Transcript Slide 1

Profiles in CML:
Overview of Practice Challenges
Moshe Talpaz, MD
Professor
Department of Internal Medicine, Hematology-Oncology
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan
Chronic Myelogenous Leukemia (CML)
• Abnormal clonal hematopoietic stem cell
disorder, increased proliferation,
decreased apoptosis and adhesion
• Chronic, accelerated, and blastic phases
• Ph t(9;22) (q34;q11) cytogenetic and
BCR-ABL molecular abnormalities
CML—A Myeloproliferative Disorder
Normal
Courtesy of John K. Choi, MD, PhD.
CML Chronic-Phase
CML Is Linked to a Single Cytogenetic
Abnormality—The Philadelphia
Chromosome
1
6
13
2
7
3
8
14
4
9
15
5
10
16
11
17
18
X
19
Stoll C, et al. Blood. 1978;52:828-838.
20
21
22
12
Y
The Philadelphia Chromosome
and BCR-ABL
Chromosome 22
Chromosome 9
9 q+
9
c-BCR 1
2-11
c-ABL
Ph (or 22q-)
22
2-11
BCR
2-11
p210BCR-ABL
p190BCR-ABL
BCR-ABL
Exons
ABL
FUSION
PROTEIN
WITH
TYROSINE
KINASE
ACTIVITY
t(9;22) translocation
Faderl S, et al. N Engl J Med. 1999;341:164-172.
Melo JV. Blood. 1996;88:2375-2384.
Introns
CML breakpoints
ALL breakpoints
BCR-ABL gene structure
Chromosome 9
t(9;22)
BCR
wwwww
wwwwwww
(q34;q11)
Chromosome 22
q11
BCR-ABL
wwwwwwwww
q34
ABL
wwwwwwww
BCR
ABL
210 KD protein
Faderl S, et al. N Engl J Med. 1999;341:164-172.
Melo JV. Blood. 1996;88:2375-2384.
The Clinical Course of Untreated CML
Advanced Phases
Chronic Phase
Accelerated Phase
Median duration
5–6 years
Median duration
6–9 months
Faderl S, et al. Ann Intern Med. 1999;131:207-219.
Pasternak, G et al. J Cancer Res Clin Oncol. 1998;124:643-660.
Blast Crisis
Median survival
3–6 months
Incidence and Mortality Of CML
Year
Number of Cases
Number of Deaths
19971
4300
2400
20072
4570
490
Based on current data,
median survival is expected to exceed 15–20 years.
1.Parker SL, et al. CA Cancer J Clin. 1997;47:5-27.
2.Jemal A, et al. CA Cancer J Clin. 2007;57:43-66..
Survival in Early Chronic Phase CML
With permission from Quintas-Cardama A, et al. Mayo Clin Proc. 2006;81:973-988.
IRIS Study in Chronic Phase CML—7-Year
Update
•
1106 patients originally enrolled, 553 per arm
•
Estimated overall survival at 7 years: 86%
•
Late-progression events
– Kaplan-Meier estimate of event-free survival at 7 years: 81%
– Kaplan-Meier estimated rate without accelerated phase/blast crisis
at 7 years: 93%
•
Safety
– Grade 3/4 events decreased in incidence after years 1–2
– No unique, previously unreported adverse events emerged
O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.
IRIS Overall Survival (ITT Principle)
Imatinib Arm
100
Probability of Survival
90
80
70
60
Estimated overall survival
at 7 years is 86%
(94% considering only
CML-related deaths)
50
40
30
20
Survival: deaths associated with CML
10
Overall survival
0
0
12
24
36
48
60
72
Months Since Randomization
Abbreviation: ITT, intent to treat.
With permission from O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.
84
96
Annual Event Rates—Imatinib Arm
• KM estimated EFS at 7 years = 81%
• KM estimated rate without AP/BC at 7 years = 93%
% with Event
8
7.5
Event
7
Loss of CHR,
6
Loss of MCR,
4
Death during treatment
AP/BC
3.3
2.8
3
2
AP/BC,
4.8
5
1.6
1.5
2.0 a
1.7
0.9
1
0.8
0.5
0.3
0
1
a
2
3
4
5
6
0.4
0
7
Year
Total events (n = 5), including loss of MCR (n = 3) and deaths (n = 2, one of which was coded a progression to
AP/BC in a patient in CHR 6 months prior to death).
Abbreviations: AP/BC, accelerated phase/blast crisis; CHR, complete hematologic response;
EFS, event-free survival; MCR, major cytogenic response; KM, Kaplan-Meier.
With permission from O’Brien SG, et al. 50th Annual ASH Meeting; December 6-9, 2008. Abstract 186.
IRIS 7-Year Update—Key Findings
• Overall survival: 86%
• Event-free survival: 81%
– 7% progression to accelerated phase/blast crisis (AP/BC)
• Complete cytogenetic response (CCR) achieved by 456/553 (82%)
patients
– 17% subsequently lost CCR
– 3% progressed to AP/BC
– 2% died from CML
– Time to CCR did not correlate with the rate of progression to AP/BC
• Major molecular response rates and depth of molecular response
increased over time
• While imatinib is efficacious, it does not work for all patients
O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.
Imatinib Resistance
• BCR-ABL specific
– Mutations
 >50 described with variable degrees of impact
50%–60%
 ~50% of patients
– Amplification or overexpression
 ~7-10 %
• BCR-ABL independent
– Cellular pharmacology
 Drug import/export
– Other pathways
 Wnt, notch
 Autocrine factors
 Lyn (other Src-family kinases)
Courtesy of M. Talpaz, MD.
40%–50%
24 Mutations in 19 Amino Acids
C
C
A
A
B
C
C A C
A‘ C C
C
C
A
A
A‘
A‘
M
M
M
M
M
C
C
C
C
M
M
M
C
C
C
A
A
A
L
A M‘ A
C‘
A C
C
C
A
C
A
C
A
C
A
C
A‘
A
A
M
A‘
A‘ M
M
P-Loop
M244V L248V
C
C
C C‘
A A
A A‘ C
M‘ M A
KD
D267G
G250E/R
T315I
T277A
Q252H
Y253F/H
F311L
M351T
F317L
L324Q
A-Loop
L387F/M
E355G
F359C/V
V379I
H396R
A397P
E255K/V
5 patients had 2 or more mutations (‘).
Gorre ME, et al. Science. 2001;293:876-880. von Bubnoff N, et al. Lancet. 2002;359:487-491. Branford S, et al. Blood.
2002;99:3472-3475. Hofmann W-K, et al. Blood. 2002;99:1860-1862. Roche-Lestienne C, et al. Blood. 2002;100:1014-1018.
Shah NP, et al. Cancer Cell. 2002;117-125. Hochhaus A, et al. Leukemia. 2002;16:2190-2196. Al-Ali HK, et al. Hematol J.
2004;5:55-60.
Role of Kinase Conformation in Imatinib
Resistance
Point mutations in BCR-ABL kinase domain restricts its
ability to adopt an inactive conformation
Mutations that
directly affect imatinib
binding
Mutations that affect the
conformation required
to bind imatinib
With permission from Schindler T, et al. Science. 2000;289:1938-1942.
With permission from Lombardo LJ, et al. J Med Chem. 2004;47:6658-6661.
Dasatinib Inhibits the Growth of
Most Imatinib Mesylate—Resistant BCRABL—Expressing Ba/F3 Cell Lines In Vitro
Relative Growth After
48 h of Drug Exposure
1.2
Parental Ba/F3 cells
1.0
T315I
0.8
0.6
E255K
Wild-type
BCR-ABL
0.4
0.2
M351T
0
0
0.5
2.5
5
25
Concentration of Dasatinib (nM)
With permission from Shah NP, et al. Science. 2004;305:399-401.
50
Ba/F3
Bcr-Abl
E255K
T315I
M351T
M244V
G250E
Q252H
Q252R
Y253F
Y253H
E255V
F317L
E355G
F359V
H396R
F486S
Spectrum and Frequency of BCR-ABL
Kinase Domain Mutations Developing
During Treatment with Imatinib,
Dasatinib, and Nilotinib
% BCR-ABL Mutation
20
Imatinib
Dasatinib
Nilotinib
15
10
5
0
The solid color corresponds to the 1st amino acid change; the broken color corresponds to the 2nd amino acid change if applicable.
With permission from Cortes J, et al. Blood. 2007; 110:4005-4011.
Case 1: AK
Neil P. Shah, MD, PhD
Assistant Professor
Division of Hematology/Oncology
UCSF School of Medicine
San Francisco, California
AK
33-Year-Old Male
• Referred for recently discovered leukocytosis of 253K
noted in blood work performed after he presented to his
primary care physician with left shoulder pain and
ongoing night sweats
• Palpable splenomegaly
• Differential: 3% basophils, immature granulocytes, and
2% blasts
• Bone marrow biopsy revealed: hypercellular marrow with
4% blasts and an M:E ratio of 10:1, consistent with a
myeloproliferative disorder
• Cytogenetics: t(9;22) in all 20 metaphases analyzed
• AK has 2 siblings and no other significant medical history
Decision Point 1
What is the appropriate first-line treatment for this
patient?
• Hematopoietic stem cell transplantation
• Imatinib
• Dasatinib
• Nilotinib
• Interferon alpha
AK
• Imatinib 400 mg daily is initiated
• AK tolerates therapy well, with the exception of
peripheral edema, mild nausea, and muscle cramps
• 1 month later, CBC reveals a complete hematologic
response (CHR)
• 6 months after initiating therapy, AK continues to have a
CHR. Bone marrow aspiration is performed, and the
t(9;22) translocation is detected in 5/20 metaphases
• 12 months after initiating therapy, only 2/20 bone marrow
metaphases contain the t(9;22) translocation
• 6 months later, despite continuing to have a CHR,
marrow metaphase analysis reveals the t(9;22)
translocation in 18/20 metaphases
Decision Point 2
What is your next step?
• Assess patient compliance
• Do a mutational analysis
• Increase imatinib dosage
• Switch to dasatinib or nilotinib
• Refer for allogeneic stem cell transplantation
• All of the above
AK
• AK states that he has been very compliant with
therapy
• BCR-ABL kinase domain mutation test is ordered;
the imatinib dose is increased to 800 mg daily
• AK experiences increased fatigue, nausea, and
edema on this dose
• 3 months after imatinib dose escalation
– CBC: WBC of 18K with immature forms and 3% basophils
– Mutation analysis: E255K mutation in a large proportion of
cells
(Incomplete) Map of BCR-ABL Kinase
Domain Mutations Associated with
Clinical Resistance to Imatinib
L298V
E292V
x
P
C
A
Abbreviations: P, P-loop; C, catalytic domain; A, activation loop.
Gorre ME, et al. Science. 2001;293:876-880. von Bubnoff N, et al. Lancet. 2002;359:487-491. Branford S, et al. Blood.
2002;99:3472-3475. Hofmann W-K, et al. Blood. 2002;99:1860-1862. Roche-Lestienne C, et al. Blood. 2002;100:1014-1018.
Shah NP, et al. Cancer Cell. 2002;117-125. Hochhaus A, et al. Leukemia. 2002;16:2190-2196. Al-Ali HK, et al. Hematol J.
2004;5:55-60.
Courtesy of Tim Hughes, MD.
Role of Kinase Conformation in Imatinib
Binding
Helix C
Imatinib
P-loop
Imatinib binds to an
inactive conformation
of BCR-ABL, and is
stabilized by a H-bond
with Thr315
Activation
loop
With permission from O’Hare T, et al. Cancer Res. 2005;652:4500-4505.
Differential Binding of Dasatinib and
Imatinib to ABL Kinase
QuickTime™ and a
Cinepak decompressor
are needed to see this picture.
With permission from Schindler T, et al. Science. 2000;289:1938-1942.
With permission from Lombardo LJ, et al. J Med Chem. 2004;47:6658-6661.
How Resistant is the E255K Mutation
to Imatinib in Vitro?
Resistance to Imatinib of Cells
Bearing BCR-ABL Mutations
Mutation
Biologic IC50 (µM)
E355G
2.38
M351T
4.38
F317L
7.50
Y253F
8.94
Q252H
3.12
G250E
>10
T315I
>10
E255K
>10
WT P210
0.60
Measured by determining concentration dependence of normalized viable cell counts.
Shah NP, et al. Cancer Cell. 2002;2:117-125.
Decision Point 3
How would you treat this imatinib-resistant
patient with a E255K mutation?
• Hematopoietic stem cell transplantation
• Switch to dasatinib
• Switch to nilotinib
How Resistant is the E255K Mutation
to Dasatinib in Vitro?
Efficacy of Dasatinib Against ImatinibResistant Kinase Domain Mutations in Vitro
Relative Growth After
48 h of Drug Exposure
1.2
Parental Ba/F3 cells
1.0
T315I
0.8
0.6
0.4
0.2
E255K
unmutated
BCR-ABL
0
0
0.5
2.5
5
25
Concentration of Dasatinib (nM)
With permission from Shah NP, et al. Science. 2004;305:399-401.
50
Ba/F3
Bcr-Abl
E255K
T315I
M351T
M244V
G250E
Q252H
Q252R
Y253F
Y253H
E255V
F317L
E355G
F359V
H396R
F486S
How Responsive is the E255K Mutation
to Dasatinib in Patients?
Dasatinib 70 mg Twice Daily in CML-CP
Response by Individual Baseline BCR-ABL
Mutation
Cellular IC50 (nM)
Dasatinib
Imatinib
n
1.3
2000
17
1500
9
1.8
1350–3900
23
Y253F/H/K
1.3–10
>10,000
14
E255K/V
5.6–13
4400–8400
10
1500
3
M244V
L248V
G250E/V
D276G
T315I
>1000
>10000
3
F317L
7.4
1050
4
M351T
1.1
930
15
400
6
E355G
F359C/I/V
2.2
1200
8
L387M
2.0
1000
2
0.6–1.13
850–4200
17
H396P/R
Other
Complete CyR
Partial CyR
Complete HR
No response
30
Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; CyR, cytogenetic response; HR, hematologic response.
With permission from Stone R, et al. 49th ASH; December 8-11, 2007. Abstract 734.
How Is Longer-Term Survival Impacted by
Dasatinib in Chronic Phase CML Patients?
Dasatinib 100 mg in Imatinib-Resistant
and -Intolerant CML-CP
Overall Survival
% Alive
100
80
100 mg once daily
24-month overall survival = 91%
60
0
0
3
6
9
12
15
18
21
24
Months
100 mg once daily
70 mg BID
140 mg once daily
50 mg BID
n
167
168
167
168
Overall survival
12 Months
24 Months
96%
91%
94%
88%
96%
94%
96%
90%
Abbreviation: CML-CP, chronic myeloid leukemia-chronic phase.
With permission from Shah NP, et al. 50th ASH; December 6-9, 2008. Abstract 3225.
27
30
Survival of Patients Who Discontinued
Imatinib Study Therapy
100
Survival 85% at 5 years after
discontinuing study
% Survival (all deaths)
90
80
70
60
50
40
Survival approximately 50%
at 5 years after stopping
imatinib study drug
30
Safety (n = 30)
Efficacy (n = 82)
Bone marrow transplant (n = 16)
Other reason (n = 80)
20
10
0
0
12
24
36
48
60
72
84
Months After Stopping Imatinib Study Therapy
With permission from O’Brien SG, et al. 50th ASH; December 6-9, 2008. Abstract 186.
96
How Resistant is the E255K Mutation
to Nilotinib in Vitro?
Activity of Nilotinib on Imatinib-Resistant
BCR-ABL Mutants in Vitro
Ba/F3 cell proliferation
IC50 (nM) on Proliferation
3000
Imatinib
Nilotinib
2500
2000
1500
1000
72-hour proliferation assay with BCR-ABL–expressing Ba/F3 cells
Weisberg E, et al. Br J Cancer. 2006;94:1765-1769. O’Hare T, et al. Cancer Res. 2005;65:4500-4505.
Weisberg E, et al. Cancer Cell. 2005;7:129-141.
F468S
M388L
L387F
A380S
F359V
F359C
E355G
E355A
M351T
S348L
D325N
F317V
F317L
F317C
T315I
F311V
E292K
K285N
E281K
E276G
E275K
E255R
E255V
E255K
E255D
Y253H
Q252H
G250V
G250E
G250A
L248V
M244V
M237I
Maternal
+ IL3
0
BCR-ABL wt
500
How Responsive is the E255K Mutation
to Nilotinib in Patients?
Phase II Nilotinib in CML-CP
Response and Progression
Based on Mutation IC50
Patients, n/N (%)
Mutation
CCyR
Progressed
No mutation
35/83 (42)
19/83 (23)
IC50 ≤150 nM
18/45 (40)
14/45 (31)
•
IC50 >150 nM
Y253H
0/8 (0)
3/8 (38)
E255K/V
0/8 (0)
6/8 (75)
F359C/V
0/10 (0)
9/10 (90)
14/33 (42)
13/33 (39)
Others
•
Response rates and
progression rates were similar
in patients without baseline
mutations and in patients with
mutations with IC50 ≤150 nM
for nilotinib
Less favorable responses
seen in patients with Y253H,
E255K/V, and F359C/V
– 8 of 26 patients were dose
escalated to 600 mg BID
– Highest rates of progression
for E255K/V and F359C/V
Abbreviations: CCyR, complete cytogenetic response; CML-CP, chronic myeloid leukemia-chronic phase.
With permission from Hughes TP, et al. Blood. 2007;110(11). Abstract 320. Blood. 2007;110(11). Abstract 320.
AK
• Dasatinib 100 mg daily is initiated
• Therapy is tolerated well except for an
occasional mild headache
• 2 weeks later, AK once again has a normal CBC
• After 6 months, bone marrow aspiration reveals
no karyotypically abnormal cells
• 12 months later, AK continues to have a
complete cytogenetic response on dasatinib
Conclusions
• Loss of response to imatinib is frequently associated with the
evolution of resistance-conferring BCR-ABL kinase domain
mutations
• Mutations confer varying degrees of resistance to imatinib, and
many are not likely to respond to imatinib dose escalation
• Dasatinib and nilotinib are effective against most imatinib-resistant
BCR-ABL kinase domain mutants in vitro and in patients
– Survival data with dasatinib compare favorably with transplant after 2
years
• Patients with select imatinib-resistant BCR-ABL kinase domain
mutations should be preferentially treated with either dasatinib or
nilotinib
– Consultation with a chronic myeloid leukemia expert is indicated when
treating patients with imatinib resistance
Case 2: WL
Michael J. Mauro, MD
Associate Professor
Center for Hematologic Malignancies, Knight Cancer Institute
Oregon Health & Science University
Portland, Oregon
WL
45-Year-Old Female
• Diagnosed with chronic myeloid leukemia (CML)
• WBC 150k
– Left shift, 3% blasts, 3% basophils, platelets 700k
• Splenomegaly 8 cm below left costal margin
• Bone marrow shows typical CML chronic phase (CML-CP)
– 95% cellular, myeloid hyperplasia, 5% blasts
– Karyotype: 100% classic t(9:22)
• Matched unrelated donor option identified; no sibling donor
Patient asks about initial treatment options
Decision Point 1
• What should be the initial therapy for this
patient?
– Imatinib 400 mg/day
– Imatinib 600 mg/day
– Imatinib 800 mg/day
– Immediate matched unrelated donor stem cell
transplantation
Imatinib 400 mg/day is the Indicated
Dose for Initial Therapy in This Patient
• Imatinib 400 mg/day
• Imatinib 600 mg/day
• Imatinib 800 mg/day
• Immediate matched unrelated donor stem cell
transplantation
WL
Follow-Up at Month 3
• Imatinib 400 mg/day was advised
• At month 3
– Complete hematologic response with mild leukopenia (WBC
2.5–4k, ANC >1500)
– Periorbital edema and myalgias present
• Peripheral blood qPCR is performed
– Results: 1.0 log reduction from baseline
How is she doing?
Any recommendations, changes?
Decision Point 2
• Response to 3-month results?
– Decrease imatinib dose to 300 mg/day due
to reduced WBC
– Continue imatinib at 400 mg/day
– Increase imatinib dose due to failure
– Change to nilotinib or dasatinib due to failure
– Move to matched unrelated donor stem cell
transplantation
CHR at 3 Months is an Adequate Response,
Although the Transcript Reduction is Marginal;
the Toxicity (Including Myelosuppression) Does
Not Warrant Dose Interruption or Reduction
• Decrease imatinib dose to 300 mg/day
due to reduced WBC
• Continue at 400 mg/day imatinib
• Increase imatinib dose due to failure
• Change to nilotinib or dasatinib due to failure
• Move to matched unrelated donor stem cell
transplantation
3-Month qPCR Predictive of Ability to
Achieve Subsequent MMR—IRIS Trial
% Achieving MMR
100
100%
>2 log reduction
90
1–2 log reduction
80
0–1 log reduction
69%
70
P <.001
60
50
40
30
20
13%
10
0
3
6
9
12
15
18
21
24
Months on Imatinib
Abbreviations: MMR, major molecular response; qPCR, quantitative polymerase chain reaction.
Hughes T, Branford S. Blood Rev. 2006;20:29-41.
27
30
WL
Follow-Up at Month 6
• Bone marrow at 6 months shows 80% Ph+ by karyotype
• She feels well; edema and myalgias manageable
• CBCs have shown fairly consistent minimal leukopenia
(total WBC 3–4k) with ANCs >1500
How is she doing now?
Would you change anything at this point?
What do you tell her about her response?
Decision Point 3
• Response to 6-month results?
– Continue imatinib at 400 mg/day
– Increase imatinib based on failure
– Change to dasatinib or nilotinib trial because of failure
– Move to matched unrelated donor stem cell
transplantation
Imatinib 800 mg/day Could be Considered
Given that the Cytogenetic Response is
Adequate (<95% Ph+) but Considered
“Suboptimal” (36%–95% Ph+) at 6 Months
• Continue imatinib at 400 mg/day
• Increase imatinib to 800 mg/day based on
suboptimal response
• Change to dasatinib or nilotinib trial because
of failure
• Move to matched unrelated donor stem cell
transplantation
ABL kinase domain mutation testing should be considered
Failure, Suboptimal Response—
European LeukemiaNet Consensus
Time
Failure
Suboptimal Response
Warnings
Diagnosis
—
—
Sokal High; del9q+;
clonal evolution
3 mo
No HR
Less than CHR
—
6 mo
No CyR
(Ph+ >95%)
Less than PCyR
(Ph+ >35%)
—
12 mo
Less than PCyR
(Ph+ >35%)
Less than CCyR
(0% Ph+)
Less than MMR
18 mo
Less than CCyR
Less than MMR
—
Anytime
Loss of CHR;
loss of CCyR
Confirmed loss of MMR;
evidence of clonal evolution
Change in qPCR;
Ph (-) clonal
cytogenetic abnormalities
Kinase mutations: high degree = IM resistance, failure; low degree = suboptimal response.
Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematological response; CyR, cytogenetic
response; HR, hematologic response; MMR, major molecular response; PCyR, partial cytogenetic response;
qPCR, quantitative polymerase chain reaction.
With permission from Baccarani M, et al. Blood. 2006;108:1809-1820.
% of Patients with Subsequent CCyR
Probability of CCyR, EFS by Cytogenetic
Response at 6 Months—IRIS Trial
(n = 81)
(n = 19)
(n = 16)
(n = 16)
CyR at 6 months (Ph+):
1%–35%
66%–95%
36%–65%
>95%
Graph: with permission from Druker B, et al. Blood. 2003.102;182a. Abstract 634.
Table: with permission from Baccarani M, et al. Blood. 2006;108:1809-1820.
% Ph+
at 6 mo
CCyR
at 12 mo
0%
N/A
1%–35%
80%
36%–90%
50%
>95%
15%
EFS
at 42 mo
95%
75%
What If This Was Imatinib Failure?
Dasatinib vs Higher Dose IM in CML-CP
for Imatinib Failure—Study Schema
Randomization 2:1
Cytogenetics at 12 weeks
Dasatinib 70 mg BID
(n = 101)
Continue therapy
or
crossover for:
CML-CP resistant
to imatinib
400–600 mg/day
Imatinib 800 mg
(n = 49)
 Progression
 Lack of MCyR
 Intolerance
ENDPOINTS:
•
•
Primary: MCyR and CCyR at 3 months
Secondary: rates of MCyR, CCyR, major molecular response; time to treatment failure;
progression-free survival
Abbreviations: CCyR, complete cytogenetic response; IM, imatinib; MCyR, major cytogenetic response.
Kantarjian H, et al. Blood. 2007;110: abstract 736.
Dasatinib vs High-Dose IM in CML-CP
Best Response (Prior to Cross-Over)
60
P = .017
53
Dasatinib
P = .0025
50
44
P = .028
40
Percent
Imatinib
33
29
30
18
20
12
10
0
MCyR
CCyR
MMR
Abbreviations: CCyR, complete cytogenetic response; IM, imatinib; MCyR, major cytogenetic response; MMR,
major molecular response.
Kantarjian H, et al. Blood. 2007;110: abstract 735.
Start-R—PFS by Prior Imatinib Dose
(400 & 600 mg) and Intervention (HighDose Imatinib or Switch to Dasatinib)
100
P = .0562
80
% PFS
P = .0033
60
Imatinib 400 mg
Imatinib 600 mg
Imatinib 400 mg
Imatinib 600 mg
40
20
Dasatinib
Dasatinib
Imatinib 800 mg
Imatinib 800 mg
0
0
3
6
9
12
15
Months
Abbreviation: PFS, progression-free survival.
With permission from Kantarjian H, et al. Blood. 2007;110: abstract 736.
18
21
24
27
30
33
Suboptimal Response and Failure Early
in the Course of Imatinib (6–12 Months)
Have Similar Outcomes
• At 6 months: failure = no cytogenetic response
(>95% Ph+)
• At 6 months: suboptimal response = minor/minimal
reduction (35%–95% Ph+)
• Suboptimal and failure category patients both have
significantly inferior likelihood of gaining remission
and remaining progression free
– Likelihood of complete cytogenetic response
 Failure at 6 months (Y/N):
 Suboptimal at 6 months (Y/N):
19% vs 92%
64% vs 97%
– Progression-free survival:
 Failure at 6 months (Y/N):
 Suboptimal at 6 months (Y/N):
Marin D, et al. Blood. 2008;112:4437-4444.
73% vs 87%
62% vs 91%
Suboptimal Response and Failure Early
in the Course of Imatinib (6–12 months)
Have Similar Outcomes
• Combine failure and suboptimal into “nonresponder”
group
– Likelihood of complete cytogenetic response:
39% “nonresponders” vs 96% “responders”
– Overall survival: 87% vs 98%
– Progression-free survival: 70% vs 92%
• Similar data for “lumping” suboptimal and failure together
at 12 months
• At 18 months, no statistical difference in overall and
progression-free survival: failure vs suboptimal
– Note: 18-month response based on molecular findings (MMR or
no MMR)
Marin D, et al. Blood. 2008;112:4437-4444.
WL
1-Year Mark
• At 6 months, imatinib was increased to 800
mg/d
– Bone marrow studies performed at 1 year
 Karyotype: 60% Ph+, 40% normal XX
 Fish: 55% of cells with fusion signal c/w Ph+
– Blood counts and side effects remain similar
How is she doing at this time?
Would you change anything at this point?
How do you counsel her regarding the results?
Decision Point 4
• What is your reaction to 12-month results?
– Optimal response; no change in therapy
– Suboptimal but adequate, no change in therapy
– Suboptimal, change therapy
– Failure, change to alternate therapy
Lack of Major Cytogenetic Response (ie, >35%
Ph+) at 12 Months is Considered “Failure” and
Therapy Change is Warranted
• Optimal response; no change in therapy
• Suboptimal but adequate, no change in therapy
• Suboptimal, change therapy
• Failure, change to alternate therapy
ABL kinase domain mutation testing should be performed
(if not done previously and repeated, if done previously)
Rate of Progression to the Accelerated Phase
or Blast Crisis on the Basis of Cytogenetic
Response After 12 Months or Molecular
Response After 18 Months of Imatinib Therapy
B
Patients Without Progression (%)
Patients Without Progression (%)
A
With permission from Druker BJ, et al. N Engl J Med. 2006;355:2408-2417.
Mechanisms of Resistance to Imatinib
• BCR-ABL kinase domain mutations1
– Most common cause for clinical resistance to imatinib
(≥50%)
– ~100 identified, occur at various regions and convey
variable degrees (activation loop <phosphorylation
loop <<kinase-binding pocket) of imatinib insensitivity
– Mutation at position 315 conveys resistance to
imatinib as well as dasatinib and nilotinib
• BCR-ABL amplification/increased expression
• Ph+ clonal evolution
1. O’Hare T, et al. Blood. 2007;110:2242-2249.
Mechanisms of Resistance to Imatinib
• Decreased drug exposure
– Decreased amount/activity of influx protein OCT-1
– Increased P-glycoprotein (ABCB1/MDR1) efflux
– 1 acid glycoprotein sequestration
• Other mechanisms
– Src-related (Lyn) kinase overexpression?1
– Others: HSP70 overexpression; p53 mutations;
PI3K/Akt/mTor activation; autocrine GM-CSF based JAK2/STAT-5 activation
1. Donato NJ, et al. Blood. 2003;101:690-698.
Suggested Common and Differentiating
Factors in Choosing Salvage Therapy
(Dasatinib or Nilotinib) After Imatinib
Factor
Potential Issue for Dasatinib
Potential Issue for Nilotinib
Myelosuppression (for both dasatinib and nilotinib)
Clinical
? Select cardiac diseases
(hypertension, hypercholesterolemia)
? Prior pancreatic disease and liver disease
? Pre-existing pleural/pericardial disease
Known QTc prolongationa
? Autoimmune disease
Required concomitant therapy with risk of
prolonging the QTc
? Rash on prior imatinib or after starting dasatinib
? Poorly controlled diabetes
Ongoing need for anticoagulation, antiplatelet
therapy
Pre-existing bleeding disorders
ABL mutation T315I (for both dasatinib and nilotinib)
Molecular
aBlack
ABL mutation at positions 317 and 299
box warning regarding QT prolongation and sudden death.
ABL mutation at positions 253, 255, 359
WL: Month 18
• ABL kinase mutation analysis done: NO MUTATION
• Based on imatinib failure, prior myelosuppression issues, etc,
nilotinib chosen, 400 mg BID
• Marrow at 15 months still shows rising burden of Ph+ cells
– Now 80% Ph+ by karyotype, FISH concurs at 80%
• Repeat ABL kinase domain mutation now shows a T315I
mutation, dominant over wild-type
Patient asks how she is doing and if
any change is needed
Nilotinib Phase II CML-CP—Efficacy
(19 Month Follow-Up)
100
% of Patients
80
76%
59%
60
65%
56%
51%
44%
41%
40
20
0
CHRa
# of Pts = 207
Overall
321
Imatinib
Imatinib
Resistant Intolerant
226
95
MCyR
Median time to CHR 1 month; MCyR 2.8 months
a
Patients without CHR at baseline.
With permission from Kantarjian H, et al. Blood. 2008;112(11): abstract 3238.
Overall
321
Imatinib
Resistant
226
CCyR
Imatinib
Intolerant
95
Nilotinib Efficacy According to Baseline
BCR-ABL Mutations in CML-CP
T315I
3%
Y253H
4%
4% E255K/V
5% F359C/V
45%
No Mutation
15%
Othersa
IC50-based groupingb
IC50 ≤150 nM
M244V, L248V, G250E,
Q252H, E275K, D276G,
F317L, M351T, E355A, E355G,
L387F, F486S
IC50 >150 nM
Y253H, E255K/V, F359C/V
IC50 >10,000 nM
T315I
24%
IC50 ≤ 150 nM
aMutations
bNilotinib
without available IC50 data.
IC50 data cited were established in Ba/F3 in vitro proliferation assay (Weisberg E. Br J Cancer. 2006;94:1765-1769.).
With permission from Hochhaus A, et al. Blood. 2008;112(11): abstract 3216.
Decision Point 5
• What is your response to 15-month results?
– Failure, change therapy
– Failure, proceed to matched unrelated donor stem
cell transplantation
Identification of Resistant Disease
Harboring a Dominant T315I Mutation Is
Grounds for Proceeding to Stem Cell
Transplantation and/or a Clinical Trial to
Stabilize Disease/Gain Response
• Failure, change therapy
• Failure, proceed to matched unrelated donor
stem cell transplantation
Other Novel Alternative ABL Inhibitors
• Bosutinib
– Spectrum similar to dasatinib, different toxicity profile
– Less myelosuppression, pleural effusions; GI toxicity, rash
– Activity looks quite promising; being studied in other tyrosine kinase
inhibitor resistance and front-line studies
• INNO-406
– ABL/Lyn inhibitor, expected to have CNS penetration
– Spectrum and toxicity appear similar to nilotinib
• MK0457
– First “t315i” inhibitor; in phase II studies
• PHA 739358, AP 24534, XL 228, SGX 393
– The next wave of “T315i” inhibitors; in preclinical or phase I
Conclusions
Moshe Talpaz, MD
Professor
Department of Internal Medicine, Hematology-Oncology
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan
Conclusions
• The development of imatinib has
revolutionized the treatment of CML
• Imatinib is a specific inhibitor of the BCRABL tyrosine kinase
Conclusions
• Some patients may be resistant to or
intolerant of imatinib or develop resistance
during treatment
• In many of these patients, resistance is
due to mutations in the BCR-ABL gene
Conclusions
• Early monitoring, by cytogenetic and
molecular methods, may help define
treatment
• BCR-ABL mutational analysis should be
focused on imatinib-resistant patients
• Determination of BCR-ABL mutation may
help define specific treatment
Conclusions
• Nilotinib and dasatinib are second-line
BCR-ABL TKIs that have been shown
effective in most patients resistant to
imatinib
• TKIs that inhibit BCR-ABL with mutations
conferring resistance to all 3 agents are
in development
Conclusions
• Allogeneic hematopoietic stem cell
transplantation (HSCT) is a potentially
curative therapy for patients resistant to
TKIs