1. March 2011 | TAS11-003c Taking the tablets, Do we / should we? Slides courtesy of David Marin

2. 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

3. March 2011 | TAS11-003c 10 1 0.1 0.01 0.001 100 BCR-ABL/ABL ratio (%) 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

4. March 2011 | TAS11-003c 10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) 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

5. 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

6. March 2011 | TAS11-003c Slide courtesy of Dr David Marin

7. 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 Proportion of patients (%) Percentage of intended dose 13.8% 12.6% 8% 25.3% 40.2% 100 Slide courtesy of Dr David Marin

8. March 2011 | TAS11-003c Percentage of intended dose ≥100%95–99%90–95%80–90%<80% Proportion of patients (%) 100 90 80 70 60 50 40 30 20 10 0 Self reporting Pill count MEMS 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

9. March 2011 | TAS11-003c Unintentional non-adherence 13/21 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

10. 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

11. 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

12. March 2011 | TAS11-003c Reasons for poor adherence ThemeSub-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

13. 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

14. 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

15. March 2011 | TAS11-003c VariablesnMMR (%)4-log (%)CMR (%) Haemoglobin ≤115 g/l >115 g/l RR 40 47 P=0.036 59.2 80.7 1.186, P=0.012 P=0.03 39.5 69.1 1.323, P=0.01 P=0.011 14.7 47.6 1.209, P=0.07 Leukocytes ≤140 x 10 9 /l >140 x 10 9 /l RR 44 43 P=0.012 78.8 63.1 0.996, P=0.008 P=0.022 56.7 37.6 0.996, P=0.015 P=0.17 35.4 28.1 0.996, P=0.11 BCR-ABL1/ABL1 ratio ≤100% >100% RR 44 43 P=0.25 71.4 52.6 0.996, P=0.44 P=0.038 53.0 26.6 0.971, P=0.002 P=0.1 32.7 8.4 0.979, P=0.13 hOCT1 transcript level ≤0.16 >0.16 RR 30 P<0.001 55.2 81.4 2.199, P<0.001 P=0.01 42.0 64.8 1.990, P=0.001 P=0.02 16.6 45.3 1.665, P=0.04 Imatinib plasma level ≤1  g/ml >1  g/ml RR 43 41 P=0.02 60.1 83.2 2.11, P=0.01 P=0.07 53.0 68.0 2.50, P=0.06 P=0.14 23.3 44.4 2.25, P=0.09 Adherence rate >90% ≤90% RR 64 23 P<0.001 93.7 13.9 1.093, P<0.001 P<0.001 76.0 4.3 1.104, P=0.002 P=0.002 43.8 0 RR= 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

16. March 2011 | TAS11-003c The level of hOCT1 measured at diagnosis is predictive for achievement of molecular response hOCT1=human organic cation transporter 1 MMR p<0.001 Months from start of imatinib therapy Cumulative incidence of MMR P<0.001 CMR Months from start of imatinib therapy Cumulative incidence of CMR P=0.02 Slide courtesy of Dr David Marin

17. 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

18. 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=0.003P=0.68 Slide courtesy of Dr David Marin

19. March 2011 | TAS11-003c 10 1 0.1 0.01 0.001 100 BCR/ABL/ABL ratio (%) 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

20. March 2011 | TAS11-003c Poor adherent patients have a higher probability of losing the CCyR and a lower EFS P<0.0001 Slide courtesy of Dr David Marin

21. March 2011 | TAS11-003c Probability of loss of CCyR according to the level of molecular response CCyr with no MMR, n=92 CCyR with MMR, n=32 P=0.04 CCyr with no MMR, n=91 CCyR with MMR, n=41 P=0.04 Marin D et al. Blood 2008; 112(12): 4437–4444. Slide courtesy of Dr David Marin

22. 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

23. March 2011 | TAS11-003c Adherence and the achievement of MMR are the only independent predictors for outcome Probability of imatinib failure 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Months from enrolment 0 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 P<0.0001 P=0.0009 P=0.003 P<0.0003 Slide courtesy of Dr David Marin

24. 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