Early molecular prediction of response to TKI

David Marin,

Imperial College London

Early molecular prediction of response to TKI

I do not believe that we have been making the best of molecular monitoring.

• Molecular monitoring is normally used to assess responses like

MR3 and MR4.5 or CMR that are achieved late on therapy (while

cytogenetics are used to assess responses early on therapy)

• The current definitions of molecular response are partially arbitrary

and with very little prognostic relevance

One example of this is MR3 (MMR)

60544842363024181260

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

ba

bil

ity

of

PF

S

Months from starting imatinib therapy

CCyR with no MMR, n=91

CCyR with MMR, n= 41

p= 0.4

18 months

Marin et al, Blood 2008

PFS is similar in patients with CCyR regardless of the depth of molecular response

PFS similar in patients with CCyR regardless of depth of molecular response

Druker BJ, et al. NEJM, 2006;355(25):2408-17.

PFS is similar in patients with CCyR regardless of depth of molecular response

Kantarjian HM, et al. Blood. 2006;108:1835-1840.

Maybe we have the concept of MMR wrong?

The real question is:

What is the additional reduction in the

transcript level that confers survival

advantage in patients already in

CCyR ?

Patient characteristics (n=282)

Characteristics

Age Median-yrRange-yr

46.313-86.4

Sex- no.(%)MaleFemale

157 (55.7)125 (44.3)

Sokal risk group - no.(%)LowIntermediateHigh

88 (31.8)111 (40.1)78 (28.1)

Interval since diagnosis – (months)MedianRange

1.50-6

Chromosomal abnormalities in addition to the Ph chromosomeno. (%) 16 (6.0)

Splenomegalyn (%)Spleen size ≥10cm below the costal margin, n (%)

186 (66.4)75 (26.8)

Marin et al, JCO 2011

48% in CCyR on imatinib

29% in CCyR but not on imatinib

7% alive but not in CCyR

94%

84%

77%

48%

10% death because the CML

6% death non CML

Outcome in 282 patients treated with imatinib

first line in Hammersmith Hospital


Using appropriate statistical methodology we can identify the cut off in the 12 month transcript level for patients in CCyR that

predicts for OS with the maximal sensitivity and specify.

BCR-ABL/ABL= 0.53%


166 out of 282 patients who received imatinib as first line therapy were in CCyR at 12 months

Transcript level

OS

(%)

EFS

(%)

>0.1%

<0.1%

125

41

p=0.5

94.2

96.3

p=0.08

80.4

93.7


166 out of 282 patients who received imatinib as first line therapy were in CCyR at 12 months

Transcript level

OS

(%)

EFS

(%)

>0.1%

<0.1%

125

41

p=0.5

94.2

96.3

p=0.08

80.4

93.7

>0.53%

<0.53%

20

146

p=0.01

81.5

94.4

p<0.0001

29.5

74.3


Can we define robust molecular levels at 3, 6 or 12 month that have

prognostic value?

Outcomecut-off(%)

Number of patients at

risk

Eight years probability of the

outcome

OS ≤9.84>9.84

21168

p<0.000193.356.9

PFS ≤9.54>9.54

20871

p<0.000192.857.0

EFS ≤9.84>9.84

21166

p <0.000165.16.9

CCyR ≤8.58>8.58

16979

p<0.000199.421.7

MR3 ≤2.81>2.81

141137

p<0.000182.521.1

CMR ≤0.61>0.61

57222

p<0.000184.71.5

Patients outcome according to the transcript level measured at 3

month


Pro

ba

bil

ity

of

su

rviv

al

Time from onset of imatinib therapy (years)

BCR-ABL/ABL<9.8% OS= 93.3%

BCR-ABL/ABL>9.8% OS= 54%

p<0.0001

Survival for 282 patients treated with imatinib first line at the Hammersmith Hospital according to

molecular response achieved at 3 months


Cum

ula

tive

inci

denc

e o

f C

MR

Time from onset of therapy (years)

8-year cumulative incidence of CMR on imatinib therapy according to the BCR-ABL transcript level at 3 months.

3-month transcript ratio ≤0.61% (n=57), 8-year CI of CMR of 84.7%,

3-month transcript ratio >0.61% (n=222), 8-years CI of CMR of 1.5%

p<0.0001


6 month

Outcomecut-off

(%)

Number of

patients at risk

Eight years probability of the outcome

OS ≤1.67>1.67

18787

p<0.000193.774.7

PFS ≤1.73>1.73

18886

p<0.000192.868.9

EFS ≤1.67>1.67

18687

p<0.000170.718.3

CCyR ≤2.70>2.70

9866

p<0.000192.024.7

MMR ≤0.73>0.73

136123

p<0.000181.620.4

CMR ≤0.21>0.21

73197

p<0.000142.76.1

12 month

Outcomecut-off

(%)

Number of

patients at risk

Eight years probability of the

outcome

OS ≤0.53>0.53

16493

p<0.000195.474.7

PFS ≤0.53>0.53

16492

p<0.000194.973.1

EFS ≤ 0.57>0.57

16878

p<0.000182.141.4

MMR ≤0.22>0.22

90114

p<0.000181.620.4

CMR ≤0.036>0.036

59182

p<0.000152.14.1

Patient outcome according to BCR-ABL transcript level measured at 6 and 12 month


These cut-offs can be used in other centres when the transcript level is expressed on the international scale

We have validated our findings using 95 patients treated with imatinib first line at the Royal Liverpool University Hospital

Transcript ratio n OS

3 month

≤9.84%

>9.84% 63

32

p=0.003

98.3

69.1

6 month

≤1.67%

>1.67% 54

40

p=0.009

98.1

7.2

12 month

≤0.53%

>0.53% 46

37

p=0.01

98.0

74.4


n3 months

BCR-ABL/ABL ratio

CCyR

(RR)

c-CCyRS

(RR)

OS

(RR)

No discontinuation186 5.8% 1 1 1

Non-haematological toxicity

237.1%

p=0.8

0.94

p=0.6

1.12

p=0.5

0.97

p=0.6

Haematological toxicity

708.9%

p<0.001

0.44

p<0.001

0.53

p<0.001

2.3

p<0.001

The predictive value of the transcript level measured at 3 months is not affected by imatinib dose reductions


What is the best moment to identify the poor risk patients?

3 months is the optimal time point to predict a patient’s outcome

Off Imatinib

CMR

BC

R-A

BL

1/A

BL

1 (

log

)

high transcript level at 3 month

low transcript level at 3 month


Results of transcript levels at 3 and 6 months are generally consistent

3 monthmilestone

9.84%

Yes

No

77%

23%

6 month (1.67%)

6 month (1.67%)

No

No

Yes

66% (L/L)(85%)

11% (L/H)

2% (H/L)

21% (H/H)(91%)

Yes

8 year CI of CCyR

p<0.001 P<0.001

Low/Low (L/L)

Low/ high (L/H)

High/Low (H/L)

High/High (H/H)

P=0.09

(L/L) Low at 3 and low at 6 months

(L/H) Low at 3 and high at 6 months

(H/H) High at 3 and high at 6 months

(H/L) High at 3 and low at 6 months

8 year probability of OS

93.5 % (L/L)

92.4 % (L/H)

55.6 % (H/H)

83.3 % (H/L)

P<0.001

(L/L) Low at 3 and low at 6 months

(L/H) Low at 3 and high at 6 months

(H/H) High at 3 and high at 6 months

(H/L) High at 3 and low at 6 months

The same principle applies to patients treated with 2G-TKI

after imatinib failure

OS and c-CCyRS in 107 patients treated with dasatinib or nilotinib after imatinib failure

3 months BCR-ABL/ABL <10%, n=77

3 months BCR-ABL/ABL >10%, n=30

Time (years)

p=0.02

Pro

bab

ility

of

OS

Time (years)

p=0.001

Pro

bab

ility

of

c-C

CyR

S

Milojkovic et al, Blood 2012

What about first line 2G-TKI?

SPIRIT 2: Study Design

Chronic phase CML

within 3 months of diagnosis

Arm AImatinib 400

Arm BDasatinib 100

Randomised open label study

Dasatinib patient characteristics

N=142

Sex

Male, n(%)

Female, N(%)

79 (55.6)

63 (44.4)

Age

Median (range) 54.5 (18-82)

Sokal risk group

Low, n(%)

Intermediate, n(%)

High n(%)

35 (29.9)

51 (43.6)

31 (26.5)

EUTOS risk group

Low, n(%)

High, n(%)

86 (83.5)

17(16.5)Marin et al, Blood 2012

Time from onset of therapy (months)

Cu

mu

lati

ve in

cid

ence

of

resp

on

se

CCyR = 91.5%

MR3 = 70.1%

MR4.5 = 39.1%

CMR = 6.5%

24 month cumulative incidences of cytogenetic and molecular responses


Cu

mu

lati

ve

in

cid

en

ce

of

CC

yR


p<0.001

BCR-ABL/ABL >10%, n=11

BCR-ABL/ABL ≤10%, n=117

Cu

mu

lati

ve

in

cid

en

ce

of

MR

4.5


p<0.001

BCR-ABL/ABL >10%, n=11

BCR-ABL/ABL ≤10%, n=117

The BCR-ABL1 transcript levels at 3 month strongly

predict for the 2 year CI of CCyR, MR3 and, MR4.5

Cu

mu

lati

ve

in

cid

en

ce

of

MR

4.5


CCyR MR4.5


Cu

mu

lati

ve

in

cid

en

ce

of

CC

yR

BCR-ABL/ABL ≤2.26%, n=88

BCR-ABL/ABL >2.26%, n=40

p<0.0001


Cu

mu

lati

ve

in

cid

en

ce

of

MR

4.5

BCR-ABL/ABL ≤0.57%, n=62

BCR-ABL/ABL >0.57%, n=66

p<0.0001

….. but the optimal cut-offs may turn out to be lower


CCyR MR4.5

Thanks to:

Dragana Milojkovic

&

John Goldman

Documents

Early molecular prediction of response to TKI