march 2011 | tas11-003c taking the tablets, do we / should we? slides courtesy of david marin
TRANSCRIPT
March 2011 | TAS11-003c
Taking the tablets, Do we / should we?
Slides courtesy of David Marin
March 2011 | TAS11-003c
• It’s one thing to take a tablet over a short period
• It’s another thing to take it for life
March 2011 | TAS11-003c
10
1
0.1
0.01
0.001
100
BC
R-A
BL/
AB
L ra
tio (
%)
Time from start of imatinib
CCyR
3 log
There is a great variability in the response to imatinib. I wonder why
0.0001
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Study design
Time from start of imatinib• hOCT1 level
• MDR-1 polymorphisms• BCR-ABL transcript type• BCR-ABL transcript level
• Sokal score• Haemoglobin
• White blood cell count• Sex• Age
We correlated all these variables with the molecular response achieved by the patient
MEMS
Imatinib plasma
level
TKD mutations
Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388.Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
• Records the time of opening the container
• Most reliable method of measuring adherence
• Our patients: not told about the chip
Microelectronic Monitoring System (MEMS 6 Trackcap)
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388.
Long-term adherence to imatinib
≥100%95–99%90–95%80–90%<80%
90
80
70
60
50
40
30
20
10
0
Pro
port
ion
of p
atie
nts
(%)
Percentage of intended dose
13.8% 12.6%8%
25.3%
40.2%
100
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Percentage of intended dose
≥100%95–99%90–95%80–90%<80%
Pro
port
ion
of p
atie
nts
(%)
100
90
80
70
60
50
40
30
20
10
0
Self reportingPill countMEMS
Lack of adherence is underestimated by conventional methods
Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388.Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Unintentional non-adherence13/21 patients
“And sometimes you just forget. It’s very strange.
It’s almost a surprise when you don’t take it”
“They [the pharmacy] had no medication for me, so I went for nearly a week with
no medication.”
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Intentional non-adherence 10/21 patients
“Oh I can’t be bothered tonight, it’s not going to kill me [to miss a dose] – sort
of thing, so I just go to sleep”
“I thought there was no way I was going [on holiday] and being tired.
So I did actually stop taking the tablets for a week before I went, and I didn’t take them for the first
half of the week I was there”
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
12/21 patients said:“The odd missed dose doesn’t matter”
“I suppose, I’m not a doctor, but I don’t think missing one pill, or 3
pills, in a month affects me at all”
“So I don’t feel I am putting myself in any danger by not taking an odd dose
now and again”
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Reasons for poor adherenceTheme Sub-theme
1.1 Unintentional non-adherence
Forgetting
Accidentally taking too much
Prescribing error
No imatinib availability at pharmacy
Frequency of unintentional non-adherence
1.2 Intentional non-adherence
Because of side effects
Because of socialising / dining out / drinking alcohol
Because of travelling
Because of diversion from planned activities
Because of temporary illness (bug / cold)
Because of risk of pregnancy
Because of side negative emotions & feelings
Because of “no real reason / lack of discipline”
Changed doses
Frequency intentional
Contemplating future non-adherence
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
6-year probability of MMR according to the measured adherence rate
P<0.001
Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388.
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
6-year probability of CMR according to the measured adherence rate
P=0.002
Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388.
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Variables n MMR (%) 4-log (%) CMR (%)
Haemoglobin ≤115 g/l>115 g/lRR
4047
P=0.03659.280.7
1.186, P=0.012
P=0.0339.569.1
1.323, P=0.01
P=0.01114.747.6
1.209, P=0.07
Leukocytes ≤140 x 109/l>140 x 109/lRR
4443
P=0.01278.863.1
0.996, P=0.008
P=0.02256.737.6
0.996, P=0.015
P=0.1735.428.1
0.996, P=0.11
BCR-ABL1/ABL1 ratio≤100%>100%RR
4443
P=0.2571.452.6
0.996, P=0.44
P=0.03853.026.6
0.971, P=0.002
P=0.132.78.4
0.979, P=0.13
hOCT1 transcript level ≤0.16>0.16RR
3030
P<0.00155.281.4
2.199, P<0.001
P=0.0142.064.8
1.990, P=0.001
P=0.0216.645.3
1.665, P=0.04
Imatinib plasma level ≤1 g/ml>1 g/mlRR
4341
P=0.0260.183.2
2.11, P=0.01
P=0.0753.068.0
2.50, P=0.06
P=0.1423.344.4
2.25, P=0.09
Adherence rate>90%≤90%RR
6423
P<0.00193.713.9
1.093, P<0.001
P<0.00176.04.3
1.104, P=0.002
P=0.00243.8
0RR= 1.135, P=0.012
Other variables are also predictive for the achievement of molecular response
Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388.
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
The level of hOCT1 measured at diagnosis is predictive for achievement of molecular response
hOCT1=human organic cation transporter 1
726660544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Months from start of imatinib therapy
Cu
mu
lativ
e in
cid
ence
of
MM
R
p=0.0003hOCT1
hOCT1
726660544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Months from start of imatinib therapy
Cu
mu
lativ
e in
cid
ence
of
MM
R
p=0.0003hOCT1
hOCT1
MMR
p<0.001
Months from start of imatinib therapy
Cum
ulat
ive
inci
denc
e of
MM
R P<0.001
726660544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Cu
mul
ativ
e in
cid
ence
of
CM
R
Months from start of imatinib therapy
p=0.02
hOCT1
hOCT1
726660544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Cu
mul
ativ
e in
cid
ence
of
CM
R
Months from start of imatinib therapy
p=0.02
hOCT1hOCT1
hOCT1hOCT1
CMR
Months from start of imatinib therapy
Cum
ulat
ive
inci
denc
e of
CM
R P=0.02
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
But adherence to therapy is the critical factor for achieving molecular response
• MMR– Adherence to imatinib therapy, RR=11.17 (P=0.001) – hOCT1 transcript level, RR=1.79 (P=0.038)
• CMR– Adherence to imatinib therapy, RR=19.35 (P=0.004)
RR: relative risk Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388.
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Imatinib plasma levels are not an independent predictor of molecular response
Total population Adherent patients
Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388.
P=0.003 P=0.68
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Study design
Time from start of imatinib• hOCT1 level
• MDR-1 polymorphisms• BCR-ABL transcript type• BCR-ABL transcript level
• Sokal score• Haemoglobin
• White blood cell count• Sex• Age
We correlated all these variables with the molecular response achieved by the patient
MEMS
Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388.
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Cu
mu
late
inci
den
ce o
f lo
ss o
f C
CyR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
Adherence rate ≤85%, n=18
Adherence rate >85%, n=69
Cu
mu
late
inci
den
ce o
f lo
ss o
f C
CyR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
Cu
mu
late
inci
den
ce o
f lo
ss o
f C
CyR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
Adherence rate ≤85%, n=18
Adherence rate >85%, n=69
Pro
bab
ility
of
imat
inib
fai
lure
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
Adherence rate ≤85%, n=18
Adherence rate >85%, n=69
Pro
bab
ility
of
imat
inib
fai
lure
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
Pro
bab
ility
of
imat
inib
fai
lure
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
Adherence rate ≤85%, n=18
Adherence rate >85%, n=69
Poor adherent patients have a higher probability of losing the CCyR and a lower EFS
P<0.0001
P<0.0001
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Probability of loss of CCyR according to the level of molecular response
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0P
rob
abil
ity
of
los
s o
f C
Cy
R
Months from starting imatinib therapy
CCyR with no MMR, n=91
CCyR with MMR, n= 41
p= 0.006
18 months
24.6%
0%
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0P
rob
abil
ity
of
los
s o
f C
Cy
R
Months from starting imatinib therapy
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0P
rob
abil
ity
of
los
s o
f C
Cy
R
Months from starting imatinib therapy
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
60544842363024181260 60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0P
rob
abil
ity
of
los
s o
f C
Cy
R
Months from starting imatinib therapy
CCyR with no MMR, n=91
CCyR with MMR, n= 41
p= 0.006
18 months
24.6%
0%
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
bab
ilit
y o
f lo
ss
of
CC
yR
Months from starting imatinib therapy
CCyR with no MMR, n= 92
CCyR with MMR, n= 32
p= 0.04
12 months
23.9%
2.6%
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
bab
ilit
y o
f lo
ss
of
CC
yR
Months from starting imatinib therapy
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
bab
ilit
y o
f lo
ss
of
CC
yR
Months from starting imatinib therapy
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
60544842363024181260 60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
bab
ilit
y o
f lo
ss
of
CC
yR
Months from starting imatinib therapy
CCyR with no MMR, n= 92
CCyR with MMR, n= 32
p= 0.04
12 months
23.9%
2.6%
CCyr with no MMR, n=92CCyR with MMR, n=32P=0.04
CCyr with no MMR, n=91CCyR with MMR, n=41P=0.04
Marin D et al. Blood 2008; 112(12): 4437–4444.
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
On multivariate analysis, the adherence
rate and having failed to achieve a major
molecular response are the only
independent predictors for loss of CCyR
and discontinuation of imatinib therapy.
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Adherence and the achievement of MMR are the only independent predictors for outcome
Pro
bab
ility
of
imat
inib
fai
lure
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
P<0.0001
CCyR, no MMR, Adherence Rate ≤85%, n=11
MMR, n=53
CCyR, no MMR, Adherence Rate >85%, n=23
p=0.003
p<0.0001
Cu
mu
late
inci
den
ce o
f lo
ss o
f C
CyR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
CCyR, no MMR, Adherence Rate ≤85%, n=11
MMR, n=53
CCyR, no MMR, Adherence Rate >85%, n=23
p=0.0009
p<0.0001
P<0.0001
P<0.0001
P=0.0009
P=0.003
P<0.0003
Slide courtesy of Dr David Marin
March 2011 | TAS11-003c
Conclusions
• A significant proportion of patients fail to take the prescribed dose of imatinib
• Adherence to therapy is the critical factor for optimal response
• Poor adherence is the main reason for imatinib failure in patient on long term therapy
• Intentional and unintentional reasons for non-adherence
• Poor understanding of consequences
Slide courtesy of Dr David Marin