Download Resistance to Targeted Therapy in Chronic Myelogenous Leukemia

Resistance to Targeted Therapy
in Chronic Myelogenous Leukemia
Andreas Hochhaus, Philipp Erben, Thomas Ernst, and Martin C. Mueller
Seminars in Hematology 44(suppl 1):S15-S24 ,2007
Prof.윤휘중 / R2 이윤정
INTRODUCTION
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Chronic myelogenous leukemia
(CML) : 1.5 cases per 100,000
people , 15% of all patients with
leukemia
Imatinib (Bcr-Abl selective
tyrosine kinase inhibitor, imatinib
mesylate (Glivec)) therapy for
CML : annual mortality rate 
15% to 20% down to 2%, based
on the current data
bcr-abl fusion gene( pluripotential
hematopoietic stem cells)
: expansion of a hematopoietic
clone  development of CML
Molecular Biology of CML
Semin Hematol 44(suppl 1):S4-S14,2007
Defining Resistance to Imatinib in CML
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Initially refractory to imatinib treatment , lose imatinib sensitivity over
time , experience relapse in chronic-phase ( CP) CML , advanced
phase of CML
Defining Resistance to Imatinib in CML
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Hematologic resistance : lack or loss of normalization of peripheral
blood counts, the differential leukocyte count, and spleen size, in
advanced phases of CML, failure to return to CP
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Cytogenetic resistance : lack or loss of major cytogenetic
response (MCR<= 35% Ph-positive [Ph] metaphases) or complete
cytogenetic response (CCR; 0% Ph metaphases)
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Molecular resistance : lack or loss of CMR (absence of detectable
Bcr-Abl transcripts by reverse-transcriptase polymerase chain
reaction (RT-PCR)).
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Molecular relapse : complete cytogenetic responders, increase in
Bcr-Abl transcript levels by five- to 10-fold.
Resistance to Imatinib Monotherapy
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Chronic Phase CML
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Early phase II studies : imatinib involved CP CML patients in
whom interferon- (IFN-) therapy had failed
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454 patients, 5% did not achieve a CHR
18 months median follow-up (primary resistance)  40% had less
than an MCR
24 months follow-up  secondary resistance or relapse was
approximately 13%.
The International Randomized Study of Interferon and STI571
(IRIS) :imatinib efficacy in 553 patients newly diagnosed with CP
CML and treated with imatinib without prior therapy
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18 months median follow-up (primary resistance)  approximately
5%
24 months follow-up  estimated rate of relapse or progression
was 10%
Pathogenesis of Resistance
1.Bcr-Abl Mutations
 Frequency of Bcr-Abl mutations in resistant patients : 42%- 90%
 The T315I mutation and some mutations : ATP phosphate-binding
loop (the “Ploop”) was greater level of resistance
 Detection of a kinase domain mutation was important
2. Activation of Alternative Pathways
 PI3K/Akt activation was found to be a critical mediator of cell
survival in vitro during the early phase of imatinib resistance
development
 Inhibiting imatinib-induced Akt activation in vitro using mTOR
inhibitors and Akt-specific siRNA, imatinib resistance can be
effectively antagonized
Pathogenesis of Resistance
3. Clonal Cytogenetic Evolution
 Clonal evolution has been demonstrated to occur during imatinib
therapy and it has also been associated with disease progression :
del9q , p53 mutations and loss of p53
4. Chromosomal Aberrations in Ph-Negative Cells
 The underlying mechanism is not completely understood
5. Pharmacologic Interaction, Drug Transport
 Overexpression of P-glycoprotein (Pgp), is encoded by the multidrug
resistance (MDR1) gene
 Differential expression of influx, facilitated by transporters such as
by the human organic cation transporter (hOCT1), and efflux,
facilitated by MDR1
 Acid 1 glycoprotein (AGP) binds to imatinib with high affinity was
inhibit its activity
Strategies to Prevent Resistance
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Optimal Dosing at Diagnosis
Full therapeutic doses as early as possible
 400 mg/d for CP CML and 600 mg/d for advanced disease can
aid in diminishing the risk of relapse.
Clinical evidence
 Phase I study : dose-escalating trial in patients with CP CML 
dose-response relationship
 Dose escalation may be the optimal approach for avoiding
imatinib resistance in patients with either newly diagnosed CML
or no prior therapy subsequent to IFN failure.
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Strategies to Treat Resistant Patients
1. Dose Escalation
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Clinical Evidence.
 54 patients with CP CML resistant or refractory to imatinib were
given doses of 300 or 400 mg imatinib, escalated from once to
twice daily.
 Improve response in patients with accelerated disease, who had
higher response rates when treated with 600 mg of imatinib
compared with 400 mg.
 Higher imatinib dosages is a higher rate of adverse effects 
myelosuppression and fluid retention
 Imatinib phase II trials demonstrated efficacy and feasibility of
administering higher-than-standard doses of imatinib in
advanced phases of CML
Strategies to Treat Resistant Patients
1. Dose Escalation
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Rationale for Use of Higher-than-standard Dose of Imatinib to
Overcome Resistance.
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Bcr-Abl kinase domain point mutations
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Three main regions of the Bcr-Abl kinase domain: (1) the Ploop, (2) the catalytic domain and intervening sequences
containing amino acids that contact imatinib (3) the activation
loop
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Imatinib resistance retain dependency on Bcr-Abl kinase
activity  respond to increasing concentrations of imatinib.
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Multidrug-resistance mechanisms  overexpression of Pgp,
increasing imatinib concentrations can assist in overcoming
resistance
Strategies to Treat Resistant Patients
2. Interruption or Cessation of Imatinib Therapy
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Clinical Evidence.
 Reduce a clone of cells bearing a Bcr-Abl Y253H (P-loop)
mutation
Rationale.
 High frequency of mutations that impair the binding of Bcr-Abl to
imatinib, such as E255K or Y253F, and the poor prognosis
portended by P-loop mutations
 Cessation or interruption of imatinib of resistant patients.
 Nonmutant Bcr-Abl leukemic clones to suppress the mutant
clone by removing its competitive advantage.
Strategies to Treat Resistant Patients
3. Upfront Combination Therapy
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Clinical Evidence
 combination of imatinib plus IFN, Cytarabine
 Dasatinib (Novel Bcr-Abl inhibitors)
 Imatinib plus lonafarnib (Farnesyltransferase inhibitors)
 The serine/threonine protein kinase mTOR is a downstream
component of the PI3K/Akt pathway  controlling cell growth
and proliferation.
 mTOR inhibitor (rapamycin) with imatinib markedly enhanced
this growth-inhibitory effect.
Strategies to Treat Resistant Patients
4. Novel Bcr-Abl Inhibitors
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Dasatinib
 Thiazolecarboxamide bind to the Abl kinase domain in both
the active (open) and inactive (closed) conformations, inhibits
Src family kinases
Nilotinib
 Aminopyrimidine  binds the Abl kinase domain in the inactive
conformation
Phase I and II studies : dasatinib and nilotinib show encouraging
hematologic and cytogenetic response rates with good tolerability
Strategies to Treat Resistant Patients
5.Treatment of Minimal Residual Disease
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Persistence of leukemic cells following imatinib therapy raises
question
Determine the duration of treatment with imatinib necessary to
sustain molecular response
Combination therapy
CONCLUSION
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Molecular-targeted therapy with imatinib has improved
treatment of CML
Resistance and relapse plays a role in the complex
interaction between imatinib and CML progression
Combination therapies with cytotoxic agents or agents
that target multiple sites within the Bcr-Abl signal
transduction pathway