Months

Report
Chronic Myeloid Leukemia:
Treatment Success and Milestones
Elias Jabbour, MD
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
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
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
664
IRIS. Survival Without AP/BC Worse If No
CGCR In Year 2 But Not Related To MMR
100
90
% without AP/BC
80
70
Rx aim: CGCR in Year 2+; no need for MMR
60
50
40
Response at 18 months
30
Estimated rate at 60 months
CCyR with >=3 log red. n= 139 100%
CCyR with <3 log red. n= 54 98%
n= 89 87%
No CCyR
20
10
p<0.001
0
0
6
12
18 24 30 36 42 48
Months since randomization
54
60
66
p=0.11
Long-Term Outcome With
Imatinib in ECP CML (ITT)
1.0
0.9
Probability
0.8
0.7
0.6
0.5
Survival
PFS
CHR
EFS
Loss of MCyR
0.4
0.3
0.2
63%
(88% per IRIS definition)
0.1
0
6
12
18
24
30
36
42
48
54
60
Time From Start of Imatinib Therapy (months)
• 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; 26:3358-3363
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 et al. 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 et al. Cancer. 2008;112:837–845.
Suboptimal Response to Imatinib 400 mg/d in CP CML:
GIMEMA CML WP Analysis of 423 Consecutive Patients
98%
98%
55%
63%
p<0.0001
p<0.0001
85%
79%
51%
33%
p<0.0001
Castagnetti. Hematologica 2009;94 abstract 0528
p<0.0001
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
EFS and Survival by 12-month ResponseCCyR vs Others with TKI Frontline Rx
Jabbour. Blood. 2011;118:4541-6.
EFS and Survival by 12-month Response-CCyR
with vs without MMR with TKI Frontline Rx
Jabbour. Blood. 2011;118:4541-6.
Hammersmith Experience. CCyR at 12
Months Associated With PFS
Landmark analysis at 12 mos
1.0
96%
P = .007
Probability of PFSa
0.8
74%
0.6
0.4
0.2
CCyR at 12 mos (n = 121)
No CCyR at 12 mos (n = 72)
0
0
12
24
36
Months
de Lavallade. J Clin Oncol. 2008;26(20):3358-3363.
48
60
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
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
Optimal Response To 2nd TKIs-Frontline.
Response (N=167)
Months on therapy
3 (N=160)
6 (N=155)
12 (N=129)
18 (n=119)
Response
Total (%)
Optimal
160 (100)
Sub-optimal
0
Failure
0
Optimal
152 (98)
Sub-optimal
Failure
0
Optimal
128 (99)
Sub-optimal
1 (1)
Failure
0
Optimal
99 (84)
Sub-optimal
14 (12)
Failure
• Median follow-up 33 months (range, 3 to 66 months)
Jabbour E et al. JCO. 2011.
3 (2)
5 (4)
Optimal Response To 2nd TKIs-Frontline.
Event-free by 3 mo Response
Jabbour E et al. JCO. 2011.
Optimal Response To 2nd TKIs-Frontline.
Event-free by 6 mo Response
Jabbour E et al. JCO. 2011.
Molecular and Cytogenetic Response at 3 Months
P<0.0001
P<0.0001
100
Dasatinib 100 mg QD
84%
81%
Imatinib 400 mg QD
% of patients
80
>1-10%
64%
PCyR
67%
60
PCyR
>1-10%
40
CCyR
≤1%
20
CCyR
≤1%
0
n//N
198/235
154/239
≤10% BCR-ABL at 3 Months

171/210
148/221
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. 2012.
PFS According to Cytogenetic Response at 3
Months
Dasatinib 100 mg QD
Imatinib 400 mg QD
81% of patients had PCyR/CCyR
67% of patients had PCyR/CCyR
100
% Not Progressed
100
P<0.0026
P<0.0001
80
80
60
60
PCyR
40
CCyR
P=0.2185
CCyR, N=139
20
PCyR
40
CCyR
CCyR, N=79
20
PCyR, N=68
PCyR, N=31
<PCyR, N=39
0
0
6
12
< PCyR, N=73
0
24
Months
For ≥PCyR vs <PCyR at 3 months
3-year PFS rates were 93.9% vs 71.3%
Jabbour E et al. EHA. 2012.
P=0.8062
36
42
0
6
12
24
Months
For ≥PCyR vs <PCyR at 3 months
3-year PFS rates were 93.7% vs 77.3%
36
42
PFS According to Response at 12 Months
% Not Progressed
Dasatinib 100 mg QD
Imatinib 400 mg QD
100
100
80
80
60
60
MMR and/or CCyR
<CCyR
40
MMR and/or CCyR
P<0.0001
<CCyR
40
MMR, N=95
20
P<0.0001
MMR, N=64
20
CCyR (no MMR), N=85
CCyR (no MMR), N=87
<CCyR, N=26
<CCyR, N=50
0
0
0
6
12
24
Months
Jabbour E et al. EHA. 2012.
36
42
0
6
12
24
Months
36
42
OS According to Response at 12 Months
Dasatinib 100 mg QD
100
100
80
80
60
% Alive
Imatinib 400 mg QD
60
MMR and/or CCyR
<CCyR
40
MMR and/or CCyR
P=0.0503
<CCyR
40
MMR, N=64
MMR, N=95
20
20
CCyR (no MMR), N=86
<CCyR, N=28
0
0
6
12
Months
Jabbour E et al. EHA. 2012.
P=0.0041
CCyR (no MMR), N=89
< CCyR, N=52
0
24
36
42
0
6
12
24
Months
36
42
TKI Frontline Therapy in CML
EFS and OS by CG Response AT 3 Mo
Event-Free Survival
Overall Survival
TKI Frontline Therapy in CML
EFS and OS by CG Response AT 6 Mo
Event-Free Survival
Overall Survival
TKI Frontline Therapy in CML
EFS and OS by MCyR AT 6 Mo
Event-Free Survival
Overall Survival
TKI Frontline Therapy in CML
EFS and OS by CG Response AT 12 Mo
Event-Free Survival
Overall Survival
TKI Frontline Therapy in CML
EFS and OS by MCyR AT 12 Mo
Event-Free Survival
Overall Survival
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
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
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 TKIsSecondline. Survival
Adverse features
For overall survival
No CCyR at 3 months
For event-free survival
No CCyR at 3 months
Jabbour. Blood 116: abstract 2289, 2011
H.R.
p-value
5.4
0.03
4.5
<0.001
Optimal Response to 2nd TKIs. Survival
Parameter
CCyR by 3 months Yes
No
3-year survival (%)
Event-free
Overall
74
98
43
79
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
33
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
My Desk On A Good Day!
JC
36
Leukemia Questions?
• Pager 713-606-1307
• [email protected]
Elias Jabbour, M.D.

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