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Elias Jabbour, MD Chronic Myeloid Leukemia: Treatment Success and Milestones
Elias Jabbour, MD
Chronic Myeloid Leukemia: Treatment Success and Milestones
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
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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=0.20CCyRPCyRNo MCyR
Response at 12 months
% w
ithou
t AP
/BC
0
10
20
30
40
50
60
70
80
90
100
Months since randomization0 6 12 18 24 30 36 42 48 54 60 66
Rx aim: major CG response (Ph ≤ 35%)
% w
ithou
t AP
/BC
0
10
20
30
40
50
60
70
80
90
100
Months since randomization0 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
Long-Term Outcome With Imatinib in ECP CML (ITT)
Prob
abili
ty1.0
0.8
0.6
0.4
0.20.1
0.9
0.7
0.5
0.3
6054481260Time From Start of Imatinib Therapy (months)
4236302418
SurvivalPFS
EFSCHR
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)
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
0.850.01
0.62
1.0
0.8
0.6
0.4
0.2
0
Prop
ortio
n al
ive
Months
Kantarjian H et al. Cancer. 2008;112:837–845.
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
Prop
ortio
n PF
S
1.0
0.8
0.6
0.4
0.2
0
0 12 24 36 48 60 72Months
Cytogenetic response at 12 mos Total Failure P-value
Complete 214 7Partial 19 3Minor 5 2Others 8 5
0.02
0.2
0.22
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%
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
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
10240
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.1419
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.
EFS and Survival by 12-month Response-CCyR 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
de Lavallade. J Clin Oncol. 2008;26(20):3358-3363.
Prob
abili
ty o
f PFS
a
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 36Months
96%
74%
Landmark analysis at 12 mos
P = .007
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
PercentagePFS OS
<0.1% 341 99 990.1-1% 240 97 98>1% 267 94 93P value 0.0023 0.0011• Outcome independent of treatment arm
Hehlman et al. JCO 2011;29:1634-42
CCyR
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 87OS 95 87 95 87
Hanfstein et al. ASH 2011; Abstract #783
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.
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
0
20
40
60
80
100
84%
64%
% o
f pat
ient
s
≤10% BCR-ABL at 3 Monthsn//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<0.0001Dasatinib 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.
PFS According to Cytogenetic Response at 3 Months
Imatinib 400 mg QD67% of patients had PCyR/CCyR
Dasatinib 100 mg QD81% of patients had PCyR/CCyR
For ≥PCyR vs <PCyR at 3 months3-year PFS rates were 93.9% vs 71.3%
For ≥PCyR vs <PCyR at 3 months3-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 42Months
% N
ot P
rogr
esse
d
<PCyR, N=39
CCyR, N=139
PCyR, N=31
PCyRCCyR
P=0.2185PCyRCCyR
P=0.8062
Jabbour E et al. EHA. 2012.
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 % N
ot P
rogr
esse
d
MMR and/or CCyR<CCyR P<0.0001
MMR and/or CCyR<CCyR P<0.0001
Jabbour E et al. EHA. 2012.
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
% A
live MMR and/or CCyR
<CCyR P=0.0503MMR and/or CCyR
<CCyR P=0.0041
Jabbour E et al. EHA. 2012.
TKI Frontline Therapy in CMLEFS and OS by CG Response AT 3 Mo
Event-Free Survival Overall Survival
TKI Frontline Therapy in CMLEFS and OS by CG Response AT 6 Mo
Event-Free Survival Overall Survival
TKI Frontline Therapy in CMLEFS and OS by MCyR AT 6 Mo
Event-Free Survival Overall Survival
TKI Frontline Therapy in CMLEFS and OS by CG Response AT 12 Mo
Event-Free Survival Overall Survival
TKI Frontline Therapy in CMLEFS 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
AnyLoss of CHR
Loss of CCgRMutation
CE
Loss of MMRMutation
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
AnyLoss of CHR
Loss of CCgRMutation
CE
Loss of MMRMutation
Stable or improving
MMR
Baccarani et al. JCO 2009; 27: 6041-51 X
No MCyR (27)
MCyR (59)
0
0.2
0.4
0.6
0.8
1
0 12 24 36Months 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
Optimal Response to 2nd TKIs-Secondline. Survival
Adverse features H.R. p-valueFor overall survival No CCyR at 3 months 5.4 0.03For event-free survival No CCyR at 3 months 4.5 <0.001
Jabbour. Blood 116: abstract 2289, 2011
Optimal Response to 2nd TKIs. Survival
3-year survival (%)Parameter Event-free OverallCCyR by 3 months Yes 74 98
No 43 79
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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
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
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My Desk On A Good Day!
JC
