Taking the tablets, Do we / should we?

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)


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

porti

on o

f pat

ient

s (%

)

Percentage of intended dose

13.8% 12.6%8%

25.3%

40.2%

100


March 2011 | TAS11-003c

Percentage of intended dose

≥100%95–99%90–95%80–90%<80%

Pro

porti

on o

f pat

ient

s (%

)100

90

80

70

60

50

40

30

20

100

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.”


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”


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”


March 2011 | TAS11-003c

Reasons for poor adherenceTheme Sub-theme1.1 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


March 2011 | TAS11-003c

6-year probability of MMR according to the measured adherence rate

P<0.001



March 2011 | TAS11-003c

6-year probability of CMR according to the measured adherence rate

P=0.002



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=0.07Leukocytes

≤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=0.11BCR-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=0.13hOCT1 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=0.04Imatinib 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=0.09Adherence 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



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

Cum

ulat

ive

inci

denc

e 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


Cum

ulat

ive

inci

denc

e of

MM

R

p=0.0003hOCT1

hOCT1

MMR

p<0.001


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

Cum

ulat

ive

inci

denc

e of

CM

R


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

Cum

ulat

ive

inci

denc

e of

CM

R


p=0.02

hOCT1hOCT1

hOCT1hOCT1

CMR


Cum

ulat

ive

inci

denc

e of

CM

R P=0.02


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.


March 2011 | TAS11-003c

Imatinib plasma levels are not an independent predictor of molecular response

Total population Adherent patients


P=0.003 P=0.68


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



March 2011 | TAS11-003c

Cum

ulat

e in

cide

nce

of l

oss

of 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

Cum

ulat

e in

cide

nce

of l

oss

of C

CyR

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1


0.0

2418126

Cum

ulat

e in

cide

nce

of l

oss

of C

CyR

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1


0.0

2418126

p<0.0001



Prob

abili

ty o

f im

atin

ib fa

ilure

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1


0.0

2418126

p<0.0001



Prob

abili

ty o

f im

atin

ib fa

ilure

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1


0.0

2418126

Prob

abili

ty o

f im

atin

ib fa

ilure

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1


0.0

2418126

p<0.0001



Poor adherent patients have a higher probability of losing the CCyR and a lower EFS

P<0.0001

P<0.0001


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

0.0Pr

obab

ility

of l

oss

of C

CyR

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

0.0Pr

obab

ility

of l

oss

of C

CyR


60544842363024181260

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0Pr

obab

ility

of l

oss

of C

CyR


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

0.0Pr

obab

ility

of l

oss

of C

CyR


CCyR with no MMR, n=91


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

Prob

abili

ty o

f los

s of

CC

yR


CCyR with no MMR, n= 92


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

Prob

abili

ty o

f los

s of

CC

yR


60544842363024181260

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Prob

abili

ty o

f los

s of

CC

yR


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

Prob

abili

ty o

f los

s of

CC

yR


CCyR with no MMR, n= 92


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.


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.


March 2011 | TAS11-003c

Adherence and the achievement of MMR are the only independent predictors for outcome

Prob

abili

ty o

f im

atin

ib fa

ilure

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1


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

Cum

ulat

e in

cide

nce

of l

oss

of C

CyR

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1


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<0.0001P=0.0009

P=0.003

P<0.0003


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


Documents

Taking the tablets, Do we / should we?