BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myelogenous Leukemia clinical therapeutics

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clinical therapeutics
BCR-ABL Tyrosine Kinase Inhibitors
for Chronic Myelogenous Leukemia
Charles A. Schiffer, M.D.
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the author’s clinical recommendations.
A 28-year-old woman is referred for advice about the management of recently diagnosed chronic myelogenous leukemia (CML). She was in excellent overall health but
was incidentally found to have an elevated white-cell count of 31,000 per cubic millimeter. Bone marrow aspirate and biopsy showed a hypercellular marrow with myeloid hyperplasia with less than 2% myeloid blasts and the presence of the Philadelphia (Ph) chromosome with no additional abnormalities. She was started on 400 mg
of imatinib mesylate daily, and 3 weeks later her blood counts are normal. She is interested in discussing her further treatment and, in particular, the advisability of allogeneic stem-cell transplantation. She has no siblings, and a preliminary computer
search of the worldwide donor list suggests that there may be only one or two fully
histocompatible donors.
The Cl inic a l Probl e m
From the Division of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of
Medicine, Detroit. Address reprint requests to Dr. Schiffer at the Division of
Hematology/Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRB 4th Fl.,
4100 John R, Detroit, MI 48201, or at
schiffer@karmanos.org.
N Engl J Med 2007;357:258-65.
Copyright © 2007 Massachusetts Medical Society.
CML is a myeloproliferative disorder that is a consequence of an acquired mutation
affecting hematopoietic stem cells. This mutation results in a balanced translocation
between chromosomes 9 and 22, initially identified in 1960, and termed the Ph chromosome [t(9;22)(q34;q11)].1,2 CML occurs at roughly the same frequency in countries
around the world and is no more common in one ethnic or racial group than in any
other. The annual incidence rate is 1.6 cases per 100,000 adults (approximately 5000
new cases per year in the United States), with a male-to-female ratio of 1.4 to 1.3 The
median age at diagnosis is approximately 55 years, with less than 10% of patients
under the age of 20 years.4
It is common for the diagnosis to be made after leukocytosis is found on routine
blood tests in asymptomatic patients; nearly 90% of patients who receive the diagnosis of CML have chronic-phase disease.3 Patients with chronic-phase CML have elevated white-cell counts with circulating immature precursors and frequently have
thrombocytosis and splenomegaly. After approximately 4 to 5 years, untreated CML
inevitably progresses to the more aggressive accelerated and blast phases, characterized by the development of constitutional symptoms and an increasing number of
leukemic blasts in the blood and bone marrow. The median survival of patients in
the blast phase is less than 6 months, with infection and hemorrhage being the most
common causes of death.
Pathoph ysiol o gy a nd Effec t of Ther a py
The Ph translocation found in CML results in the juxtaposition of a portion of the
human homologue of the Abelson murine leukemia (ABL) gene from chromosome 9
258
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Clinical Ther apeutics
and the breakpoint cluster region (BCR) gene of
chromosome 22, which in virtually all cases results
in the formation of a BCR-ABL fusion protein with
a molecular mass of 210 kd. The BCR-ABL protein
contains the active tyrosine kinase region of ABL,
producing a cytokine-independent, constitutive
proliferative signal and affects a variety of downstream pathways. This signal results in contin­
uous cell growth and replication.5 Retroviral transfection with BCR-ABL alone is sufficient to initiate
a myeloproliferative disorder in murine models,6,7
a finding that encouraged efforts to develop pharmacologic approaches to inhibit this discrete
process.
Morphologically, chronic-phase CML resembles
a benign expansion of myelopoiesis. However, the
chronic phase is a genetically unstable state, and
the high proliferative rate allows for the accumulation of additional molecular and chromosomal
abnormalities, a process termed “clonal evolution.”
Clonal evolution leads to impairment of hematopoietic differentiation, ultimately resulting in acute
leukemia (blast-phase CML). Approximately one
third of acute leukemias resemble B-lineage acute
lymphocytic leukemia (ALL), whereas the rest of
such cases are similar to acute myeloid leukemia
(AML), often with an undifferentiated phenotype.
Imatinib mesylate (Gleevec, Novartis) is an inhibitor of multiple tyrosine kinases, including ABL,
BCR-ABL, platelet-derived growth factor receptor
(PDGFR), and c-kit. By preventing the phosphorylation of BCR-ABL, imatinib selectively inhibits
downstream signaling and the growth of BCRABL–positive cells, inducing apoptosis of these
cells. In May 2001, the Food and Drug Administration (FDA) approved the use of imatinib in the
treatment of CML.
Single-nucleotide mutations in the BCR-ABL gene
producing conformation changes in the BCR-ABL
protein, which can affect the binding of imatinib
to specific activation or kinase sites, can be detected in approximately half the patients who are
resistant to imatinib.8-10 At least 40 such mutations
have been characterized, some of which result in
only modest changes in sensitivity to imatinib,
whereas others produce complete resistance to the
drug. Other mechanisms of resistance are not well
characterized in patients in whom mutations are
not detected.
To address this problem, newer inhibitors of
BCR-ABL have been developed; of these, dasatinib
(Sprycel, Bristol-Myers Squibb) and nilotinib (Ta-
signa, Novartis) are furthest along in clinical
evaluation. These agents are much more potent in
vitro than imatinib and have activity against most,
but not all, of the acquired BCR-ABL mutations.10
Dasatinib was approved by the FDA in June 2006
for use in patients who are resistant to or cannot
tolerate imatinib. Nilotinib has not yet been approved for clinical use.
Cl inic a l E v idence
Allogeneic stem-cell transplantation is the only
proven curative treatment for CML.11,12 Because of
the possibility of premature death and symptoms
related to chronic graft-versus-host disease, contemplation of transplantation is difficult for otherwise asymptomatic patients in the chronic phase.
Before the development of imatinib, the principal
alternative to bone marrow transplantation was
therapy with a high daily dose of interferon alfa,
alone or in combination with a low dose of cytarabine, which was recommended for most patients
with newly diagnosed CML.13-16
The benefit of imatinib was definitively shown
in the International Randomized Study of Interferon and STI571 (IRIS) trial, a comparison of
imatinib with interferon plus cytarabine in 1106
newly diagnosed patients.17 In this trial, the estimated rates of complete cytogenetic response (absence of Ph-positive cells in the bone marrow) at
18 months were 76% for patients in the imatinib
group and 14% for those in the interferon–cytarabine group. The rates of freedom from progression to the accelerated phase or blast phase were
97% and 92%, respectively. After 5 years of followup, the estimated cumulative rate of complete cytogenetic response was 87%, progression-free survival was 83%, and overall survival was 89% in
the imatinib group.18
Imatinib has also been evaluated in phase 2 trials in patients with more advanced disease. Rates
of hematologic and cytogenetic responses were
much lower than in patients with chronic-phase
disease, with an estimated survival at 4 years of
approximately 40% in the accelerated phase19,20
and less than 10% in blast crisis20,21; median survival for patients with ALL or lymphoid blast crisis
was 4.9 months.22 Thus, imatinib is often used as
a “bridge” toward allogeneic transplantation in
such patients.
Dasatinib and nilotinib have been evaluated in
phase 1 and subsequent large phase 2 trials in
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259
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patients with CML or Ph-positive ALL who were
resistant to or could not tolerate imatinib.23-27 In
one dasatinib trial, complete cytogenetic response
was achieved in 39% of 127 imatinib-resistant patients with chronic-phase CML.25 In one nilotinib
trial, a complete cytogenetic response was achieved
in 40% of 320 patients with chronic-phase CML,27
all of whom had received previous treatment with
imatinib. Since these drugs have been in use for
only 1 to 2 years, further follow-up is needed to
assess the durability of response and the development of longer-term side effects.
Cl inic a l Use
Most physicians recommend an initial trial of imatinib for essentially all patients with CML. The
chief alternative is allogeneic hematopoietic stemcell transplantation, which is typically reserved for
patients who do not have a response to imatinib
or for the occasional patient with intolerable side
effects. Possible exceptions include children or adolescents with matched sibling donors, in whom
death associated with transplantation is estimated at 10 to 15%. HLA typing of patients and their
siblings should be performed at the time of diagnosis if patients are considered to be potential candidates for transplantation.
For patients with chronic-phase CML, imatinib
is initiated at a daily oral dose of 400 mg, a regimen that begins as soon as the diagnosis is made.
Patients in the accelerated phase or blast crisis are
treated with 600 mg daily. The cost of imatinib
is approximately $32,000 per year in the United
States for the standard 400-mg daily dose. Dose
adjustment is not required in patients with renal
dysfunction or with mild-to-moderate hepatic dysfunction. Imatinib should be taken with a meal
and a large glass of water to reduce the incidence
of nausea.
Imatinib is a substrate for the CYP3A4 metabolic pathway and can inhibit other cytochrome
P-450 pathways. Careful monitoring of the international normalized ratio in patients receiving
warfarin is advisable. CYP3A4 inhibitors that can
increase imatinib levels include diltiazem, verap­
amil, itraconazole, ketoconazole, clarithromycin,
erythromycin, and grapefruit juice, whereas rifampin, phenobarbital, phenytoin, and St. John’s
wort can decrease blood levels of imatinib.28
Imatinib may be teratogenic, and both men and
women are strongly counseled to avoid conception
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while they are taking the drug. This recommendation presents young patients with a dilemma, since
the limited evidence that is available also suggests
that interruption of imatinib therapy during pregnancy may be associated with a loss of treatment
response.29 Thus, patients who choose to have
children after the diagnosis of CML face a potentially significant, and poorly defined, risk whether
they continue imatinib or not.
Initially, patients should undergo clinical evaluation and have a complete blood count and serum
chemical analysis performed every 2 weeks. When
a complete hematologic response is achieved (defined as normal white-cell and platelet counts and
no evidence of splenomegaly), follow-up can be
performed monthly with a longer-term monitoring of response every 3 to 4 months.
The goal of treatment with imatinib is to reduce
the number of cells containing the Ph chromosome, decreasing the probability of the development of new mutations leading to blast crisis. The
level of the Ph chromosome and BCR-ABL can be
monitored in a variety of ways, including standard
cytogenetics (sensitivity, approximately 5%), fluorescence in situ hybridization (FISH; sensitivity,
approximately 1%), and reverse-transcriptase polymerase chain reaction (RT-PCR; sensitivity, approximately 1/104 to 1/106). FISH and RT-PCR
analysis can be performed on peripheral blood,
obviating the need for repetitive bone marrow examination.30-32 Monitoring should be performed
approximately every 3 months. When the results
of FISH become negative or there is a major drop
in the transcript number on RT-PCR analysis, bone
marrow biopsy should be performed to confirm a
complete cytogenetic response.
Thereafter, it is recommended that patients be
evaluated every 3 to 4 months with clinical examination, assessment for side effects, and RT-PCR
analysis. Since RT-PCR reporting is not standardized among laboratories in the United States, it is
advisable to send serial samples to the same laboratory when assessing changes over time. Results
can fluctuate, and if there is an apparent rise in
levels, the values should be repeated before changes in treatment are initiated. Even in patients who
become RT-PCR “negative,” it is usually possible to
detect residual BCR-ABL–positive cells when their
bone marrow is cultured in vitro. Clinically, it has
been observed that almost all patients, including
some who had negative results on RT-PCR, have
had a relapse after discontinuation of imatinib.33
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Clinical Ther apeutics
Hence, it is recommended that imatinib be continued indefinitely.
Approximately 15 to 20% of patients with
newly diagnosed CML do not have a complete cytogenetic response to imatinib. A small number
have side effects that prevent further treatment
with the drug, and a small number who have a
cytogenetic response will relapse with a Ph-chromosome recurrence, often heralded by a rise in the
BCR-ABL transcript number. For those who do not
have an initial response or who have a relapse, it
is important to confirm that the patient is taking imatinib as prescribed. A serum level may be
checked if doubt remains after the patient’s compliance has been reviewed. For patients who have
a complete cytogenetic response followed by a relapse, one option is to increase the dose of imatinib to 400 mg twice daily, although preliminary
results of a randomized trial suggest that changing to dasatinib is superior to increasing the dose
of imatinib from 600 to 800 mg daily.34 Dasatinib
or nilotinib should be used for patients who are
resistant to or cannot tolerate imatinib. In the absence of comparative trials, the choice between
these drugs should be based on an assessment of
potential side effects in individual patients.
For any patient in whom treatment with imatinib fails, it is important to reconsider the option
of stem-cell transplantation. Patients with mutations such as the T315I mutation, in whom CML
is known to be highly resistant to all the available
drugs, should be considered for transplantation or
for treatment with an experimental agent.
very high doses of imatinib could induce mitochondrial damage and apoptosis in cultured myocardial cells and in vivo in mice.36 However, in a
review of approximately 1200 patients treated at
the M.D. Anderson Cancer Center, the incidence of
congestive heart failure was identical to that of
age-matched subjects in the Framingham study.37
Some patients with heart disease were able to continue treatment with imatinib concurrent with
appropriate cardiac management. Other large analyses did not show an increase in the incidence of
congestive heart failure in imatinib-treated patients.38
Increased urinary phosphate excretion, decreased blood calcium and phosphorous levels,
and increased levels of parathyroid hormone have
been noted in a relatively small group of patients.39
The explanation for these findings is not clear,
although inhibition of PDGFR has been postulated, and confirmation is needed. Nonetheless, this
observation raises concern about acceleration of
osteomalacia over time. Longer follow-up of imatinib-treated patients with monitoring for the occurrence of these side effects and others not yet
detected is imperative.
The short-term toxicity profile of dasatinib and
nilotinib differ from each other and from that of
imatinib. Both dasatinib and nilotinib can produce
myelosuppression requiring dose adjustments,
whereas dasatinib can produce pleural and occasionally pericardial effusions in 15 to 20% of
patients, more commonly in those with more advanced CML. Nilotinib can produce usually asymptomatic elevations in unconjugated bilirubin and
lipase. Side effects of imatinib do not usually reA dv er se Effec t s
cur when patients are subsequently treated with
Imatinib treatment is associated with a variety of dasatinib or nilotinib, a finding that suggests that
adverse effects, most of which are typically mild the mechanisms of the toxic effects may not be
to moderate in intensity and generally abate after related only to the inhibition of tyrosine kinases.
the first few months of treatment (Table 1). Most
patients do not require dose reduction or interrupA r e a s of Uncer ta in t y
tion of therapy, and almost all patients can receive
long-term treatment with the recommended daily There has been interest in evaluating higher initial
dose of 400 mg taken with food. Transient neu- doses of imatinib on the basis of the superiority of
tropenia or thrombocytopenia, which can occur higher-dose imatinib in the accelerated phase and
during the first 1 to 2 months of treatment, is due a retrospective analysis comparing the conventionto variability in the pace of regeneration of normal al dose of 400 mg daily with 400 mg twice daily
hematopoiesis after imatinib suppression of Ph- in patients in the chronic phase.40 Patients receivderived hematopoiesis.
ing the higher dose had more rapid and higher iniA recent study described 10 patients in whom tial rates of complete cytogenetic response and
congestive heart failure developed after long-term major molecular response, albeit with more side
imatinib use, with experiments suggesting that effects, a much higher financial cost, and a suggesn engl j med 357;3 www.nejm.org july 19, 2007
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261
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Table 1. Adverse Events Associated with Imatinib Therapy.*
Event
Treatment and Comments
Nausea
Imatinib should be taken with meals; infrequent need of antiemetic drugs
Diarrhea
Potentially chronic problem generally responds to antispasmotic drugs; other causes
(e.g., lactase deficiency, infection) should be considered
Neutropenia
Very uncommon after initial 1–2 mo; dose reduction or temporary cessation of imatinib
with return to 400-mg dose on recovery; growth-factor support needed only rarely
Hepatic dysfunction (usually
elevated aminotransferase levels)
Early and usually transient occurrence; rare reports of hepatic failure, with one fatal
case associated with the concomitant use of high doses of acetaminophen; acetaminophen and excessive alcohol use should be avoided
Rash
Usually mild, macular or papular, and transient; if more severe, imatinib should be
stopped and restarted at a lower dose; use of corticosteroids can benefit some patients; rarely, severe recurrent rashes preclude continued therapy with imatinib
Fluid retention
Of variable severity, usually manifested by peripheral edema and responsive to intermittent use of diuretics; generalized swelling with skin tightness in some patients
Periorbital edema
Very common and has poor response to diuretics but generally decreases during the
day when the patient is not recumbent
Fatigue
Generally mild but can be persistent; incidence is not well quantified
Muscle cramps, myalgias,
and arthralgias
Perhaps the most prominent long-term side effect, occasionally with elevated creatine
kinase levels; cause is unknown; decreased cramping reported with calcium or magnesium replacement, quinine, and (anecdotally) with yoga; some improvement in
myalgias and arthralgias with nonsteroidal analgesics
Gynecomastia
Uncommon; associated with decreased testosterone levels and improves with testosterone replacement35
Congestive heart failure
Uncertain association with imatinib36-38
Hypophosphatemia
Further study required39
Macrocytic anemia
Generally mild occurrence in about 10% of patients; vitamin B12 deficiency should be
ruled out; very occasionally, more profound anemia can be treated with erythropoietin; cause is unknown, with speculation about c-kit inhibition
*Unless otherwise stated, most toxic effects are mild to moderate and generally abate after the first few months
of treatment.
tion that patients receiving the standard dose eventually derive a similar overall benefit. A prospective, randomized comparison has been completed,
and the results should be available soon.
Trials comparing dasatinib and nilotinib with
imatinib for the initial therapy of CML are in early
stages. These more potent BCR-ABL inhibitors may
have a more profound effect on the CML stem cell,
possibly allowing consideration of treatment cessation. This possibility is of particular interest to
younger patients interested in having children.29,41
Preliminary in vitro data suggest that dasatinib
may not eliminate these progenitors, however.42
Combinations of BCR-ABL inhibitors, used either
concurrently or sequentially, are also under consideration.
Approximately 5 to 10% of patients receiving
imatinib have clonal cytogenetic changes in Phnegative cells43-45 (Fig. 1). Sometimes these chang262
es are transient, particularly with respect to trisomy 8, which may come and go on repeated
sampling without any apparent clinical effect.
There has been speculation that inhibition of normal tyrosine kinases by imatinib might allow
damage to occur in normal hematopoietic precursors, but this remains a hypothesis.
The implications of these cytogenetic changes
are uncertain. Longer follow-up is necessary to
determine whether the incidence of new clonal
changes will increase further. These clones cannot
be detected by FISH or RT-PCR analysis of peripheral blood, and many centers repeat bone marrow
examinations every 1.5 to 2 years for cytogenetic
studies. To date, the occurrence of frank myelodysplasia and evolution to AML has been low, no­t­
ed most commonly in patients with monosomy 7;
many clinicians consider allogeneic transplantation if this chromosomal deletion is detected.
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Clinical Ther apeutics
Guidel ine s
The clinical practice guideline of the National
Comprehensive Cancer Network, which was last
updated in February 2007, and guidelines of the
National Cancer Institute, last updated March 1,
2007, are very similar and recommend that imatinib be used as the preferred first-line treatment
for patients with newly diagnosed CML.46,47 For
patients who do not have a cytogenetic response
to imatinib, recommendations include the use of
higher doses of imatinib or alternative tyrosine
kinase inhibitors, allogeneic stem-cell transplantation, and enrollment in a clinical trial of an investigative therapy.
Two recent studies offered consensus statements about standardization of the methodology
for molecular monitoring of patients with chronicphase disease and suggested measures of response
to be achieved at intervals after the initiation of
treatment.31,32 Failure to reach these goals would
indicate that a modification of therapy should be
considered.
R ec om mendat ions
Figure 1. Clinical Course of CML after the Development of Cytogenetic
Abnormalities in Philadelphia-Chromosome–Negative Cells.
The possible clinical outcomes are shown in a patient with chronic myelogenous leukemia (CML) in whom cytogenetic abnormalities developed in
cells that tested negative for the Philadelphia (Ph) chromosome after
2 years of imatinib treatment. Typically, 100% of the cells in metaphase are
Ph-positive at the time of diagnosis. There is little information about
whether other clones are present in small numbers at diagnosis among the
overwhelming number of Ph-positive cells. In an analysis of bone marrow
obtained from two patients in whom trisomy 8 developed, such clones
could not be detected by fluorescence in situ hybridization with the use of
centromeric probes (unpublished data). After 6 months of treatment, there
was a partial cytogenetic response; at 1 year, there was a complete cytogenetic remission. The figure shows three possible scenarios: the disappearance and then recurrence of the new clonal changes in patients continuing
to have complete cytogenetic remission; uncommon progression to myelodysplasia or acute myeloid leukemia (AML); and relapse of the CML with
the disappearance of the new clone, possibly related to suppression by the
now dominant Ph-positive clone. With further treatment and partial suppression of the Ph-positive clone, it is common to have varying mixtures of
the clones, sometimes including the development of clones with other cytogenetic abnormalities in Ph-negative cells.
Although the young patient described in the vignette is a potential candidate for hematopoietic
stem-cell transplantation, my recommendation is
that she continue to take imatinib at the standard
dose of 400 mg daily with the intention of continuing long-term treatment if she has a response.
Initially, she should have a physical examination
and blood tests monthly, RT-PCR analysis or FISH
to check for the BCR-ABL translocation every
3 months, and subsequent bone marrow examination to assess the cytogenetic response. She
should be strongly cautioned to use contraception
because of the risk to the fetus if she should become pregnant while taking imatinib. Computer
searches for unrelated donors and umbilical cord including increasing the dose of imatinib and
blood units48 should be conducted intermittently. switching to either dasatinib or nilotinib.
Dr. Schiffer reports receiving lecture fees from Novartis and
If the patient does not have a complete cytogenetic
grant support from Novartis and Bristol-Myers Squibb and servresponse or if her disease recurs, transplantation ing on the companies’ advisory boards. No other potential conshould be reconsidered along with other options, flict of interest relevant to this article was reported.
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