Cardiotoxicities of Tyrosine Kinase Inhibitors to Treat CML and CLL: Heart Attacks, Strokes, and Atrial Fibrillation Oh My!

Michael J. Mauro, MD Leader, Myeloproliferative Neoplasms Program Memorial Sloan Kettering Cancer Center, New York, NY Disclosures:

• Consultant, Advisory Board Member: – Novartis, Bristol Myers Squibb, Takeda, Pfizer • Clinical Trial Steering Committee: – Novartis, Bristol Myers Squibb, Takeda • Clinical Trial Funding (to Institution, MSKCC): – Novartis, Bristol Myers Squibb, Sun Pharma in Oncology and the Problem of ‘Late Cardiovascular Events’

• CLL: – Atrial Fibrillation, Ventricular Arrhythmias, Bleeding • CML: Tyrosine Kinase Inhibitors – Vascular Occlusive Events; Pulmonary Arterial Hypertension • Others likely to develop as targeted therapy continues to quickly expand

• CLL, the most common , previously was a disease treated expectantly, and ‘best’ (young/fit) with ; now high risk pts better treated and ?cure

• CML has set the paradigm for targeted therapy and is highly treatable and (potentially) functionally curable for all patients – and Herceptin development contemporaneous Novel Agents for CLL BCR-associated Kinase and BCL-2 Inhibitors

• Syk (spleen tyrosine kinase): 1. fostamatinib (R935788) 2. entospletinib (GS-9973) • Btk (Bruton’s tyrosine kinase): 1. ibrutinib (PCI-32765) 2. acalabrutinib (ACP-196) 3. tirabrutinib (GS-4059) • PI3K (phosphatidylinositol 3-kinase): X 1. idelalisib (GS-1101) 2. duvelisib (IPI-145) mitochondria 3. umbralisib (TG-1202) • BCL-2: 1. (ABT-199)

Adapted from Niiro H. Nat Rev Immunol 2:945 Cumulative Incidence of Discontinuation of Ibrutinib in CLL by Cause

Cumulative Incidence 2 Yrs 3 Yrs 4 Yrs

CLL Progression 5.0% 10.8% 19.1%

Transformation 7.3% 9.1% 9.6%

Other Event 18.7% 23.9% 25.0% Woyach J. JCO. 2017; 35:1347. CML At present, five oral kinase inhibitors approved in the US for Ph+ Leukemia: a ‘spoil of riches’; more on the way? 2001 1st Gen. TKI Novartis (1st line) Imatinib (STI571)

2007/2010 2007/2010 nd BMS Novartis 2 Gen. TKIs st nd (1st, 2nd line) (1 , 2 line) (BMS354825) (AMN107)

2012/2015 2012 South Korea IL-YANG: Pfizer only (1st, 2nd line) (1st, 2nd, 3rd line) (IY5511) (SKI606)

3rd Gen. TKI 2012 th Ariad 4 Gen. TKI (allosteric): (2nd?/3rd line) ABL001

Ponatinib (AP24534) CML is an increasingly prevalent and survivable cancer

lifespan

prevalence

200000

180000

160000

140000 10x greater steady state number 120000 of CML patients in US by 2050 100000 • Incidence 4700 per year 80000 Number of Cases Age-matched mortality ratio vs • normal population = 1.50 60000 • Accounts for increased US 40000 population to 410 million in 2050

20000 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Huang et al, Cancer 118:3123-3127, 2012. Bower H et al, J Clin Oncol 34:2851-57, 2016. 100 EURO-SKI: Survival without loss of MMR • Median time to molecular recurrence: 2.5 mo. (range,0.8 to 22.2) n=200; MR4 or greater, >2y (inclusion) 80 Relapses, n=86 Relapses within 6 months , n=77 60 • 57 out of the 61 pts restarted TKI (imatinib, n=56; dasatinib , n=1) and 55 achieved 2nd CMR at a median of 4.2 months 40 Relapsemol-free survival at 6 months : 61% (54-68) • Median follow-up of 63 mo. : Relapse free survival - None of the MR patients have CML progression event 20 Cumulative incidence of MR Saussele S, et al. EHA. 2014: [abstract LB-6214] 0 Months since stop of imatinib 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months from discontinuation of TKI Ready for prime time: ‘treatment free remission’

(TKI cessation for patients in deep molecular remission) Treatment Free Remission in the label for Nilotinib as of 12/22/17 Front-line nilotinib in CML: CVEs over time (5y data- ENESTnd)

Larson RA, et al. J Clin Oncol. 2014;32:5s (suppl; abstr 7073). CLL

New agents, new problems Ibrutinib in CLL

• Front-line CLL • Relapsed CLL • Mantle cell • Waldenströms

• Effective in P53 mutated disease (high risk) Ibrutinib-associated bleeding

• Irreversibly binds BTK and TEC kinasesGPVI collagen / CRP dep’d activation abolished • CLEC-2 signaling inhibited (mediates thrombus stability after platelet adhesion to damaged endothelium) • Inhibits GPIb-VWF interaction (tethers plts to injured vessel wall) • Inhibits αIIbβ3 signaling (Fibrinogen-integrin αIIbβ3 induced platelet activation) Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis • 22 manuscripts, 4 randomized trials, 2152 pts • Pooled rate of major bleeding- 17 studies: 2.76 per 100 person- years (vs 1.9 per 100 for non-ibrutinib therapy) • RESONATE: ibrutinib = 44% vs. = 12% • HELIOS: ibrutinib = 31% vs. placebo = 15% • Acalabrutinib: all grades = 34%; grade >3 = 0%

major bleeding

Caron F et al, Blood Advances 1:772-78, 2017 Potential Mechanism of AF: AP and APD perturbation by overlapping pathways

Alexandre J et al Pharmacology and Therapeutics 189 89-103, 2018 Ibrutinib AF and Hypertension

Atrial fibrillation • Ibrutinib = 5% vs. ofatumumab = 1% • Possibly due to ibrutinib metabolism • HELIOS: I + BRi = 7.7% vs. P + BR = 2.4% • RESONATE2: ibrutinib = 7.4% vs chlorambucil = 1% • Acalabrutinib = 3%

Hypertension • HELIOS: ibrutinib = 10% vs. placebo = 5% • RESONATE2: ibrutinib = 14% vs. chlorambucil = 0% • Acalabrutinib: not reported The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis • 20 manuscripts, 4 randomized trials

: R/R MCL, IB vs

: HELIOS: BR +/- IB in CLL

: RESONATE: IB vs Ofatumumab in CLL

: RESONATE-2: IB vs Chlorambucil in CLL

Surveillance methods? Case definitions? Underestimate? Unmasking preexisting AF?

• Pooled rate of AF- all studies, 26mo follow-up: 3.3 per 100 person- years (vs 0.84 per 100 for non-ibrutinib therapy) • Framingham data: age 65-74, 1-2/100 person years Leong DP et al, Blood 128:138-40, 2016 Ventricular Arrhythmias and Sudden Death in Patients Taking Ibrutinib

• Index cases-> FAERS data for 2y after approval date

• 13 additional cases (VA) with 6 sudden death – 10/13 no CV history; median age = 61; median 65d after ibrutinib start

• Clinical trial experience (n~1000): incidence rate 788 events per 100,000 person-years – HELIOS trial: bendamustine/ +/- ibrutinib: 7 vs 0 >Gr3 VA, cardiac arrest, sudden death-> 1991 vs 0 per 100,000 person years

Lampson BL et al Blood 129:2581-84, 2017 Activity of Ibrutinib on Other Kinases; Acalabrutinib vs Ibrutinib

Irreversible Reversible ACP-196 Ibrutinib Kinase IC50(nM) IC50(nM) Kinase IC50 (nM) Kinase IC50 (nM) Btk 1.2 0.43 BTK 0.46 FGR 2.31 BLK 0.52 CSK 2.30 Tec 29 1.8 BMX/ETK 0.76 Brk 3.34 Bmx 39 0.87 EGFR 5.55 HCK 3.67 Itk >1000 168 ErbB2 9.40 YES 6.50 Txk 291 2.0 ITK 10.70 FRK 29.20 EGFR >1000 5.0 JAK3 16.13 LCK 33.24 ErbB2 912 6.2 TEC 77.76 RET 36.5 ErbB4 13.2 2.7 FLT3 73.0 Blk >1000 0.10 ABL 86.12 Jak3 >1000 48 FYN 96.0

Honigberg LA. PNAS 2010; 107:13075. CML

Trying to avoid collateral damage whilst headed for functional cure Cardiomyopathy associated with imatinib

Decreased EF Myocyte injury

Myocyte

Injury via endoplasmic reticulum stress response

Mediated via c-Jun N-terminal kinase

Kerkela R et al. Nat Med 2006; 12(8):908-16. PAD associated with nilotinib: biochemical and ABI changes

Kim TD et al. Leukemia 2013; 27:1316-21. PAD associated with nilotinib: clinical impact

Kim TD et al. Leukemia 2013; 27:1316-21. Summary of VOEs: phase I and phase II (PACE) trials

Treatment-Emergent Treatment-Emergent Adverse Events Serious Adverse Events Treatment- Treatment- All, All, Related, Related, n/N (%) n/N (%) n /N (%) n/N (%) Phase I 37/81 (46) 7/81 (9) 16/81 (20) 5/81 (6) All patients (N=81) Phase I CML and Ph+ ALL 31/65 (48) 7/65 (11) 14/65 (22) 5/65 (8) (N=65) Phase II (PACE) 109/449 (24) 45/449 (10) 67/449 (15) 27/449 (6) All patients (N=449)

27% Dec 2013 USPI

Phase I Data as of 26 Sep 2013; PACE Data as of 03 Sept 2013 Meta-analysis: imatinib versus subsequent generation TKIs, VOEs

Douxfils J et al, Lancet Oncology, 2016 Data from French PH Registry 2006-2010

Incidence: Characterization of PAH with dasatinib: 13/2900 (0.45%) 8:1 female:male

Median interval: 34 mths (8-48)

Montani et al. Circulation. 2012 May 1;125(17):2128-37 Clinical, functional, and hemodynamic parameters after dasatinib discontinuation

•All but 1 pt improved after withdrawal of dasatinib

•Symptomatic and functional improvement seen but did not return to normal hemodynamics

•2 pts died from RV failure and SCD

Other cases reported: • Dumitrescu et al. Eur Respir J. 2011 Jul;38(1):218-20 • Rasheed et al. Leuk Res. 2009 Jun;33(6):861-4 • Mattei et al. Bone Marrow Transplant. 2009 Jun;43(12):967-8 • Hennigs et al. BMC Pulm Med. 2011 May 23;11:30zz

Montani et al. Circulation. 2012 May 1;125(17):2128-37

Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site

• pro-atherogenic and anti-angiogenic effects in vivo – aortic root plaque – hind limb ischemia – BM microvessel density (n.b. may be treatment effect)

Hadzijusufovic E et al, Leukemia 2017 epub 9/8/2017 Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site

Hadzijusufovic E et al, Leukemia 2017 epub 9/8/2017 Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension •  serum markers EC injury/dysfunction in vitro, in pt samples

Healthy Control CML, no PAH, on IM CML, no PAH, at DX CML, no PAH, on DAS

Guignabert C E et al, J Clin Inv 126(9), 3207-18, 2016 Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension • exaggerated response to monocrotaline and chronic hypoxia • Induced apoptosis of pulmonary EC

Guignabert C E et al, J Clin Inv 126(9), 3207-18, 2016 Ponatinib exerts anti-angiogenic effects in the zebrafish and human umbilical vein endothelial cells via blocking VEGFR signaling pathway

• antiangiogenic effect of PON demonstrated by reduction/elimination of intersegmental and subintestinal vessels (ISV / SIV)

First it was pastrami, now ponatinib too?

Ai N, et al, Oncotarget 9:62, 31958-70, 2018 Ponatinib exerts anti-angiogenic effects in the zebrafish and human umbilical vein endothelial cells via blocking VEGFR signaling pathway

Ai N, et al, Oncotarget 9:62, 31958-70, 2018 Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation

• In cultured human aortic ECs (HAECs) treated with ponatinib –  NF-kB/p65 phosphorylation and NF-kB activity –  inflammatory gene expression, cell permeability, cell apoptosis – extracellular signal-regulated kinase 5 (ERK5) transcriptional activity – KLF2/4, eNOS – ERK5 SUMOylation transcriptional activity

Paez-Mayorga J et al, Front. Cardiovasc Med 06 Sept 2018 (ePUB) Figure adapted from SpringerLink Encyclopedia of Signaling Molecule, 2018 edition Dasatinib reversibly disrupts endothelial vascular integrity by increasing non-muscle myosin II contractility in a ROCK-dependent manner

• Dasatinib may active ROCK kinase as an off target effect-> EC dysregulation, permeability-> pleural effusions, PAH?

• Ponatinib potentially thought to have similar effect?

Kreutzman A et al, Clin Can Res 23(21), 6697-6707, 2017 A phosphoproteomic signature in endothelial cells Leukocyte Adhesion predicts vascular toxicity of tyrosine kinase inhibitors used in CML

Wound Healing • HUVEC ‘toxicity’ assessed with in vitro exposure

Cell Survival Gopal A et al, Blood Advances 2(14) 1680-84, 2018 A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CML

• Mass spec study of 96 sentinel phosphopeptides validated to be representative of cellular states in response to drug perturbations

Gopal A et al, Blood Advances 2(14) 1680-84, 2018 What to do? a call to action (slow march?) Monitoring on TKI trials: minimal imaging, biochemical assessments

Entry criteria related to CV/vascular disease: PACE Phase II trial

Monitoring Schedule: PACE Phase II trial

Cortes JC, et al, N Engl J Med 2013; 369:1783-1796 (Supplemental Materials) MI ‘Complete Molecular CVA Remission’ PAD Guidelines at present for Dyslipidemia ‘Treatment Free management of CV risk: DM/Glu Intol Remission’

= Recommended work-in-progress Imatinib Bosutinib Dasatinib Nilotinib Ponatinib = As clinically indicated Baseline Assessment Cardiovascular assessment Blood pressure check ‘ABCDE’ Step Approach to CV Intervention Fasting glucose Fasting lipid panel A: Awareness of cardiovascular disease signs and symptoms * Echocardiogram A: Aspirin (in select patients) Electrocardiogram A: Ankle-brachial index measurement at baseline and follow- Ankle-brachial index up to document peripheral arterial disease 1-month follow up B: Blood pressure control Cardiovascular assessment C: Cigarette/tobacco cessation Blood pressure check 3- to 6-month follow-up C: Cholesterol (regular monitoring and treatment if indicated) Cardiovascular assessment D: Diabetes mellitus (regular monitoring, dose of Blood pressure check radiation/chemotherapy, and treatment if indicated) Fasting glucose D: Diet and weight management Fasting lipid panel * E: Exercise (echocardiogram) Echocardiogram Electrocardiogram Ankle-brachial index *Patients treated with dasatinib should be considered for echocardiogram if cardiopulmonary Barber M, Mauro M and Moslehi J, Blood 2017 symptoms are present. Cardiovascular (CV) and Metabolic Risk in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Receiving First-line BCR-ABL Tyrosine Kinase Inhibitors (TKIs) in the United States (CA180-653)

CA180-653 Study Design ‘dealer’s choice’ of therapy Imatinib cohort

Newly diagnosed Δ in CV risk patients with Ph+ Δ in metabolic risk Dasatinib cohort CML-CP aged ≥18 years CV AEs (N = 200) CML response Nilotinib cohort during SOC visits Data Collection

• Extraction of medical records • Ankle-brachial Index (ABI) • Biomarkers: Fasting lipid panel, Homocysteine, • Coronary calcium scoring Insulin, c-peptide, hsTNT, hs-CRP, NT-proBNP, • Echocardiography sST2, GD-15, HbA1c, glucose, LOX-1 sequencing • Cytogenetic and molecular assessments • Urine for albuminuria • ECG

CA180-653 (NCT03045120) is a prospective cohort study intended to characterize the impact of imatinib, dasatinib, and nilotinib on CV and metabolic risk factors in patients with newly diagnosed CML-CP in the United States Hypertension observed on Ponatinib: warrants monitoring for and intervention… PFA and aggregation studies demonstrate inhibition with dasatinib and ponatinib

Quintas-Cardama A, et al. Blood 2009; 114(2):261-63 Neelakantan P et al. Haematologica 2012; 97(9):1444 Retrospective analysis of known and novel biomarkers of risk

• MVA showed cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism associated with CV events • IVS4-14 G/G LOX-1 polymorphism strongest predictive factor for a higher incidence of CV events in nilotinib patients • unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients Boccia M et al, Oncotarget, 2016 Role of additional markers of clonal hematopoiesis Coronary Artery Disease: ARCH mutations in NIL patients: Traditional RF and ARCH mutations Association with AOD?

Jaiswal S et al, NEJM 371: 2488-98, 2014; Hadzijusufovic E et al, Leukemia 2017 epub 9/8/2017 Role of additional markers of clonal hematopoiesis ARCH mutations in NIL patients: Association with AOD?

Jaiswal S et al, NEJM 371: 2488-98, 2014; Hadzijusufovic E et al, Leukemia 2017 epub 9/8/2017 Questions/Future: ‘Good Problems’

• Using CML as an example-> ‘functional curable’ cancer but ~5-6y therapy needed (new paradigm), potentially indefinite for many – How to risk stratify, risk mitigate, track AE development?

• Needed: – Prospective evaluation, rapid engagement for collaboration, MOA based research and intervention

• Cardio-Oncology collaboration will be essential for our success in oncology! Thank you for the kind invitation! [email protected] 212-639-3107