Switching from Imatinib to 2G TKI : When & how ? Giuseppe Saglio, MD U n i v e r s i t y o f Tu r i n Tu r i n , I t a l y

Parameters to evaluate response to imatinib

• Degree of leukemic burden reduction • Time to achieve it

Monitoring Response in CML: Hierarchic Order Of Responses Leukemic Burden

BCR-ABL%

1013

Hematologic remission

1011

Overall survival More stable response Low risk of progression

CCyR

2 logs 1%

1010

MMR 109

MR4.5 CMR Possibility to discontinue therapy

100%

1012

1 log 2/3 logs

0,1%

108

0.0032% 107 106 105

Optimal Response to imatinib 400 mg per day

CHR within 3 months minor U n t i l t h e a c h i e v e m eWith n t oatf least MMR ( “ sCyR afe haven”)

also a patient with an optimal response c a n p r o g r e s s , b uPCyR t t h e rat i s k6i months s very low.

CCyR at 12 months MMR at 18 months

ELN reccomendations 2009; Baccarani et al. JCO 2009

Criteria for Failure and Suboptimal Response to Imatinib SWITCH Time (mo)

Failure

?? Suboptimal Response

Optimal

3

No CHR

No CG Response

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 CCyR Mutation CE

Loss of MMR Mutation

Stable or improving MMR

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

ELN recommendations in case of failure, intolerance, or suboptimal response to imatinib ● For patients who experience imatinib failure … drug therapy should be changed to dasatinib or nilotinib. (The detection of some mutations may help to decide between dasatinib and nilotinib.) ● For instances of intolerance, the choices are dasatinib and nilotinib. ● For instances of suboptimal response to imatinib...there is no solid, confirmed evidence that a change in treatment will improve the response, but there are at least two other options - namely an increase of imatinib dose or a change to a 2nd-generation TKI. ELN, Baccarani et al. J Clin Oncol. 2009; 27(35):6041-51.

Are all types of suboptimal response the same? Probably not! Cytogenetic and Molecular suboptimal responses are different

Cytogenetic Criteria for Suboptimal Responses to Imatinib 400 mg per day Time (mo)

Response Failure

Suboptimal

Optimal

3

No CHR

No CG Response

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

Cytogenetic monitoring ELN 2006 Diagnosis

3 months (ELN 2009)

> 95% Ph-pos

6 months

< PCyR

12 months

PCyR

ELN reccomendations: Baccarani et al. Blood 2006 & JCO 2009

EFS by Response to Imatinib at 6 and 12 Months  281 pts; imatinib frontline (400 mg in 73, 800 mg in 208)

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

p35%

124

87%

p-value 0.036

PFS According to BCR-ABL Level at 3 Monthsa Dasatinib 100 mg QD

Imatinib 400 mg QD

% Not Progressed

84% had ≤10% BCR-ABL

64% had ≤10% BCR-ABL

100

100

80

80

60

60

40 BCR-ABL at 3 months ≤1%

20

3-Year PFS ≤10% = 93.1% >10% = 68.2%

40

BCR-ABL at 3 months

20

≤1% >1–10% >10%

P=0.0003

>1–10%

3-Year PFS ≤10% = 95.9% >10% = 75.3%

P10%

0

0 0

6

12

18

24

30

36

42

0

6

≤1% 112 >1-10% 85 >10% 36

aCalculated

112 83 33

105 81 28

18

24

30

36

42

28 106 51

20 76 37

7 25 13

Months

Months Subjects at risk 98 93 81 79 22 19

12

89 75 16

60 52 11

24 21 6

≤1% 32 >1-10% 121 >10% 84

31 119 81

from total number of evaluable patients with PCR assessments at 3 months

30 116 71

Subjects at risk 30 29 112 108 59 56

OS According to BCR-ABL Level at 3 Monthsa Dasatinib 100 mg QD

Imatinib 400 mg QD

84% had ≤10% BCR-ABL

64% had ≤10% BCR-ABL 100

100

80

% Alive

80 60

60

40

40

3-year OS: ≤10% = 95.9% >10% = 85.9%

BCR-ABL at 3 months ≤1%

20

>1–10%

P=0.0348

0

6

20

>1–10%

>10%

0

18

24

30

36

42

0

6

Months ≤1% 112 >1-10% 86 >10% 37 aCalculated

112 85 37

Subjects at risk 110 109 106 84 83 83 35 34 33

P=0.0036

>10%

0 12

3-year OS: ≤10% = 96.0% >10% = 88.0%

BCR-ABL at 3 months ≤1%

12

18

24

30

36

42

30 116 70

28 96 55

11 33 20

Months

104 79 27

85 66 22

29 25 9

≤1% 32 >1-10% 122 >10% 85

32 121 85

from total number of evaluable patients with PCR assessments at 3 months

Subjects at risk 32 32 31 120 118 118 82 80 76

Molecular and Cytogenetic Response at 3 Monthsa P1-10%

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% N=24

≤ 1% N=43

>1– ≤10% N=133

>10% N=88

MMR

n=120

n=89

n=24

n=41

n=133

n=88

by 1 year (%)

76

40

4

71

31

2

by 2 years (%)

89

67

29

78

52

20

n=144

n=89

n=24

n=43

n=133

n=88

by 2 years (%)

40

12

4

33

8

0

by 3 years (%)

50

18

4

53

14

1

CMR4.5

Evaluable patients (n) excluded patients with unevaluable/missing PCR assessments at 3 months, atypical transcripts at baseline, or patients who achieved response within 3 months

? ELN 2013 ? Diagnosis

Responders

Non responders

3 months

< PCyR or PCyR or >10% BCR-ABL

6 months

1% BCR-ABL

12 months

MMR / < 0,1% BCR-ABL

MMR / > 0,1% BCR-ABL

Thank you!