early molecular prediction of response to tki
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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
Marin et al, JCO 2011
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%
Marin et al, JCO 2011
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
Marin et al, JCO 2011
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
Marin et al, JCO 2011
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
Marin et al, JCO 2011
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
Marin et al, JCO 2011
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
Marin et al, JCO 2011
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
Marin et al, JCO 2011
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
Marin et al, JCO 2011
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
Marin et al, JCO 2011
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
Marin et al, JCO 2011
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
Marin et al, Blood 2012
Cu
mu
lati
ve
in
cid
en
ce
of
CC
yR
Time from onset of therapy (months)
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
Time from onset of therapy (months)
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
Marin et al, Blood 2012
CCyR MR4.5
Time from onset of therapy (months)
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
Time from onset of therapy (months)
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
Marin et al, Blood 2012
CCyR MR4.5
Thanks to:
Dragana Milojkovic
&
John Goldman
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