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

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. IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos
Rx aim: major CG response (Ph ≤ 35%)
Response at 12 months
Estimated rate at 60 months  
CCyR
n= %
p=0.20
PCyR
n= %
p<0.001
n= %
No MCyR 4 4

5. IRIS. Survival Without AP/BC Worse If No CGCR In Year 2 But Not Related To MMR
Rx aim: CGCR in Year 2+; no need for MMR
Response at 18 months
Estimated rate at 60 months
n= %
n= % n= %
CCyR with >=3 log red.
p=0.11
CCyR with <3 log red.
p<0.001
No CCyR 5

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 60 54 48 12 6
Time From Start of Imatinib Therapy (months) 42 36 30 24 18
Survival
PFS
EFS
CHR
Loss of MCyR
63%
(88% per IRIS definition)
EFS: death, progression to AP/BP, loss of CHR, loss of MCyR, or  WBC, failure to achieve MCyR, intolerance
de Lavallade H et al. J Clin Oncol. 2008; 26: 6

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

8. MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS
Landmark analysis at 12 mos
1.0
0.8
0.6
0.4
0.2
Proportion PFS
Cytogenetic response at 12 mos
Total
Failure
P-value
Complete
214 7
Partial 19 3
Minor 5 2
Others 8
0.02
0.2
0.22
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 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
The data shown on this slide highlight the relationship between the degree of early cytogenetic response and prognostic outcomes. For example, for patients with suboptimal cryptogenic response at 6 months of imatinib treatment, the probability of achieving event-free survival at 4 years is less than 35% compared to almost 80%
in those who achieve early CCR.
Reference:
Castagnetti F, Gugliotta G, Breccia M et al. Suboptimal response to imatinib 400mg daily for chronic myeloid leukemia in early chronic phase: A GIMEMA CML WP analysis of 423 consecutive patients. Haematologica 2009; 94[suppl.2]:255 abstract 0628.
Castagnetti. Hematologica 2009;94 abstract 0528 9

10. 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)
6 month response
12 month response
Alvarado. Cancer. 2009;115:

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

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

13. Hammersmith Experience. CCyR at 12 Months Associated With PFS
Landmark analysis at 12 mos
1.0
96%
74%
P = .007
0.8
0.6
Probability of PFSa
0.4
0.2
CCyR at 12 mos (n = 121) No CCyR at 12 mos (n = 72) 12 24 36 48 60
Months
de Lavallade. J Clin Oncol. 2008;26(20):

14. Outcome by 12-Month Response in CML CP
848 pts randomized to IM 400mg, IM 800mg, or IM IFN
Median FU: 40 months
12-month
BCR-ABL/ABL (IS) N
Percentage
PFS OS
<0.1%
341 99
0.1-1%
240 97 98
>1%
267 94 93
P value
0.0023
0.0011
Outcome independent of treatment arm
CCyR
Hehlman et al. JCO 2011;29:

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 OS 95
Hanfstein et al. ASH 2011; Abstract #783

16. Optimal Response To 2nd TKIs-Frontline. Response (N=167)
Months on therapy
Response
Total (%)
3 (N=160)
Optimal
160 (100)
Sub-optimal
Failure
6 (N=155)
152 (98)
3 (2)
12 (N=129)
128 (99)
1 (1)
18 (n=119)
99 (84)
14 (12)
5 (4)
In summary, the outcome of patients with CML in chronic phase post imatinib failure treated with second generation TKIs is mainly dependent on the previous cytogenetic response to imatinib therapy and performance status.
Patients with poor performance status and no previous cytogenetic response to imatinib therapy have a low likelihood of responding to second generation TKI with poor event-free survival, and therefore should be offered additional treatment options.
The achievement of a 12-month MCyR after therapy with second generation TKI may compensate for the presence of one or two unfavorable baseline factors.
Thank you for your attention
Median follow-up 33 months (range, 3 to 66 months)
Jabbour E et al. JCO

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

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

19. Molecular and Cytogenetic Response at 3 Months
Dasatinib 100 mg QD
84%
81%
Imatinib 400 mg QD
64%
PCyR
67%
>1-10%
% of patients
PCyR
>1-10%
CCyR
≤1%
CCyR
≤1%
n//N / / / /221
≤10% BCR-ABL at 3 Months
PCyR/CCyR at 3 Months
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

20. PFS According to Cytogenetic Response at 3 Months
Dasatinib 100 mg QD
81% of patients had PCyR/CCyR
Imatinib 400 mg QD
67% of patients had PCyR/CCyR
100 80 60 40 20 6 12 24 36 42
100 80 60 40 20 6 12 24 36 42
P<0.0026
P<0.0001
% Not Progressed
PCyR
CCyR
P=0.2185
PCyR
CCyR
P=0.8062
CCyR, N=139
CCyR, N=79
PCyR, N=31
PCyR, N=68
<PCyR, N=39
< PCyR, N=73
Months
Months
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%
Jabbour E et al. EHA

21. PFS According to Response at 12 Months
Dasatinib 100 mg QD
Imatinib 400 mg QD
100 80 60 40 20 6 12 24 36 42
100 80 60 40 20 6 12 24 36 42
MMR and/or CCyR
<CCyR
P<0.0001
MMR and/or CCyR
<CCyR
P<0.0001
% Not Progressed
MMR, N=95
MMR, N=64
CCyR (no MMR), N=85
CCyR (no MMR), N=87
<CCyR, N=26
<CCyR, N=50
Months
Months
Jabbour E et al. EHA

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

23. TKI Frontline Therapy in CML EFS and OS by CG Response AT 3 Mo
Event-Free Survival
Overall Survival
EFS by PCR 3 month response
P=0.003

24. TKI Frontline Therapy in CML EFS and OS by CG Response AT 6 Mo
Event-Free Survival
Overall Survival
EFS by PCR 3 month response
P=0.003

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
EFS by CG 12 month response P=0.009
OS by CG 12 month response P=0.037

28. Criteria for Failure and Suboptimal Response to Imatinib
Time (mo)
Response
Failure
Suboptimal
Optimal 3
No CHR
No CG Response
<65% Ph+ 6
>95% Ph+
≥35% Ph+
≤35% Ph+ 12
1-35% Ph+
0% Ph+ 18
≥5% Ph+
No MMR
MMR
Any
Loss of CHR
Loss of CCgR
Mutation CE
Loss of MMR
Stable or improving MMR
Baccarani et al. JCO 2009; 27:

29. Criteria for Failure and Suboptimal Response to ImatinibX
Criteria for Failure and Suboptimal Response to Imatinib
Time (mo)
Response
Failure
Suboptimal
Optimal 3
No CHR
No CG Response
<65% Ph+ 6
>95% Ph+
≥35% Ph+
≤35% Ph+ 12
1-35% Ph+
0% Ph+ 18
≥5% Ph+
No MMR
MMR
Any
Loss of CHR
Loss of CCgR
Mutation CE
Loss of MMR
Stable or improving MMR
Baccarani et al. JCO 2009; 27:

30. PFS and Response to 2nd TKI
113 CML CP pts receiving nilotinib (n=43) or dasatinib (n=70) after imatinib failure
No MCyR (27)
MCyR (59)
0.2
0.4
0.6
0.8 1 12 24 36
Months on second TKI
PFS (%)
12 mo
% AP/BP/Death/CHR loss Next Year
MCyR 3%
No MCyR
17%
p = 0.003
Achieving a major cytogenetic response is a known major determinant of outcome in previous generations of therapy including interferon alpha and imatinib.
In a previous report from our institution, patients who achieved a major cytogenetic response after 12 months of therapy with second generation TKI had at least a better progression-free survival.
Tam. Blood 112: 516-8, 2008 30

31. Optimal Response to 2nd TKIs-Secondline. Survival
% 3-month
% 3-year
Parameter
Category No
CCyR
p-value
EFS p OS
Clonal evolution 94 30
0.35 54
0.46 87
0.22
Yes 28 41 48 71
CML duration (year)
0-3 27 46
0.3
0.56 78
0.89
4-5 32 56 83 ≥6 55 29
CHR at the start of 2nd TKI 39 42
0.21 53
0.63 90
0.40
yes 84 52 81
Best response to imatinib
Intolerant 8 75
0.001 50
<0.001
100
0.02
MCyR 44 67
mCyR 22 18
No CyR 13
No data 6 33 40
Performance status 89
0.49 91 ≥1 38 59
%ph at the start
≤90 35 58 66
0.03
0.41
>90 82 24 45 80
Prior IFN
0.12
0.76 79
0.85 70 51
Mutation status
None 36
0.09
Low IC50 23
Int IC50 12 25
Not done 43 NA
Adverse features
H.R.
p-value
For overall survival
No CCyR at 3 months
5.4
0.03
For event-free survival
4.5
<0.001
% 3-month
% 3-year
Parameter
Category No
CCyR
p-value
EFS p OS
Clonal evolution 94 30
0.35 54
0.46 87
0.22
Yes 28 41 48 71
CML duration (year)
0-3 27 46
0.3
0.56 78
0.89
4-5 32 56 83 ≥6 55 29
CHR at the start of 2nd TKI 39 42
0.21 53
0.63 90
0.40
yes 84 52 81
Best response to imatinib
Intolerant 8 75
0.001 50
<0.001
100
0.02
MCyR 44 67
mCyR 22 18
No CyR 13
No data 6 33 40
Performance status 89
0.49 91 ≥1 38 59
%ph at the start
≤90 35 58 66
0.03
0.41
>90 82 24 45 80
Prior IFN
0.12
0.76 79
0.85 70 51
Mutation status
None 36
0.09
Low IC50 23
Int IC50 12 25
Not done 43 NA
In the univariate analysis for event-free survival, factors associated with poor event-free survival were older age (> 55 years), lack of any cytogenetic response to previous imatinib therapy, an ECOG performance status ≥1 at the start of second generation TKI therapy, and more than ≥ 90% Philadelphia-positive metaphases at the start of second generation TKI therapy.
Kinase domain sequencing was performed in only 88 patients. When added to the analysis, the presence of KD mutations with intermediate IC50 at the start of second generation TKI was associated with poor event-free survival.
In the subsequent multivariate analysis, the lack of any cytogenetic response to previous imatinib therapy (p<0.001), and an ECOG performance status ≥1 at the start of second generation TKI therapy (p=0.007) were selected as independent factors associated with poor event-free survival.
Jabbour. Blood 116: abstract 2289, 2011 31

32. Optimal Response to 2nd TKIs. Survival
% 3-month
% 3-year
Parameter
Category No
CCyR
p-value
EFS p OS
Clonal evolution 94 30
0.35 54
0.46 87
0.22
Yes 28 41 48 71
CML duration (year)
0-3 27 46
0.3
0.56 78
0.89
4-5 32 56 83 ≥6 55 29
CHR at the start of 2nd TKI 39 42
0.21 53
0.63 90
0.40
yes 84 52 81
Best response to imatinib
Intolerant 8 75
0.001 50
<0.001
100
0.02
MCyR 44 67
mCyR 22 18
No CyR 13
No data 6 33 40
Performance status 89
0.49 91 ≥1 38 59
%ph at the start
≤90 35 58 66
0.03
0.41
>90 82 24 45 80
Prior IFN
0.12
0.76 79
0.85 70 51
Mutation status
None 36
0.09
Low IC50 23
Int IC50 12 25
Not done 43 NA
% 3-month
% 3-year
Parameter
Category No
CCyR
p-value
EFS p OS
Clonal evolution 94 30
0.35 54
0.46 87
0.22
Yes 28 41 48 71
CML duration (year)
0-3 27 46
0.3
0.56 78
0.89
4-5 32 56 83 ≥6 55 29
CHR at the start of 2nd TKI 39 42
0.21 53
0.63 90
0.40
yes 84 52 81
Best response to imatinib
Intolerant 8 75
0.001 50
<0.001
100
0.02
MCyR 44 67
mCyR 22 18
No CyR 13
No data 6 33 40
Performance status 89
0.49 91 ≥1 38 59
%ph at the start
≤90 35 58 66
0.03
0.41
>90 82 24 45 80
Prior IFN
0.12
0.76 79
0.85 70 51
Mutation status
None 36
0.09
Low IC50 23
Int IC50 12 25
Not done 43 NA
In the univariate analysis for event-free survival, factors associated with poor event-free survival were older age (> 55 years), lack of any cytogenetic response to previous imatinib therapy, an ECOG performance status ≥1 at the start of second generation TKI therapy, and more than ≥ 90% Philadelphia-positive metaphases at the start of second generation TKI therapy.
Kinase domain sequencing was performed in only 88 patients. When added to the analysis, the presence of KD mutations with intermediate IC50 at the start of second generation TKI was associated with poor event-free survival.
In the subsequent multivariate analysis, the lack of any cytogenetic response to previous imatinib therapy (p<0.001), and an ECOG performance status ≥1 at the start of second generation TKI therapy (p=0.007) were selected as independent factors associated with poor event-free survival.
3-year survival (%)
Parameter
Event-free
Overall
CCyR by 3 months
Yes 74 98 No 43 79 32

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
- Less than CCyR → Careful monitoring;
? New generation TKIs/ASCT

35. New Proposed Algorithm
CML Salvage Therapy:
New Proposed Algorithm
Start 2nd TKI
Check CG at 3 and 12 mos:
At 3 mo
- CCyR → Home free
- Less than CCyR → Careful monitoring;
? New generation TKIs vs ASCT
At 12 mo
- Less than CCyR → ? New generation TKIs versus ASCT

36. My Desk On A Good Day! JC 36

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