1. Elias Jabbour, MD
Chronic Myeloid Leukemia:
Treatment Success and Milestones

2. Are Surrogate Endpoints Predictive
of Outcome in CML?
•12-mo CCyR on IFN Rx associated with
better EFS and survival
•12-mo CCyR on imatinib Rx associated
with better EFS and survival
•12-mo MMR on imatinib Rx associated
with better EFS and (?) survival
•Early CCyR (3 and 6-mo) on 2nd TKI Rx
associated with better EFS

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. Blood 114:1126; 2009

4. 4
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
10
20
30
40
50
60
70
80
90
100
Monthssince randomization
0 6 12 18 24 30 36 42 48 54 60 66
Rx aim: major CG response (Ph ≤ 35%)

5. %withoutAP/BC
0
10
20
30
40
50
60
70
80
90
100
Months since randomization
0 6 12 18 24 30 36 42 48 54 60 66
IRIS. Survival Without AP/BC Worse If No
CGCR In Year 2 But Not Related To MMR
n= 139 100%
n= 54 98%
n= 89 87%
Estimated rate at 60 months
p<0.001
p=0.11
Response at 18 months
CCyR with >=3 log red.
CCyR with <3 log red.
No CCyR
Rx aim: CGCR in Year 2+; no need for MMR

6. Long-Term Outcome With
Imatinib in ECP CML (ITT)Probability
1.0
0.8
0.6
0.4
0.2
0.1
0.9
0.7
0.5
0.3
6054481260
Time From Start of Imatinib Therapy (months)
4236302418
Survival
PFS
EFS
CHR
Loss of MCyR
63%
de Lavallade H et al. J Clin Oncol. 2008; 26:3358-3363
• EFS: death, progression to AP/BP, loss of CHR, loss of MCyR, or  WBC,
failure to achieve MCyR, intolerance
(88% per IRIS definition)

7. 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 et al. Cancer. 2008;112:837–845.

8. 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 et al. Cancer. 2008;112:837–845.

9. Suboptimal Response to Imatinib 400 mg/d in CP CML:
GIMEMA CML WP Analysis of 423 Consecutive Patients
98%
55%
98%
63%
79%
33%
85%
51%
p<0.0001 p<0.0001
p<0.0001p<0.0001
98%
55%
98%
63%
79%
33%
85%
51%
p<0.0001 p<0.0001
p<0.0001p<0.0001
Castagnetti. Hematologica 2009;94 abstract 0528

10. 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.

11. EFS and Survival by 12-month Response-
CCyR vs Others with TKI Frontline Rx
Jabbour. Blood. 2011;118:4541-6.

12. EFS and Survival by 12-month Response-CCyR
with vs without MMR with TKI Frontline Rx
Jabbour. Blood. 2011;118:4541-6.

13. Hammersmith Experience. CCyR at 12
Months Associated With PFS
de Lavallade. J Clin Oncol. 2008;26(20):3358-3363.
ProbabilityofPFSa
CCyR at 12 mos (n = 121)
No CCyR at 12 mos (n = 72)
0
0.2
0.4
0.6
0.8
1.0
12 24 48 600 36
Months
96%
74%
Landmark analysis at 12 mos
P = .007

14. 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

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. Months on therapy Response Total (%)
3 (N=160)
Optimal 160 (100)
Sub-optimal 0
Failure 0
6 (N=155)
Optimal 152 (98)
Sub-optimal 3 (2)
Failure 0
12 (N=129)
Optimal 128 (99)
Sub-optimal 1 (1)
Failure 0
18 (n=119)
Optimal 99 (84)
Sub-optimal 14 (12)
Failure 5 (4)
• Median follow-up 33 months (range, 3 to 66 months)
Optimal Response To 2nd TKIs-Frontline.
Response (N=167)
Jabbour E et al. JCO. 2011.

17. Optimal Response To 2nd TKIs-Frontline.
Event-free by 3 mo Response
Jabbour E et al. JCO. 2011.

18. Optimal Response To 2nd TKIs-Frontline.
Event-free by 6 mo Response
Jabbour E et al. JCO. 2011.

19. Molecular and Cytogenetic Response at 3 Months
0
20
40
60
80
100
84%
64%
%ofpatients
≤10% BCR-ABL at 3 Months
n//N 198/235 154/239 171/210 148/221
>1-10%
≤1%
>1-10%
≤1%
P<0.0001
CCyR
CCyR
PCyR
PCyR
PCyR/CCyR at 3 Months
81%
67%
P<0.0001
Dasatinib 100 mg QD
Imatinib 400 mg QD
 BCR-ABL of <10% and ≤1% are not fully concordant with ≥PCyR and CCyR, respectively
 96% and 83% of dasatinib and imatinib pts with ≥PCyR had <10% BCR-ABL, respectively
 68% and 26% of dasatinib and imatinib pts with CCyR had ≤1% BCR-ABL, respectively
Jabbour E et al. EHA. 2012.

20. PFS According to Cytogenetic Response at 3
Months
Imatinib 400 mg QD
67% of patients had PCyR/CCyR
Dasatinib 100 mg QD
81% of patients had PCyR/CCyR
For ≥PCyR vs <PCyR at 3 months
3-year PFS rates were 93.9% vs 71.3%
For ≥PCyR vs <PCyR at 3 months
3-year PFS rates were 93.7% vs 77.3%
P<0.0001
P<0.0026
< PCyR, N=73
CCyR, N=79
PCyR, N=68
Months
100
80
60
40
20
0
0 6 12 24 36 42
100
80
60
40
20
0
0 6 12 24 36 42
Months
%NotProgressed
<PCyR, N=39
CCyR, N=139
PCyR, N=31
PCyR
CCyR
P=0.2185
PCyR
CCyR
P=0.8062
Jabbour E et al. EHA. 2012.

21. Dasatinib 100 mg QD Imatinib 400 mg QD
PFS According to Response at 12 Months
Months Months
<CCyR, N=50
MMR, N=64
CCyR (no MMR), N=87
100
80
60
40
20
0
0 6 12 24 36 42
100
80
60
40
20
0
0 6 12 24 36 42
<CCyR, N=26
MMR, N=95
CCyR (no MMR), N=85
%NotProgressed
MMR and/or CCyR
<CCyR
P<0.0001
MMR and/or CCyR
<CCyR
P<0.0001
Jabbour E et al. EHA. 2012.

22. OS According to Response at 12 Months
Dasatinib 100 mg QD Imatinib 400 mg QD
MMR, N=95
CCyR (no MMR), N=86
<CCyR, N=28 < CCyR, N=52
MMR, N=64
CCyR (no MMR), N=89
Months Months
100
80
60
40
20
0
0 6 12 24 36 42
100
80
60
40
20
0
0 6 12 24 36 42
%Alive
MMR and/or CCyR
<CCyR
P=0.0503
MMR and/or CCyR
<CCyR
P=0.0041
Jabbour E et al. EHA. 2012.

23. TKI Frontline Therapy in CML
EFS and OS by CG Response AT 3 Mo
Event-Free Survival Overall Survival

24. TKI Frontline Therapy in CML
EFS and OS by CG Response AT 6 Mo
Event-Free Survival Overall Survival

25. TKI Frontline Therapy in CML
EFS and OS by MCyR AT 6 Mo
Event-Free Survival Overall Survival

26. TKI Frontline Therapy in CML
EFS and OS by CG Response AT 12 Mo
Event-Free Survival Overall Survival

27. TKI Frontline Therapy in CML
EFS and OS by MCyR AT 12 Mo
Event-Free Survival Overall Survival

28. 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 et al. JCO 2009; 27: 6041-51

29. 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 et al. JCO 2009; 27: 6041-51

30. 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

31. Optimal Response to 2nd TKIs-
Secondline. Survival
Adverse features H.R. p-value
For overall survival
No CCyR at 3 months 5.4 0.03
For event-free survival
No CCyR at 3 months 4.5 <0.001
Jabbour. Blood 116: abstract 2289, 2011

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

33. 33
CML. Criteria For Failure On Any TKI
• No major CG response at 6 mos
(Ph > 35%)
• No CG CR at 12 mos
• CG relapse or hematologic relapse
• Not failure criteria
- QPCR  in CGCR

34. CML 2013. Frontline Therapy:
New Proposed Algorithm
•Start TKI
•Check CG at 3/6 and 12 mos:
• At 3/6 mo
- CCyR → Home free
- PCyR → Recheck at 12 mo
- Less than MCyR → Careful monitoring;
? New generation TKIs
• At 12 mo
- CCyR → Home free
- Less than CCyR → Careful monitoring;
? New generation TKIs/ASCT

35. 36
My Desk On A Good Day!
JC

36. Leukemia Questions?
•Pager 713-606-1307
•ejabbour@mdanderson.org
Elias Jabbour, M.D.