Ana Barac, MD, PhD, FACC

Associate Professor of Medicine and Oncology, Georgetown University

Director, Cardio-Oncology Program, MedStar Heart and Vascular Institute

Charleston Cardio-Oncology Symposium, November 2019

Cardiovascular toxicities of novel anti-

cancer agents

Disclosures

• Associate Editor: JACC Cardio-Oncology

• Co-Director: ACC Live Course on Advancing CV Care of

Oncology Patient

• Research support, investigator-initiated study: Genentech, Inc

• Honoraria: Bristol Myers Squibb

• DSMB: CTI Biopharma

Objectives• Understand rapidly evolving categories of cancer therapeutics:

– Anthracyclines an conventional chemotherapy

– HER2 targeted agents

– VEGF-pathway inhibitors

– Tyrosine kinase inhibitors

– Immune Checkpoint Inhibitors

– CAR-T cells

• Implement continued education about prevention and treatment

of CV effects of cancer treatments

Barac A et al. JACC 2015: 65: 2739

Cardio-Oncology = Cardiovascular Health of Patients

with Cancer and Cancer Survivors

modified in Campia U, Moslehi J, Barac A et al. Circulation 2019; 139:e579

Comprehensive CV Care in 2019 Oncology World

Cancer/Cancer Treatment

Host Interaction

CV Risk factors and CV disease

Cancer treatment-related CV toxicities

VALVULARDISEASE

Therapeutic chest radiation

CORONARY ARTERY DISEASE

PERIPHERAL ARTERIAL EVENTS

ATRIAL FIBRILLATION Ibrutinib

Anthracyclines, HER2-agents,VSPIs, Proteasome inhibitors, Immune checkpoint inhibitorsCAR-T cells

Therapeutic chest radiation, AIs, CVRFs

VSPIs: Sunitinib, sorafenib, bevacizumab, lenvatinib,

TKIs: Ponatinib, Nilotinib

DVT AND THROMBOSIS

CARDIACAMYLOIDOSIS

Multiple myeloma

PARTNERSHIP IN CARE

Thalidomide,Lenalidomide, Pomalidomide

HEART FAILURE: Stage A - D HYPERTENSION

Case 1: Patient with Gastric

Cancer▪61yo man w metastatic gastric cancer presented with 1 week

of progressive shortness of breath and rapid deterioration

requiring hemodynamic and ventilatory support:

▪HPI

▪FOLFOX for 1 year

▪Capecitabine, bevacizumab, atezolizumab (PD-L1)-

clinical trial

▪Stable disease minimal tumor burden (liver) x 10 months

▪No cardiac history, no prior CV evaluation

11/18/2019 7ECG Echo

• ECG with NSR and PVCs w bigeminy

• LVEF ~ 30%, RV function moderately

down

• Troponin <1 , NTproBNP >10,000

The best Next step in management:

A.Referral to palliative care for cancer progression

B.Antibiotics for pneumonia/sepsis due to

chemotherapy-related immunosuppression

C.LHC to exclude coronary spasm 2nd to

capecitabine

D.Steroids and myocardial biopsy to exclude

autoimmune process 2nd to atezolizumab

E.Medical management of HF related to bevacizumab

Case 1: Patient with Gastric

Cancer

Case 1: Old and New Therapies with CV

Effects• Capecitabine

– Oral preparation of 5FU – coronary spasm

• Bevacizumab

– Antibody to VEGF – hypertension, LV

dysfunction

• Atezolizumab (PD-L1 antibody)

– Immune checkpoint inhibitor - myocarditis

VEGF Inhibitors

• Bevacizumab

• Sunitinib, sorafenib,

lenvatinib,

cabozantinib, axitinib

Adverse Effects

• Hypertension

• Heart failure

• Ischemia/EmbolismMoslehi J. NEJM 2016, 375:15

VEGF Signaling Pathway Inhibitors

from Jain V, Barac A. Curr Treat Options Cardiovasc Med. 2017 May;19:36.

Mechanism of Action of Immune Checkpoint

InhibitorsTumor Suppresses

Host’s Immune System

via

Immune Checkpoints

(CTLA-4, PD1)

Immune Checkpoint

Inhibitors (Anti CTLA-4,

Anti PD1) Block the

Tumor’s Inhibitory Signal

Activate T-cells

James Allison, PhDTasuku Honjo, MD, PhD

New Approach to Treating Cancer By Inhibition

of Negative Immune Regulation

Nobel Prize in Physiology or Medicine 2018

Copyright 2018 Andy Brunning/Compound Interest.

Adverse Effects of Immune Checkpoint Inhibitors

..ITIS

Varricchi G et al. ESMO Open 2017; 2(4): e000247.

When You See

• Ipilimumab (anti CTLA-4)

• Nivolumab (anti PD1)

• Pembrolizumab (anti PD1)

• Atezolizumab (anti PD-L1)

• Avelumab (anti PD-L1)

• Durvalumab (anti PD-L1)

• Tremelimuman (anti CTLA-4)

Case 1: Old and New Therapies with CV

Effects• Capecitabine

– Oral preparation of 5FU – coronary spasm

• Bevacizumab

– Antibody to VEGF – hypertension, LV

dysfunction

• Atezolizumab (PD-L1 antibody)

– Immune checkpoint inhibitor - myocarditis

The best Next step in management:

A.Referral to palliative care for cancer progression

B.Antibiotics for pneumonia/sepsis due to

chemotherapy-related immunosuppression

C.LHC to exclude coronary spasm 2nd to

capecitabine

D.Steroids and myocardial biopsy to exclude

autoimmune process 2nd to atezolizumab

E.Medical management of HF related to bevacizumab

Case 1: Patient with Gastric

Cancer

• High dose steroids: 1mg/kg prednisone bid – up to

1g solumedrol until biopsy results

• LHC: no obstructive CAD

• Myocardial biopsy: no lymphocytic infiltrate, no

necrosis, minimal fibrosis

• ECG / Telemetry

– NSR and frequent PVCs (~12% burden)

– No AV block

Case 1: Suspected Autoimmune Myocarditis

• No evidence of myocarditis, Heart failure likely related to

bevacizumab

• Steroids tapered, HF treatment continued

– furosemide, carvedilol, candesartan, spironolactone

– 15,000 PVCs/day - improved with amiodarone

– 9 months later LVEF 40-45%

• Cancer treatment

– Interval progression: resumed capecitabine: switched to

carboplatinum-Taxol

– Started on therapy with nivolumab (anti-PD1 antibody)

Case 1: Clinical Course

67 years-old man with metastatic

melanoma treated ipilimumab (anti-

CTLA4) and nivolumab (anti-PD1).

One week after the first infusion:

• Rash treated with steroids (40mg of

prednisone daily)

• Progressive shortness of breath

In the local ED:

• Respiratory distress, pleural effusions

• Hypotensive

• ECG: Bigeminy

Case 2: Patient with Melanoma

Day 21 after ICI - infusion

Laboratory

- Troponin 27 ng/ml,

- NTproBNP 7953

- Creatine kinase 605

ECG

- Progression to complete heart block

Transferred to Advanced HF center

- RHC

- LHC- no coronary disease

- Transvenous pacemaker

- Endomyocardial Biopsy

Case 2: Patient with Melanoma

ECG – day 3 at a local hospital

Jain V, Barac A et al. J Immunother 2018;41:332–335

Endomyocardial Biopsy

• Patchy intense lymphocytic infiltration and

myocyte necrosis, consistent with lymphocytic

myocarditis

• Immunohistochemistry:

Case 2: Patient with Lymphocytic Myocarditis

H&E

CD3 + CD20 -

T-Cell + B-Cell -

Jain V, Barac A et al. J Immunother 2018;41:332–335

• High dose steroids

• Clinical progression with shock and

hypotension despite hemodynamic

support and steroids

• Antithymocyte globulin (ATG)

added to the steroid regimen

• Hemodynamic stabilization: off

inotropes with improved LVEF

• Prolonged hospital course:

ventilator associated pneumonia,

transition

• Seizure related to disease

progression

Case 2: Patient with Lymphocytic Myocarditis

Mahmood SS, Neilan T et al. JACC 2018;71:1755

22Monoclonal Antibodies:

NomenclatureMonoclonal antibody -mab

Murine -mo-mab

Chimeric -xi-mab infli-xi-mab

Humanized -zu-mab tras-tu-zu-mab

Human -mu-mab ipi-li-mu-mab

Tumor-directed -tu-xx-mab tras-tu-zu-mab

Immune-directed -li-xx-mab atezo-li-zu-

mab

CV-directed -ci-xx-mab beva-ci-zu-mab

Cardiovascular Assessment and Cancer Treatment

Postow M et al. NEJM 2018:378:158

Majority of patients receiving cancer treatments

NEVER receive cardiac assessment prior to

treatment

Chang HM, Yeh E. JACC 2017;70:2536

✓Anthracyclines

✓HER2 targeted tx

Trastuzumab

Pertuzumab

T-DM1

LVEF assessment

Conventional therapies

VEGF inhibitors

Immune check point

inhibitors

Proteasome

inhibitors

NO Routine Cardiac Imaging

Kenigsberg B, Barac A. JACC Heart Failure 2018: 6:87

Cardiology and Oncology Professional Society Statements

Cancer Drugs and CV Effects in 2019:

Take Home Points

• NO single “cardiotoxicity” of cancer treatments

• Different Mechanisms, Presentations and Treatments

– Anthracyclines/ HER2 targeted agents: Cardiomyopathy

– VEGF-pathway inhibitors:

– Tyrosine kinase inhibitors: Atherosclerosis and Vascular Toxicity

– Immune Checkpoint Inhibitors: Myocarditis and Pericardits

– CAR-T cells: Cytokine Release Syndrome

• Continued education about CV effects of Cancer treatments is

Critical

LiveCourse

COURSE DIRECTORSAna Barac, MD, PhD, FACC

Bonnie Ky, MD, MSCE, FACC

JANUARY 25 – 27, 2019 The Ritz-Carlton

Washington, DCFor more

information

and to register visit

ACC.org/CVOncology

Advancing the Cardiovascular Care of the

OncologyPatient

ACC.org/CVOncology

Feb 14-16, 2020

The Ritz Carlton, Washington DC

THANK YOU!