1. Atrial fibrillation in a patient taking targeted cancer therapy
Μαρία Μπόνου
Διευθύντρια,
Καρδιολογικό τμήμα ΓΝΑ «Λαϊκό»

2. AF in a patient taking targeted cancer therapy
55 year old male
history of atypical CLL with Richter’s transformation to MCL
refractory to chemotherapy with
- FCR (fudaravine, cyclophosphamide, rituximab)
- R-CHOP (rituximab, cyclophosphamide, doxorubicin,
vincristine, prednisone)
- Obinutuzumab
Initiated therapy with ibrutinib

3. AF in a patient taking Ibrutinib
On the 15th day of treatment
The patient developed atrial fibrillation with rapid ventricular response (180 bpm)
His arterial pressure was borderline (90/50 mmHg)
He had not developed symptoms and signs of peripheral hypoperfusion

4. AF in a patient taking ibrutinib
Blood count:
Hb 10,1 g/dl, WBCs 6640 K/μl (poly 4200 K/μl, lymph
1790 K/μl, mono 520 K/μl)
Platelet count /μL
Biochemistry:
Urea 45 mg/dl, Creatinine 0.77 mg/dl, SGOT 18 U/lt,
SGPT 11 U/lt, Tbil 0.43 mg/dl, γGT 19 U/lt,
Na 143mEq/lt, K 5.0 mEq/lt
Cardiac echo: Ejection fraction 40%

5. AF in a patient taking ibrutinib
Rhythm control
Amiodarone
Electrical cardioversion
CHA2DS2-VASc score = 0
HASBLED score = 0
Rate control+ anticoangulant for 3 weeks → Cardioversion ?

7. Epidemiology of AF in cancer patients
Atrial fibrillation
Direct relationship
Cancer
2,5% AF in cancer pts versus 1% in the general population
Targeted cancer therapies induced AF

8. Targeted therapies
Tyrosine kinase inhibitor
Monoclonal antibodies

9. Τargeted therapies and Antiarrhythmic drug interactions
Tyrosine Kinase Inhibitors
FDA-Approved Indications
Clinically Significant Drug Metabolism/Elimination
Clinically Significant Adverse Effects
Afatinib
NSCLC
P-gp substrate
Axitinib
RCC
CYP3A4 substrate
Bosutinib
CML
CYP3A4 substrate; P-gp inhibitor
QT prolongation
Cabozantinib
Medullary thyroid cancer
Ceritinib
CYP3A4 substrate & strong inhibitor; P-gp substrate
QT prolongation, Bradycardia
Crizotinib
CYP3A4 substrate & moderate inhibitor; CYP2B6 moderate inhibitor; P-gp substrate and inhibitor
Dasatinib
ALL, CML
CYP3A4 substrate & weak inhibitor
Ibrutinib
CLL, MCL, WM
Imatinib
ALL, CEL, CML, GIST, ASM, DFSP, MDS/MPD
CYP3A4 substrate & moderate inhibitor; P-gp substrate
Lapatinib
Breast cancer
CYP3A4 substrate; CYP2C8 moderate inhibitor; P-gp substrate & inhibitor
Lenvatinib
Thyroid cancer
Nilotinib
CYP3A4 substrate & moderate inhibitor; CYP2D6 moderate inhibitor; CYP2C8 moderate inhibitor; P-gp inhibitor
Osimertinib
CYP3A4 substrate; BRCP inhibitor
Pazopanib
RCC, STS
CYP3A4 substrate; P-gp substrate
Regorafenib
Colorectal cancer, GIST
Bradycardia
Ruxolitinib
Myelofibrosis, Polycythemia vera
Sorafenib
RCC, HCC, Thyroid carcinoma
CYP2C9 moderate inhibitor; CYP2B6 moderate inhibitor
Sunitinib
RCC, GIST, PNET
Vandetanib
P-gp inhibitor
Atrial Fibrillation

10. Τargeted therapies and Antiarrhythmic drug interactions
Amiodarone,
Dronedarone,
Calcium channel blockers
- interaction with all the targeted therapies dose adjustment or discontinuation
® Moderate CYP3A4 inhibitors
Class IA, IC, and III antiarrhythmics
QT prolongation
Carvedilol, propranolol, nadolol
Drug-drug interactions
Metoprolol, atenolol, pindolol
Mild drug-drug interactions
Mexiletine (IB antiarrhythmic)
No significant drug-drug interactions
Co-administration may lead to increased levels of one or both drugs due to:
Impaired hepatic cytochrome p450 metabolism or
Inhibition of P-glycoprotein-mediated transport of the targeted therapy

11. Ibrutinib and AF Τreatment of
RESONATE trial
July 17, 2014
Τreatment of
relapsed or refractory chronic lymphocytic leukemia (CLL)
mantle cell lymphoma (MCL)
small lymphocytic lymphoma
THE LANCET
Oncology
Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial
- 12% AF (advanced age, prior exposure to anthracyclines)
Wang et al. Lancet Oncol 2016; 48–56
3% AF
0% AF

12. BTK and TEC kinases decrease PI3K-Akt signalling, which has a cardioprotective role under conditions of stress
Ibrutinib has significant intrinsic anticoagulant activity due to unclear mechanisms (up to 55% mild to moderate bleeding events ).
Morisson. Nature Biotechnology 2014, McMullen JR. Blood 2014, Lipsky AH. Haematologica 2015; 1571–8

13. Anticoagulation for AF in patients with cancer
Τhromboembolic risk
Cancer promotes a pro-thrombotic state
(procoagulant and fibrinolytic agents, proinflammatory cytokines, alterations of vascular endothelium)
CHA2DS2 score underestimates thromboembolic risk
CHADS2 predicts thromboembolism only in pts with baseline AF and not with new-onset AF
CHA2DS2-VASc score has not been validated
Some VEGFR inhibitors increase the risk of thromboembolism (sunitinib, sorafenib)

14. Anticoagulation for AF in patients with cancer
Βleeding risk
HASBLED score underestimates bleeding risk
HASBLED does not take into account a) the platelet count,
b) the functional status of platelets
Drug-drug interactions with warfarin and DOACs
Ιbrutinib intrinsic anticoagulant activity
(inhibits glycoprotein VI- and GP1b- mediated platelet function)

15. Tyrosine Kinase Inhibitors
Oral Anticoagulants
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Afatinib
Axitinib
Bosutinib
Cabozantinib
Ceritinib
↑OAC levels
Crizotinib
Dasatinib
↑OAC levels & effect
↑OAC effect
Erlotinib
Gefitinib
Ibrutinib
↑OAC levels & effect
Imatinib
Lapatinib
Lenvatinib
Nilotinib
Osimertinib
Pazopanib
Ponatinib
Regorafenib
Ruxolitinib
Sorafenib
Sunitinib
Vandetanib
Vitamin K antagonists (VKAs)
Pts were excluded from phase 2/3 clinical trials
Only 12% of pts achieve INR
6-fold higher risk of hemorrhage risk in pts with DVT and malignancies
Lee YJ . Int J Cardiol. 2016;203:372–8
Ambrusx DB. Thromb. Res ; 21-6
Low-molecular-weight heparin (LMWH)
Lack of data in cancer and AF (approved only in DVD and cancer)
Lee AY et al. N Engl J Med. 2003;349:146–53
Direct oral anticoagulants (DOACs)
Lack of data (only 3–9% in pts with DVT)
Renal and hepatic function changes
Drug-drug interactions (P-glycoprotein mediated transport )
Direct thrombin inhibitors inhibit atrial fibrosis, reduce the duration of AF episodes and slow down the progression of the arrhythmogenic substrate.
Jumeau C. JACC: Basic to Translational Science 2016;328-39

16. Atrial fibrillation in a patient taking targeted cancer therapy
Discontinuation of ibrutinib for 2 days
Amiodarone 300 mg in 60 minutes
Restoration of normal sinus rhythm
The patient has continued treatment with ibrutinib, with no subsequent event of AF.

17. AF during ibrutinib therapy
Clinical practice guidelines are urgently needed
Thompson et al. British Journal of Haematology 2016;462–466

18. Ιbrutinib with recent onset (<48 hours) AF
In conclusion
Ιbrutinib with recent onset (<48 hours) AF
Rapid sinus rhythm restoration is of paramount significance in order to circumvent the need of anticoagulation.
Amiodarone may be administered if other drugs are contra-indicated (especially in patients with borderline arterial pressure or heart failure); ibrutinib should be reduced to half dose or temporarily discontinued for the period of amiodarone treatment
Upon rapid sinus rhythm restoration amiodarone should be discontinued and ibrutinib should be re-instated in full dose.
If AF recurs, permanent discontinuation of ibrutinib should be considered.
Capelios C, Bonou M, et al. Hamostaseologie 2017 in press

19. Thank you