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What are the risks and benefits of Tyrosine Kinase Inhibitors ?
Wendy OsborneConsultant Haematologist
Freeman Hospital, Newcastle
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Outline of presentation
• Discuss common side effects
• Risk benefit decisions of choice of drug
• Strategies to reduce side effects
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Pre-imatinib era
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Current Tyrosine kinase inhibitors
• Imatinib• Nilotinib• Dasatinib • Bosutinib• Ponatinib
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Imatinib is a safe drug…Iris 8 year follow upAll 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%
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Rashes
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Periorbital oedema
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Monitoring of liver function
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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.
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Nilotinib
• Enestnd follow up suggests that it is better tolerated than imatinib , but….
• Concerns about cardiovascular risk
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• Is Dasatinib any better?
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Pleural effusion
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Pleural effusion
• 20% incidence (SPIRIT 2 and Dasision)
• More common with higher doses/split doses dasatinib
• Most occur within 12 months
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Pulmonary arterial hypertension
• Estimated incidence 0.45%
• Late complication, 8-48 months after starting
• Reversible
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Bosutinib
• Bosutinib: GI side effects• 84% Diarrhoea• 44% Nausea• 35% vomiting
Start with low dose and build up. Warn patients and give loperimide
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Ponatinib
• Available for patients with T315I mutation
• Effective drug but …
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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]
Category AE SAE AE SAE
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
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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
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Vascular occlusive events
EPIC was terminated October 2013. Safety concerns/achieving endpoints if dose change.
Ponatinib not to be used first line.
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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.
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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
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Risk reduction
• Assess cardiovascular risk factors
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Modifications if side effects
• Reduce the dose of drug
• Dose interruptions
• Alternative TKI
• Address risk factors
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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