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Treatment of Newly Diagnosed CML
Mechanisms of Imatinib Resistance
Neil Shah, MD, PhD
Assistant Professor
Division of Hematology/Oncology
UCSF School of Medicine
San Francisco, CA
Chronic Myelogenous Leukemia
Background
Chronic Myelogenous Leukemia (CML)
•
•
•
•
CML is a malignant myeloproliferative disorder that
originates from neoplastic transformation of hematopoietic
progenitor cells
All patients express the BCR-ABL hybrid gene and its
protein product – an active tyrosine kinase protein that
triggers intracellular abnormal signaling pathways,
resulting in disordered myelopoiesis with accelerated cell
growth, decreased apoptosis, and weakened cellular
adhesion
Characterized by either a biphasic or triphasic progressive
course
The cytogenetic hallmark of the disease is the presence
of the Philadelphia chromosome
Kantarjian et al., 2007.
CML – Phases of Disease
Phase
Chronic
Phase
Accelerated
Phase
Blast
Phase
Characteristics
•
Indolent course, often asymptomatic and found incidentally on routine
physical exam
•
Predominance of mature white blood cells
•
Approximately 90% of patients are diagnosed at this stage
•
Median survival is 4–7 years (pre-tyrosine kinase inhibitor [TKI] therapy)
•
Transition generally occurs over a period of 1 year or more. Duration is 6
months to 1 year
•
Associated with progressive leukocytosis, thrombocytosis or
thrombocytopenia, basophilia, increased blasts, splenomegaly, fever,
bone pain
•
Clonal evolution may be present
•
Lasts only a few months – survival is poor if untreated
•
Associated with increasing blasts (>20%), progressive splenomegaly
despite treatment, and clonal evolution
National Comprehensive Cancer Network, 2007;
National Cancer Institute, 2007; Calabretta & Perrotti, 2004; Cortes et al., 2006.
Historical Perspective
Medical Treatment of CML
1954
FDA approval of busulfan for the palliative treatment of CML
1960
Philadelphia chromosome discovered in CML cells
1983
First published report on interferon activity in CML
– First molecular description of the BCR-ABL gene
1993
Preclinical testing of STI571 (imatinib) – the first therapy developed to target a
known gene-based cause of cancer
1995
Interferon alfa-2a approved for treatment of Philadelphia chromosome-positive
CML patients who are minimally pretreated (within 1 year of diagnosis)
2001
Imatinib FDA-approved as first-line therapy for CML
2006
Dasatinib FDA-approved for treatment of all phases of CML in with resistance or
intolerance to prior imatinib therapy
2007
Nilotinib FDA-approved for imatinib-resistant or -intolerant chronic and
accelerated phase CML
Savona & Talpaz, 2006.
Selection of Initial Treatment Strategies
for Patients with CML
Treatment Selection
•
Options for treating patients with newly diagnosed CML
have changed since the introduction of imatinib
•
NCCN recommendations for treatment of newly
diagnosed CML (chronic or accelerated phase) include
three primary options:
– Imatinib
– Stem cell transplant
– Clinical trial
NCCN, 2007.
Imatinib Mesylate for Patients with Newly
Diagnosed CML in Chronic Phase:
Long-Term Benefit
(Update from the IRIS Study)
Patients on Study/Discontinuations
At 6 Years
First-line
imatinib
(N = 553)
• On imatinib study treatment
66%
• Discontinuation/crossover
34%
– Side effects/other AEs
5%
– Deaths (CML - unrelated)
2%
– Lack of efficacy/progression
14%
– Withdrawal of consent
6%
– Other reason (incl. SCT, lost to follow-up)
8%
AE, adverse event; CML, chronic myeloid leukemia; SCT, stem cell transplant
Event-Free Survival and Survival Without
AP/BC on First-Line Imatinib (IRIS Study)
100
90
% without event
80
70
Estimated rate at 60 months (with 95% CI)
60
Survival without AP/BC
Event-free Survival
50
40
93%
83%
(90-96)
(80-87)
Events
6.3% AP/BC (N = 35)
5.1% loss of MCyR (N = 28)
2.5% loss of CHR (N = 14)
1.6% CML-unrelated deaths (N = 9)
30
20
10
0
0
6
12
18
24
30
36
42
48
54
60
66
Months since randomization
Druker et al., 2006.
Overall Survival on First-Line Imatinib
(ITT Principle)
100
90
80
% aAlive
70
60
50
40
Estimated rate at 60 months (with 95% CI)
30
20
Without CML-related deaths
95.4%
(93-98)
Overall Survival
89.4%
(86-92)
10
0
0
6
12
18
24
30
36
42
48
Months since randomization
54
60
66
Druker et al., 2006.
Declining Annual Event Rates
8
7.5
% Annual Rates
7
Event
6
•
•
4.8
5
•
•
4
AP/BC
3.3
2.8
3
2
Loss of CHR
Loss of MCyR
AP/BC
Death during treatment
1.6
1.5
1.5
0.9
1
0.8
0.5
0.4
0
0
Year
1st
2nd
3rd
4th
5th
6th
Epidemiology
Estimated New Cases
Estimated Deaths
CML
Both
Men
Women
Both
Men
Women
1997
4,300
2,400
1,900
2,400
1,400
1,000
2007
4,570
2,570
2,000
490
240
250
The annual mortality rate has been reduced from 15% to 20% to ~2% and
median survival is expected to exceed 15 to 20 years based on current data.
Parker et al., 1997.
Jemal et al., 2007.
Alvarez et al., 2007.
IRIS Study at 6-Year Follow-up
Conclusions
•
Imatinib is confirmed as the standard first-line therapy for
all CML patients
– 88% overall survival with imatinib exceeds that of all other CML
therapies with less than 5% patients dying from CML
– During the 6th year there was 0% transformation to AP/BC
– 82% of patients treated with imatinib achieved a CCyR
– 63% of all imatinib randomised patients are still in CCyR and on
study treatment
– Responses are durable and the annual risk of progression is
decreasing with time
– No new safety findings seen with long term follow-up
Allogeneic Stem Cell Transplantation
Influence of Age on Survival Post-HSCT
in Chronic Phase (CP) CML
< 20 years (N = 14)
Probability of Survival
1.0
≥ 20 and < 30 years (N = 50)
0.8
0.6
≥ 30 and < 40 years (N = 81)
0.4
≥ 50 years (N = 19)
≥ 40 and < 50 years (N = 51)
0.2
0
0
5
10
Years
15
20
N = 215, 1982-1997.
Thomas ED et al. Ann Intern Med. 1986;104:155-163 and findings noted by Radich J, MD (written communication, January 2007).
Findings noted by Radich J, MD (written communication, January 2007).
Related Transplants
(≥ 1992)
Cumulative Proportion Surviving
Survival in Early Chronic Phase
by Year of Referral
Years from Referral
Univ. of Texas, MD Anderson Cancer Center Database 1965-2005
Selection of Initial Treatment Options for
CML Patients: Conclusions
•
With six years of follow-up data available, imatinib can
be considered standard first-line therapy for adult CML
patients
– 88% overall survival with imatinib in chronic phase CML exceeds
that of all other CML therapies (< 5% patients dying from CML)
– During the 6th year of imatinib therapy, there was 0%
transformation to AP/BC
•
Bone marrow transplantation has known curative
potential, but is associated with substantial treatmentrelated morbidity and mortality
•
Patients with advanced phase CML should be
considered for allo-SCT following TKI-induced remission
whenever possible
Laboratory Tests
to Determine Response
Methods of Assessing Treatment Response
Type of Response
Test
Hematologic
Complete Blood Count
Cytogenetic
Bone Marrow Metaphase*
Molecular
Peripheral Blood PCR
* Cytogenetic response is based on analysis of at least 20 metaphases
Deininger, 2005; National Comprehensive Cancer Network, 2007.
The Philadelphia Chromosome
and BCR-ABL
Chromosome 22
9 q+
9
Chromosome 9
c-BCR 1
2-11
Ph (or 22q-)
22
2-11
2-11
BCR
BCR-ABL
c-ABL
P210 BCR-ABLl
P185 BCR-ABL
Exons
ABL
Fusion
protein with
tyrosine
kinase activity
t (9;22) translocation
Introns
CML breakpoints
ALL breakpoints
BCR-ABL gene structure
Faderl et al.,1999; Melo, 1996.
Diagnostic Evaluation: Bone Marrow
Diagnostic
Study
Aspirate
Biopsy
Clinical Significance
• Evaluation of morphological abnormalities of hematopoietic precursors (myeloid vs.
lymphoid and stage of maturation).
• Used for flow cytometry, fluorescence in situ hybridization (FISH), or polymerase
chain reaction (PCR) analysis and cytogenetics.
• Evaluate cellularity, topography, presence of fibrosis
• Evaluate for possible non-random chromosomal abnormalities. Usually based on
evaluation of 20 or more metaphases.
Cytogenetics
• Two metaphases is considered non-random.
• Useful for detection of emerging additional chromosomal abnormalities in patients
with or without the presence of the Philadelphia chromosome.
• Still the only FDA-approved test for defining complete cytogenetic remission.
FISH
• Low false positive rate.
• Does not replace regular cytogenetics to detect additional cytogenetic abnormalities.
Hughes, 2006.
Definitions of Treatment Response
Level of Response
Definition
Complete hematological response
Normal CBC and differential, no
extramedullary disease
Major cytogenetic response
0-35% Ph-positive metaphases*
- Partial cytogenetic response
1%-35% Ph-positive metaphases*
- Complete cytogenetic response
0% Ph-positive metaphases*
Major molecular response
≥ 3-log reduction of BCR-ABL mRNA
from baseline
Complete molecular remission
Negativity by RT-PCR
* Cytogenetic response is based on analysis of at least 20 metaphases
Deininger, 2005; National Comprehensive Cancer Network, 2007.
Frequency of Response Evaluation
•
NCCN recommends hematologic, cytogenetic, and
molecular measures at baseline and at regular intervals
after initiation of TKI therapy
– Hematological parameters are monitored regularly to evaluate
for response and treatment toxicity
– Bone marrow metaphase cytogenetics at diagnosis and every 6
and 12 months thereafter until a complete cytogenetic response
is achieved
– PCR at diagnosis and every 3 months thereafter
NCCN, 2007.
Molecular Analysis in CML
•
Real-time PCR reaction is highly useful for analysis of
treatment response in CML, since the majority of chronic
phase patients will achieve a CCyR
•
PCR should be assessed on peripheral blood and should
be consistently performed by a single specialized
laboratory to minimize variance
•
The real time PCR provides additional prognostic
discrimination to the karyotype
•
Increasing BCR-ABL levels measured by PCR may
provide an early indication for disease resistance or
progression
Hughes, 2006.
Imatinib Overall Estimated Log Reduction
of BCR-ABL: IRIS Study Updated Results
100
8%
90
19%
18%
13%
29%
Patients (%)
80
20%
70
34%
60
25%
50
4 log
3 to < 4 log
2 to < 3 log
< 2 log
No CCyR
40
30
20
75%
50%
32%
26%
24%
3
6
12
18
24
10
0
Time (months)
Adapted from Hughes T et al. N Engl J Med. 2006;349:1423-1432.
CML Monitoring Strategy
Test
Time
Indication
Cytogenics
Diagnosis
Establish disease stage
Q 6 months
Assess imatinib response until CCyR
After CCyR
Q 12 months to look for newly acquired
cytogenetic changes post-BCR-ABL
increases
Diagnosis
Establish BCR-ABL transcript level
After CCyR
Q 3 months
Monitor for MMR (> 3 log decrease) or
increase in BCR-ABL
Diagnosis
Advanced phase disease
Anytime
If no/poor response, relapse, or
increasing BCR-ABL
PCR
ABL point mutation
analysis
National Comprehensive Cancer Network. Clinical Practice Guideline in Oncology v.1.2007: Chronic Myelogenous Leukemia.
Definitions of Imatinib Resistance
Imatinib Resistance and Intolerance in
Chronic Phase CML: Definitions
• Resistance can be defined as primary (lack of acceptable initial response) or
secondary (loss of an established response)
– Primary hematologic resistance refers to failure to achieve a CHR
within 3-6 months of initiating imatinib (~2-4 % of cases*)
– Primary cytogenetic resistance can be defined as:
• Lack of any cytogenetic response by 6 months
(~22% of cases* - IRIS study)
• Lack of MCyR by 12 months (~15% of cases* - IRIS)
• Lack of CCyR by 18 months (~25% of cases* - IRIS)
• Secondary resistance refers to progression after an established hematologic
or cytogenetic response
• Intolerance can be defined as the inability to tolerate at least 400 mg imatinib
daily despite reasonable supportive measures (< 5% with G3/G4 toxicities; %
of patients with persistent G2 toxicities leading to drug discontinuation
presently not well-defined)
*These categories are NOT mutually exclusive
Imatinib Event-free Survival
by MCyR at 12 Months
Patients without events (%)
100
90
80
P <.001
70
60
50
40
30
Estimated rate at 42 months
20
MCyR
No MCyR
10
N = 436
N = 66
91% (95% CI, 88-94)
66% (95% CI, 53-78)
0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months since randomization)
Adapted from O’Brien SG et al. N Engl J Med. 2003;348:994-1004; Findings noted by Druker B, MD
(written communication, January 2007).
EFS by Response at 12 Months
Impact of Major Molecular Remission (MMR)
100
90
80
70
60
50
Estimated rate at 54 months
40
CCyR with ≥ 3 log reduction
30
97%
89%
72%
CCyR with <3 log reduction
No CCyR
20

 P = 0.017
P < 0.001
10
0
0
6
12
18
24
30
36
42
Months since randomization
48
54
60
Imatinib Survival
Without Accelerated Phase/Blast
Crisis by Molecular Response: IRIS Study
Patients without AP/BC (%)
100
90
80
70
60
50
Response at 18 months
40
Estimated rate at 60 months
 P = 0.11
30
CCyR with  3 log reduction (N = 139) 100%
20
CCyR with < 3 log reduction (N = 54)
98%
No CCyR
87%
 P < 0.001
54
60
10
(N = 88)
0
0
6
12
18
24
30
36
42
48
66
Time (months since randomization)
Druker B et al. N Engl J Med. 2006;355:2408-2417.
Imatinib Resistance at 42-48 Months
Not resistant to imatinib
Resistant to imatinib
Early
Chronic
Phase
= 16%
Late
Chronic
Phase
= 26%
Accelerated
Phase = 73%
•
•
Blast
Phase = 95%
Early chronic phase patients (disease duration not greater than 6 months)
were followed for 42 months
All other patients had been previously treated with interferon and were
followed for 48 months
Shah et al. Hematology
(Am Soc Hematol Educ Program). ;183-187, 2005.
Clinical Resistance to Imatinib
Mechanisms
Clinical Resistance to Imatinib
Mechanisms
•
Primary Resistance
– Insufficient inhibition of BCR-ABL
• Can be due to low plasma levels, activity of drug pumps, etc
Primary Cytogenetic Resistance
Correlation of Response with Imatinib Plasma Levels
Day 29
551 pts Rx with imatinib 400 mg/D
Trough PK plasma levels on day 1 and 29
100
1 yr
4 yr
Percentage
80
60
40
20
0
<647
ng/ml
6471170
ng/ml
>1170
ng/ml
<647
ng/ml
6471170
ng/ml
CCR
MMR
P = 0.005
P = 0.03
>1170
ng/ml
Larson et al. ASH 2006.(Abst# 429)
Clinical Resistance to Imatinib
Mechanisms
•
Primary Resistance
– Insufficient inhibition of BCR-ABL
• Can be due to low plasma levels, activity of drug pumps, etc
– Individual variation in normal bone marrow reserve (low levels of
normal hematopoietic stem cells in some patients)
Clinical Resistance to Imatinib
Mechanisms
•
Primary Resistance
– Insufficient inhibition of BCR-ABL
• Can be due to low plasma levels, activity of drug pumps, etc
– Individual variation in normal bone marrow reserve (low levels of
normal hematopoietic stem cells in some patients)
•
Secondary resistance
– Outgrowth of one or more clones harboring an imatinib-resistant
BCR-ABL kinase domain mutation (most common)
BCR-ABL Kinase Domain Mutations Associated
with Clinical Resistance to Imatinib
(Incomplete Map)
L298V
E292V
x
P
C
A
Gorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; Roche-L’Estienne et al, 2002; Shah et al,
2002; Hochhaus et al, 2002; Al-Ali et al, 2004
Courtesy Tim Hughes
Clinical Resistance to Imatinib
Mechanisms
•
Primary Resistance
– Insufficient inhibition of BCR-ABL
• Can be due to low plasma levels, activity of drug pumps, etc
– Individual variation in normal bone marrow reserve (low levels of
normal hematopoietic stem cells in some patients)
•
Secondary resistance
– Outgrowth of one or more clones harboring an imatinib-resistant
BCR-ABL kinase domain mutation (most common)
– Overproduction of BCR-ABL (e.g. via genomic amplification)
BCR-ABL Gene Amplification Associated With
Clinical Imatinib Resistance
MB13
Imatinib
MB14
Imatinib
Chemotherapy
Gorre et al, Science, 293:876, 2001
Clinical Resistance to Imatinib
Mechanisms
•
Primary Resistance
– Insufficient inhibition of BCR-ABL
• Can be due to low plasma levels, activity of drug pumps, etc
– Individual variation in normal bone marrow reserve (low levels of
normal hematopoietic stem cells in some patients)
•
Secondary resistance
– Outgrowth of one or more clones harboring an imatinib-resistant
BCR-ABL kinase domain mutation (most common)
– Overproduction of BCR-ABL (e.g. via genomic amplification)
– BCR-ABL-independent mechanisms (poorly understood)
Role of Kinase Conformation
in Imatinib Resistance
•
Point mutations in BCR-ABL kinase domain can destabilize the
inactive conformation
Mutations that
directly affect
imatinib binding
Mutations that affect the
conformation required
to bind imatinib
Shah NP et al. Cancer Cell. 2002;2:117-125.
Mode of Dasatinib Binding to
ABL Kinase
Nilotinib has a Better Fit to the Binding Pocket
Imatinib (Glivec®) IC50 669 nM
Nilotinib (Tasigna®) IC50 25nM
• Rationally designed highly specific inhibitor of BCR-ABL
• 30x more potent than imatinib; maintains target specificity
• No significant effect on other kinases
• (Src, FLT3, VEGFR, EGFR, InsR, RET, MET, IGFR, etc)
Comparison of Imatinib and Two New BCR-ABL
Inhibitors: Nilotinib and Dasatinib
25-fold more potent than imatinib
325-fold more potent than imatinib
•
Preclinical evidence predicts that nilotinib and dasatinib will have significant activity
against BCR-ABL kinase domain mutations and BCR-ABL overexpression, the two
most common mechanisms of imatinib resistance
•
Both agents lack activity against the BCR-ABL T315I mutation
Shah et al. 2004; Weisberg et al. 2005; O'Hare et al.2005; Permission pending.
Bosutinib
A Dual Inhibitor of Src and Abl Kinases
Cl
Cl
HN
O
O
N
O
CN
N
N
Src Enzyme (Elisa) IC50 = 1.2 nM
Src Enzyme (Lance) IC50 = 3.8 nM
Abl Enzyme IC50 = 1.4 nM
K562 Cell IC50 = 20 nM
KU812 Cell IC50 = 4.3 nM
Boschelli et al. J Med Chem. 2005;48:3891-3902.
Golas et al. Cancer Res. 2003;63:375-381.
Golas et al. Cancer Res. 2005;65:5358-5364.
Puttini et al. Cancer Res 2006; 66:11314-22
SKI-606 (Bosutinib)
Preclinical Summary
• Orally bioavailable, potent dual Src/Abl inhibitor
• Minimal inhibitory activity against PDGF-R, c-kit
• Inhibits BCR-ABL signaling in CML cells
• Active against imatinib-resistant mutants of BCR-ABL,
except T315I
Investigational Abl Kinase Inhibitors
•
Second generation - T315I-ineffective
(in vitro)
– Bosutinib
– INNO-406
•
Third generation - T315I-effective (in vitro)
– MK-0457 (VX-680)
– PHA-739358
– XL228
– AP23464
MK-0457 in Advanced Leukemias
• Aurora kinase/BCR-ABL inhibitor
• N = 44; median follow-up 6 months
• All imatinib pretreated
• 50% dasatinib pretreated; 50% nilotinib pretreated
• Major toxicity – myelosuppression
• Doses > 20 mg/day (primarily in T315I-positive patients)
– 3 patients achieved MinHR
– 3 patients achieved MHR
– 1 patient achieved MinCyR
– 2 patients achieved PCyR
– 1 patient achieved CCyR
Giles et al., 2007.
Imatinib Intolerance
Definitions
•
For clinical trial purposes of second generation TKIs, a
strict definition of imatinib intolerance has been utilized
– e.g. grade 3/4 non-hematologic toxicity or grade 4 hematologic
toxicity persisting for >7 days
•
With the approval of dasatinib and nilotinib, imatinib
intolerance should include an inability to tolerate a
minimally effective dose of imatinib (at least 300 mg daily)
– It is not expected that a trial of a second generation agent (to
determine if the side effect profile is preferable to imatinib) will
impair the long-term outcome of the patient, or the ability of the
patient to be successfully retreated retreated with imatinib if the
second generation agent is found not to be more tolerable
Key Concepts
•
Long-term data confirm a survival advantage in CP patients treated with
imatinib
– CML-related deaths after six years are lower than what would be expected
with allo-SCT
•
Careful monitoring is essential to determine if patients are responding
adequately to TKI therapy, and to identify patients who may benefit from
alternative treatment strategies
•
The mechanism of action of dasatinib and nilotinib and other novel TKIs
involves their activity against imatinib-resistant BCR-ABL kinase domain
mutants and increased potency of BCR-ABL inhibition
•
Patients who are unable to tolerate at least 300 mg imatinib daily, or who
are considering skipping doses due to side effects, may be considered
imatinib-intolerant and eligible for alternative treatment strategies
•
Allo-SCT should be used as a bridge to consolidate TKI-mediated
remissions in advanced phase CML whenever possible
Case Study
•
A 32-year old man is referred for recently discovered leukocytosis of
234K, which was noted in blood work performed after he presented to
his primary care physician with left shoulder pain and ongoing night
sweats
•
He was found to have substantial splenomegaly
•
His differential was notable for the presence of 4% basophils, immature
granulocytes, and 8% blasts
•
Bone marrow biopsy reveals a hypercellular marrow with 9% blasts
and an M:E ratio of 10:1, consistent with a myeloproliferative disorder
•
Cytogenetics reveal a t (9;22) in all 20 metaphases analyzed
•
He has four siblings, and no other medical history, and would like to
know how he should be treated
Case Study
Question 1
Which therapeutic option would you recommend?
 Allo-SCT as soon as possible, with imatinib until pre-transplant
workup can be completed
 Imatinib 400 mg daily with deferral of allo-SCT unless there is
evidence of resistance to imatinib/TKI therapy
 Imatinib 600 mg daily with deferral of Allo-SCT unless there is
evidence of resistance to imatinib/TKI therapy
 Dasatinib 100 mg daily
 Nilotinib 400 mg bid
 Interferon 3 MU tiw
 Clinical trial
Case Study
Question 1
Which therapeutic option would you recommend?
 Allo-SCT as soon as possible, with imatinib until pre-transplant
workup can be completed
 Imatinib 400 mg daily with deferral of allo-SCT unless there is
evidence of resistance to imatinib/TKI therapy
 Imatinib 600 mg daily with deferral of Allo-SCT unless there is
evidence of resistance to imatinib/TKI therapy
 Dasatinib 100 mg daily
 Nilotinib 400 mg bid
 Interferon 3 MU tiw
 Clinical trial
Recommended approach:
•
•
Imatinib 400 mg daily
Clinical trial
Case Study
•
The patient initiates imatinib 400 mg daily, which he
tolerates generally well, with the exception of peripheral
edema and nausea
•
One month later, CBC reveals a complete hematologic
response (CHR)
•
He visits your office three months after initiating imatinib,
and continues to have a CHR
Case Study
Question 2
How would you monitor the patient’s disease?
A.
B.
CBC alone every 6-12 weeks
Choice (A) with a bone marrow biopsy every six months until
achievement of a CCyR
C. CBC every 6-12 weeks with peripheral blood BCR-ABL FISH
every three months
D. Choice (C) with a bone marrow biopsy every six months until
achievement of a CCyR
E. CBC every 6-12 weeks with peripheral blood BCR-ABL PCR
every three months
F. Choice (E) with a bone marrow biopsy every six months until
achievement of a CCyR
Case Study
Question 2
How would you monitor the patient’s disease?
A.
B.
CBC alone every 6-12 weeks
Choice (A) with a bone marrow biopsy every six months until
achievement of a CCyR
C. CBC every 6-12 weeks with peripheral blood BCR-ABL FISH
every three months
D. Choice (C) with a bone marrow biopsy every six months until
achievement of a CCyR
E. CBC every 6-12 weeks with peripheral blood BCR-ABL PCR
every three months
F. Choice (E) with a bone marrow biopsy every six months until
achievement of a CCyR
Recommended approach: E + F
•
CBC q 6-12 weeks with peripheral blood BCR-ABL PCR q 3
months, with bone marrow biopsy q 6 months until
achievement of a CCyR
Case Study
•
Six months after initiating imatinib therapy, the patient
continues to have a CHR
•
PCR analysis reveals a one-log decline in disease
burden compared with baseline
•
You inform him that a bone marrow biopsy will be
performed to allow an accurate assessment of his
chromosome response
•
You state that you wish to observe some level of
cytogenetic response
•
The patient is wondering about the likelihood of having
no cytogenetic response at this time
Case Study
Question 3
You inform him that the percent of chronic phase CML
patients who receive imatinib as primary therapy and have
no cytogenetic response after six months is approximately:






4%
8%
13%
18%
22%
27%
Case Study
Question 3
You inform him that the percent of chronic phase CML
patients who receive imatinib as primary therapy and have
no cytogenetic response after six months is approximately:






4%
8%
13%
18%
22%
27%
Answer:
•
22%
Case Study
Question 4
In reality, the patient’s marrow reveals 9 of 20 Ph+
metaphases. Your recommendation at this time is:






Continue imatinib 400 mg daily
Increase imatinib to 400 mg twice daily
Switch to dasatinib 100 mg once daily
Switch to dasatinib 70 mg twice daily
Switch to nilotinib 400 mg twice daily
Referral for allo-SCT
Case Study
Question 4
In reality, the patient’s marrow reveals 9 of 20 Ph+
metaphases. Your recommendation at this time is:






Continue imatinib 400 mg daily
Increase imatinib to 400 mg twice daily
Switch to dasatinib 100 mg once daily
Switch to dasatinib 70 mg twice daily
Switch to nilotinib 400 mg twice daily
Referral for allo-SCT
Recommended approach:
•
Continue 400 mg daily
Case Study
•
•
•
Twelve months after initiating imatinib, the patient’s bone
marrow biopsy reveals 3/20 Ph+ metaphases.
Six months later, bone marrow biopsy reveals 8/20 Ph+
metaphases.
The patient assures you that he has been compliant with
therapy.
Case Study
Question 5
You inform him that his loss of cytogenetic response is
most likely due to:




A low plasma level of imatinib
A resistant mutation in the BCR-ABL kinase domain
Overexpression of BCR-ABL
Activation of a parallel oncogenic pathway, such as SRC
Case Study
Question 5
You inform him that his loss of cytogenetic response is
most likely due to:




A low plasma level of imatinib
A resistant mutation in the BCR-ABL kinase domain
Overexpression of BCR-ABL
Activation of a parallel oncogenic pathway, such as SRC
Answer:
•
A resistant mutation in the BCR-ABL kinase domain
Case Study
•
You send his blood for mutation testing
– Results indicate the presence of an imatinib-resistant BCR-ABL
kinase domain mutation, L387M
•
He wants to know if there are other promising drugs
available for him
•
You inform him that two agents, dasatinib and nilotinib, are
approved for patients with imatinib-resistant chronic phase
CML
•
He asks how these drugs will work when imatinib has failed
Case Study
Question 6
You inform him that dasatinib and nilotinib are effective
because:






A. They are effective against all imatinib-resistant mutations
B. They are effective against most imatinib-resistant mutations
C. They are more potent than imatinib
A+C
B+C
None of the above
Case Study
Question 6
You inform him that dasatinib and nilotinib are effective
because:






A. They are effective against all imatinib-resistant mutations
B. They are effective against most imatinib-resistant mutations
C. They are more potent than imatinib
A+C
B+C
None of the above
Answer: B + C
•
They are effective against most imatinib-resistant mutations AND
they are more potent than imatinib
Treatment of Newly Diagnosed CML
Mechanisms of Imatinib Resistance
Concluding Remarks