1. Elias Jabbour, MD
University of Texas – M. D. Anderson
Cancer Center
CML and Imatinib Resistance:
Which TKI and When?

2. 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

3. 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

4. IRIS 8-Year Update
37%
Unacceptable
Outcome
Deininger et al; Blood 2009; 114: Abst# 1126

5. 5
IRIS. Survival Without AP/BC Worse If No
Major CG Response at 12 mos
Estimated rate at 60 months
n= 86 93%
n= 73 81%
n= 350 97%
} p<0.001} p=0.20CCyR
PCyR
No MCyR
Response at 12 months
%withoutAP/BC
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
M o n th s s in c e r a n d o m iz a tio n
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6
Rx aim: major CG response (Ph ≤ 35%)

6. 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

7. NCCN Treatment Recommendations
3-Month Follow-up Therapy
BCR-ABL
transcript levels
≤10% by QPCR
International
Scale (IS)
or
PCyR on bone
marrow
cytogenetics
BCR-ABL
transcript
levels >10% by
QPCR using the
IS
or
<PCyR on bone
marrow
cytogenetics
Continue
same dose
of IM,
DAS, or
NIL
• Evaluate patient
compliance and
drug-drug
interactions
• Mutational
analysis
Monitor
with
QPCR
every
3 mo
DAS 100 mg daily
NIL 400 mg BID
Evaluation and
discussion of HSCT
Clinical trial
3-mo
evaluation
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.
No
relapse
Relapse

8. Adherence Is the Most Important Factor
Contributing to Molecular Responses
Marin D et al. J Clin Oncol. 2010;28(14):2381-2388.
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.
0.1
12
Time Since Start of Imatinib Therapy (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0 6 18 24 30 36 42 48 54 60 66 72
ProbabilityofMMR Adherence >90% (n = 64)
Adherence ≤90% (n = 23)
P<0.001

9. EFS by Response to IM at 6 and 12 Mos
0 12 24 36 48 60 72
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Failure
Suboptimal
Optimal
p<0.0001
No.
9
10
240
Events (%)
6 (67)
5 (50)
14 (6)
0 12 24 36 48 60 72
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Failure
Suboptimal
Optimal
p<0.0001
No.
14
19
213
Evaluable (%)
8 (57)
3 (16)
8 (4)
6 month response 12 month response
•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)
Alvarado. Cancer. 2009;115:3709-18.

10. MDACC Retrospective Analysis:
MCyR at 6 Months Associated With OS
Patients with MCyR have better OS than patients that do not
Landmark analysis at 6 mos
0 12 24 36 48 60 72
Cytogenetic response at 6 mos Total Dead P-value
Complete 201 5
Partial 39 1
Minor 10 3
Othersa
9 3
0.85
0.01
0.62
1.0
0.8
0.6
0.4
0.2
0
Proportionalive
Months
Kantarjian H. Cancer. 2008;112:837–845.

11. MDACC Retrospective Analysis:
CCyR at 12 Months Associated With PFS
Patients with CCyR have better PFS than patients that do not.
Similar results were observed in patients achieving CCyR at 18 and 24 mos.
Landmark analysis at 12 mos
ProportionPFS
1.0
0.8
0.6
0.4
0.2
0
0 12 24 36 48 60 72
Months
Cytogenetic
response at
12 mos Total Failure P-value
Complete 214 7
Partial 19 3
Minor 5 2
Others 8 5
0.02
0.2
0.22
Kantarjian H. Cancer. 2008;112:837–845.

12. EFS and Survival by 12-month Response-CCyR
with vs without MMR with TKI Frontline Rx
Jabbour E et al. Blood. 2011.

13. 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)
N
Percentage
PFS OS
<0.1% 341 99 99
0.1-1% 240 97 98
>1% 267 94 93
P value 0.0023 0.0011
•Outcome independent of treatment arm
Hehlman et al. JCO 2011;29:1634-42
CCyR

14. Probabilityofsurvival
Time from onset of imatinib therapy (years)
BCR-ABL/ABL<9.8% OS= 93.3%
BCR-ABL/ABL>9.8% OS= 54%
p<0.0001
Survival After Imatinib Therapy by
Molecular Response Achieved at 3
Months
Marin et al, JCO 2011; [Epub ahead of print
• Optimal PCR value determined by Receiver operating
characteristic (ROC) curve

15. 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
% 5-year
outcome
Cytogenetics
(% Ph+)
Molecular
[BCR-ABL/ABL (IS)]
≤35% >35% ≤10% >10%
PFS 94 87 93 87
OS 95 87 95 87
Hanfstein et al. ASH 2011; Abstract #783

16. OS by Response to TKI at 3
Months at MDACC
Naqvi et al. ASH 2011; Abstract #3784

17. EFS by Response to TKI at 3
Months at MDACC
Naqvi et al. ASH 2011; Abstract #3784

18. Failure On Imatinib And Strategies
Imatinib Failure ↑ Imatinib
Second
Generation
TKI
• Ph 100% at 6 mos _ +
• Ph ≥ 35% at 12
mos
+ +
• No CGCR in yr 2 + +
• CG relapse + +
• Hematologic
relapse
_
+

19. Imatinib Dose Escalations
% 2-yr
Resistance1,2
No. % CG CR TFS OS
Cytogenetic 63 52 80 90
Hematologic 21 5 51 67
• Similar results from IRIS 3
1
Kantarjian Blood 101:473, 2003 2
Jabbour Blood 113:2154, 2008 3
Kantarjian Cancer
115:551, 2008

20. 2nd
Generation TKI in CML
Parameter Dasatinib Nilotinib Bosutinib
Potency (fold vs IM) 325 30 20-50
Target Src & Abl Abl Src & ABL
BCR-ABL binding Active + Inactive Inactive Intermediate
Resistant mutations T315I T315I T315I
Mutations with
intermediate sensitivity
E255K/V, V299L,
F317L
E255K/V, Y253F/H,
Q252H, F359V
E255V/K,
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
Clinical activity Highly active Highly active Highly active

21. Phase II Studies of Dasatinib
After Imatinib Failure
Response
Percent by Disease Stage
CP
n=387
AP
n=174
MyBP
n=109
LyBP
n=48
ALL
n=46
Hematologic 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.

22. Baccarani. Blood 112:abst 450, 2008
Optimal Dose and Schedule of Dasatinib
IN CML CP after Imatinib Failure
% Parameter
100mg
QD
N=166
50mg
BID
N=166
140mg
QD
N=163
70mg
BID
N=167
MCyR 63 61 63 61
CGCR 50 50 50 54
24-months PFS 80 76 75 76
Neutropenia, G3-4 35 47 44 45
Thrombocytopenia, G3-4 23 36 41 38
Pleural effusion, G3-4 2 4 5 5
Interruption 58 66 69 71
Reduction 33 45 54 57
Shah. Blood 112:abst 3225, 2008

23. Phase II Studies of Nilotinib After
Imatinib Failure
Response
Percentage
CP
n =321
AP
n =137
MyBP
n =106
LyBP
n =30
•HR 77 54 24 20
CHR 76 26 12 13
•Cytogenetic
Major 59 31 38 50
Complete 44 19 28 33
Blood 112:abst 3229, 3238, 2008.

24. 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 Percent
- CGCR 46
- MMR 28 (56% of CGCR)
- 24-mos PFS 64
- 24-mos OS 87
Kantarjian. Blood 114:abst 1129; 2009

25. Nilotinib in CML Chronic Phase. Survival and PFS
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33
Time in mos
84%
73%
64%
95% 91% 88%
Kantarjian. Blood 112:abst 3238, 2008
%Progression-freesurvival

26. Bosutinib in CML-CP post
imatinib failure
• 288 pts Rx with bosutinib 500 mg/D:
Imatinib resistant 200; intolerant 88
• Parameter Percent
-CHR 86
-MCyR 53
-CCyR 41
-MMR if CCyR 64
-2-yr PFS 79
2-yr OS 92
• Side effects: diarrhea 9%, rash 9%
Cortes. Blood 118: 4567;2012

27. 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
Response, %
IM + D
resistant
(n = 37)
IM + D
intolerant
(n = 50)
IM + NI
resistant
(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

28. 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

29. 2nd
-Generation TKI in CML CP
Post- Imatinib Failure
Toxicity Dasatinib Nilotinib Bosutinib
Pleural effusion ++ - -
Liver + + +
Transaminases + + ++
Bilirubin - ++ -
Rash + + ++
Diarrhea - - ++
Lipase - (+) ++ -
Glucose - ++ -
Hypophosphatemia ++ ++ +
Bleeding + - -
QTc ++ ++ -

30. 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

31. Better Outcome on Dasatinib with
Earlier Intervention
• Patients on dasatinib studies analyzed by
failure status on imatinib: loss of MCyR vs
loss of CHR
• Status at IM Failure No.
Percentage
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

32. Dasatinib Early Intervention
EFS & OS
Quintás-Cardama. Cancer 115: 2912-21, 2009
Event-Free Survival Overall Survival
Time to intervene:
Loss of MCyR

33. Prognosis with 2nd
TKIs. Survival
•Adverse factors: PS ≥1 and lack of CyR to imatinib
Jabbour. Blood 117: 1822-7, 2011

34. No MCyR (27)
MCyR (59)
0
0.2
0.4
0.6
0.8
1
0 12 24 36
Months on second TKI
PFS(%)
PFS and Response to 2nd
TKI
Response @
12 mo
% AP/BP/Death/CHR
loss Next Year
MCyR 3%
No MCyR 17%
• 113 CML CP pts receiving nilotinib (n=43) or dasatinib
(n=70) after imatinib failure
Tam. Blood 112: 516-8, 2008
p = 0.003

35. Optimal Response to 2nd
TKIs. Survival
3-year survival (%)
Parameter Event-free Overall
CCyR by 3 months Yes 74 98
No 43 79

36. 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 (?)

37. 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.

38. Ponatinib Phase 2 Study - PACE
Response by Baseline Mutation CP-CML
Baseline Mutations in at Least 2 Patients (Excluding T315I)
P-Loop Non P-Loop
NumberofPatients
MCyR
CP-CML
N=267
n/N (%)
R/I, no
mutation 66/136 (49)
R/I, any
non-T315I
mutation
38/67 (57)
T315I
mutation 45/64 (70)
Cortes J, et al. Blood. 2012;120: Abstract 163.

39. Ponatinib Phase 2 Study - PACE
Response in Advanced Phase
n (%)
AP-CML
N=83
BP-CML N=62
Ph+ ALL
N=32Myeloid
N=52
Lymphoid
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)
CCyR 20 (24) 8 (15) 3 (30) 12 (38)
MMR#
13 (16) N/A N/A N/A
*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.

40. 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
Response, % CP
N=81
AP
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.

41. 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

42. 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

43. 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

44. Questions?
ejabbour@mdanderson.org
Marcos.delima@uhhospitals.org