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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 Inhibitors ? 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
Current Tyrosine kinase inhibitors • Imatinib • Nilotinib • Dasatinib • Bosutinib • Ponatinib
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%
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.
Nilotinib • Enestnd follow up suggests that it is better tolerated than imatinib , but…. • Concerns about cardiovascular risk
Pleural effusion • 20% incidence (SPIRIT 2 and Dasision) • More common with higher doses/split doses dasatinib • Most occur within 12 months
Pulmonary arterial hypertension • Estimated incidence 0.45% • Late complication, 8-48 months after starting • Reversible
Bosutinib • Bosutinib: GI side effects • 84% Diarrhoea • 44% Nausea • 35% vomiting Start with low dose and build up. Warn patients and give loperimide
Ponatinib • Available for patients with T315I mutation • Effective drug but …
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
Vascular occlusive events EPIC was terminated October 2013. Safety concerns/achieving endpoints if dose change. Ponatinib not to be used first line.
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.
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
Risk reduction • Assess cardiovascular risk factors
Modifications if side effects • Reduce the dose of drug • Dose interruptions • Alternative TKI • Address risk factors
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