CML and Imatinib Resistance:
Which TKI and When?
Elias Jabbour, MD
University of Texas – M. D. Anderson
Cancer Center
CML and Imatinib Resistance:
Which TKI and When?
Marcos de Lima, MD
Stem Cell Transplantation Program
Case Western Reserve University
University Hospitals Seidman Cancer Center
Cleveland - OH
Results with Imatinib in Early CP
CML – The IRIS Trial at 8-Years
• 304 (55%) patients on imatinib on study
• Projected results at 8 years:
– CCyR 83%
• 82 (18%) lost CCyR, 15 (3%) progressed to
AP/BP
– Event-free survival 81%
– Transformation-free survival 92%
• If MMR at 12 mo: 100%
– Survival 85% (93% CML-related)
• Annual rate of transformation: 1.5%, 2.8%,
1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4%
Deininger et al; Blood 2009; 114: Abst# 1126
IRIS 8-Year Update
17%
5%
37%
Unacceptable
Outcome
53%
15%
3%
7%
No CCyR
Lost CCyR
CCyR Other
Safety
Lost-regained CCyR
Sustained CCyR on study
Deininger et al; Blood 2009; 114: Abst# 1126
IRIS. Survival Without AP/BC Worse If No
Major CG Response at 12 mos
100
90
% without AP/BC
80
70
Rx aim: major CG response (Ph ≤ 35%)
60
50
40
Response at 12 months
30
CCyR
PCyR
No MCyR
20
10
Estimated rate at 60 months
n= 350
n= 86
n= 73
97%
93%
81%

p<0.001
 p=0.20
0
0
6
12
18
24
30
36
42
48
Months since randomization
54
60
665
Criteria for Failure and Suboptimal
Response to Imatinib
Time (mo)
Response
Failure
Suboptimal
Optimal
3
No CHR
No CG
Response
< 65% Ph+
6
No CHR
>95% Ph+
≥35% Ph+
≤35% Ph+
12
≥35% Ph+
1-35% Ph+
0% Ph+
18
≥5% Ph+
No MMR
MMR
Any
Loss of CHR
Loss of CCgR
Mutation
CE
Loss of MMR
Mutation
Stable or
improving
MMR
Baccarani. JCO 2009; 27: 6041-51
NCCN Treatment Recommendations
3-Month Follow-up Therapy
BCR-ABL
transcript levels
≤10% by QPCR
International
Scale (IS)
or
PCyR on bone
marrow
cytogenetics
Continue
same dose
of IM,
DAS, or
NIL
Monitor
with
QPCR
every
3 mo
No
relapse
Relapse
3-mo
evaluation
BCR-ABL
transcript
levels >10% by
QPCR using
the IS
or
<PCyR on bone
marrow
cytogenetics
• Evaluate patient
compliance and
drug-drug
interactions
• Mutational
analysis
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous
leukemia. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Revised September 13, 2012.
DAS 100 mg daily
NIL 400 mg BID
Evaluation and
discussion of HSCT
Clinical trial
Adherence Is the Most Important Factor
Contributing to Molecular Responses
1.0
0.9
Probability of MMR
0.8
Adherence >90% (n = 64)
Adherence ≤90% (n = 23)
P<0.001
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
6 12 18 24 30 36 42 48 54 60 66 72
Time Since Start of Imatinib Therapy (months)
Adherence monitored over a period of 3 months using a microelectronic
monitoring device in the imatinib bottle cap. Patients were not aware of the
device.
Marin D et al. J Clin Oncol. 2010;28(14):2381-2388.
EFS by Response to IM at 6 and 12 Mos
• 281 pts; imatinib frontline (400mg in 73, 800mg in 208)
• Suboptimal response at 6-12 months: 12-17% with
400mg, 1-4% with 800mg (p=0.002)
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
6 month response
0.6
12 month response
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
Failure
Suboptimal
Optimal
0.1
No.
9
10
240
Events (%)
6 (67)
5 (50)
14 (6)
Failure
Suboptimal
Optimal
0.1
p<0.0001
No.
14
19
213
Evaluable (%)
8 (57)
3 (16)
8 (4)
p<0.0001
0.0
0.0
0
12
24
36
48
Months
Alvarado. Cancer. 2009;115:3709-18.
60
72
0
12
24
36
Months
48
60
72
MDACC Retrospective Analysis:
MCyR at 6 Months Associated With OS
Landmark analysis at 6 mos
1.0
Proportion alive
0.8
0.6
Cytogenetic response at 6 mos
0.4
0.2
Total
Dead
Complete
201
5
Partial
39
1
Minor
10
3
Othersa
9
3
P-value
0.85
0.01
0.62
0
0
12
24
36
Months
48
60
Patients with MCyR have better OS than patients that do not
Kantarjian H. Cancer. 2008;112:837–845.
72
MDACC Retrospective Analysis:
CCyR at 12 Months Associated With PFS
Landmark analysis at 12 mos
1.0
Proportion PFS
0.8
0.6
Cytogenetic
response at
12 mos
Total Failure P-value
Complete 214
7
0.02
Partial
19
3
0.2
Minor
5
2
0.22
Others
8
5
0.4
0.2
0
0
12
24
36
48
60
72
Months
Patients with CCyR have better PFS than patients that do not.
Similar results were observed in patients achieving CCyR at 18 and 24 mos.
Kantarjian H. Cancer. 2008;112:837–845.
EFS and Survival by 12-month Response-CCyR
with vs without MMR with TKI Frontline Rx
Jabbour E et al. Blood. 2011.
Outcome by 12-Month Response
in CML CP
• 848 pts randomized to IM 400mg, IM 800mg,
or IM 400 + IFN
• Median FU: 40 months
12-month
BCR-ABL/ABL (IS)
Percentage
N
PFS
OS
<0.1%
341
99
99
CCyR
0.1-1%
240
97
98
>1%
267
94
93
0.0023 0.0011
P value
• Outcome independent of treatment arm
Hehlman et al. JCO 2011;29:1634-42
Survival After Imatinib Therapy by Molecular
Response Achieved at 3 Months
• Optimal PCR value determined by Receiver operating characteristic
(ROC) curve
Probability of survival
BCR-ABL/ABL<9.8% OS= 93.3%
BCR-ABL/ABL>9.8% OS= 54%
p<0.0001
Time from onset of imatinib therapy (years)
Marin et al, JCO 2011; [Epub ahead of print]
CML IV: Long-Term Impact of
Response at 3 Months
• 1223 pts randomized to imatinib 400, imatinib +
IFN, imatinib + ara-C, imatinib 800
• 3 month analysis: PCR in 692 pts, cytogenetics in
460
• 3 mo transcript levels predictive of achievement
of CCyR and MMR
Cytogenetics
Molecular
% 5-year
(% Ph+)
[BCR-ABL/ABL (IS)]
outcome
≤35%
>35%
≤10%
>10%
PFS
94
87
93
87
OS
95
87
95
87
Hanfstein et al. ASH 2011; Abstract #783
OS by Response to TKI at 3
Months at MDACC
Naqvi et al. ASH 2011; Abstract #3784
EFS by Response to TKI at 3
Months at MDACC
Naqvi et al. ASH 2011; Abstract #3784
Failure On Imatinib And Strategies
Imatinib Failure
• Ph 100% at 6 mos
• Ph ≥ 35% at 12
mos
• No CGCR in yr 2
• CG relapse
• Hematologic
relapse
 Imatinib
Second
Generation
TKI
_
+
+
+
+
+
+
_
+
+
Imatinib Dose Escalations
Resistance1,2 No.
Cytogenetic
63
Hematologic 21
% CG CR
52
5
% 2-yr
TFS OS
80
90
51
67
• Similar results from IRIS 3
1Kantarjian
Blood 101:473, 2003 2Jabbour Blood 113:2154, 2008 3Kantarjian Cancer
115:551, 2008
2nd Generation TKI in CML
Parameter
Potency (fold vs IM)
Target
BCR-ABL binding
Resistant mutations
Mutations with
intermediate sensitivity
Dasatinib
Nilotinib
Bosutinib
325
30
20-50
Src & Abl
Abl
Src & ABL
Active + Inactive
Inactive
Intermediate
T315I
T315I
T315I
E255K/V, V299L, E255K/V, Y253F/H,
E255V/K,
F317L
Q252H, F359V
V299L, F317L
Standard dose (CP)
100mg QD
400mg BID
500mg QD
Grade 3-4 neutropenia &
thrombocytopenia
33% / 22%
31% / 33%
12% / 21%
Other notable toxicities
Pleural effusion,
bleeding
Bilirubin, lipase
elevation
Diarrhea, rash
C-kit inhibition (vs
imatinib)
Increased
Similar
None
PDGFR inhibition (vs
imatinib)
Increased
Similar
None
Highly active
Highly active
Highly active
Clinical activity
Phase II Studies of Dasatinib
After Imatinib Failure
Percent by Disease Stage
Response
Hematologic
CP
AP
MyBP LyBP
n=387 n=174 n=109 n=48
ALL
n=46
91
64
50
39
49
CHR
91
50
26
29
35
NEL
-
14
7
6
7
Cytogenetic
62
40
47
58
62
Complete
53
33
27
46
54
Partial
9
7
7
6
2
Blood 110:abst 470 and 734, 2007.
Optimal Dose and Schedule of Dasatinib
IN CML CP after Imatinib Failure
% Parameter
MCyR
CGCR
24-months PFS
Neutropenia, G3-4
Thrombocytopenia, G3-4
Pleural effusion, G3-4
Interruption
Reduction
Baccarani.
Blood
112:abst
450,2008
2008
Shah. Blood
112:abst
3225,
100mg 50mg 140mg 70mg
QD
BID
QD
BID
N=166 N=166 N=163 N=167
63
61
63
61
50
50
50
54
80
76
75
76
35
47
44
45
23
36
41
38
2
4
5
5
58
66
69
71
33
45
54
57
Phase II Studies of Nilotinib After
Imatinib Failure
Response
•HR
CHR
•Cytogenetic
Major
Complete
Percentage
CP
AP
MyBP LyBP
n =321 n =137 n =106 n =30
77
54
24
20
76
26
12
13
59
44
Blood 112:abst 3229, 3238, 2008.
31
19
38
28
50
33
Nilotinib in Chronic Phase CML Post
Imatinib Failure
• 321 pts; nilotinib 400 mg BID; median
FU 19 mos; median nilotinib 788 mg/D;
median days off 20
• Outcome
- CGCR
- MMR
- 24-mos PFS
- 24-mos OS
Kantarjian. Blood 114:abst 1129; 2009
Percent
46
28 (56% of CGCR)
64
87
Nilotinib in CML Chronic Phase. Survival and PFS
95%
100
88%
84%
90
% Progression-free survival
91%
73%
80
64%
70
60
50
40
30
20
10
0
0
3
6
9
12
15
Time in mos
Kantarjian. Blood 112:abst 3238, 2008
18
21
24
27
30
33
Bosutinib in CML-CP post
imatinib failure
• 288 pts Rx with bosutinib 500 mg/D:
•
Imatinib resistant 200; intolerant 88
Parameter
Percent
-CHR
-MCyR
-CCyR
-MMR if CCyR
-2-yr PFS
2-yr OS
86
53
41
64
79
92
• Side effects: diarrhea 9%, rash 9%
Cortes. Blood 118: 4567;2012
Response to Bosutinib 3rd Line Therapy
• Dual Src & Abl inhibitor, no effect over c-kit or
PDGFR
• 118 pts who failed imatinib (600mg) & dasatinib
or nilotinib
IM + D
IM + D
IM + NI
resistant intolerant resistant
Response, %
(n = 37)
(n = 50)
(n = 27)
CHR
50
80
77
MCyR
31
30
32
CCyR
14
28
27
PCyR
17
2
8
MMR
3
35
11
2-yr PFS
22
61
50
2-yr OS
66
85
100
IM, imatinib; D, dasatinib; NI, nilotinib.
Khoury. Blood 119:3403;2012
2nd Generation TKI in CML CP Post-Imatinib
Resistance
Response
Percentage
Dasatinib
Nilotinib
Bosutinib
FU (mo)
>24
>24
24*
CHR
89
77
86
MCyR
59
56
54
CCyR
44
41
41
24 mo PFS**
80%
64%
79%
24 mo OS**
91%
87%
92%
* Median
** All patients
Shah et al. Haematologica 2010; 95: 232-40
Kantarjian et al. Blood 2011; 117: 1141-45
Cortes et al. Blood 2011; 118; 4567-76
2nd-Generation TKI in CML CP
Post- Imatinib Failure
Toxicity
Pleural effusion
Liver
Dasatinib
++
+
Nilotinib
+
Bosutinib
+
+
+
++
+
++
+
++
- (+)
-
++
++
++
-
Hypophosphatemia
++
++
+
Bleeding
QTc
+
++
++
-
Transaminases
Bilirubin
Rash
Diarrhea
Lipase
Glucose
2nd-Generation TKI in CML CP
Post- Imatinib Failure
Toxicity
Dasatinib Nilotinib Bosutinib
Anemia
13
11
13
Neutropenia
35
31
18
Thrombocytopenia
23
30
24
Shah et al. Haematologica 2010; 95: 232-40
Kantarjian et al. Blood 2011; 117: 1141-45
Cortes et al. Blood 2011; 118; 4567-76
Better Outcome on Dasatinib with
Earlier Intervention
• Patients on dasatinib studies analyzed by
failure status on imatinib: loss of MCyR vs
loss of CHR
Percentage
• Status at IM Failure
No. CCyR
MMR
Loss of MCyR
151
72
60
Loss of CHR & MCyR
33
42
29
Loss of CHR (never MCyR)
109
26
26
Quintás-Cardama. Cancer 115: 2912-21, 2009
Dasatinib Early Intervention
EFS & OS
Event-Free Survival
Overall Survival
Time to intervene:
Loss of MCyR
Quintás-Cardama. Cancer 115: 2912-21, 2009
Prognosis with 2nd TKIs. Survival
•Adverse factors: PS ≥1 and lack of CyR to imatinib
Jabbour. Blood 117: 1822-7, 2011
PFS and Response to 2nd TKI
• 113 CML CP pts receiving nilotinib (n=43) or dasatinib
(n=70) after imatinib failure
1
0.8
Response @
12 mo
% AP/BP/Death/CHR
loss Next Year
MCyR
3%
No MCyR
17%
PFS (%)
0.6
No MCyR (27)
p = 0.003
0.4
0.2
MCyR (59)
0
0
12
24
Months on second TKI
Tam. Blood 112: 516-8, 2008
36
Optimal Response to 2nd TKIs. Survival
Parameter
CCyR by 3 months Yes
No
3-year survival (%)
Event-free
Overall
74
98
43
79
How Do You Choose The Second
Generation TKIs
• Disease characteristics
•
•
- AP/BP: favor dasatinib (?) and combinations
- chronic: see below
Mutations
-T315I → none
- nilotinib IC50 > 150nM → avoid
- dasatinib IC50 > 3nM → avoid
Patient Hx
- Hypertension, CHF, lung problems, COPD →
avoid dasatinib, consider bosutinib/nilotinib
- Severe diabetes, pancreatitis Hx,
atherosclerosis → avoid nilotinib, consider
bosutinib/dasatinib
- QTc problems → be cautious with all (?)
Ponatinib Phase 2 Study - PACE
Response Characteristics CP-CML
•
93% failed ≥2 TKI, 58% failed ≥3 TKI
Response Rate, n (%)
N=267
Any Cytogenetic Response
180 (67)
MCyR
149 (56)
CCyR
124 (46)
MMR
91 (34)
MR4.5
39 (15)
BCR-ABL ≤10% at 3 months, n/N(%)
142/240 (59)
1 prior approved TKI
14/16 (88)
Median Time to Response*, months [range]
MCyR
2.8 [1.6 – 11.3]
MMR
5.5 [1.8 – 19.2]
• 91% MCyR sustained at 12 months (K-M)
Cortes J, et al. Blood. 2012;120: Abstract 163.
MCyR
R/I, no
mutation
CP-CML
N=267
n/N (%)
66/136 (49)
R/I, any
non-T315I 38/67 (57)
mutation
T315I
mutation
Number of Patients
Ponatinib Phase 2 Study - PACE
Response by Baseline Mutation CP-CML
45/64 (70)
P-Loop
Non P-Loop
Baseline Mutations in at Least 2 Patients (Excluding T315I)
Cortes J, et al. Blood. 2012;120: Abstract 163.
Ponatinib Phase 2 Study - PACE
Response in Advanced Phase
AP-CML
N=83
n (%)
BP-CML N=62
Ph+ ALL
Myeloid Lymphoid
N=32
N=52
N=10
MaHR*
47 (57)
15 (29)
4 (40)
13 (41)
Any CyR**
46 (55)
19 (37)
5 (50)
15 (47)
MCyR
32 (39)
10 (19)
4 (40)
15 (47)
20 (24)
8 (15)
3 (30)
12 (38)
13 (16)
N/A
N/A
N/A
CCyR
MMR#
*MaHR = primary endpoint; 14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR
assessment counted as non-responders
**CCyR + PCyR + minor CyR + minimal CyR
#MMR was assessed on the International Scale using peripheral blood; Patients missing a valid baseline MMR
assessment , or who met the criteria for MMR at baseline, were counted as non-responders
Kantarjian HM, et al. Blood. 2012;120: Abstract 915.
Omacetaxine for CML CP After
Failure to ≥2 TKI
• 122 pts with CML CP (n=81) or AP (n=41) with ≥2
prior TKI
• Omacetaxine 1.25 mg/m2 BID x14d, then x7d
CP
AP
Response, %
N=81
N=41
Primary endpoint
MCyR 20%
MaHR 27%
CCyR 10%
CHR 24%
Median duration, mo
17.7
9
Median PFS, mo
9.6
4.7
Median OS, mo
33.9
16
• 11 pts (9 CP, 2 AP) ongoing response
• Median 35 cycles over median 39 months
• Median response duration: 14 mo CP, 24 mo AP
Kantarjian HM, et al. Blood. 2012;120: Abstract 2767.
Allo SCT. Second or Third Salvage?
•
•
•
•
•
•
Imatinib failure in AP, BP: use new TKI as bridge to MRD, then
alloSCT ASAP
T315I mutation in any CML phase: use AP 24534, other T315I
inhibitors, HHT, HU, others as bridge to MRD, then allo SCT
ASAP
Imatinib failure in CP:
– if IC50 , clonal evolution, or no major CG in 12 mos 
allo SCT (risk should also be reasonable: young, good
match)
– If not  TKI until failure
Age  70 yrs or if poor match: may decide to forgo curative
allo SCT option for several years of CML control;
Young patient (?)
Financial considerations
Monitoring Patients with CML
While on TKI Therapy
• Adequate monitoring required to optimize
outcome / Not too much, not too little
• CCyR is associated with survival benefit
• MMR is associated with durable CCyR and may
therefore decrease probability of relapse
• CMR offers hope for treatment discontinuation
(clinical trials only)
• Results should be interpreted in the context of
alternative options
• Not failure criterion /
QPCR  in CCyR
CML in 2013
• Imatinib,nilotinib,dasatinib are
standard
frontline Rx (except p190 CML)
• Dose optimization and adequate
monitoring
• Sub-optimal response
–  dose imatinib (400mg → 800mg)
– New TKI
• Failure
– Dasatinib, nilotinib, bosutinib
– Allogeneic SCT
• T315I: ponatinib, omacetaxine
Questions?
ejabbour@mdanderson.org
Marcos.delima@uhhospitals.org