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What are the risks and benefits of Tyrosine Kinase I nhibitors ?

What are the risks and benefits of Tyrosine Kinase I nhibitors ?. Wendy Osborne Consultant Haematologist Freeman Hospital, Newcastle. Outline of presentation. Discuss common side effects Risk benefit decisions of choice of drug Strategies to reduce side effects. Pre- imatinib era.

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What are the risks and benefits of Tyrosine Kinase I nhibitors ?

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  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 Dasatinibany better?

  12. Pleural effusion

  13. Pleural effusion • 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 …

  17. PACE - Incidence of Vascular Events

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

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

  20. 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.

  21. 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

  22. Risk reduction • Assess cardiovascular risk factors

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

  24. 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

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