Transcript What are the risks and benefits of different treatments in

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
Pre-imatinib era
Current Tyrosine kinase inhibitors
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Imatinib
Nilotinib
Dasatinib
Bosutinib
Ponatinib
Imatinib is a safe drug…
Iris 8 year follow up
Oedema
Nausea
Cramps
Diarrhoea
Rash/skin
Fatigue
Headache
Abdo pain
Joint pain
All grade AE
60%
50%
49%
45%
40%
39%
37%
37%
31%
Grade 3/4 AE
2%
1%
2%
3%
3%
2%
<1%
4%
3%
Rashes
Periorbital oedema
Monitoring of liver function
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
• Is Dasatinib any better?
Pleural effusion
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
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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 …
PACE - Incidence of Vascular
Events
Phase 2 (PACE)
N=449
Datacut Date
Median Follow-up [exposure]
Category
Arterial Thrombotic Events, n (%)
23 Jul 2012 (USPI)
03 Sep 2013
12
[340 patient-yrs]
AE
SAE
24
[578 patient-yrs]
AE
SAE
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)
15 (3)
10 (2)
23 (5)
13 (3)
Method 1 [ARIAD & EMA]
62 (14)
41 (9)
91 (20)
62 (14)
Method 2 [FDA]
81 (18)
47 (10)
109 (24)
67 (15)
Venous Thromboembolism, n (%)
Vascular Occlusion, n (%)
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 CPCML
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