Cindy Herrera, PharmD, BCPS, BCOP...HL: Hodgkin Lymphoma // CVD: cardiovascular disease // CHD:...
Transcript of Cindy Herrera, PharmD, BCPS, BCOP...HL: Hodgkin Lymphoma // CVD: cardiovascular disease // CHD:...
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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
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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
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Leading Causes of Death in the US
Centers for Disease Control and Prevention. Number of Deaths for Leading Causes of Death 2012. 4
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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
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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
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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.
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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
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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
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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.
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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.
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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.
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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.
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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
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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.
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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
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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.
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Long Term Consequences in Lymphoma: Combating
Cardiotoxicity
Cindy Herrera, PharmD, BCPS, BCOP