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

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

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

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 18000 /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%

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 ?

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

Targeted therapies Tyrosine kinase inhibitor Monoclonal antibodies

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

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

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

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

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)

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)

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 2.0-3.0 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. 2016; 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

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.

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

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

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