1. What are the risks and benefits of Tyrosine Kinase Inhibitors ? Wendy Osborne Consultant Haematologist Freeman Hospital, Newcastle

2. Outline of presentation Discuss common side effects Risk benefit decisions of choice of drug Strategies to reduce side effects

3. Pre-imatinib era

4. Current Tyrosine kinase inhibitors Imatinib Nilotinib Dasatinib Bosutinib Ponatinib

5. Imatinib is a safe drug… Iris 8 year follow up All grade AE Grade 3/4 AE Oedema 60% 2% Nausea 50% 1% Cramps 49% 2% Diarrhoea 45% 3% Rash/skin 40% 3% Fatigue 39% 2% Headache 37% <1% Abdo pain 37% 4% Joint pain 31% 3%

6. Rashes

7. Periorbital oedema

8. Monitoring of liver function

9. What else have we learned from IRIS? Grade 3/4 adverse events decreased in incidence after years 1 and 2 With >400 000 patient years of estimated imatinib exposure there is no evidence that imatinib increases risk of other malignancies.

10. Nilotinib Enestnd follow up suggests that it is better tolerated than imatinib, but…. Concerns about cardiovascular risk

11. Is Dasatinib any better?

12. Pleural effusion

13. 20% incidence (SPIRIT 2 and Dasision) More common with higher doses/split doses dasatinib Most occur within 12 months

14. Pulmonary arterial hypertension Estimated incidence 0.45% Late complication, 8-48 months after starting Reversible

15. Bosutinib Bosutinib: GI side effects 84% Diarrhoea 44% Nausea 35% vomiting Start with low dose and build up. Warn patients and give loperimide

16. Ponatinib Available for patients with T315I mutation Effective drug but …

18. Phase 2 (PACE) N=449 Datacut Date 23 Jul 2012 (USPI)03 Sep 2013 Median Follow-up [exposure] 12 [340 patient-yrs] 24 [578 patient-yrs] CategoryAESAEAESAE Arterial Thrombotic Events, n (%)51 (11)34 (8)77 (17)53 (12) Cardiovascular, n (%)29 (6)21 (5)41 (9)28 (6) Cerebrovascular, n (%)13 (3)8 (2)35 (8)18 (4) Peripheral vascular, n (%)17 (4)7 (2)36 (8)16 (4) Venous Thromboembolism, n (%)15 (3)10 (2)23 (5)13 (3) Vascular Occlusion, n (%) Method 1 [ARIAD & EMA]62 (14)41 (9)91 (20)62 (14) Method 2 [FDA]81 (18)47 (10)109 (24)67 (15) PACE - Incidence of Vascular Events

19. Evaluation of Ponatinib vs Imatinib in CML: EPIC Phase 3, randomized, open-label trial of oral ponatinib vs. oral imatinib in patients with newly diagnosed CP- CML

20. Vascular occlusive events EPIC was terminated October 2013. Safety concerns/achieving endpoints if dose change. Ponatinib not to be used first line.

21. FDA approval for ponatinib Treatment of adult patients with T3151-positive chronic myeloid leukaemia or Ph+ ALL Patients in whom no other TKI is indicated label to describe the vascular occlusion events.

22. EMA decision re ponatinib Not to be used in patients with a history of heart attack or stroke, unless the potential benefits of treatment outweigh the risks. Cardiovascular risk factors actively managed. Patients should be monitored for evidence of vascular occlusion or thromboembolism. Review 10/10/14: stop if no response 3 months

24. Risk reduction Assess cardiovascular risk factors

28. Modifications if side effects Reduce the dose of drug Dose interruptions Alternative TKI Address risk factors

29. Conclusions All drugs have side effects. Risk benefit of disease control verses side effect profile. Reduction of cardiovascular risk factors More patients are interested in reducing dose or stopping TKI