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Taking the tablets, Do we / should we?

Taking the tablets, Do we / should we? . Slides courtesy of David Marin. It’s one thing to take a tablet over a short period It’s another thing to take it for life . There is a great variability in the response to imatinib . I wonder why. 100. 10. CCyR. 1. 3 log. BCR-ABL/ABL ratio (%).

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Taking the tablets, Do we / should we?

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  1. Taking the tablets, Do we / should we? Slides courtesy of David Marin

  2. It’s one thing to take a tablet over a short period • It’s another thing to take it for life

  3. There is a great variability in the response to imatinib. I wonder why 100 10 CCyR 1 3 log BCR-ABL/ABL ratio (%) 0.1 0.01 0.001 0.0001 Time from start of imatinib Slide courtesy of Dr David Marin

  4. Study design Imatinib plasma level MEMS TKD mutations 100 10 1 BCR/ABL/ABL ratio (%) 0.1 0.01 0.001 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 Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388. Slide courtesy of Dr David Marin

  5. Microelectronic Monitoring System (MEMS 6 Trackcap) • Records the time of opening the container • Most reliable method of measuring adherence • Our patients: not told about the chip Slide courtesy of Dr David Marin

  6. Slide courtesy of Dr David Marin

  7. Long-term adherence to imatinib 100 90 80 70 60 Proportion of patients (%) 50 40.2% 40 30 25.3% 20 13.8% 12.6% 8% 10 0 <80% 80–90% 90–95% 95–99% ≥100% Percentage of intended dose Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388. Slide courtesy of Dr David Marin

  8. Lack of adherence is underestimated by conventional methods Self reporting Pill count MEMS 100 90 80 70 60 Proportion of patients (%) 50 40 30 20 10 0 <80% 80–90% 90–95% 95–99% ≥100% Percentage of intended dose Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388. Slide courtesy of Dr David Marin

  9. 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

  10. 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. 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. Reasons for poor adherence Theme 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

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

  17. But adherence to therapy is the critical factor for achieving molecular response Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388. • 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 Slide courtesy of Dr David Marin

  18. Imatinib plasma levels are not an independent predictor of molecular response Adherent patients P=0.003 P=0.68 Total population Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388. Slide courtesy of Dr David Marin

  19. Study design 100 10 1 0.1 BCR/ABL/ABL ratio (%) 0.01 0.001 MEMS 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 Marin D et al. J Clin Oncol 2010; 28(14): 2381–2388. Slide courtesy of Dr David Marin

  20. 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

  21. 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. 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. 1.0 0.9 p=0.003 0.8 0.7 P<0.0001 p<0.0001 0.6 P<0.0001 Probability of imatinib failure 0.5 P=0.003 0.4 0.3 P<0.0003 MMR, n=53 0.2 CCyR, no MMR, Adherence Rate ≤85%, n=11 0.1 CCyR, no MMR, Adherence Rate >85%, n=23 0.0 P<0.0001 0 6 12 18 24 P=0.0009 Months from enrolment Adherence and the achievement of MMR are the only independent predictors for outcome Slide courtesy of Dr David Marin

  24. 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

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