Long Term Consequences in Lymphoma: Combating Cardiotoxicity

Cindy Herrera, PharmD, BCPS, BCOPClinical Heme/Onc / BMT PharmacistNorthwestern Memorial Hospital

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Cardiac Long-Term ToxicitiesCynthia Herrera, PharmD, BCPS, BCOP

Disclosures

• The speaker for this presentation has the following disclosure:

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Name Company Role

Cynthia Herrera, PharmD, BCPS, BCOP None N/A

Off-label use disclosure:

• This session might include a discussion of off-label treatment and investigational agents not approved by the FDA for use in the US

Leading Causes of Death in the US

Centers for Disease Control and Prevention. Number of Deaths for Leading Causes of Death 2012. 4

Cancer – A New Chronic Disease

5 year survival rates for HL & NHL have improved by 15-25% over the last 25 years

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US Mortality & Incidence Files, National Center for Health Statistics, Centers for Disease Control and Prevention.

Hodgson DC et al. Clin Adv Hem Onc 2015:13(2);103-112.

Leukemia & Lymphoma Society. Facts & Statistics. 03/26/19HL: Hodgkin Lymphoma // NHL: Non-Hodgkin Lymphoma

High Risk of Cardiac Mortality in HL

• Compared to the general population: 4-7 fold increased risk of CHD/HF are observed 35 years or more after HL treatment

• Cumulative incidence of any type of cardiovascular disease = 50% at 40 years after HL diagnosis

• Treatment before 21 years of age had highest risk of death from CVD

• Risk of cardiac disease directly related to radiation doses & anthracycline exposure

6Van Nimwegen FA, et al. JAMA 2015;175(6):1007-1017.HL: Hodgkin Lymphoma // CVD: cardiovascular disease // CHD: coronary heart disease // HF: heart failure

American Society of Clinical Oncology

• In 2017 ASCO released a clinical practice guidelines for the prevention & monitoring of cardiac dysfunction in survivors of adult cancer

• Patients with cancer who meet any of the following criteria should be considered at increased risk for developing cardiac dysfunction:• High-dose anthracycline (eg, doxorubicin at ≥ 250 mg/m2, epirubicin at ≥ 600

mg/m2)

• High-dose radiotherapy (≥ 30 Gy) where the heart is in the treatment field

• Lower-dose anthracycline (eg, doxorubicin at < 250 mg/m2, epirubicin at < 600 mg/m2) in combination with lower-dose radiotherapy (< 30 Gy) where the heart is in the treatment field

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Armenian SH, et al. J Clin Oncol: 2017;35:893-911.

Cardiotoxicity Within Our Treatments

• Myocardial dysfunction

• Myocardial ischemia

• Arterial Hypertension

• Arrhythmias

• Pulmonary Hypertension

• Thromboembolic Disease

• Valvular Heart Disease

• Pericarditis & Pericardial Effusion

• Peripheral Artery Disease

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Anthracyclines

Radiation Therapy

Ibrutinib

Cyclophosphamide

Lenalidomide

RADIATION

• Produces late onset intimal thickening in the coronary arteries & microvascular damage → reduced myocardial perfusion

• RT related late cardiac effects are dose related• Goal to keep the mean heart dose <15 Gy with mediastinal RT

• Risk decreased significantly when doses less than 30 Gy are used (30 Gy =10%, 25 Gy= 6%, 20 Gy =5%, 0 Gy= 3% )

• Mean heart radiation dose per 1 Gy increase was a significant predictor of CVD

9RT: radiation therapy // CAD: coronary artery disease // CVD: cardiovascular disease

Hogeson DC. Clin Adv Hem Onc 2015:13(2);103-112.

Schellong G et al. Pediatr Blood Cancer 2010:55(6):1145-1152.

Ng AK. Blood 2014:124(23);3373-3379.

Armenian SH, et al. J Clin Oncol: 2017;35:893-911.

Maraldo MV et al. Lancet Hematology 2015;2:e492-502.

• Preventative strategies: • Per ASCO recommendations, clinicians should select

lower RT doses when clinically appropriate or tailored radiation fields with exclusion of as much of the heart as possible

ANTHRACYCLINES• Well documented: decreased systolic function, dilated cardiomyopathy,

and heart failure

• Directly toxic to the myocardium• Free radical medicated oxidative damage• Induction of cellular apoptosis

• Incidence of HF = 8-25% with a dosage of 550 mg/m2• An analysis of 6040 patients found the dose of anthracyclines per 50mg/m2 increase

in cumulative dose was a significant predictor of CVD

• Other considerations:• ACEi/BB as cardio-protection• Utilizing dexrazoxane

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HF: heart failure // ACEi: angiotensin-converting-enzyme inhibitor // BB: beta-blocker

CVD: cardiovascular disease Hogeson DC. Clin Adv Hem Onc 2015:13(2);103-112.

CYCLOPHOSPHAMIDE• What it looks like: tachyarrhythmias, hypotension, heart failure, myocarditis,

and pericardial disease• Present typically within first 48 hours of drug administration – can be seen up to 10 days

after initation

• Incidence of acute heart failure: 7-33% (TD>150mg/kg)

• Recommendations for monitoring: ECG may predict the earliest changes in acute heart failure

• MOA: metabolites causing oxidative stress & direct endothelial capillary damage

→direct damage to the myocardium

→edema, interstitial hemorrhage, & formation of microthrombi

→acute heart failure & arrhythmias

11Dhesi S et al. J Investig Med High Impact Case Rep 2013;1(1):2324709613490346.

IBRUTINIB

• Most common CV toxicity: atrial fibrillation (1-10%)• Pooled relative risk of AF against alternative therapies = 3.9 (vs 0.84, p<0.0001)

– incidence increased in men

• MOA: unintentionally inhibits PI3K-Akt pathway in cardiac myocytes• Patients with AF showed significantly lower cardiac PI3K-Akt activity than

those in sinus rhythm → become highly susceptible to AF• Important for the prevention of stress induced cardiomyopathy

• Mean time to onset of atrial fibrillation: 7.6 months• However, risk is highest in the 1st several months of therapy

• Significant risk factors for development: history of AF, Framingham Heart Study AF risk score

12CV: cardiovascular // AF: atrial fibrillation

Leong DP, et al. Blood 2016:128;138-140.

Wiczer TE et al. Blood Adv 2017:1(20);1739-1748.

McMullen JR, et al. Blood 2014:124:3829-3830.

IMMUNE THERAPY

• Rare with both adoptive T cell therapy & ICI• CART: in the context of cytokine release syndrome → projected

mechanism of cardiomyopathy similar to that observed with stress-induced (takotsubo) / sepsis – induced cardiomyopathy • Off-target cross reactivity to affinity enhanced T cells

• ICI: specifically myocarditis, observed more in combination ICI therapy & in patients with diabetes

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CART: chimeric antigen receptor T cells ICI: immune checkpoint inhibitors MP: methylprednisone

CART:

•Resuscitation

•Tocilizumab → steroids if no response in 24h

ICI: •Pulse steroids (MP 1g/day x 3-5 days)

Asnani A. Curr Onc Rep 2018:20(44);1-7.

NCCN. Management of Immunotherapy-Related Toxicities (Version 1.2019). Accessed March 2019.

What do we do with this information?

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Summary of follow-up recommendations for long-term HL survivors according to NCCN and COG

NCCN after 5 years in HL survivors

✓Annual lipids

✓Annual blood pressure

✓Aggressive management of CV risk factors

✓Stress test / echocardiogram at 10 year intervals after treatment complete

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Van Nimwegen FA, et al. JAMA 2015;175(6):1007-1017.

Carver JR, et al. Semin Oncol 2013;40(2):229–238.

Plana JC, et al. J Am Soc Echocardiogr 2014;27:911-39.

NCCN. Survivorship(Version 1.2019). Accessed March 2019.HL: Hodgkin’s lymphoma / CHD: congestive heart disease / HF: heart failure / CVD: cardiovascular disease

Children’s Oncology Group

✓Fasting glucose & lipid profile every 2 years

✓Echocardiograms at the conclusion of treatment and then every 1-5 years of life depending on age of treatment, anthracycline dose & chest irradiation

Preventative Intervention

• Studies have suggested early intervention with cardioprotective medication may decrease the rate of cardiac remodeling & progression to heart failure• Early initiation has been associated with higher likelihood of LVEF

recovery

• Theoretical benefit must be weighed against the side effects of treatment → dizziness / hypotension observed in 22%, fatigue observed in 10% (compared to 3% & 0%, respectively)

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NCCN. Survivorship(Version 1.2019). Accessed March 2019.

Cardinale D, et al. J Am Coll Cardiol 2010;55:213-220.

Silber JH, et al. J Clin Oncol 2004;22:820-828.

Take Away

• Our lymphoma patients are a KNOWN population at high risk of developing CVD

• HL: 4-6 fold increase of developing CHD/HF― Observed 35+ years after treatment ― Risk of CVD has not decrease in the more recent decades

• Asymptomatic disease (via imaging abnormalities) is more common than symptomatic disease

― Can be found in ~50% of all survivors of anthracycline- or radiation-based therapy

• Although there is acceptance of the potential risks and need for surveillance, there is currently a lack of agreement about the details of follow-up testing

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Van Nimwegen FA, et al. JAMA 2015;175(6):1007-1017.

Carver JR, et al. Semin Oncol 2013;40(2):229–238.

HL: Hodgkin’s lymphoma / CHD: congestive heart disease / HF: heart failure / CVD: cardiovascular disease

Cardiovascular Disease & Cancer

• Estimated 15 million people with CVD & 14 million people with cancer

• Biological mechanisms common in CVD & cancer: • Systemic inflammation → Atherosclerosis → Thrombosis

• Modifiable CVD Risks:• Obesity• Diabetes• Hypertension• Hyperlipidemia• Tobacco, Alcohol• Physical activity

18Koene RJ, et al. Circulation 2016;133(11):1104-1114.

Long Term Consequences in Lymphoma: Combating

Cardiotoxicity

Cindy Herrera, PharmD, BCPS, BCOP

Cynthia.Herrera@nm.org