SWITCHING OF TKI IN CML

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

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=0.20CCyRPCyRNo 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 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

Long-Term Outcome With Imatinib in ECP CML (ITT)

Pro

bab

ility

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

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

0.85

0.01

0.62

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n a

live

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.


Pro

po

rtio

n P

FS

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 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.

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

Hammersmith Experience. CCyR at 12 Months Associated With PFS

de Lavallade. J Clin Oncol. 2008;26(20):3358-3363.

Pro

bab

ility

of

PF

Sa

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%


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

Percentage

PFS OS

<0.1% 341 99 990.1-1% 240 97 98>1% 267 94 93

P value 0.0023 0.0011

• Outcome independent of treatment armHehlman 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 87

OS 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


Optimal Response To 2nd TKIs-Frontline. Event-free by 6 mo Response


Molecular and Cytogenetic Response at 3 Months

0

20

40

60

80

100

84%

64%

% o

f p

atie

nts

≤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<0.0001Dasatinib 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<0.0001P<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

% N

ot

Pro

gre

ssed

<PCyR, N=39

CCyR, N=139

PCyR, N=31

PCyR

CCyRP=0.2185

PCyR

CCyRP=0.8062


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

Pro

gre

ssed

MMR and/or CCyR

<CCyRP<0.0001

MMR and/or CCyR

<CCyRP<0.0001


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

<CCyRP=0.0503

MMR and/or CCyR

<CCyRP=0.0041


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 MCyR AT 6 Mo




TKI Frontline Therapy in CMLEFS and OS by MCyR AT 12 Mo


Criteria for Failure and Suboptimal Response to Imatinib

Time (mo)Response


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 CHRLoss of CCgR

MutationCE

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


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 CHRLoss of CCgR

MutationCE

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

PF

S (

%)

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-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

Optimal Response to 2nd TKIs. Survival

3-year survival (%)

Parameter Event-free Overall

CCyR by 3 months Yes 74 98

No 43 79

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

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

36

My Desk On A Good Day!

JC

Leukemia Questions?

•Pager 713-606-1307•[email protected]

Elias Jabbour, M.D.

Health & Medicine

SWITCHING OF TKI IN CML