Download Current Status of Therapy for Chronic Myeloid Leukemia: A Review

Current Status of Therapy for Chronic Myeloid Leukemia: A
Review of Drug Development
Swami Padmanabhan; Saritha Ravella; Tyler Curiel; Francis Giles
Future Oncol. 2008;4(3):359-377. ©2008 Future Medicine Ltd.
Posted 07/15/2008
Abstract and Introduction
Abstract
Chronic myeloid leukemia (CML) has led the way for developing rational drug
development in cancer. Most cases of CML diagnosed and treated in chronic phase are
extremely well controlled with imatinib monotherapy, and primary resistance is very
uncommon. Even though the treatment failure rate is low, the emergence of drug
resistance and the lack of eradication of the hematopoietic stem cell clone has prompted
a wave of drugs to address one or both these problems. Several clinical trials (Phase I
and II) of dasatinib or nilotinib in the treatment of imatinib-resistant or -intolerant Ph
chromosome-positive leukemia have already reported a remarkable rate of hematologic
response greater than 90% for chronic-phase patients. These drugs minimize the risk of
acquired drug resistance that is particularly seen within the first 24-36 months of
therapy, and can prevent early failure in these patients, Furthermore, rational, noncrossresistant combinations that include a T315I inhibitor and drugs that can eradicate the
hematopoietic stem cell clone may extend the coverage to virtually all patients with bcrabl. Here we review the 6-year impact of the 'magic pill', Gleevec®, (Glivec®), including
the emerging problems with its treatment, the efficacy data of dasatinib and nilotinib
and the very promising data of the newer generation of drugs for CML.
Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative disorder that can occur in a
bi- or tri-phasic course. CML occurs with an incidence of approximately 1-1.5 cases per
100,000 population, and accounts for approximately 7-15% of newly diagnosed cases of
leukemia in adults.[1] As per the NCI's Surveillance, Epidemiology, and End Results
(SEER) Cancer Statistics Review, it is estimated that 4830 men and women (2800 men
and 2030 women) will be diagnosed with CML, and 450 men and women will die from
the disease in 2008. The median age at presentation is around 66 years. In the
preimatinib era, the median survival was 4-6 years (range <1 year to >10 years).
Survival after the development of an accelerated phase is usually less than 1 year and
only a few months after blastic transformation.
The typical course of disease is characterized by an initial chronic phase lasting for 3-6
years, followed by an accelerated, then blastic phase usually of short duration. A total of
75-80% of patients go through an accelerated phase before the blastic phase. The
definition for accelerated phase is not uniform, which needs to be verified when
evaluating treatments. Specific criteria associated with a survival shorter than 18
months by multivariate analysis have been proposed, including the presence of ≥15%
blasts, or ≥30% blasts and promyelocytes, or ≥20% basophils in blood or platelet count
<100. A cytogenetic clonal evolution is also considered criteria for acceleration. Recent
analysis suggests its prognostic effect depends on the specific abnormality, its
predominance in marrow metaphases and the time of appearance.
The cytogenetic hallmark of CML is a reciprocal t(9,22)(q34;q11) chromosomal
translocation that creates a derivative 9q+ and a small 22q-, known as the Ph
chromosome. The latter harbors the bcr-abl fusion gene encoding the chimeric bcr-abl
protein with a deregulated tyrosine kinase activity, the expression of which has been
shown to be necessary and sufficient for the transformed phenotype of CML cells. The
activation of multiple signal transduction pathways in bcr-abl transformed cells leads to
increased proliferation, reduced growth-factor dependence and apoptosis, and perturbed
interaction with the extracellular matrix and stroma. CML is a quintessential example in
human neoplasia, wherein a single oncogenic fusion abnormality plays a central role in
its pathology.
Bcr-abl as the Target for Drug Development: Paradigm Shift With
Imatinib
This understanding of the cytogenetic and molecular pathophysiology underlying CML
has paved a way for the development of effective targeted molecular therapies. This
ultimately led to the development of imatinib mesylate (STI-571, Gleevec®, Glivec®),
an oral inhibitor of bcr-abl kinase activity. The clinical success of imatinib mesylate in
the treatment of CML, especially the high durable response rates in patients with
chronic phase CML, has validated the therapeutic strategy of rationally targeting the
causative molecular abnormality of CML. In the international randomized study of IFNα versus STI571 (IRIS) study, of 343 patients in whom at least 20 cells in metaphase
had been cytogenetically analyzed in 3 months, 152 had a major cytogenetic response
(no more than 35% Ph+ cells in metaphase).[2] Whereas CML progressed in only five of
the patients with major cytogenetic response (3.3%), disease progression was
documented in 22 of the 191 patients without such a response (11.5%; p = 0.005 by the
log rank test). This is evident from the higher rates of complete hematologic response
(95 vs 56% of patients; p < 0.001) and major cytogenetic response (85 vs 22% of
patients; p < 0.001). A median follow-up of 19 months demonstrated that imatinib
mesylate was associated with predominantly better responses than IFN-α and Ara-C
combination therapy. On the basis of these results, imatinib mesylate was approved in
2001 by the US FDA for treatment of patients with Ph+ CML in blastic-phase,
accelerated-phase and chronic-phase patients who failed IFN-α therapy. Subsequently,
in 2002, imatinib mesylate also received accelerated approval for the treatment of newly
diagnosed Ph+ CML in chronic phase. Imatinib has changed the management of CML
and has become the current standard of treatment for CML.
Dose & Duration of Imatinib Therapy & the Race for the Cure
Imatinib Dose Schedules
The optimal dose of imatinib is yet to be clearly defined. Although the maximum
tolerated dose was not identified in the Phase I study, 400 mg per day is the dose
selected for subsequent studies, as imatinib at 400 mg daily could achieve a blood
concentration higher than IC50 in vitro.[3,4] Moreover, reliable clinical responses were
seen at doses of 300-400 mg daily, especially in chronic-phase patients.
In Phase II trials of accelerated- and blastic-phase CML patients, imatinib at 600
mg/800 mg daily demonstrated greater efficacy over 400 mg.[5,6]
There is also a correlation of clinical responses with the steady-state trough plasma
concentrations (Cmin) of imatinib mesylate and its major active metabolite,
CGP74588.[7] A total of 551 patients in the IRIS study had trough pharmacokinetic
samples (24 h post dose) obtained at day 1 and steady state (day 29). The overall mean
coefficient of variation (CV) for the steady-state trough levels (Cmin) is a reflection of
imatinib mesylate clearance and metabolism in CML patients. Pharmacokinetic trough
levels obtained for imatinib could be divided into three groups - the lower and upper
quartile ranges (below Q1 = 25th percentile, above Q3 = 75th percentile) and the
interquartile range. Times to complete cytogenetic response (no Ph+ metaphases) and
the major molecular response within these complete cytogenetic response patients were
different in these three groups. Mean (±SD) trough plasma imatinib concentrations were
significantly higher in the group with major molecular response (34 patients) than in the
group without (1452.1 ± 649.1 ng/ml versus 869.3 ± 427.5 ng/ml, p < 0.001), whereas
there was no difference in the imatinib daily dose. For trough plasma imatinib
concentrations and their discrimination potential for major molecular response, the area
under receiver-operating characteristic curve was 0.775, with best sensitivity (76.5%)
and specificity (70.6%) at a plasma threshold of 1002 ng/ml. By 4 years, an estimated
53% achieved major molecular response despite low steady-state Cmin levels compared
with 80% for patients with high Cmin (and 72% for patients within the interquartile
range). These results suggest that achieving and maintaining an adequate plasma
concentration (by therapeutic drug monitoring) of imatinib mesylate is important for a
good clinical response.
High-dose imatinib mesylate (800 mg daily), as front-line treatment has been studied in
newly diagnosed chronic-phase CML patients. Responses in 175 patients (with a
median follow-up of 30 months) have been evaluated in comparison with historical
controls (n = 50) receiving standard-dose imatinib (median follow-up of 53 months).[8]
A complete cytogenetic response with imatinib was achieved in 90% of high-dosetreated patients, in contrast to only 78% of standard-dose-treated patients (p = 0.03). At
12 months, the major molecular response rates were 54% with high dose, versus 24%
with standard dose (p = 0.001), and complete molecular response rates at 24 months
were 27 and 10%, respectively. Based on the pharmacokinetic data from the IRIS
studies it is very likely that due to higher Cmin patients receiving high-dose imatinib
mesylate (800 mg daily) upfront (in newly diagnosed patients) they achieve complete
cytogenetic response at a rapid rate, but not necessarily at a significantly higher rate.
The results of these studies are somewhat difficult to compare, owing to differences in
follow-up. In addition, the reverse transcriptase (RT)-PCR technology was not
standardized. Nonetheless, the emerging picture is that the rates of major molecular
remission and complete cytogenetic response in the combination studies are comparable
with the IRIS trial, but higher in patients treated with 800 mg imatinib daily, while the
rates of major molecular response and complete molecular response are generally higher
compared to standard-dose imatinib. This increased efficacy comes at the cost of
increased toxicity. For example, the incidence of grade 3/4 neutropenia was 63% in
patients treated with imatinib and pegylated IFN, and 41% experienced grade 3/4
nonhematologic toxicity. As a result, only a fraction of the planned IFN dose was
actually administered. Taken together, these results clearly suggest that early
intensification of therapy may increase the frequency of profound remissions, although
at the price of more toxicity. Standard-dose and high-dose imatinib are currently
compared in a Phase III intergroup study taking place in the USA, and are part of
several multi-armed studies in Europe. Initial results suggest higher rates of major
molecular response and complete molecular response, although it is being observed that
the standard-dose arm is catching up with time.
Duration of Imatinib Therapy
The optimal duration of imatinib therapy is yet to be determined. In 2006, 5-year
follow-up data for imatinib mesylate from the Phase III, multicentered, randomized,
open-label, international IRIS trial of 1106 patients showed long-term survival and
safety in newly diagnosed Ph+ CML in chronic phase.[9] An estimated 89% (95% CI:
86-92%) of patients were alive at 5 years, while the overall survival (OS) in the IFN
arm was 86%. In addition, an estimated total of 93% of patients had not progressed to
advanced phases of Ph+ CML, while only approximately 2.4% of patients discontinued
imatinib mesylate owing to drug-related adverse events. Furthermore, the annual rates
of progression events decreased with the passing years, with 1.5% in the first year, 2.8%
in the second year and tapering down to less than 1% in the fourth and fifth years.
Approximately 382 out of 553 (69%) patients randomized to imatinib mesylate were
still receiving first-line therapy, while only 16 out of 553 in the group given IFN plus
Ara-C continued their treatments. From the latter group, 359/553 (65%) had crossed
over to imatinib mesylate. The progression-free survival (PFS) in the intent-to-treat
group was 83.2% (95% CI: 79-87) for imatinib mesylate and 64.1% (95% CI: 59-69) in
the IFN arm. In terms of confirmed responses, the complete hematologic response rate
was 96.6%, the major cytogenetic response rate was 85.2%, and the complete
cytogenetic response rate was 73.1%. The evolving imatinib mesylate data from the
IRIS trial are summarized in Table 1 .
Given this outstanding response with imatinib mesylate, it is prudent to continue this
treatment indefinitely. Furthermore, there is currently no evidence to indicate that
imatinib mesylate can be discontinued safely even after attaining undetectable bcr-abl
transcript levels. Most patients who have stopped imatinib mesylate therapy have
experienced molecular or cytogenetic relapse even after achieving a sustained complete
molecular response for a considerable duration of time.[10-12] Thus, the current
recommendation suggests continuation of imatinib mesylate therapy indefinitely unless
the patient experiences unacceptable toxicity or treatment failure.
It is also not clear if imatinib mesylate can be stopped when patients achieved major
molecular response or complete molecular response. To date, information is mostly
limited to anecdotal observations of patients who stopped therapy in complete
cytogenetic response or complete molecular response for various reasons, such as sideeffects or pregnancy.[10,11,13] Most of them had disease recurrence, which should not be
confused with relapse, since rechallenge with imatinib mesylate usually restored
response. The only patients who maintained response were individuals who had
received imatinib mesylate for relapse after allogeneic transplantation or who had been
treated with IFN-α before they commenced imatinib. Thus, it can be surmised from all
these clinical data that imatinib alone is not capable of eradicating the leukemic stem
cell clone.[14]
Adverse Events to Imatinib
The majority of CML patients treated with imatinib mesylate experienced adverse
events at some time. Most events were of mild-to-moderate grade, but the drug was
discontinued for adverse events in 1% of patients in the chronic phase, 2% in the
accelerated phase and 5% in blast crisis. The most frequently reported drug related
(>25%) adverse events were nausea, vomiting, edema and muscle cramps. Edema was
most frequently periorbital or in lower limbs, and the frequency of severe edema was 15%. These events appear to be dose-related, were more common in the blast crisis and
accelerated phase studies (where the dose was 600 mg/day), and are more common in
the elderly. The fluid retention events were usually managed by interrupting imatinib
mesylate treatments and with diuretics, or other appropriate supportive care measures.
In a recent 2006 report, imatinib was associated with cardiotoxicity and congestive heart
failure,[15] although this toxicity is a rare event in clinical practice.[16] One such reported
serious and life-threatening event was seen in a patient with blast crisis who
subsequently died after pleural effusion, congestive heart failure and renal failure.
Grade 3-4 hematologic adverse events were infrequent, except for neutropenia (14%)
and thrombocytopenia (8%).[2]
Monitoring the Disease Responses & Measuring Minimal Residual
Disease
Even though routine cytogenetic analysis is still considered the gold standard for
evaluating response in CML, the studies are often somewhat cumbersome in practice
and require analysis in metaphase. As most patients are able to achieve complete
cytogenetic responses with tyrosine kinase inhibitors (TKIs), sensitive and accurate
monitoring of bcr-abl is required to measure residual disease. In CML patients who
achieved a complete cytogenetic response, fluorescence in situ hybridization (FISH) is
more sensitive than conventional cytogenetics to monitor Ph negativity, and thus a
biologic response to treatment.[17] Since FISH studies typically involve looking for the
bcr-abl fusion fluorescence in at least 200 interphase cells, this precludes the sensitivity
of FISH in making judgments on the extent of residual disease. Furthermore, since most
CML studies have assessed long-term outcomes by monitoring cytogenetics and not
FISH, quantitative RT-PCR (qRT-PCR) is currently used for assessing the depth of the
molecular response and measurement of residual disease with a sensitivity of up to 10-8.
Molecular remission can thus be defined in this fashion as a reduction in the
quantification of bcr-abl transcripts to an undetectable level, and can be considered as a
surrogate marker for cure and/or long-term disease control. It has been shown that such
precision might help to predict disease outcome in a better way. Major molecular
response is defined as a reduction of bcr-abl transcript levels by 3 or more logs,
compared with a standardized baseline, obtained from newly diagnosed and untreated
CML patients. So for the standardized baseline in the IRIS trial, which was the average
ratio from 30 patients and was 36%, the major molecular response was defined as
achieving levels of 0.036% or less. A complete molecular response is defined as
undetectability of bcr-abl transcripts if confirmed on a second occasion. Given the
variations in the technical aspects of the assay, there is a need for standardization.
Therefore, to maximize the consistency and reliability of the qRT-PCR or real-time
quantitative PCR (RQ-PCR) techniques, a recent consensus proposal suggested
optimization of several procedural aspects of the complex RQ-PCR technique used for
measuring bcr-abl transcripts (measuring the molecular response of imatinib mesylate
therapy).[18-20] An International Scale (IS) was proposed to generate comparable values
when tested in any laboratory, and the scale is fixed to a major molecular response at a
value of 0.1%. It allows for differences generated by various RQ-PCR methods and
controls. The ongoing validity of conversion is reliant on maintaining performance of
analysis within a laboratory. The speed and amount of response are both believed to
play an important role in the determination of prognosis. In the IRIS trial, patients who
achieved a major molecular response at 18 months had 100% progression-free survival
(without progression to accelerated phase/blastic phase at 5 years), whereas patients
who failed to achieve complete cytogenetic response had a PFS of 83% (p < 0.001).[9]
Major molecular remission rates and PFS (at 12 months, 40 and 2%, respectively) were
also found to be better with imatinib mesylate therapy. The patients who achieved a
complete cytogenetic response by 12 months had only a 3% probability of progression
to acute phase or loss of complete hematologic remission of major molecular remission
over the subsequent 12 months, compared with a 15% probability of progression for
those patients who did not achieve a major molecular remission. This study
demonstrates that achievement of major molecular remission, complete cytogenetic
response and complete molecular response are valid efficacy end points in CML, as they
correlate with clinical benefit.
The unsolved challenges with imatinib mesylate include:

Residual disease, even in those who have undetectable bcr-abl transcripts,
relapses with discontinuation of imatinib mesylate;

Development of resistance, especially in the advanced stages: CML patients in
phases other than chronic-phase CML do not show a better treatment response
and survival, as is seen in chronic-phase CML patients, despite dose increases to
800 mg daily. In addition, since the introduction of imatinib, median survival in
blast crisis has increased from 2-3 months to only 7.5 months, with few longterm survivors;

Intolerance;

Long-term effects of imatinib mesylate therapy on chromosomal aberrations in
the bone marrow[21,22] (the chromosomal changes most commonly reported with
imatinib are trisomy 8 and monosomy 7), on bone and mineral metabolism[23] or
cardiac function are unknown.[15]
We will now illustrate the first two of these issues and how further drug development
can address these.
Role of Measurement of Residual Disease in CML in the Understanding
of Relapse & Imatinib Mesylate Resistance
There is substantial variation in the responses observed among different patients.
Residual disease in imatinib-treated patients persists because of bcr-abl kinase activity
due to likely overlapping mechanisms, explaining imatinib mesylate resistance and an
ineradicable reservoir of stem-cell activity. A recent 5-year update of the IRIS trial
provided a separate estimate of imatinib mesylate resistance.[9] After 5 years, 31% of
patients (171 of 553 patients) who received imatinib as first-line therapy discontinued it
(including 4% for adverse events [AEs], 11% for unsatisfactory therapeutic effect and
2.5% to cross-over to IFN-α treatment). Even in this group, approximately 33% of
imatinib-treated patients had not achieved a complete hematologic response, and 39%
had not achieved a major cytogenetic response. Primary resistance to imatinib only
occurred occasionally in chronic-phase, showing a low and decreasing annual rate of
progression (resulting in death) after 1, 2, 3 and 4 years of therapy of 3.4, 7.5, 4.8 and
1.5%, respectively - possibly as a result of patients with the worse prognosis
progressing relatively early.[24]
Leukemic Stem Cells
The presence of minimal residual disease in patients treated with imatinib mesylate may
be due to the reservoir of disease, the diseased quiescent hematopoietic stem cell (HSC)
subpopulation (which is approximately 0.5% of Ph+ HSC population) present within the
cells, insensitive to imatinib mesylate therapy. The etiology of disease 'persistence'
(residual disease) at the molecular level may be multifactorial. Primitive HSC cells are
resistant to imatinib mesylate, and exhibit drug-transport mechanisms, for example PgP,
a MDR1 resistance gene product, evolving mutations in the kinase domain. The relative
resistance of CML HSCs (lin-CD34+CD38-cells) to imatinib mesylate may be explained
at least in part by their elevated expression of bcr-abl, and the higher tyrosine kinase
activity than is seen in the more prevalent lin-CD34+CD38+ leukemic cells. Expression
of the three transporter genes (OCT1, ABCB1 and ABCG2) was studied in a bcr-abltransduced BaF3 cell line, in which p210 bcr-abl expression was modulated (by a
tetracycline inducible system) and allowed to undergo differentiation. The most
primitive (lin-CD34+CD38-) cells revealed very low expression of OCT1 (low imatinib
mesylate uptake) and highly elevated expression of ABCB1 and ABCB2 (high drug
efflux), and bcr-abl (elevated kinase activity), suggesting HSC-mediated imatinib
mesylate resistance.
There is also emerging data on some of the new drugs under development suggesting
that these recalcitrant clones can be inhibited. BMS-214662, a cytotoxic
farnesyltransferase inhibitor (FTI), has been shown to target primitive progenitor cells
(PPC) in CML.[25] In long-term culture-initiating cell (LTC-IC) assays with both
chronic-phase CML and normal CD34+ progenitors, addition of BMS-214662 to
dasatinib in vitro has been shown to dramatically reduce the PPC colonies and also
overcome kinase domain mutation transfectants in Baf3 cell lines.
Advanced CML & Development of Resistance Due to Bcr-abl Inhibition
In contrast to responses seen in the chronic phase, most patients with CML in
accelerated phase and blast crisis fail to achieve a complete cytogenetic response and
frequently develop resistance to therapy and relapse. Imatinib resistance is uncommon
in patients with early chronic-phase CML, whereas its estimated 2-year incidence is 1020% in chronic-phase CML post-IFN-α failure, 40-50% in accelerated-phase CML, and
70-80% in blast-phase CML or Ph+ acute lymphoblastic leukemia (ALL).
Approximately 60% of patients with advanced stage CML (blast crisis) do respond
initially; while responses to imatinib treatment in chronic-phase CML are durable,
remissions observed in blast crisis patients are typically short-lived, with relapse
occurring within 6 months despite continued therapy. Furthermore, even in imatinib-
treated patients, subsequent failure to respond has typically been associated with
acquired resistance within the leukemic cell to imatinib mesylate. Underlying
mechanisms that account for this include clonal evolution (as the CML patients progress
through the different phases), gene amplification or point mutation in the bcr-abl kinase
domain, and overactivity of the networking kinases, such as the Src family kinases. Of
these, point mutations within the Abl kinase domain of the bcr-abl gene are emerging as
the most frequent mechanism for resistance to imatinib mesylate and resultant
reactivation of kinase activity. The risk of mutation development is particularly high in
patients who are beyond the chronic phase, as well as those with a long duration of
disease prior to imatinib therapy.
ATP-competitive TKIs inhibit bcr-abl activity by blocking the ATP-binding site on the
bcr-abl kinase domain. Some ATP-competitive TKIs bind only to the inactive
conformation of bcr-abl, which blocks the protein in its inactive conformation and
prevents its activation. This accounts for the specificity of these agents, as the inactive
conformation of bcr-abl is structurally unique, whereas the active conformation is
structurally similar to that of other kinases. Some ATP-competitive TKIs bind to bcr-abl
through an extremely complex and energetically-inefficient 'induced fit' mechanism, so
these drugs have only a modest affinity for the target. This induced fit binding can be
impaired by the substitution of even a single amino acid in the bcr-abl kinase domain.
Shah et al. have conducted comprehensive bcr-abl kinase domain sequencing analysis
of 45 CML patients who demonstrated imatinib resistance.[26] Mutations were detected
in over 90% of patients (29/32) who relapsed after an initial response to imatinib,
including those with chronic phase, myeloid blast crisis and lymphoid blast crisis CML.
Mutations were also detected in 4/13 chronic phase patients with stable disease and
correlated with subsequent clinical relapse.
In general, the most resistance-conferring mutations are distributed throughout the Abl
kinase domain. The most resistant mutations occur in the P-loop and are close to or near
residues that are in direct contact with the drug. Thus, there is a range of resistance
based on the location, from a few-fold for some of the A-loop mutants, up to complete
resistance for the T315I mutation. To date, more than 30 mutant forms of bcr-abl have
been detected in patients. Of these, the most common arising in CML appears to be
Glu255Lys/Val, Thr315Ile and Met351Thr. The mutants possess varying degrees of
imatinib desensitization, with the most resistant mutants being Tyr253His, Thr315Ile,
Gly250Glu and Glu255Lys. Structural studies suggest that most point mutations in the
bcr-abl kinase domain cause resistance to imatinib by impairing the flexibility of the
kinase domain, restricting its ability to adopt the inactive conformation required for
optimal imatinib binding, rather than by directly interfering with drug contact residues.
This leads to reactivation of bcr-abl kinase activity within the leukemic cell, despite the
presence of imatinib.
The Thr315Ile (T315I) mutation is one of the most resistant mutations in vitro.
Investigators have demonstrated that the T315I mutant is highly resistant to imatinib
with a IC50 value greater than tenfold higher than wild-type bcr-abl.[27] The IC50 values
in the T315I mutant greatly exceed the therapeutically attainable concentration of
imatinib.[28] It has been recommended that because the T315I mutation completely
prevents imatinib binding, its detection in a patient should probably lead to cessation of
imatinib, and the use of other therapy should be considered.
This has stimulated the development of new kinase inhibitors that are able to override
resistance to imatinib. Based on data from recently published clinical trials of dasatinib
(BMS-354825)[29-43] and nilotinib (AMN107),[44-49] it is obvious that neither of these
agents will be beneficial in patients with the T315I mutation either.
The 'Sons of Imatinib'
The new inhibitors of Abl tyrosine kinase can be distinguished by their nature of
binding to the ATP site - namely, competitive-ATP inhibitors and noncompetitive ATP
inhibitors. The drugs developed in this class are the 2-phenylaminopyrimidin-based
compounds, such as nilotinib (AMN107), and the Src/Abl inhibitors, such as dasatinib
(formerly BMS-354825), AP23464, bosutinib and PD166326. The affinity of the
competitive ATP inhibitors is many folds higher than the first generation, imatinib, and
hence they are efficacious in most imatinib mesylate-resistant patients. Both dasatinib
and nilotinib appear to have activity in CML patients with mutations within the abl
kinase domain, including in the P-loop, A-loop and catalytic domains. Dasatinib and
nilotinib have recently undergone testing in clinical trials (summarized in Table 2 ), and
the clinical data are discussed below.
Dasatinib
Dasatinib (SPRYCELTM, Bristol-Myers Squibb, NJ, USA), is an orally available novel
multitargeted TKI, with approximately 325-fold higher potency against native bcr-abl,
and also blocks several other critical oncogenic proteins, such as Src family kinases
(Src, Lck, Lyn, c-KIT, PDGFR-β, and ephrin A receptor kinase) at low nanomolar
concentrations.[50,51] Unlike imatinib mesylate, dasatinib binds both the active and
inactive conformations of the abl protein and has demonstrated preclinical activity
against 21 out of 22 imatinib-resistant bcr-abl mutants.[26-28]
Dasatinib Development. In late 2003, dasatinib entered clinical trials and was
clinically assessed in one dose-finding study and five subsequent studies involving more
than 900 imatinib mesylate-resistant or -intolerant patients (the START program).
In the dasatinib Phase I dose-escalation clinical trial (CA180002), 63 evaluable patients
with CML and Ph+ ALL resistant or intolerant to imatinib have been treated with
dasatinib, showing both efficacy and durability of response.[29] Nine patients have gone
off study due to progressive disease. Of these, three had T315I detected prior to
treatment, and two patients had the T315I mutation at the time of disease progression.
The Phase II dose of dasatinib was chosen as 70 mg twice a day (plasma half-life of 3-4
h; Cmax of 90 nM)[30-34] for the Phase II studies. START-R is an international trial of
dasatinib 70 mg twice daily and imatinib mesylate 800 mg/day in patients with chronicphase CML resistant to prior imatinib mesylate 400-600 mg/day. In total, 150 patients
were randomized (2:1): 101 to dasatinib, 49 to imatinib mesylate. With a minimum
follow-up of 10 months, the complete hematologic response rate was 92% (93 dasatinib
patients) versus 82% (40 imatinib mesylate patients), and the major cytogenetic
response rate was 48% for dasatinib versus 33% for imatinib mesylate. Of importance,
the primary difference was the complete cytogenetic response rate of 35% (35/101) for
dasatinib versus 16% (8/49) for imatinib mesylate, suggesting that dasatinib can achieve
deeper responses in this patient population. Of patients with no prior cytogenetic
response to imatinib mesylate, 44% (17/39) achieved a major cytogenetic response with
dasatinib, versus 7% (1/15) with higher dose imatinib mesylate. Major cytogenetic
response rates of 40% for dasatinib and 20% for imatinib mesylate were achieved in
patients with baseline imatinib mesylate-resistant bcr-abl mutations, with 47% of
dasatinib patients versus 0 imatinib mesylate patients with difficult-to-treat P-loop
mutations achieving a major cytogenetic response. Patients with no prior cytogenetic
response to imatinib mesylate were able to achieve major cytogenetic response with
dasatinib, but dose escalation of imatinib mesylate was not effective. A total of 23% of
dasatinib patients versus 80% of imatinib mesylate patients had treatment failure. Grade
3/4 nonhematologic toxicity was minimal in both arms. All grades of superficial edema
and fluid retention were more common with imatinib mesylate than dasatinib, whereas
pleural effusion was seen only with dasatinib. Cytopenia was more frequent and severe
with dasatinib.
CA180035, a randomized, global multicenter, open-label trial of dasatinib 140 mg once
a day versus 70 mg twice a day, was conducted in patients with accelerated- or blasticphase CML or Ph+ ALL, which were resistant to or intolerant of imatinib mesylate.[35]
Patients were stratified by phase of disease (accelerated, myeloid blast, or lymphoid
blast/Ph+ ALL) and by prior imatinib mesylate (resistant or intolerant). The primary
objective of the study was to compare the major hematologic response rate between the
two regimens. Dose escalation to 180 mg once a day or 90 mg twice a day was allowed
for inadequate response, and dose reduction to 100 or 80 mg once a day or 50 or 40 mg
twice a day for drug toxicity. From June 2005 through March 2006, 612 patients were
randomized. Of all patients who received prior imatinib mesylate, 42% had more than
600 mg/day, and 37% were treated for more than 3 years. Other prior therapy included
IFN in 42% of patients, chemotherapy in 57% of patients and stem-cell transplant in
14% of patients. The major hematologic response rate was 35%, including 21%
complete hematologic response, and the major cytogenetic response rate was 33%,
including 23% complete cytogenetic response. The most common nonhematologic
drug-related toxicities included diarrhea (24%, grade 3/4: 3%), headache (17%, grade
3/4: 1%), nausea (17%, grade 3/4: 2%), pleural effusion (15%, grade 3/4: 4%), and
fatigue (12%, grade 3/4: 3%). Hematologic toxicity included neutropenia grade 3 and
grade 4 in 22 and 40% of patients, respectively, and thrombocytopenia grade 3 and 4 in
16 and 50% of patients, respectively.
A FDA-approved summary of interim results from four single-arm Phase II studies
showed efficacy data in 445 patients.[36] In patients with chronic-phase CML, the major
cytogenetic response rate was 45%, with a complete cytogenetic remission rate of 33%.
Major cytogenetic response rates were 59, 32, 31 and 42% in patients with acceleratedphase CML, myeloid CML, lymphoid-blast CML and Ph+ ALL, respectively.
Molecular Responses in Imatinib Mesylate-resistant Patients. In addition, dasatinib
was associated with molecular responses in patients with imatinib-resistant/intolerant
CML and multiple bcr-abl kinase domain mutations.[37-41] Similar response rates were
attained irrespective of whether patients had bcr-abl mutations within the kinase
domain. In a study of imatinib mesylate-refractory patients treated with dasatinib,[37] 46
different bcr-abl mutations involving 36 amino acids were detected in 202/394 patients
(51%) prior to the treatment. A total of 162 patients showed one mutation, 33 patients
showed two mutations, six patients showed three mutations, and one patient showed
four mutations. Mutations were observed in 84 patients in chronic phase (42%), 47
patients in accelerated phase (60%), 23 patients in myeloid blast crisis (43%), and 48
patients in lymphoid blast crisis and ALL (74%). In patients with mutations,
hematologic response was 91% in chronic phase, 62% in accelerated phase, 41% in
myeloid blast crisis and 34% in lymphoid blast crisis/ALL (p < 0.01). Major and
complete cytogenetic response did not differ significantly (47 and 34% in chronic
phase, 35 and 27% in accelerated phase, 33 and 28% in myeloid blast crisis, 53 and
51% in lymphoid blast crisis/ALL, respectively). Major cytogenetic response rates were
comparable in patients bearing no mutations (44%), mutations within the P-loop (43%),
SH2 domain (47%), activation loop (56%) or other sites (49%), but not for T315I (0%,
p < 0.001). Sorting individual patients by the underlying mutation and cellular IC50
values of dasatinib revealed clearly higher hematologic and cytogenetic response rates
in those with lower IC50 values. In line with the virtual insensitivity to dasatinib in vitro,
none of the 17 patients carrying a T315I mutation showed any hematologic response.
Two distinct patterns of response were observed:

A parallel decrease of the bcr-abl load and the mutated clone

A decrease of the bcr-abl load followed by a decrease of the mutated clone after
a delay of up to 4-6 months
Up until now, five patients developed new mutations associated with dasatinib
resistance (T315I, n = 2, accelerated phase and myeloid blast crisis patients; F317L +
F486S, n = 2, lymphoid blast crisis and myeloid blast crisis patients; E507G, n = 1,
chronic-phase patient).
Adverse Events to Dasatinib & Dose Optimization. Most dasatinib patients also
experienced adverse drug reactions at some time,[29-43] most of which were dose
dependent. The drug was discontinued for adverse reactions in 6% of patients in
chronic-phase CML, 5% in accelerated-phase CML and 11% in myeloid blast-phase
CML. The most frequently reported adverse events included fluid retention events, such
as pleural effusion;[42] gastrointestinal events, including diarrhea, nausea, abdominal
pain and vomiting; and bleeding events. The most frequently reported serious AEs
included pyrexia (9%), pleural effusion (8%), febrile neutropenia (7%), gastrointestinal
bleeding (6%), pneumonia (6%), thrombocytopenia (5%), dyspnea (4%), anemia (3%),
cardiac failure (3%) and diarrhea. In a published correspondence in the New England
Journal of Medicine, the authors report the rate of drug-related pleural effusion as 21%
in a series of five Phase II studies involving a total of 511 patients with chronic-phase,
accelerated-phase, blast-crisis or Ph+ ALL.[52] Furthermore, in the Phase I study, ten
patients (four in chronic-phase CML and six in blast crisis) underwent thoracentesis and
two underwent pleurodesis.
In the dasatinib dose-optimization study of 100 mg/day versus 140 mg/day as reported
by Shah et al.,[43] the hematologic and cytogenetic response (complete hematologic
response, major cytogenetic response and complete cytogenetic response) were similar
among all arms. The PFS significantly favored 100 mg once a day as compared with 70
mg twice a day (p = 0.032). The 100 mg/day dose arm exhibited significantly superior
toxicity profile and superior tolerability compared with other arms. Thus the clinically
optimal dose of dasatinib without the inadvertent side effect is 100 mg/day, and longterm follow-up of this study will help determine the durability of this response.
Dasatinib received FDA approval in June 2006 for the treatment of adults in all phases
of CML (with chronic-phase, accelerated-phase, or myeloid or lymphoid blastic-phase
CML) with resistance or intolerance to prior therapy including imatinib. It is also
approved for the treatment of adults with Ph+ ALL, which is resistant or intolerant to
previous therapy.
Nilotinib
Nilotinib (Tasigna®; Novartis, Basel, Switzerland) is a novel aminopyrimidine ATPcompetitive inhibitor of bcr-abl. This TKI also binds to other kinases, such as KIT,
PDGFR, ABL-related kinase ARG and ephrin receptor EPHB4, with the exception of
the Src-family of tyrosine kinases. Nilotinib was designed to fit into the ATP-binding
site of the bcr-abl protein with higher affinity than imatinib. Crystallographic models
show that it requires less of a topographical fit in order to inhibit bcr-abl; thus, in
addition to being more potent than imatinib (IC50 <30 nM) against wild-type bcr-abl,
nilotinib is also significantly active against 32/33 imatinib-resistant bcr-abl mutants,
with the exception of T315I.[44,45] Because of the selectivity and broad efficacy of
nilotinib in known mutants, it has the potential to benefit patients in all stages of Ph+
CML by achieving and maintaining the best possible response, including one at the
molecular level. Hence, the clinical trials designed and discussed thus far include
individuals likely to respond, such as de novo patients, patients intolerant of less
selective therapy, patients who become resistant to imatinib mesylate and patients who
achieve a suboptimal molecular response on less selective therapy.
Nilotinib Clinical Development. The first in-human study (CAMN107A2101), is a
Phase I/II multicenter, dose escalation study of oral nilotinib on a continuous daily
dosing schedule in adult patients with imatinib-resistant/-intolerant CML in chronic
phase, accelerated phase or blastic crisis, relapsed/refractory Ph+ ALL and other
hematologic malignancies. The Phase I portion is complete and the Phase II is ongoing.
In the Phase I portion of the (CAMN107A2101) study, 119 patients with CML-chronic
phase, accelerated phase, BC and Ph+ ALL and resistant to imatinib were treated with
nilotinib in dose cohorts from 50 to 1200 mg on a once-daily dosing schedule.[46] No
dose-limiting toxicity dose level has been defined to date. Efficacy was assessed in 114
patients in the Phase I portion. In this study, nilotinib was not associated with the
edema, as seen frequently with imatinib. Among patients with chronic, accelerated and
blast-phase CML, hematological/cytogenetic responses were achieved in 92/53, 72/48
and 39/27%, respectively. The best responses were seen at doses of 400 mg twice a day.
Two of the imatinib-resistant Ph+ ALL patients also responded. Pharmacokinetic
analysis of patients receiving 400 mg twice a day, which was the dose selected for
Phase II trials, showed mean peak and trough plasma levels of 3.6 and 1.7 M,
respectively, with an apparent half-life of 15 h. Nilotinib is now being studied in three
ongoing Phase II trials conducted in patients with imatinib-resistant or -intolerant CML.
Currently, data is available from one clinical trial cohort of 145 patients who were
administered nilotinib at a dose of 400 mg twice a day. Results from this study indicate
that nilotinib achieved complete hematologic response in 69, 16 and 4% of patients with
chronic-phase, accelerated-phase, and blastic-phase disease, respectively, and major
cytogenetic responses were seen in 46, 28 and 29% of patients. The trial design also
allowed for dose escalation to 600 mg twice a day for Ph+ ALL, accelerated-phase
CML, chronic-phase CML and blast-crisis CML patients, to allow higher drug exposure
for suboptimal responders. In a recently published update of this Phase II open-label
study, nilotinib 400 mg was administered orally twice daily to 280 patients with
Ph+CML in chronic phase after imatinib failure or intolerance.[47] Patients had at least 6
months of follow-up and were evaluated for hematologic and cytogenetic responses, as
well as for safety and OS. At 6 months, the rate of major cytogenetic response (Ph
≤35%) was 48%: complete (Ph 0%) in 31%, and partial (Ph 1-35%) in 16%. The
estimated survival at 12 months was 95%. Adverse events were mostly mild-tomoderate, and there was minimal cross-intolerance with imatinib. Grade 3-4
neutropenia and thrombocytopenia were observed in 29% of patients; pleural or
pericardial effusions were observed in 1% (none severe).
Clinical data suggest that nilotinib may overcome most of the mutation-associated
resistance to imatinib mesylate (except T315I), and may have an important therapeutic
role in imatinib mesylate resistance and in front-line CML therapy to prevent emergence
of resistant clones. Prior to nilotinib, 28 different bcr-abl mutations involving 22 amino
acids were detected in 61/101 patients (60%). Nine patients showed two, three patients
three and one patient four mutations. Mutations were observed in 37 patients in chronic
phase (49%), 15 patients in accelerated phase (68%) and nine patients in blast crisis
(60%). In patients with mutations, the overall rate of hematologic response was 70%
(78% in chronic phase, 75% in accelerated phase, 25% in blast crisis), compared with
88% in patients without mutations. In chronic-phase CML, complete cytogenetic
response was achieved within 3-6 months in patients with mutations with high in vitro
sensitivity to nilotinib.[48] Response dynamics depend on the individual type of the
mutation, which may be the basis for individualized dosage of nilotinib according to the
mutation pattern. Based on these results, nilotinib is now approved by the FDA for the
treatment of chronic-phase and accelerated-phase Ph+ CML in adult patients resistant to
or intolerant to prior therapy that included imatinib.
Nilotinib in imatinib mesylate-resistant or intolerant accelerated chronic myeloid
leukemia. A Phase II trial was designed to characterize the efficacy and safety of
nilotinib (400 mg twice daily) in patients with imatinib-resistant or -intolerant
accelerated-phase chronic myelogenous leukemia with hematologic response as the
primary efficacy end point.[49] A total of 119 patients were enrolled and had a median
duration of treatment of 202 days (range, 2-611 days). An hematologic response was
observed in 56 patients (47%; 95% CI: 38-56%). Major cytogenetic response was
observed in 35 patients (29%; 95% CI: 21-39%). The median duration of hematologic
response has not been reached. Overall survival rate among the 119 patients after 12
months of follow-up was 79% (95% CI: 70-87%). Non-hematologic adverse events
were mostly mild to moderate. Severe peripheral edema and pleural effusions were not
observed. The most common grade 3 or higher hematologic adverse events were
thrombocytopenia (35%) and neutropenia (21%). Grade 3 or higher bilirubin and lipase
elevations occurred in 9 and 18% of patients, respectively, resulting in treatment
discontinuation in one patient.
Adverse Events for Nilotinib. Safety data are available for 371 patients with CMLaccelerated phase and accelerated phase enrolled in the Phase II part of study
(CAMN107A2101), and 428 patients with chronic-phase CML, accelerated-phase
CML, blast-crisis CML, Ph+ ALL, hypereosinophilic syndrome, systemic mastocytosis
and gastrointestinal stromal tumor enrolled in other ongoing clinical trials. The safety
and tolerability profile of nilotinib is favorable at 400 mg taken orally twice a day, with
commonly reported AEs in Phase I and II studies being myelosuppresion (grade 3-4 in
10-20% of patients), mild-to-moderate rashes, pruritis, nausea and vomiting, diarrhea,
fatigue, constipation, arthralgia and peripheral edema.[53-56] Severe clinical
consequences, such as febrile neutropenia, sepsis, pneumonia and bleeding associated
with thrombocytopenia occurred infrequently in both disease phases. The reported
nonlaboratory AEs were manageable with symptomatic treatment and were reversible.
Elevations in serum lipases were commonly observed (all grades ~38%). Patients with
elevated lipase were generally asymptomatic, those with symptoms of abdominal pain
were reported in 3-5%, and both were transient and easily managed with brief treatment
interruptions. Low-grade elevations of bilirubin and hepatic transaminases were
frequently observed; elevations of bilirubin occurred early, were transient, and the more
severe cases were managed with brief treatment interruptions or dose reductions, rarely
requiring treatment discontinuation. Of interest, a significant increase in relative risk of
hyperbilirubinemia was seen in patients with the (TA)7(TA)7 genotype at the
(A[TA]nTAA) element of the UGT1A1, suggesting that genetic susceptibility may
contribute to the development of hyperbilirubinemia in some patients.[57]
Nilotinib has demonstrated a modest dose-dependent potential for QT interval
prolongation as observed in both CML patients and healthy male volunteers. In general,
cardiac events occurred in patients with other risk factors for cardiac disease, and the
incidence of these events seems to reflect the underlying cardiac risk for a population of
the same age.
Other ATP-competitive Bcr-abl Inhibitors
Bosutinib
Bosutinib (SKI-606; Wyeth, NJ, USA) is an orally available, dual Src/Abl kinase
inhibitor shown to be 200-fold more potent than imatinib as an inhibitor of bcr-abl
phosphorylation in biochemical assays.[53,58] However, unlike dasatinib, bosutinib does
not block KIT or PDGFR.[58] The phosphorylation of the autoactivation site of the Srcfamily kinases (LYN and/or HCK) is also decreased by bosutinib therapy. It had been
demonstrated that bosutinib has in vitro activity against all imatinib-resistant mutants,
except T315I. In nude mice, bosutinib caused complete regression of large K562
(leukemia cell line) xenografts, when administered orally for 5 days at a once-daily dose
of 100 mg/kg body weight.[53] Ongoing Phase I/II clinical trials in imatinib-resistant
CML and Ph+ ALL reported evidence of bosutinib's efficacy, safety and tolerability.[54]
In the Phase I portion of this Phase I/II study, patients in chronic phase with imatinib
relapsed or refractory disease were eligible for treatment with bosutinib once-daily
dosing. A total of 18 patients have been enrolled in the following dose cohorts
(mg/day): 400 (three patients), 500 (three patients) and 600 (12 patients), and have been
on treatment for 30-192 days. A total of 17 out of 18 patients remain on study; one
patient discontinued with disease progression. The following bosutinib-related AEs
have been reported (n = 15, Grade 1/2): diarrhea (87%), nausea (33%), vomiting (20%),
abdominal pain (13%), rash (13%), asthenia (13%) and increased AST/ALT levels
(7%). Two patients treated at 600 mg experienced Grade 3 toxicity: rash and
thrombocytopenia. Five patients (four patients at 600 mg and one patient at 500 mg) had
dose reductions for rash, thrombocytopenia, diarrhea, fever and increased AST/ALT
levels. No pleural effusion or pulmonary edema has been reported. Of the seven patients
who entered the study in hematologic relapse and have completed 1 month of treatment,
all have achieved complete hematologic response. Of the seven patients on treatment for
12 weeks (time of first cytogenetic assessment), three have achieved complete
cytogenetic response and one patient has had a minimal cytogenetic response. A total of
six out of seven patients who have achieved complete hematologic response had
pretreatment imatinib-resistant bcr-abl mutations: M351T, F359V, T315I, and
F359(V,F); and two patients had multiple mutations (L248[L,V] and H396[H,R];
H396[H,P] and E286[E,G] and M351[T,M]). The three patients with complete
cytogenetic response had the following mutations: M351T, M244V, H396(H,P),
E286(E,G) and M351(T,M). Based on the emergence of one dose-limiting toxicity of
grade 3 rash, and additional grade 2, grade 1 and dermatologic toxicities observed at
600 mg, 500 mg has been selected as the dose for the Phase II portion of the study.
INNO-406
INNO-406 (Innovive, NY, USA; originally developed by Nippon Shinyaku as NS-187)
is a dual bcr-abl and LYN TKI, structurally related to imatinib and nilotinib, and is
currently being studied as a potential treatment for CML patients in a Phase I trial.
INNO-406 demonstrated a 25- to 55-fold greater potency than imatinib against the bcrabl-positive leukemia cell lines K562 and KU812, and against Ba/F3 mouse
hematopoietic cells designed to express parental p210 bcr-abl.[55] As INNO-406 is a
selective inhibitor of LYN kinase and not a broad Src-family kinase inhibitor,[55] it may
be less toxic in comparison with the broad Src-family inhibitors. However, further
clinical data is needed to prove if this can be of any clinical benefit. Once again, INNO406 inhibits various imatinib-resistant mutants, except T315I.
AP23464
AP23464 is a potent ABL kinase and SFK inhibitor that inhibits proliferation and
promotes apoptosis in CML cell lines.[56] Furthermore, AP23464 has antiproliferative
activity against cell lines expressing a different imatinib-sensitive bcr-abl mutant
(Q252H, Y253F, E255K, M351I or H396P). AP23464 had no inhibitory effect on bcrabl T315I mutants.
Non-ATP-competitive Inhibitors of Bcr-abl
Aurora Kinase Inhibitors
Aurora kinases are a family of serine/threonine kinases that are essential for protein
phosphorylation events regulating the mitotic progression of the cell cycle.[59] The
investigation of Aurora kinase inhibitors as potential therapeutic agents in cancer is
based on the fact that Aurora kinases are overexpressed in various human cancers.
MK-0457. MK-0457 (Merck, NJ, USA; originally developed by Vertex
Pharmaceuticals as VX-680) is an Aurora kinase inhibitor that targets bcr-abl mutants
resistant to all available TKIs, including the T315I mutant. It is a potent inhibitor of all
three Aurora kinases and FLT3 in the nanomolar range, and also a moderate-to-strong
inhibitor of other kinases, including ABL and JAK2, which are potential targets for a
variety of myeloproliferative disorders.[60,61] In Phase I clinical trials, MK-0457 has
been studied as a 5-day intravenous infusion (20 mg/m2/h, delivering plasma levels of
1-3 µM), administered every 2-3 weeks to patients with a wide range of relapsed or
refractory leukemias, including CML and Ph+ ALL patients.[61] This treatment regimen
is well-tolerated, with mucositis being one of the few reported side effects, and has
shown efficacy in patients with highly refractory CML, including some who express
bcr-abl with the T315I mutation. Efficacy seems to correlate with the level of
phosphorylation of CRKL, a downstream element in the bcr-abl signaling pathway. A
Phase II study has been started to assess the efficacy of MK-0457 in patients with CML
and Ph+ ALL who carry the T315I mutation, and in patients resistant or intolerant to
second-generation bcr-abl inhibitors.
PHA-739358. PHA-739358 (Nerviano Medical Sciences) is an orally bioavailable
inhibitor of Aurora kinases A, B and C. It has significant inhibitory action against tumor
growth in several animal tumor models at well-tolerated doses because of its potent
antiproliferative activity on a broad range of cancer cell lines.[62] PHA-739358 has
currently entered a Phase II clinical study in CML patients who have relapsed after
treatment with imatinib.
ON012380
ON012380 (Onconova Therapeutics, PA, USA) inhibits the kinase activity by a nonATP competitive allosteric mechanism, which involves bcr-abl inhibition by interacting
with the substrate-binding sites of the protein kinases, rather than involving the ATP
binding site.[63] In mice, it causes regression of leukemias induced by injection of cells
expressing the most resistant T315I mutant, by promoting apoptosis of bcr-abl and
mutant bcr-abl-expressing cells with an IC50 in the nanomolar range. However, the drug
has not yet entered clinical trials.
Stem-cell Transplantation
The role of allogeneic stem-cell transplantation has changed from first-line therapy to a
second-line or third-line therapy, given the success of bcr-abl inhibitors. However,
allogeneic stem cell transplant is still the only documented treatment that offers
potential cure as the graft versus leukemia does seem to eradicate this reservoir of
'quiescent' stem cells. However, stem-cell transplantation as a therapeutic option needs
to be weighed against the possible associated treatment-related life-threatening
morbidity, such as infections, graft versus disease, risk of secondary malignancy and,
ultimately, transplant-related mortality. Recent estimates of current outcomes after
stem-cell transplantation include data that were analyzed from 131 chronic-phase CML
patients undergoing stem-cell transplantation (bone marrow or peripheral blood) from
related donors at a single institution in the USA between the years 1995 and 2000.[64]
The probability of disease-free survival at 3 years was estimated to be 78%, while
survival and disease recurrence rates were estimated at 86 and 8%, respectively.
Updated data from all European patients undergoing stem-cell transplantation for CML
between 2000 and 2003 (n = 3018) was collated by The Chronic Leukemia Working
Party of the European Group for Blood and Marrow Transplantation.[65] Analysis of this
data estimated the 2-year survival rate as 61%, the transplant-related mortality rate as
30%, and the rate of disease recurrence as 22%.
As per the guidelines developed for the American Society of Hematology,[66]
approximately 50% of patients who underwent allogeneic stem-cell transplantation from
a matched related donor in their first chronic phase were alive as well as leukemia-free
after 5 years. Subsequent follow-up studies conformed to these data, demonstrating
survival extending to 10 and 15 years.[67,68] Survival following stem-cell transplantation
is mainly dependent on five defined risk factors:

Age of the patient

Stage (phase) of CML at transplantation

Transplantation from HLA-mismatched donor (unrelated donor)

Male recipient/female donor

Time from diagnosis to transplantation
All these factors can be used to evaluate the relative transplant risk.[69] Furthermore,
there are opportunities to treat the residual or recurrent disease after transplantation, as
cytogenetic and molecular monitoring of the disease enables detection of early posttransplant relapse. Several studies now show that relapse in this setting responds well to
therapy with donor lymphocyte infusions, IFN-α or imatinib.[70-72] In fact, CML was the
first hematologic disease where donor lymphocyte infusion has been shown to induce
durable remissions in most patients with a relapse.[73]
A recently published study from the MD Anderson Cancer Center evaluated outcomes
of 64 CML patients with advanced-phase disease (80% beyond first chronic phase) not
eligible for myeloablative preparative regimens owing to older age or comorbid
conditions; these patients were treated with fludarabine-based reduced-intensity
conditioning regimens.[74] The transplant characterisitics include: donor type matched
related (n = 30), one antigen-mismatched related (n = 4), or one antigen-matched
unrelated (n = 30). With median follow-up of 7 years, OS and PFS were 33 and 20%,
respectively, at 5 years. The incidence of treatment-related mortality was 33, 39 and
48% at 100 days, and 2 and 5 years after hematopoietic stem-cell transplantation,
respectively. In multivariate analysis, only disease stage at time of hematopoietic stem
cell transplantation was significantly predictive for both OS and PFS. The authors
conclude that reduced-intensity conditioning hematopoietic stem cell transplantation
provides adequate disease control in chronic-phase CML patients, but alternative
treatment strategies need to be explored in patients with advanced disease as treatmentrelated mortality rates in this high-risk population do increase over time.
Currently, there is no evidence for increased transplant-related toxicity either with prior
imatinib mesylate use or the use of novel TKI therapy before allogeneic stem-cell
transplantation.[75,76] The results of a recent retrospective study of 12 patients who were
treated with dasatinib or nilotinib or both for imatinib mesylate-resistant CML before
hematopoietic stem cell transplantation has not shown an increase in transplant-related
toxicity.[76]
To summarize, current guidelines recommend allogeneic stem-cell transplantation as
second-line or third-line treatment after kinase inhibitors failure, except in those patients
with high disease risk and very low transplantation risk,[69] in those patients who prefer
an alternative treatment, or for economic reasons.
Conclusions
The current recommendation is to start imatinib as the first-line therapy in a newly
diagnosed CML patient. Despite the fact that imatinib has revolutionized the
management of CML based on the encouraging positive results even after a follow-up
of 5 years, it still has some unresolved challenges. These include minimal residual
disease, resistant mutations, and unknown long-term effects on chromosomes, cardiac
function, and bone and mineral metabolism. Some of these problems are answered by
the newer second-generation TKIs and other targeted therapies based on the different
converging signaling events with the bcr-abl as in figure1; however, none so far has
been proven to eradicate the HSC clone. Currently, research work (investigation) is
focused on newer ways to overcome these pitfalls from the existing therapies.
Figure 1.
Bcr-abl, Src family and emerging cellular pathways for drug development in chronic
myelogenous leukemia. ABL = Abelson tyrosine kinase; Akt = Protein kinase B; BCR
= Breakpoint cluster region; CRKL = V-crk sarcoma virus CT10 oncogene homolog
(avian)-like; FAK = Focal adhesion kinase; FTI = Farnesyl transferase inhibitor; Grb-2
= Growth factor receptor-bound protein 2; Hck = Hemopoietic cell kinase; JAK = Janus
kinase; Lyn = V-yes-1 Yamaguchi sarcoma viral related oncogene homolog; MAPK =
Mitogen-activated protein kinase; P = Phosphate group; PI3K = Phosphatidylinositol-3kinase; SFK = Src family kinases; SHC = Src homology 2 domain-containing; SRC =
Homolog of Rous sarcoma virus; Stat = Signal transducer and activator of transcription.
Future Perspective
There is a growing hypothesis supported by in vitro data that a combination of multiple
Abl kinase inhibitors, such as nilotinib, dasatinib, imatinib and T315I inhibitors, could
be used to delay or prevent the emergence of drug-resistant clones. As these optimal
sequential and/or combinatorial treatment options are evolving, there is strong evidence
to show that these treatment decisions should be based on rational evaluation of the
emerging bcr-abl mutations. Preliminary data suggest that synergy between imatinib
and nilotinib, or dasatinib and BMS-214662, may occur at the level of the CML stem
cell owing to the ability of both imatinib and nilotinib to inhibit or act as substrates of
the multidrug efflux transporter ABCG2, which confers resistance toward several
anticancer drugs.[25,77] Thus, CML undoubtedly can be referred to as a 'poster child' that
not only helps comprehend the underlying molecular mechanisms causing cancer, but
also paves the way for successful tailor-made drug development and combinations in
order to achieve a cure.
Table 1. Summary of Clinical Trial Data of Imatinib
Cytogenetic
Follow-up
Complete
time
hematologic
(months) response (%)
Major
response
(%)
Complete
response
(%)
69
Estimated
response rates
12
96
85
19
95
85
Cumulative
best observed
response
rates*
60
97
92
Molecular
response
(%)
Ref.
40%
87
*In CML patients who remained on first-line imatinib mesylate therapy.
Imatinib survival rates: overall survival: 89%; overall survival excluding non-CML
deaths: 95%; event-free survival: 83%; survival without progressing to AP/BP: 93%.
AP = Accelerated phase; BP = Blastic phase; CML = Chronic myeloid leukemia.
Data taken from the imatinib IRIS trial Phase III (n = 1106).[9]
Table 2. Summary of Clinical Trial Data of the Different Bcr-abl
Inhibitors in Patients Who Received Imatinib Mesylate*
[2]
[9]
Hematologic
response (%)
Drug
Cytogenetic
response (%)
Number of patients
Partial
Complete
Major
Complete Ref.
CP (40)
92
92
45
35
AP (11)
82
45
27
18
My BP (23)
61
35
35
26
Ly BP and Ph+ ALL (10)
80
70
80
30
CP (186) Imatinib
mesylate resistant (127)
Imatinib mesylate
intolerant (59)
–––
90 87 97
52 39
80
39 28 64
[30]
AP (174) Imatinib
mesylate resistant (161)
Imatinib mesylate
intolerant (13)
64
45
39
32
[31,38]
My BP (74)
34
26
31
27
[32]
Ly BP (42)
35
26
50
43
[32]
Ph+ ALL (36)
50
33
58
58
[39]
CP (17)
11/12 =
92‡
11/12 =
92‡
35
35
[45]
AP (56)
38/51 =
74‡
26/51 =
51‡
27
14
My BP (24)
42
8
21
4
Ly BP (9)
33
0
11
11
CP (279) Imatinib
mesylate resistant (193)
Imatinib mesylate
intolerant (86)
137/185
= 74‡
137/185 =
74‡
52
34
[46]
AP (64) Imatinib mesylate
resistant (52) Imatinib
mesylate intolerant (12)
36
23
36
22
[48]
My BP (87)
27
21
NA
NA
[47]
Ly BP (27)
30
26
NA
NA
Ph+ ALL active (37)
24
24
NA
NA
Dasatinib
Phase
I
Phase
II
[29]
Nilotinib
Phase
I
Phase
II
*Careful consideration of the various differing factors, such as patient selection criteria,
response criteria and duration of treatment and duration of follow-up between individual
trials is necessary when comparing different agents in different trials.
‡
Responses are evaluated only in patients with active disease.
ALL = Acute lymphoblastic leukemia; AP = Accelerated phase; BP = Blastic phase;
CML = Chronic myeloid leukemia; CP = Chronic phase; Ly = Lymphoid; My =
Myeloid; NA = Not available; Ph+ = Philadelphia chromosome positive.
References
Papers of special note have been highlighted as either of interest (•) or of considerable
interest (••) to readers.
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24. Kantarjian HM, Rarson RA, Guilhot F, O'Brien SG, Druker BJ; on Behalf of
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patients with newly diagnosed chronic myeloid leukemia (CML) in chronic
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29. Talpaz M, Shah NP, Kantarjian HM et al.: Dasatinib in imatinib-resistant
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30. Hochhaus A, Kantarjian HM, Baccarani M et al.: Dasatinib induces notable
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31. Guilhot F, Apperley J, Kim DW et al.: Dasatinib induces significant
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36. Brave M, Goodman V, Kaminskas E et al.: Sprycel for chronic myeloid
leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia
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(2008).
37. Müller MC, Erben P, Schenk T et al.: Response to Dasatinib after imatinib
failure according to type of preexisting BCR-ABL mutations. Blood 108(11)
(2006) (ASH Annual Meeting Abstracts: 748).
38. Ottmann O, Dombret H, Martinelli G et al.: Dasatinib induces rapid hematologic
and cytogenetic responses in adult patients with Philadelphia chromosome
positive acute lymphoblastic leukemia with resistance or intolerance to imatinib:
interim results of a phase 2 study. Blood 110(7), 2309-2315 (2007).
39. Cortes J, Kim DW, Guilhod F et al.: Dasatinib (SPRYCEL®) in patients (pts)
with chronic myelogenous leukemia in accelerated phase (AP-CML) that is
imatinib-resistant (im-r) or -intolerant (im-i): updated results of the CA180-005
'START-A' Phase II Study. Blood 108(11) (2006) (ASH Annual Meeting
Abstracts: 2160).
40. Dombret H, Ottman O, Rosti G et al.: Dasatinib (SPRYCEL) in patients (pts)
with Philadelphia chromosome-positive acute lymphoblastic leukemia who are
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41. Baccarani M, Kantarjian HM, Apperley JF et al.: Efficacy of dasatinib
(SPRYCEL) in patients (pts) with chronic phase chronic myelogenous leukemia
(CP-CML) resistant to or intolerant of imatinib: updated results of the
CA180013 START-C Phase II study. Blood 108(11) (2006) (ASH Annual
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42. Quintas-Cardama A, Kantarjian HM, Munden R et al.: Pleural effusion in
patients (pts) with chronic myelogenous leukemia (CML) treated with dasatinib
after imatinib failure. Blood 108(11) (2006) (ASH Annual Meeting Abstracts:
2164).
43. Shah NP, Kim DW, Kantarjian HM et al.: Dasatinib 50 mg or 70 mg BID
compared to 100 mg or 140 mg QD in patients with CML in chronic phase (CP)
who are resistant or intolerant to imatinib: one-year results of CA180034. J.
Clin. Oncol. 25(Suppl.), 18S (2007) (ASCO Annual Meeting Proceedings:
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•• This ASCO 2007 presentation shows the optimal clinically effective dose of
dasatinib with the best tolerability profile.
44. Weisberg E, Manley P, Mestan J et al.: AMN107 (nilotinib): a novel and
selective inhibitor of BCR-ABL. Br. J. Cancer 94(12), 1765-1769 (2006).
45. O'Hare T, Walters DK, Stoffregen EP et al.: In vitro activity of Bcr-Abl
inhibitors AMN107 and BMS-354825 against clinically relevant imatinibresistant Abl kinase domain mutants. Cancer Res. 65(11), 4500-4505 (2005).
46. Kantarjian HM, Giles F, Wunderle L et al.: Nilotinib in imatinib-resistant CML
and Philadelphia chromosome-positive ALL. N. Engl. J. Med. 354(24), 25422551 (2006).
•• Clinical efficacy of nilotinib, a more potent and selective second-generation
bcr-abl inhibitor in patients with CML who are imatinib resistant or intolerant.
47. Kantarjian HM, Giles F, Gattermann N et al.: Nilotinib (formerly AMN107), a
highly selective Bcr-Abl tyrosine kinase inhibitor, is effective in patients with
Philadelphia chromosome-positive chronic myelogenous leukemia in chronic
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49. Le Coutre P, Ottmann OG, Giles F et al.: Nilotinib (formerly AMN107), a
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Sidebar: Executive Summary

Chronic myeloid leukemia (CML) is a myeloproliferative stem-cell disorder
with a tri-phasic course, with a pathagnomonic t(9,22) giving rise to the bcr-abl
fusion protein that drives the disease course.

Imatinib is the first signal transduction inhibitor binding competitively to the
ATP-binding site of bcr-abl, which has shown a remarkable clinical response
including complete cytogenetic and molecular response in over 80% of CML
patients in the chronic phase.

Stem-cell transplant still plays a potentially curative role in a subset of CML
patients; drug development, such as for BMS-214662, is also focused on
eradicating the hematopoietic stem-cell clone.

Imatinib treatment is a subset that is marred by the development of over 30
mutations in the bcr-abl region reducing its activity; second-generation bcr-abl
inhibitors, such as nilotinib and the combined src/abl inhibitor dasatinib, have
already overcome almost all these mutations, except for T315I.

ATP-non-competitive inhibitors, such as MK-0457 and ON012380, are able to
overcome the T315I mutation.

Future treatments for CML will be towards developing a rational combination of
these drugs that can overcome resistance and also deplete the abnormal stem
cell, paving the way for a cure.
Disclaimer
No writing assistance was utilized in the production of this manuscript.
Reprint Address
Francis Giles, CTRC Institute for Drug Development, University of Texas Health,
Science Center at San Antonio, 7979 Wurzbach Road, Suite 400, San Antonio, TX
78229, USA; E-mail: [email protected]
Swami Padmanabhan, Saritha Ravella, Tyler Curiel, Department of
Hematology/Oncology, Institute for Drug Development, Cancer Therapy and Research
Center, San Antonio, TX, USA
Francis Giles, CTRC Institute for Drug Development, University of Texas Health,
Science Center at San Antonio, 7979 Wurzbach Road, Suite 400, San Antonio, TX
78229, USA
Disclosure: The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert testimony, grants or patents
received or pending, or royalties.