What are the risks and benefits of Tyrosine Kinase Inhibitors ?

Wendy OsborneConsultant 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

• Imatinib• Nilotinib• Dasatinib • Bosutinib• Ponatinib

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%

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

• 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 …

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

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

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