Response-related Prognostic Factors:
The Molecular Response
Giuseppe Saglio
The amount of BCR-ABL transcripts roughly mirrors the number
of residual BCR-ABL positive cells.
BCR-ABL/ABL %
100
10
1
0,1
Complete
(0%)
Partial
(1-35%)
Minor
Minimal & None
(36-65%) (66-95%) (>95%)
Amount of BCR-ABL in the PB after 3 months of imatinib therapy
in the different cytogenetic-response groups
Survival Without AP/BC by Level of CyR
at 12 Months on First-line Imatinib
100
% without AP/BC
90
80
70
60
50
40
Response at 12 months
30
n= 350
n= 86
n= 73
CCyR
PCyR
No MCyR
20
10
Estimated rate at 54 months
97%
95%
81%
}
p<0.001
} p=0.20
0
0
6
12
18
24
30
36
42
48
Months since randomization
54
60
Survival Without AP/BC by Molecular Response
at 12 Months on First-line Imatinib
100
% without AP/BC
90
80
70
60
50
Estimated rate at 54 months
40
30
n= 136 100%
CCyR with >=3 log red.
n= 94 95%
CCyR with <3 log red.
n= 138 89%
No CCyR
20
10
p=0.007
}
} p<0.001
0
0
6
12
18
24
30
36
42
48
Months since randomization
54
60
Possible explanation:
• the molecular analysis is more precise in
discriminating between response
subgroups than cytogenetic analysis
Consequence:
• The patient must be followed not only by
cytogenetics but also by RQ PCR
Question
Once reached, is MMR stable over time?
PFS by Molecular Response at 12 Months on
First-line Imatinib
100
% without progression
90
80
70
Although very small,
Estimated rate at 54 month
a risk of losing MMR exists!
60
50
40
CCyR with >=3 log reduction
CCyR with <3 log reduction
No CCyR
30
20
10
97%
89%
72%
}
p<0.001
42
48
54
} p=0.017
0
0
6
12
18
24
30
36
Months since randomization
60
% BCR-ABL log reduction in 124 CCyR
pts at 1 and 4 years: IRIS Trial
100%
90%
22
80%
53%
70%
60%
41
31
80%
>= 4 log reduction
3 - < 4 log reduction
50%
40%
30%
39
39
< 2 log reduction
20%
12
10%
0%
2 - < 3 log reduction
8
8
Year 1
Year 4
Question
Are all molecular remissions the same?
20% MMR
30%
52%
The probability
to achieve
MMR
LOW
INTERMED
HIGH
correlates to the Sokal risk
However, when a high or intermediate risk
patient achieves a Major Molecular Remission,
the risk of subsequent progression is as small
as that of low risk patients.
(Goldman J et al., ASH 2005)
Question
Is the time to reach MMR relevant in
terms of prognosis?
IRIS Q-PCR Study: Overall Estimated Log
Reduction of bcr-abl with First-line Imatinib
% of all patients
100%
20%
90%
39%
80%
52%
70%
60%
54%
4 log
MMR
50%
3-<4 log
2-<3 log
40%
<2 log
30%
20%
10%
No CCyR
75%
50%
32%
26%
24%
0%
3 months
6 months
12 months
18 months
Months since start of treatm ent
Radich J, et al. Blood. 2003;102:181a. Abstract 635 and oral presentation.
24 months
Iacobucci, I. et al. J Clin Oncol; 24:454-459 2006
Association of early and late cytogenetic response
with progression-free (A) and overall (B) survival
Iacobucci, I. et al. J Clin Oncol; 24:454-459 2006
RISE in BCR-ABL
• A rise in BCR-ABL of more than 2-fold identifies patients at
high risk to become imatinib resistant
• In 60% of these cases, presence BCR-ABL mutations
• Mutation detection can be important
Branford S et al. Blood 2004
Question
Which increase in BCR-ABL transcript
level must trigger search for mutation?
Still an open question!
– 2 fold rise (Branford et al., Blood 2004)
– consecutive rises
(Wang et al., Haematologica 2006)
Timing
Diagnosis
3 Months
After 1 year
6 Months
9 Months
12 Months
15 Months
18 Months
• RQ PCR during the first year:
– To assess the response
• RQ PCR on PB every 3 months after the first year:
– to identify the late responders (continously
decreasing BCR/ABL%)
– to detect a possible rise in BCR-ABL
EXIT