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Transcript of Profiles in CML: Overview of Practice Challenges Moshe Talpaz, MD Professor Department of Internal...
Profiles in CML: Overview of Practice Challenges
Moshe Talpaz, MDProfessor
Department of Internal Medicine, Hematology-OncologyUniversity 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
Courtesy of John K. Choi, MD, PhD.
Normal CML Chronic-Phase
CML Is Linked to a Single Cytogenetic Abnormality—The Philadelphia
Chromosome
1 2 3 4 5
6 7 8 10 119 12
13 14 15 16 17 18
19 20 21 22
X Y
Stoll C, et al. Blood. 1978;52:828-838.
The Philadelphia Chromosome and BCR-ABL
BCR-ABL
ABLFUSION
PROTEINWITH
TYROSINEKINASE
ACTIVITY
22
BCR
Ph (or 22q-)
99 q+
1
p210BCR-ABL
p190BCR-ABL2-11
2-11
Chromosome 9
c-BCR
Chromosome 22
c-ABL
2-11
Exons
Introns
CML breakpoints
ALL breakpoints
t(9;22) translocation BCR-ABL gene structure
Faderl S, et al. N Engl J Med. 1999;341:164-172.
Melo JV. Blood. 1996;88:2375-2384.
ABL
Chromosome 9Chromosome 22
wwwwwww
BCRwwwww
BCR-ABL
wwwwwwwwq34
wwwwwwwwwq11
t(9;22)(q34;q11)
BCR ABL
210 KD protein
Faderl S, et al. N Engl J Med. 1999;341:164-172.
Melo JV. Blood. 1996;88:2375-2384.
Chronic PhaseAccelerated
PhaseBlast Crisis
Advanced Phases
The Clinical Course of Untreated CML
Faderl S, et al. Ann Intern Med. 1999;131:207-219.Pasternak, G et al. J Cancer Res Clin Oncol. 1998;124:643-660.
Median duration5–6 years
Median duration6–9 months
Median survival3–6 months
Incidence and Mortality Of CML
Based on current data, median survival is expected to exceed 15–20 years.
Year Number of Cases Number of Deaths
19971 4300 2400
20072 4570 490
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
With permission from O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.
Abbreviation: ITT, intent to treat.
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96
Months Since Randomization
Pro
babi
lity
of S
urvi
val
Survival: deaths associated with CML
Overall survival
Estimated overall survivalat 7 years is 86%
(94% considering onlyCML-related deaths)
Annual Event Rates—Imatinib Arm• KM estimated EFS at 7 years = 81%
• KM estimated rate without AP/BC at 7 years = 93%
7.5
4.8
1.7
0.80.3
1.5
2.8
1.6
0.90.5
00.4
2.0
3.3
0
1
2
3
4
5
6
7
8
1 2 3 4 5 6 7Year
% w
ith E
vent
Event
Loss of CHR,
Loss of MCR,
AP/BC,
Death during treatment
AP/BC
aTotal 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.
a
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% 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)
50%–60%
40%–50%
Courtesy of M. Talpaz, MD.
24 Mutations in 19 Amino Acids
P-Loop KD A-Loop
M244V
Q252H
Y253F/H
E255K/V
T315I M351T
E355G
L387F/M
H396R
CCAA
BCCC
CCAAA‘A‘MMMMM
CCCCMMM
CCCAAAL
CCAAAAA‘MM
AA‘
CAAM‘
CCC‘AA‘M
L248V
CA‘
C‘A
F317L
AC
F311L
A
F359C/V
CCCCAA‘
CA
A397P
T277A
M‘
D267G
A M
V379I
G250E/R
L324Q
C
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
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.
Mutations thatdirectly affect imatinib binding
Mutations that affect the conformation requiredto bind imatinib
Dasatinib Inhibits the Growth of MostImatinib Mesylate—Resistant BCR-ABL—
Expressing Ba/F3 Cell Lines In Vitro
With permission from Shah NP, et al. Science. 2004;305:399-401.
Ba/F3Bcr-AblE255K
M351TM244VG250EQ252HQ252RY253FY253HE255VF317LE355GF359VH396RF486S
T315I
Parental Ba/F3 cells
M351T
0
0.2
0.4
0.6
0.8
1.0
1.2
0 2.5 5 25 50
Rel
ativ
e G
row
th A
fter
48
h o
f D
rug
Exp
osu
re
Concentration of Dasatinib (nM)
Wild-typeBCR-ABL
E255K
T315I
0.5
With permission from Cortes J, et al. Blood. 2007; 110:4005-4011.
Spectrum and Frequency of BCR-ABL Kinase Domain Mutations Developing
During Treatment with Imatinib, Dasatinib, and Nilotinib
The solid color corresponds to the 1st amino acid change; the broken color corresponds to the 2nd amino acid change if applicable.
0
5
10
15
20 ImatinibDasatinibNilotinib
G25
0E
Y25
3H/F
E25
5K
V29
9L
F311
1
T315
I
F317
L
M35
1T
E35
5G/A
F359
C/V
H39
6R/P
% B
CR
-AB
L M
uta
tio
n
Case 1: AK
Neil P. Shah, MD, PhDAssistant Professor
Division of Hematology/OncologyUCSF School of MedicineSan Francisco, California
AK33-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
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.
E255K/V
M244V M351T
Y253H/F
E279K
F317L
E355G/D
F359C/V/D/I
H396R/PQ252H/R
S417Y
E459K/Q
F486S
E450G/Q M388L
G250E/A/F
D276G
T277A
L387F/M
V379I
A397P E453G/KT315I/N
F311L/I
V289A
L298VL248V
E281A
L364I
G383D
E292V
xP C A
Abbreviations: P, P-loop; C, catalytic domain; A, activation loop.Abbreviations: P, P-loop; C, catalytic domain; A, activation loop.
Courtesy of Tim Hughes, MD.Courtesy of Tim Hughes, MD.
Role of Kinase Conformation in Imatinib Binding
Imatinib binds to an inactive conformation of BCR-ABL, and is stabilized by a H-bond with Thr315
Imatinib
With permission from O’Hare T, et al. Cancer Res. 2005;652:4500-4505.
Helix C
Activationloop
P-loop
Differential Binding of Dasatinib and Imatinib to ABL Kinase
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.
QuickTime™ and aCinepak decompressor
are needed to see this picture.
How Resistant is the E255K Mutation to Imatinib in Vitro?
Resistance to Imatinib of CellsBearing 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-resistantpatient 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 Imatinib-Resistant Kinase Domain Mutations in Vitro
With permission from Shah NP, et al. Science. 2004;305:399-401.
Ba/F3Bcr-AblE255K
M351TM244VG250EQ252HQ252RY253FY253HE255VF317LE355GF359VH396RF486S
T315I
Parental Ba/F3 cells
0
0.2
0.4
0.6
0.8
1.0
1.2
0 2.5 5 25 50
Rel
ativ
e G
row
th A
fter
48
h o
f D
rug
Exp
osu
re
Concentration of Dasatinib (nM)
unmutatedBCR-ABL
E255K
T315I
0.5
How Responsive is the E255K Mutation to Dasatinib in Patients?
With permission from Stone R, et al. 49th ASH; December 8-11, 2007. Abstract 734.
Dasatinib 70 mg Twice Daily in CML-CP Response by Individual Baseline BCR-ABL
MutationCellular IC50 (nM)
Dasatinib Imatinib n
M244V 1.3 2000 17
L248V 1500 9
G250E/V 1.8 1350–3900 23
Y253F/H/K 1.3–10 >10,000 14
E255K/V 5.6–13 4400–8400 10
D276G 1500 3
T315I >1000 >10000 3
F317L 7.4 1050 4
M351T 1.1 930 15
E355G 400 6
F359C/I/V 2.2 1200 8
L387M 2.0 1000 2
H396P/R 0.6–1.13 850–4200 17
Other 30
Complete CyRPartial CyRComplete HRNo response
Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; CyR, cytogenetic response; HR, hematologic response.Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; CyR, cytogenetic response; HR, hematologic response.
How Is Longer-Term Survival Impacted by Dasatinib in Chronic Phase CML Patients?
Dasatinib 100 mg in Imatinib-Resistantand -Intolerant CML-CP
Overall Survival
Months
% A
live
100
80
60
0
100 mg once daily 24-month overall survival = 91%
0 3 6 9 12 15 18 21 24 27 30
Overall survival
n 12 Months 24 Months
100 mg once daily 167 96% 91%
70 mg BID 168 94% 88%
140 mg once daily 167 96% 94%
50 mg BID 168 96% 90%
With permission from Shah NP, et al. 50th ASH; December 6-9, 2008. Abstract 3225.
Abbreviation: CML-CP, chronic myeloid leukemia-chronic phase.Abbreviation: CML-CP, chronic myeloid leukemia-chronic phase.
Survival of Patients Who Discontinued Imatinib Study Therapy%
Su
rviv
al (
all
dea
ths)
0
10
20
30
40
50
60
70
80
90
100
Months After Stopping Imatinib Study Therapy
0 12 24 36 48 60 72 84 96
Safety (n = 30)Efficacy (n = 82)Bone marrow transplant (n = 16)Other reason (n = 80)
Survival 85% at 5 years after discontinuing study
Survival approximately 50% at 5 years after stopping
imatinib study drug
With permission from O’Brien SG, et al. 50th ASH; December 6-9, 2008. Abstract 186.
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
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.
Ma
tern
al
+ I
L3
BC
R-A
BL
wt
M2
37
I
M2
44
V
L2
48V
G25
0A
G25
0E
G25
0V
Q25
2H
Y25
3H
E25
5D
E25
5K
E25
5V
E25
5R
E27
5K
E27
6G
E28
1K
K28
5N
E29
2K
F3
11V
T3
15I
F3
17C
F3
17L
F3
17V
D32
5N
S34
8L
M3
51
T
E35
5A
E35
5G
F3
59C
F3
59V
A38
0S
L3
87F
M3
88
L
F4
68S
0
500
1000
1500
2000
2500
3000
IC5
0 (
nM
) o
n P
roli
fera
tio
n
Imatinib
Nilotinib
How Responsive is the E255K Mutationto Nilotinib in Patients?
Phase II Nilotinib in CML-CPResponse 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)
Others 14/33 (42) 13/33 (39)
• 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
With permission from Hughes TP, et al. Blood. 2007;110(11). Abstract 320. Blood. 2007;110(11). Abstract 320.
Abbreviations: CCyR, complete cytogenetic response; CML-CP, chronic myeloid leukemia-chronic phase. Abbreviations: CCyR, complete cytogenetic response; CML-CP, chronic myeloid leukemia-chronic phase.
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, MDAssociate Professor
Center for Hematologic Malignancies, Knight Cancer InstituteOregon Health & Science University
Portland, Oregon
WL45-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
WLFollow-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
% A
chie
vin
g M
MR
50
60
70
80
90
100
20
30
40
10
0
P <.00169%
100%
3 6 9 12 15 18 24 3021 27
Months on Imatinib
13%
>2 log reduction
1–2 log reduction
0–1 log reduction
Hughes T, Branford S. Blood Rev. 2006;20:29-41.
Abbreviations: MMR, major molecular response; qPCR, quantitative polymerase chain reaction.
3-Month qPCR Predictive of Ability to Achieve Subsequent MMR—IRIS Trial
WLFollow-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
ABL kinase domain mutation testing should be considered
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
With permission from Baccarani M, et al. Blood. 2006;108:1809-1820.
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.
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
CyR at 6 months (Ph+): 1%–35% 36%–65%66%–95% >95%
(n = 81)
(n = 16)
(n = 16)
(n = 19)
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.
Probability of CCyR, EFS by Cytogenetic Response at 6 Months—IRIS Trial
% Ph+at 6 mo
CCyRat 12 mo
EFSat 42 mo
0%
1%–35%
N/A
80%95%
36%–90%
>95%
50%
15%75%%
of
Pa
tien
ts w
ith S
ub
seq
ue
nt
CC
yR
Dasatinib 70 mg BID(n = 101)
Imatinib 800 mg (n = 49)
CML-CP resistant to imatinib 400–600 mg/day
Randomization 2:1 Cytogenetics at 12 weeks
Continue therapyor
crossover for:ProgressionLack of MCyRIntolerance
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.
What If This Was Imatinib Failure?Dasatinib vs Higher Dose IM in CML-CP
for Imatinib Failure—Study Schema
53
44
2933
18
12
0
10
20
30
40
50
60
MCyR CCyR MMR
Dasatinib
Imatinib
Pe
rce
nt
P = .017
P = .0025
P = .028
Abbreviations: CCyR, complete cytogenetic response; IM, imatinib; MCyR, major cytogenetic response; MMR, major molecular response.Kantarjian H, et al. Blood. 2007;110: abstract 735.
Dasatinib vs High-Dose IM in CML-CPBest Response (Prior to Cross-Over)
P = .0033
P = .0562
% P
FS
100
80
60
40
20
0
Imatinib 400 mg Dasatinib
0 3 6 9 12 15 18 21 24 27 30 33Months
Imatinib 400 mg Imatinib 800 mgImatinib 600 mg Dasatinib
Imatinib 600 mg Imatinib 800 mg
Abbreviation: PFS, progression-free survival.With permission from Kantarjian H, et al. Blood. 2007;110: abstract 736.
Start-R—PFS by Prior Imatinib Dose (400 & 600 mg) and Intervention (High-Dose Imatinib or Switch to Dasatinib)
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): 19% vs 92% Suboptimal at 6 months (Y/N): 64% vs 97%
– Progression-free survival: Failure at 6 months (Y/N): 73% vs 87% Suboptimal at 6 months (Y/N): 62% vs 91%
Marin D, et al. Blood. 2008;112:4437-4444.
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.
WL1-Year Mark
• At 6 months, imatinib was increasedto 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
With permission from Druker BJ, et al. N Engl J Med. 2006;355:2408-2417.
B
Pat
ient
s W
ithou
t P
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A
Pat
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%)
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 JAK-2/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
Clinical
Myelosuppression (for both dasatinib and nilotinib)
? Select cardiac diseases(hypertension, hypercholesterolemia)
? Pre-existing pleural/pericardial disease
? Autoimmune disease
? Rash on prior imatinib or after starting dasatinib
Ongoing need for anticoagulation, antiplatelet therapy
Pre-existing bleeding disorders
? Prior pancreatic disease and liver disease
? Poorly controlled diabetes
Known QTc prolongationa
Required concomitant therapy with risk of prolonging the QTc
Molecular
ABL mutation T315I (for both dasatinib and nilotinib)
ABL mutation at positions 317 and 299 ABL mutation at positions 253, 255, 359
aBlack box warning regarding QT prolongation and sudden death.
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 ifany change is needed
Nilotinib Phase II CML-CP—Efficacy(19 Month Follow-Up)
With permission from Kantarjian H, et al. Blood. 2008;112(11): abstract 3238.
# of Pts =
Median time to CHR 1 month; MCyR 2.8 monthsaPatients without CHR at baseline.
207
CHRa
76%
95
ImatinibIntolerant
65%
321
Overall
44%
ImatinibResistan
t
41%
0
100
80
60
40
20
321
Overall
59%
226
ImatinibResistan
t
56%
MCyR
ImatinibIntolerant
226 95
51%
CCyR
% o
f P
atie
nts
Nilotinib Efficacy According to Baseline BCR-ABL Mutations in CML-CP
3%4%
4%
5%
15%
24%
45%No Mutation
IC50 ≤ 150 nM
Y253H
E255K/V
F359C/V
T315I
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
aMutations without available IC50 data.bNilotinib 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, MDProfessor
Department of Internal Medicine, Hematology-OncologyUniversity 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 BCR-ABL 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-lineBCR-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 arein development
Conclusions
• Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for patients resistant to TKIs