-BCR

fusion gene on chromosome 9q+ is not depicted.)

BCR-ABL

produces a chimeric
messenger RNA (not shown) from which a fusion BCR-ABL oncoprotein is translated. The length of the BCR-ABL protein varies and
is determined by the breakpoint within the

BCR

gene. Chronic-phase CML is driven by the constitutively active BCR-ABL tyrosine
kinase protein, which activates multiple pathways, leading to the malignant expansion of myeloid cells through the stimulation of
mitosis, the disruption of cytoadherence and regulatory control by stromal cells, and the inhibition of apoptosis. Differentiation and
maturation of the leukemic clone are relatively intact in chronic-phase CML, but BCR-ABL is also thought to promote genomic in-
stability, leading to secondary mutations and to the blast phase. Imatinib mesylate inhibits the tyrosine kinase activity of the BCR-
ABL oncoprotein, thus blocking the leukemogenic effects of the Ph chromosome. Dimerization and activation of the normal c-kit
receptor by its ligand stem-cell factor are shown in Panel B. The proto-oncogene

c

-

kit

encodes a transmembrane tyrosine kinase
receptor located on the long arm of chromosome 4 (4q11q12). In gastrointestinal stromal tumors, in-frame deletions and point
mutations in

c

-

kit

produce ligand-independent constitutive activation of c-kit (Panel C). Mutations of

c

-

kit

in the juxtamembrane
domain in gastrointestinal stromal tumors (exon 11) are found in approximately 60 percent of cases. Mutations also occur in the
extracellular domain (exon 9) and in the more distal phosphokinase domain (exon 13). ATP denotes adenosine triphosphate, ADP
adenosine diphosphate, and P phosphate.
Translocation
A
B
C
BCR
22
9 9q
+
Ph
22q

ABL
BCR
ABL
Transcription and translation
BCR-ABL fusion
protein
Constitutive tyrosine kinase
Phosphorylation of multiple substrates
Mitogenic signaling and genomic
instability increased
Apoptosis and stromal regulation
decreased
Chronic myelogenous leukemia
Imatinib
P P
P P
Stem-cell factor Platelet-derived growth factor or
c-kit or platelet-derived
growth factor receptor
ADP ATP
Signal transduction
Gene expression
Stem-cell factor
X
Mutant c-kit
ADP ATP
Signal transduction
Gene expression
Inhibition by
imatinib
X

686

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The New Engl and Jour nal of Medi ci ne

210-kD BCR-ABL protein characteristic of CML; ap-
proximately two thirds have a smaller chimeric BCR-
ABL protein of 185 to 190 kD that has more potent
tyrosine kinase and oncogenic activity.

5,25,31

The continuously (or constitutively) active BCR-
ABL oncoprotein phosphorylates substrates of remark-
able diversity, including RAS, that activate multiple
signaling pathways (Fig. 3).

4-6,32

Because RAS serves
as a critical control point for signal transduction from
cell membrane to nucleus,

32-37

the BCR-ABLmedi-
ated overexpression of RAS appears to alter signal
transduction in a target stem cell, leading to abnormal
mitosis and neoplastic expansion. In addition, BCR-
ABL reduces cellular adhesion to stromal matrix,

38-41

which may disrupt the interaction between hemato-
poietic cells and stromal cells and membrane signaling
mediated by cytoadhesion molecules, allowing myeloid
progenitor cells to remain longer in the proliferative
phase before undergoing differentiation.

42

BCR-ABL
also diminishes cellular responsiveness to apoptotic
stimuli, providing a survival advantage to the leuke-
mic clone.

43-46

In theory, since chronic-phase CML is
dependent on the tyrosine kinase activity of BCR-
ABL, a potent BCR-ABL inhibitor might eliminate the
leukemic clone and restore normal Ph-chromosome
negative hematopoiesis.
Although the mechanism for blastic transformation
is unknown, possible scenarios have been considered.
For example, BCR-ABL promotes genomic instability
in the leukemic clone,

47

which may lead to secondary
mutations (e.g., trisomy 8). Blast-phase cells may be
more dependent on these secondary oncogenic aber-
rations than on the tyrosine kinase activity of BCR-
ABL. As the leukemic clone becomes unable to differ-
entiate, blast cells accumulate, leading inexorably to a
blast crisis.

RATIONALE FOR THE DEVELOPMENT
OF IMATINIB

Because of their unregulated activity in various hu-
man cancers, BCR-ABL, protein kinase C, and the epi-
dermal growth factor receptor were among the first
protein kinases targeted for selective inhibition.

3

In
1988 Yaish and colleagues described a family of com-
pounds called tyrphostins with specificity for epider-
mal growth factor receptor,

48

proving that pharmaco-
logic inhibitors could target a specific tyrosine kinase.
At about this time chemists at CibaGeigy (which later
became Novartis) screened their compound libraries
for molecules with tyrosine kinase inhibitory activity
and identified 2-phenylaminopyrimidine compounds
as the most promising agents. Because the initial in-
hibitors were of low specificity and potency, similar
compounds were synthesized that had better struc-
tureactivity relations with different kinase targets.

3

Imatinib was developed as a specific inhibitor of the
PDGF receptor.

49

However, it was also a powerful
and relatively selective inhibitor of all ABL tyrosine
kinases, including the 210-kD BCR-ABL and the
BCR-ABL of 185 to 190 kD. The only other tyrosine
kinase inhibited by imatinib was c-kit, the receptor for
stem-cell factor.

49,50

Other tyrosine kinase receptors,
such as epidermal growth factor receptor, FLT1, and
FLT3, were unaffected.

49,51

Druker and colleagues

3,52

recognized that the BCR-
ABL protein was an ideal target for imatinib, since the

BCR-ABL

mutation is present in almost all patients
with CML, the BCR-ABL protein is unique to leuke-
mic cells and expressed at high levels, and its tyrosine
kinase activity is essential for its ability to induce leu-
kemia. In 1996, Druker et al. reported that imatinib
specifically inhibited or killed proliferating myeloid
cell lines containing BCR-ABL but was minimally
harmful to normal cells.

52

When cells from patients
with CML were grown in colony-forming assays in
vitro, imatinib reduced the formation of BCR-ABL
positive colonies by about 95 percent at concentrations
of 1 M. Other laboratories confirmed or extended
these observations.

53-55

Imatinib also suppressed the
growth of cells from patients with Ph-chromosome
positive ALL, including those with the BCR-ABL of
185 to 190 kD.

53,54

The striking in vitro results led to experiments to
determine the effectiveness of imatinib in vivo. Since
apoptosis could be averted in cells expressing BCR-
ABL if exposure to imatinib was limited to 16 hours or
less, Druker and colleagues reasoned that continual
suppression of BCR-ABL would require long-term
treatment with a well-tolerated oral formulation.

3,56

When given in a regimen that ensured the continual
inhibition of BCR-ABL, oral imatinib therapy sup-
pressed or eradicated the growth of BCR-ABLpos-
itive human tumors in mice, with minimal side ef-
fects.

56,57

STANDARD TREATMENT OF CML
AND THE NEED FOR BETTER THERAPY

Patients with chronic-phase CML are treated with
hydroxyurea or interferon alfa. Hydroxyurea is an oral
agent that typically returns blood counts to normal,
shrinks the spleen, and has few toxic effects (Table
1).

59,60

In contrast, interferon alfa must be adminis-
tered subcutaneously, is toxic, and controls blood
counts in only about two thirds of patients. Never-
theless about 25 percent of these patients have a ma-
jor cytogenetic response (defined as the disappear-
ance of the Ph chromosome from at least 66 percent
of marrow cells in metaphase) and about 10 percent
have a complete cytogenetic response (defined as the
reversion to Ph-chromosomenegative status). Inter-
feron alfa therapy extends survival by about one to two
years as compared with hydroxyurea.

61-71

The addi-

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687

tion of cytarabine to interferon alfa therapy may pro-
vide further benefit.

72

Because interferon alfa reduc-
es the number of Ph-chromosomepositive clones
and improves survival, it is the drug of choice for pa-
tients who are unable to undergo allogeneic stem-cell
transplantation. For patients with refractory disease or
those who cannot tolerate interferon alfa, autologous
stem-cell transplantation is an alternative, but it may
not increase survival, and relapse is inevitable.

5,16

Blast-phase CML is resistant to both hydroxyurea
and interferon alfa. Multiagent chemotherapy induc-
es responses in only about 20 percent of patients
with myeloblastic transformation and 50 percent of
those with lymphoblastic transformation. However,
even patients who have a response typically relapse
quickly and die of progressive disease.

73-76

Allogeneic stem-cell transplantation is the only
curative therapy for CML and is the standard treat-
ment for patients less than 40 years of age who have
an HLA-identical sibling.

5,16,18,77-82

Many survivors
have donor-derived normal hematopoiesis for more
than 10 years. The outcome is determined by several
factors, including the patients age, the interval from
diagnosis to allogeneic stem-cell transplantation, the
degree of HLA matching, and the phase of CML.

83

The likelihood of leukemia-free survival is about 60
to 70 percent among patients with chronic-phase
CML who receive allografts from HLA-identical sib-
lings, but ranges from 0 to 15 percent among simi-
lar patients with blast-phase CML.
Advanced age and the lack of a matched donor
make allogeneic stem-cell transplantation involving an
HLA-identical sibling unfeasible in all but about 15
percent of patients with newly diagnosed CML. Allo-
geneic stem-cell transplantation involving an unrelated
donor is an option for an additional 10 to 15 percent
of patients, but morbidity and mortality are gener-
ally higher.

84,85

However, excellent leukemia-free sur-
vival rates have been reported in young patients who
receive transplants from unrelated donors who are
HLA-matched with the use of high-resolution molec-
ular methods. For older patients and those with co-
existing conditions that preclude conventional trans-
plantation, allogeneic stem-cell transplantation after
low-intensity, nonablative conditioning seems to be
a promising approach.

70

PHASE 1 TRIALS OF IMATINIB FOR CML

Chronic Phase

On the basis of the promising preclinical data, in
June 1998 Druker and coworkers initiated a phase 1
trial designed to determine the safety and efficacy of
imatinib in patients with chronic-phase CML.

10

Pa-
tients who had no response to interferon alfa or who
were unable to tolerate the drug were eligible. Re-
markably, of 54 patients who received oral doses of
at least 300 mg per day, 53 (98 percent) had normal
leukocyte and platelet counts, usually within four
weeks after the initiation of treatment. Cytogenetic
responses occurred in 29 patients (54 percent), in-
cluding 17 (31 percent) who had major responses and
7 (13 percent) who had complete responses. The time
from the initiation of treatment to a cytogenetic re-
sponse was substantially shorter with imatinib than
with interferon alfa. Phosphorylation of CRK-onco-
genelike protein (CRKL), a major substrate of
BCR-ABL kinase, was markedly reduced in leukemic
cells, demonstrating the effect of the imatinib on its
target. Side effects were mild to moderate (Table 2)
and were usually reversible when the dose was re-
duced or treatment was suspended.
A once-daily oral dose of 400 mg of imatinib was

*Prolonged therapy with interferon alfa appears to worsen the outcome, but not if treatment with
the drug is stopped at least three months before transplantation.

58

T

ABLE

1.

C

OMPARISON



OF

H

YDROXYUREA

, I

NTERFERON

A

LFA

,

AND

I

MATINIB

M

ESYLATE



FOR



THE

T

REATMENT



OF

CML.

VARIABLE HYDROXYUREA INTERFERON ALFA IMATINIB MESYLATE
Mechanism of action Ribonucleotide re-
ductase inhibitor
Not known Selective inhibitor
of BCR-ABL
Oral administration Yes No Yes
High cost of drug No Yes Yes
Induces rapid hematologic responses Yes No Yes
Induces cytogenetic responses No Yes Yes
Commonly toxic No Yes No
Active against blast phase No No Somewhat
Improves survival No Yes Unknown
May worsen results of allogeneic
stem-cell transplantation
No Perhaps* Unknown
688 N Engl J Med, Vol. 346, No. 9 February 28, 2002 www.nejm.org
The New Engl and Jour nal of Medi ci ne
rapidly absorbed, with a maximal mean plasma con-
centration of 2.3 g per milliliter (4.6 M). The ter-
minal half-life ranged from 13 to 16 hours, and the
levels of imatinib increased by a factor of 2 or 3 after
one month.
10,11
At doses of 300 mg or higher, plasma
levels were equivalent to the effective in vitro con-
centration of 1 M. The smallest dose that inhibit-
ed the phosphorylation of CRKL was 400 mg, and
this dose was thus recommended for use in future
studies.
The sole patient in the study who had no hema-
tologic response had low plasma imatinib levels that
were attributed to concomitant phenytoin therapy.
10
Imatinib is a competitive inhibitor of the cytochrome
P-450 enzymes CYP3A4 and CYP2D6 and is itself
metabolized by CYP3A4. Drugs such as phenytoin,
which increase the activity of CYP3A4, may lead to
subtherapeutic levels of imatinib. Conversely, drugs
that block CYP3A4 may inhibit the metabolism of
imatinib, leading to high plasma levels of imatinib and
increasing its toxicity. Whether imatinib interacts with
warfarin is not known.
Blast Phase
In a companion study Druker et al. treated 58 pa-
tients with blast-phase CML and relapsed or refrac-
tory Ph-chromosomepositive ALL with 300 to 1000
mg of imatinib daily. The overall rates of response
among patients with myeloblastic crisis and lympho-
blastic crisis were 55 percent and 70 percent, respec-
tively.
11
Almost 80 percent of patients had a reduc-
tion of at least 50 percent in peripheral-blood blasts,
usually within the first week after the initiation of
treatment.
Of the subgroup of 38 patients who were receiv-
ing imatinib for myeloblastic crisis, 17 (45 percent)
had a partial hematologic response (defined by a re-
duction in the marrow blast count to 15 percent or
less) and 4 (11 percent) had a complete response
(defined by a decrease in the blood and marrow blast
count to less than 5 percent, a neutrophil count of
more than 1000 per cubic millimeter, and a platelet
count of more than 100,000 per cubic millimeter).
Three patients had a major cytogenetic response.
Most responses were brief, but seven patients (18 per-
cent) remained in complete or partial remission for
3 to 12 months during treatment.
The results for 10 patients with CML in lympho-
blastic transformation and 10 with Ph-chromosome
positive ALL were similar; thus, their data were
combined. Of these 20 patients, 10 had a partial he-
matologic response and 4 had a complete response.
Two patients had a major cytogenetic response. Nev-
ertheless, all patients who had a response relapsed
within four months.
Side effects in patients who received imatinib for
advanced leukemia were similar to those in patients
with chronic-phase CML.
10,11
Serious adverse events
possibly due to imatinib occurred in 13 patients, usu-
ally at doses of 800 to 1000 mg per day. Only three
patients had febrile neutropenia; no deaths were at-
tributable to the drug.
PHASE 2 TRIALS OF IMATINIB FOR CML
Reports of three multi-institutional phase 2 stud-
ies involving more than 1000 patients with chronic-
phase and advanced-phase CML (Table 2) confirm
data on the efficacy and safety of imatinib that were
reported in phase 1 studies.
86-88
One of these studies
is reported in detail elsewhere in this issue.
86
More
than 90 percent of patients with interferon-resistant
chronic-phase CML had a complete hematologic re-
sponse, and almost half had a major cytogenetic re-
sponse.
*Data are from Druker et al.
10,11
(and unpublished data), Kantarjian et
al.,
86
Talpaz et al.,
87
and Sawyers et al.
88
The adverse events that are listed
occurred in at least 30 percent of patients but were not necessarily related
to the drug.
Edema was superficial in most patients. Among patients with accelerat-
ed-phase or blast-phase CML, 3 percent and 6 percent, respectively, had
more extensive fluid retention, including one patient who died with pleural
and pericardial effusions associated with cardiac and renal failure.
A case report of a patient with generalized exanthematous pustulosis
has been published.
89
One patient who was also taking acetaminophen had fatal hepatotoxicity.
TABLE 2. FREQUENCY OF ADVERSE EFFECTS AND HEMATOLOGIC
AND CYTOGENETIC RESPONSES AMONG PATIENTS WHO WERE
RECEIVING IMATINIB THERAPY FOR CML.*
VARIABLE
CHRONIC-
PHASE CML
(N=532)
ACCELERATED-
PHASE CML
(N=235)
BLAST-
PHASE CML
(N=260)
percent
Dose
400 mg/day 100 33 14
600 mg/day 0 67 86
Side effect
Nausea 58 71 69
Edema 56 71 69
Cramps 50 37 26
Diarrhea 37 53 41
Vomiting 30 55 52
Rash 39 43 34
Headache 30 29 26
Fatigue 31 36 28
Arthralgia 30 29 24
Neutrophils, <1.010
3
/mm
3
34 58 63
Platelets, <5010
3
/mm
3
17 43 60
Hemoglobin <8 g/dl 5 39 51
Drug treatment stopped due
to serious adverse events
2 2 5
Complete response
Hematologic 95 34 7
Cytogenetic 41 17 7
DRUG THERAPY
N Engl J Med, Vol. 346, No. 9 February 28, 2002 www.nejm.org 689
Complete cytogenetic responses occurred in more
than 40 percent of patients with chronic-phase CML,
a higher rate than that associated with interferon
therapy. Hematologic and cytogenetic responses were
less common in patients with accelerated- or blast-
phase CML than in patients with chronic-phase CML
(Table 2), but the results were favorable relative to
those achieved with conventional therapy.
Most patients who were receiving imatinib had
mild-to-moderate side effects (Table 2), similar to
those noted in the phase 1 trials. Adverse events were
more common in advanced disease, but it was unclear
whether this was due to the phase of the disease or
to the higher doses of imatinib that were used. Serious
adverse events, including bone marrow necrosis
90
and severe rash,
89
have been reported.
Resistance of CML to Imatinib
The relative resistance of blast-phase CML to ima-
tinib is consistent with the hypothesis that second-
ary mutations (and not BCR-ABL itself ) are the pri-
mary driving force in the transformed leukemic clone.
Nevertheless, Gorre and colleagues
91
demonstrated
that point mutations in BCR-ABL may be the pri-
mary mechanism of acquired resistance to imatinib,
suggesting that the tyrosine kinase activity of BCR-
ABL remains crucial in advanced disease. Other po-
tential mechanisms of resistance include amplification
of the BCR-ABL gene, overexpression of the BCR-
ABL protein, enhanced expression of the multidrug-
resistance gene, and excessive binding of imatinib by
protein.
91-97
Whatever the mechanism, the high inci-
dence of resistance suggests that imatinib should be
combined with other chemotherapeutic agents
11,98,99
in future trials involving patients with Ph-chromo-
somepositive blast-phase disease. Whether higher
doses of imatinib (more than 1000 mg per day)
might overcome resistance could also be evaluated.
Unanswered Questions
How should imatinib be used relative to other
treatments for chronic-phase CML? Since patients
with CML have a median survival of about five years
and a variable course, follow-up data on patients who
have been treated with imatinib are limited. Although
the rates of response among patients with chronic-
phase CML have been dramatic, the durability of re-
sponse and the possible long-term effects are un-
known.
In patients with newly diagnosed CML, hydroxy-
urea is the standard short-term therapy to control
blood counts before the initiation of interferon alfa
therapy or allogeneic stem-cell transplantation. Should
imatinib replace hydroxyurea for short-term control?
Both hydroxyurea and imatinib are oral agents that
can be taken once daily with few toxic effects (Table
1). Imatinib, which induces cytogenetic responses, ap-
pears to be the superior agent. Nevertheless, thus far,
all the patients who have received imatinib for chron-
ic-phase disease had previously received interferon
alfa.
10,86
It is not known whether imatinib will be as ef-
fective against new-onset CML or will jeopardize any
subsequent treatment with interferon alfa.
Which patients with CML should proceed directly
to allogeneic stem-cell transplantation, a potentially
curative treatment,
5,16,70,77-85
without first undergo-
ing a trial of imatinib? Among patients who are
younger than 40 years of age, who have chronic-
phase CML, and who have an HLA-identical sibling
donor, the leukemia-free survival rate approaches 70
percent after transplantation but is associated with a
substantial cost in terms of toxicity. Whether ima-
tinib alone or in combination can cure chronic-
phase CML is unknown, but only a fraction of pa-
tients have become BCR-ABLnegative on the basis
of PCR results.
97
Until more is known about the
long-term effects of imatinib, allogeneic stem-cell
transplantation remains the primary treatment for
young patients with CML who have an HLA-matched
related donor.
70
Will treatment with imatinib enhance or jeopard-
ize the results of subsequent transplantation? Patients
with CML who undergo allogeneic stem-cell trans-
plantation in the first one to two years after diagno-
sis fare better than those who undergo transplanta-
tion later.
5,16,80-83
Delaying transplantation for a trial
of imatinib may render the leukemia more resistant
to the curative effects of this approach. In studies of
allogeneic bone marrow transplantation, subgroups of
patients who had previously received busulfan
80,82
or
interferon alfa
58,100,101
had worse outcomes than those
who had received hydroxyurea.
Since imatinib has several advantages over interfer-
on alfa (Table 1), should a trial of imatinib precede a
trial of interferon alfa in older patients or those who
lack a suitable donor? Interferon alfa prolongs survival,
but we do not know whether imatinib does so. Thus,
imatinib is currently being compared with combined
interferon alfa and cytarabine in a randomized trial.
For patients who have had no response to interferon
alfa therapy, however, imatinib is clearly the drug of
choice.
10

Imatinib will be combined with other agents to in-
crease the rate of cytogenetic response and improve
survival rates among patients with Ph-chromosome
positive leukemias. The use of a combination of ima-
tinib and interferon alfa is especially intriguing for the
treatment of chronic-phase CML.
71
Combining ima-
tinib with inhibitors of other key cellular enzymes,
such as the farnesyltransferases,
102
is another rational
strategy. Imatinib might also be used in vitro to purge
stem cells harvested for autologous transplantation.
690 N Engl J Med, Vol. 346, No. 9 February 28, 2002 www.nejm.org
The New Engl and Jour nal of Medi ci ne
Imatinib appears to have potent activity in patients
with CML who relapse after allogeneic transplanta-
tion.
103
IMATINIB FOR GASTROINTESTINAL
STROMAL TUMORS
Until about 1990, most gastrointestinal sarcomas
were considered to be leiomyosarcomas because they
resembled smooth muscle histologically. However,
clinical oncologists observed a distinctly lower rate
of response to standard doxorubicin-based regimens
among leiomyosarcomas that arose in the gut than
among those that arose in the uterus, trunk, or arms
and legs. As early as 1983 careful immunocytochem-
ical studies of gastrointestinal sarcomas documented
their frequent absence of muscle markers that were
typical of leiomyosarcomas located elsewhere in the
body. Tumors in the subgroup without muscle or
Schwann-cell (i.e., S-100 antigen) markers were even-
tually termed gastrointestinal stromal tumors. Almost
all these tumors expressed c-kit and often CD34,
which are also expressed on hematopoietic progeni-
tor cells.
The proto-oncogene c-kit encodes a transmembrane
tyrosine kinase receptor located on the long arm of
chromosome 4 (4q11q12). Its ligand is stem-cell
factor. This proto-oncogene has a role in the develop-
ment of normal hematopoiesis as well as in the migra-
tion of germ cells and is also expressed in normal hu-
man mast cells, immature myeloid cells, melanocytes,
epithelial breast cells, and the interstitial cells of Ca-
jal (the gastrointestinal pacemaker cells). The im-
munohistochemical profile of the interstitial cells of
Cajal is similar to that of gastrointestinal stromal tu-
mors (they are positive for c-kit and CD34 and neg-
ative for desmin and S-100 antigen), and gastrointes-
tinal stromal tumors are thought to originate from
these cells. However, because omental and mesenteric
primary stromal tumors have an immunohistochemi-
cal profile typical of that of gastrointestinal stromal
tumors and interstitial cells of Cajal are absent in
these locations, gastrointestinal stromal tumors may
arise from multipotential mesenchymal stem cells.
104
In approximately 60 percent of cases of gastroin-
testinal stromal tumors, there are mutations in c-kit
105
in the juxtamembrane domain, such as in-frame de-
letions (3 to 18 bp) and point mutations in exon 11.
The reported rate of mutation ranges from 21 to 88
percent.
106
Mutations in exon 13 and exon 9 have
been found in most of the remaining cases. The mu-
tations cause the receptor to be activated constitutive-
ly without its ligand. Gastrointestinal stromal tumors
with mutant c-kit are more likely to be high-grade
tumors, characterized by more frequent recurrences
and a higher mortality rate than gastrointestinal stro-
mal tumors with normal c-kit. Stable transfection of
the mutant gene leads to malignant transformation
of murine lymphoid cells (Ba/F3).
105
Approximately 70 percent of gastrointestinal stromal
tumors develop in the stomach, 20 percent in the
small intestine, and less than 10 percent in the esoph-
agus, colon, and rectum. Gastrointestinal stromal tu-
mors are typically more cellular than other gastrointes-
tinal sarcomas. They occur predominantly in patients
who are 40 to 70 years old but in rare cases may occur
in younger persons.
104,106
Survival rates are correlated
with the location of the tumor: the rates are highest
for esophageal and stomach tumors and lowest for
small-bowel tumors. Age, the mitotic index, and size
of the tumor (less than 5 cm vs. 5 cm or more) are
also independent prognostic factors.
104,106,107
A Finnish patient with metastatic gastrointestinal
stromal tumor had a rapid and sustained complete re-
sponse to treatment with 400 mg of imatinib daily
for more than 12 months.
12
In a European trial of
36 patients with gastrointestinal stromal tumors, oral
doses of imatinib that ranged from 300 to 1000 mg
daily inhibited tumor growth in 32 patients, 19 of
whom had more than a 50 percent decrease in tu-
mor volume.
14
Of 36 U.S. patients with unresectable
or metastatic gastrointestinal stromal tumors who
were randomly assigned to receive 400 mg or 600
mg of imatinib daily, 19 (53 percent) had a partial
response (defined by a decrease of at least 50 percent
in the size of the lesion); the results were similar with
either dose. The disease progressed in four patients
(11 percent), but in none of those who had had an
initial response.
13
In both studies, the severity and
frequency of adverse effects were similar to those re-
ported in studies of patients with CML. At twice-dai-
ly doses of 500 mg in the European dose-escalation
study, nausea and vomiting, edema, and dyspnea were
dose-limiting effects. The most common side effects
(which generally resolved after the first eight weeks)
were nausea and vomiting, rash, edema (particularly
periorbital), and conjunctivitis (which in rare cases oc-
curred with bleeding sclerae). Myelosuppression was
infrequent, although anemia did occur. Intratumoral
and gastrointestinal bleeding developed in fewer
than 5 percent of patients.
14
IMATINIB FOR OTHER LEUKEMIAS
AND SOLID TUMORS
In addition to gastrointestinal stromal tumors, c-kit
is expressed in a variety of other human cancers, in-
cluding mast-cell tumors, neuroblastoma, germ-cell
tumors, melanoma, small-cell lung cancer, breast
and ovarian cancers, and acute myelogenous leuke-
mia.
49,50,108-111
Up to 70 percent of the cells of small-
cell lung cancer express both c-kit and stem-cell fac-
tor.
108,112
Although gain-of-function mutations of c-kit
occur in both mast-cell neoplasms and gastrointestinal
DRUG THERAPY
N Engl J Med, Vol. 346, No. 9 February 28, 2002 www.nejm.org 691
stromal tumors, the mutations are different, and mast-
cell neoplasms have not proved responsive to imatinib.
In contrast to the ligand-independent activation of
c-kit in gastrointestinal stromal tumors, mastocytosis,
and germ-cell tumors, in small-cell lung cancer and
neuroblastoma c-kit may be activated by stem-cell fac-
tor through autocrine growth regulation.
49,50,109
Ex-
pression of c-kit (or PDGF) does not imply that a
given tumor will respond to imatinib. The tumor must
be dependent on the activity of c-kit for imatinib to
produce an antitumor effect.
Aberrant PDGF receptors appear to deregulate
the growth of a variety of cancers, such as myelopro-
liferative disorders, gliomas, carcinomas, melanoma,
and sarcomas, including dermatofibrosarcoma protu-
berans.
49,51,113,114
In preclinical studies, imatinib in-
hibited the proliferation of both glioblastoma cell
lines expressing PDGF receptors in vitro and in nude
mice
51,115
and human prostate-cancer cells expressing
high levels of PDGF and its receptors that had been
implanted in the bones of nude mice, particularly
when imatinib was combined with paclitaxel.
116
Inhi-
bition of PDGF receptors by imatinib may decrease
interstitial pressure and thus increase the delivery of
chemotherapeutic agents within tumors.
117
Imatinib
is active against chronic myeloproliferative disorders
associated with a translocation between chromo-
somes 5 and 12,
118
in which there is a rearrangement
and overexpression of the gene for PDGF receptor b.
CONCLUSIONS
Imatinib is highly active and has an acceptable level
of toxicity when given alone for the treatment of
chronic-phase CML and gastrointestinal stromal tu-
mors. Imatinib also has limited activity against blast-
phase CML and relapsed Ph-chromosomepositive
ALL, conditions resistant to standard chemotherapy
and even to allogeneic stem-cell transplantation. Tri-
als of imatinib are planned or ongoing in patients
with acute myelogenous leukemia and in those with
solid tumors that express the PDGF receptor or c-kit.
The effect of imatinib in combination with other
agents is also being evaluated in laboratory models
and in the clinic. Our increasing capacity to target an-
ticancer agents at better-defined neoplastic pathways
may change the paradigm for anticancer treatment.
We are indebted to John Goldman for his helpful comments and
to Brian Druker for providing helpful comments and data on ad-
verse events.
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Copyright 2002 Massachusetts Medical Society.