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CARDIO ONCOLOGY
- 1. Chemotherapy-Induced Cardiotoxicity Clinical Pearls for the Advanced Practice Provider Elaine P. Macomb, ARNP Mayo Clinic Cardiovascular Department March 9, 2018 Cardiovascular Complications of Cancer Therapy: The Emerging Field of Cardio-Oncology Michael Fradley, MD Florida Chapter of the American Society of Clinical Oncology 10th Annual Great Strides Together APP/Physician Team Conference March 9, 2018
- 3. Disclosures: • Novartis Pharmaceuticals – Consulting Fees
- 4. Cardiotoxicity Background • Heart disease and cancer are the top 2 leading causes of death in the United States • Advances in cancer therapies have led to an improvement in survivorship • Cardiotoxicity – reported up to 50% patients up to 20 years later occurring after completion of therapy
- 5. Objectives • Define and explain mechanism • Cardiovascular complications • Identify signs and symptoms • Management of cardiotoxicity • Long-term monitoring
- 6. Definition of Cardiotoxicity • Heart injury – functional or structural due to cancer therapy • Reduction of LVEF – globally or regionally • Signs or symptoms of heart failure • Reduction of LVEF at least 5%-<55% with signs and symptoms of HF • Reduction of LVEF at least 10%-<55% without signs and symptoms of HF • Subclinical cardiovascular changes – diastolic dysfunction, LV strain – Early response
- 7. Mechanism of Cardiotoxicity • Acute, chronic, late • Direct cellular toxicity on cardiomyocytes induces oxidative stress • Reversible or irreversible
- 8. Objectives • Define and explain mechanism • Cardiovascular complications • Identify signs and symptoms • Management of cardiotoxicity • Long-term monitoring
- 10. Scope Of The Problem 1 of 3 adults have CV disease (82 million) 12 million cancer patients; 14 million cancer survivors Approximately 30% of patients receiving cancer therapy will have cardiovascular complications Some complications may not become apparent for 10-20 years after completion of treatments
- 11. Trends in 5-Year Cancer Survival www.pancreaticcanceraction.org
- 12. CV Disease: Common after Cancer Treatment Gregory T. Armstrong et al. JCO 2013;31:3673-3680 A. Coronary Artery Disease B. Valve Disease C. Arrhythmias D. Heart Failure
- 13. Cardiomyopathy and Heart Failure
- 14. Chemotherapy Induced LV Dysfunction Yeh and Bickford. JACC. 2009; 53: 2231-247. Zamorano et al. Eur Heart J. 2017; 19(1): 9-42.
- 15. Anthracycline Induced Cardiomyopathy Felker et al. New Engl J Med. 2000; 342; 1077-1084.
- 16. Anthracycline Induced Cardiomyopathy Von Hoff et al. American Journal of Medicine. 1977; 62: 200-8.
- 17. Anthracycline Induced Cardiomyopathy: Risk Factors • Cumulative Dose • Age • Female Gender • Concomitant use of additional chemotherapy or XRT • Underlying CV disease
- 18. LV Dysfunction and Targeted Therapies • HER2+ Targeted Therapies • Trastuzumab • Pertuzumab • Sunitinib
- 19. Trastuzumab and LVEF Slamon et al. New Engl J Med. 2011; 365: 1273-83.
- 20. Significant Heart Failure Associated with Trastuzumab Ewer and Ewer. Nat. Rev Cardiovasc Med. 2010; 7: 564-75.
- 21. Mechanism of Trastuzumab Cardiotoxicity Hansel et al. Nat Rev Drug Discov. 2010; 9: 387-395.
- 22. Trastuzumab Cardiotoxicity Increases Over Time Bowles et al. J Natl Cancer Inst. 2012; 104: 1293-1305
- 23. Trastuzumab and Anthracycline Cardiotoxicity: Fibrosis and Apoptosis Riccio et al. Hum Vaccin Immunother. 2016; 12: 1124-31.
- 24. TKI Induced LV DysfunctionPercentwithGrade2-4 LVEFDecline Hall PS et al. JACC Heart Fail. 2013; 1(1): 72-8.
- 25. Risk of CHF with Sunitinib Richards et al. JCO 2011;29:3450-3456
- 26. Carfilzomib Induced Cardiotoxicity Siegel et al. Haematologica. 2013; 98: 1753-61.
- 27. Techniques to Improve the Identification of Cardiotoxicity: Beyond Ejection Fraction • Biomarkers • Strain Imaging
- 28. Troponins and Development of Cardiotoxicity Cardinale et al. Circulation. 2004; 109: 2749-54.
- 29. Strain Imaging to Diagnose Chemotherapy Induced Cardiomyopathy Measure of myocardial deformation Identification of subclinical LV dysfunction prior to EF changes Potential role for early cardiovascular intervention
- 30. Abnormal Strain and Trastuzumab Exposure Hare et al. Am Heart J. 2009; 158: 294-301.
- 31. Heart Failure…Just the Tip of The Cardio-Oncology Iceberg
- 32. Coronary Artery Disease, Myocardial Infarction, and Peripheral Arterial Disease
- 33. Therapies Associated With Vascular Disease Radiation Tyrosine Kinase Inhibitors - Nilotinib - Ponatinib
- 34. CV Complications of Radiation Important part of treatment for many cancers including breast, lung and lymphoma Complications typically seen 5-10 years post exposure Complications include: - Premature CAD - Carotid Disease - Valvular disease (especially aortic and mitral disease) - Pericardial and myocardial disease - Heart failure - Conduction abnormalities
- 35. Risk Factors for Radiation Induced CV Disease Increase risk with increased dose (total dose >30 Gy or fractioned dose >2Gy/day) Heart volume exposed Time since exposure Adjunctive chemo/hormone therapy Presence of CV risk factors (diabetes, obesity, smoking, hypertension, dyslipidemia) Younger age
- 36. Darby et al. New Engl J Med. 2013; 368: 987-98. Coronary Events Associated with Radiation Therapy For Breast Cancer
- 37. Radiation and Carotid Artery Disease Huang et al. Radiat Oncol. 2013; 8: 261.
- 38. CML and Nilotinib: ENESTnd Trial Larson RA, et al. Leukemia 2012;26:2197-203. 2. Nilotinib prescribing information, 2013. 3. NCCN Guidelines v.4.2013 ENESTnd 3-Yr Update Hematologic AEs and Biochemical Abnormalities Grade 3/4 AEs, % Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) Imatinib 400 mg QD (n = 280) Neutropenia 11.8 10.8 21.4 Thrombocytopenia 10.4 12.3 8.9 Anemia 3.9 4.7 5.7 Lipase increase 7.5 7.9 3.9 ALT increase 4.3 9.4 2.5 Total bilirubin increase 3.9 7.9 0.4 Hyperglycemia 6.1 5.4 0 Nilotinib Toxicities • Prolongation of QTc and vascular adverse events • Coronary events • Peripheral Arterial Occlusive Disease PAOD
- 39. Nilotinib and Cardiovascular Events No of Patients: 28/279 44/277 7/280 Larson RA, et al. Blood. 2014;124:4541.
- 40. CML and Ponatinib: Cardiovascular Events Serious AE % AE % Serous AE % AE % Cardiovascular 5 6 6 10 Cerebrovascular 2 3 4 7 Peripheral Vascular 2 4 4 7 Venous Thromboembolism 2 3 3 5 Total Vascular Occlusion 11 16 17 29 US Ponatinib Insert (7/23/12) Median Follow up: 12 Mos (340 pt-years) PACE Trial (9/3/13) Medial Follow Up: 24 Mos (578 pt-years) Cortes JE et al. Blood. 2014;124:3135.
- 41. 5-Fluorouracil Induced Myocardial Ischemia and Infarction Cheat pain is a common symptom among patients treated with 5-FU Etiology is thought secondary to vasospasm though myocarditis is also possible Risk increased with continuous infusions Nitrates or calcium channel blockers may prevent episodes
- 42. QT Interval Prolongation and Arrhythmias
- 43. Malignancy and QT Prolongation Brell. Prog Cardiovasc Dis. 2010; 53: 164-72.
- 44. Chemotherapy Associated with QT Prolongation Chemotherapy Agents Incidence (%) Frequency of Use Small Molecule Tyrosine Kinase Inhibitors Sunitinib Vandetinib Nilotinib Dasatinib <1-3 15-18 1-3 <1 ++ + ++ ++ Histone Deacetylase Inhibitors Vorinostat 3.5-6 + Miscellaneous Aresenic 26-93 +
- 45. Cancer and Atrial Fibrillation O’Neal et al. Am J Cardiol. 2015; 116(12): 1858-62.
- 46. Chemotherapy and the Risk of Atrial Fibrillation Adapted from Guglin et al. Europace. 2009; 11: 1579-1586. Adapted from McMullen et al. Blood. 2014; 124: 3829-3830
- 47. Hypertension
- 48. VEGF Inhibitors and Hypertension PercentDevelopingGrade2-4 Hypertension Hall PS et al. JACC Heart Fail. 2013; 1(1): 72-8.
- 49. Mechanism of VEGF Induced Hypertension http://omicsonline.org/JGSGTimages/2157-7412-2-105-g001.html
- 50. VEGF Inhibitors and Hypertension: Marker of Efficacy? Rini et al. JNCI J Natl Cancer Inst. 2011;103:763- 773
- 51. VEGF Inhibitor Induced Hypertension: Treatment Options • First Line Therapies • ACE Inhibitors/Angiotensin Receptor Blockers • Dihydropyridine Calcium Channel Blockers (CCBs) • Second Line Therapies • Beta blockers and Diuretics • Novel/Investigational Therapies • Nitric Oxide Donating Medications • Endothelin-1 Receptor Antagonists Kaplan-Meier Estimate of Overall Survival Stratified by Antihypertensive Use McKay et al. Clin Cancer Res 2015;21:2471-2479
- 53. Valvular Heart Disease: Etiology and Risk Factors Most often associated with chest radiation May also be associated with anthracycline exposure Aortic and mitral valves most commonly affected Regurgitant lesions more common than stenotic Presents 10+ years post treatments
- 54. Prevalence of Valvular Abnormalities in Hodgkin Lymphoma Survivors Bijl et al. Am J Cardiol. 2016; 117:691-6.
- 55. Myocarditis
- 56. Mechanism of Check Point Inhibitors La-Beck et al. Pharmacotherapy: 2015; 35: 963-976.
- 57. Immune Checkpoint Inhibitor Cardiotoxity Heinzerling et al. J Immunother Cancer. 2016;4: 50. Nishimura et al. Science. 2001;291:319-322
- 58. Objectives • Define and explain mechanism • Cardiovascular complications • Identify signs and symptoms • Management of cardiotoxicity • Long-term monitoring
- 59. Signs and Symptoms of Cardiotoxicity • Asymptomatic- diagnosis made by routine echocardiogram • Symptoms Fatigue Decrease endurance or exercise tolerance Chest discomforts Palpitations Shortness of breath Swelling
- 60. Signs and Symptoms of Cardiotoxicity • Exam – Tachycardia, S3 gallop, JVD, Rales, cardiomegaly, Edema • Echocardiogram – Decline in LVEF, diastolic dysfunction, myocardial strain • Cardiac biomarkers – Elevated Troponins, BNP, NT- proBNP levels
- 62. Objectives • Define and explain mechanism • Cardiovascular complications • Identify signs and symptoms • Management of cardiotoxicity • Long-term monitoring
- 63. Management • Identify high risk patients for cardiotoxicity and modify CV risk factors • Adjust protocols – choose less cardiotoxic, dose reduction, slower infusion • Early detection • Collaborate with cardiology • Early institution ACC/AHA HF guideline-directed medical therapy – beta blockers, ACEi/ARBs, aldosterone-antagonists, diuretics • Dexrazoxane – cardio protectant recommended by the American Society of Clinical Oncology (ASCO) against anthracycline-induced toxicity • Devices – Consider prognosis, cancer cure, life expectancy of least more than one year
- 64. ACC/AHA Guidelines Heart Failure
- 66. Objectives • Define and explain mechanism • Cardiovascular complications • Identify signs and symptoms • Management of cardiotoxicity • Long-term monitoring
- 67. Long Term Monitoring • Long-term follow up indicated as cardiotoxicity may develop later (5-20 years) • Serial echocardiograms every 3 months • Reasonable to continue HF treatment indefinitely unless contraindicated
- 69. Global Cardio-Oncology Summit 2018 September 27-28, 2018 Tampa, Florida, USA Save the Date!
- 70. Thank You
Editor's Notes
- NOTES: Cancer therapy (alone or with radiotherapy) increase survival and lower recurrence but can be limited by risk of cardiotoxicity QT: Brady arrhythmias, heart blocks, tachyarrhythmias Radiation: pericarditis, pericardial effusions, epicardial coronary artery damage/inflammation->fibrosis, heart disease, valvular calcifications/thickening, stenosis, regurgitation.
- NOTES: Cardiac Review and Evaluation Committee on trastuzumab-associated cardiotoxicity and the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines Symptoms: Shortness of breath, fatigue, decreased endurance, chest discomforts, orthopnea, PND Signs: Tachycardia, S3 gallop, JVD, edema, cardiomegaly, pleural effusions
- NOTES: Acute- develops from initiation of treatment up to 2 weeks after completion of tx Chronic – develops within 1 year after completion of tx Late – develops more than 1 year after completion of tx Reversible- Depending upon chemotherapy agent, dose, route of administration and sequential and/or concomitant use of other chemotherapies
- NOTES: Cancer therapy (alone or with radiotherapy) increase survival and lower recurrence but can be limited by risk of cardiotoxicity QT: Brady arrhythmias, heart blocks, tachyarrhythmias Radiation: pericarditis, pericardial effusions, epicardial coronary artery damage/inflammation->fibrosis, heart disease, valvular calcifications/thickening, stenosis, regurgitation.
- Cardiotoxicity is a common adverse effect of many treatments, and can affect patient survival and quality of life independent of the oncological prognosis 17% of survivors of childhood cancer will have significant CV disease by age 50
- In 2011, estimated 12 million cancer survivors living in USA.
- Childhood cancer survivor study cantered at St. Jude. 10724 adult 5+ year survivors of childhood cancers and 3100 siblings. A: CAD, B: Valve disease C: arrhythmia; D HF Incidence of CAD, HF, arrhythmia, valve disease by 45 year of age was 5.3%, 4.8%, 1.3%, 1.5% respectively. Among siblings, very low. RT and anthracycline exposure additive with HF.
- Significant attention has been given to Anthracyclines and HER2 targeted therapies like Herceptin however also important to recognize its seen with other agents including certain TKIs like Sunitib and PI like carfilzomib. Bortezomib may not be particularly cardiotoxic. Concern is esp great with anthracyclines. If 400mg/m2, then 3-5% incidence. If greater than 7000mg/m2 over 20% incidence. Recognize that most protocols keep dose under 450mg/m2
- Note that these patients had a fairly poor early prognosis but plateaued after 5 years. Early risk may be related to cancer itself. Acute: <1%. Immediately after infusion and typically reversible. Early onset chronic progressive form: 1.6-2.1% during therapy or within 1 year. Late onset chronic progressive form: >1 year. 1.6-5% Median time to development of effects approx. 7 years but can be up to 10-20 years later. In older patients >65 years, rates can be as high as 10%. Recently published work by D. Cardinale showed 9% overall cardiotoxicity with 98% occurring in first year (older patient population ) and most asymptomatic. In addition to elderly young patients quite vulnerable often b/c pediatric heart still developing. In study looking at >32000 childhood cancer survivors, rate of CV complications at 8.1%. Remember that many of these survivors have cancers that are treated with anthracyclines and XRT. RR of HF at 5.2 (most common). If identified early, then often reversible. If identified late, then typically hard to treat. While it is recommended that pediatric patients have lifelong follow up for CV dysfunction many do not and they don’t present until irreversible damage has happened. As such, many of these patients require device based therapies.
- Increased probability of CHF with increasing dose. Threshold around 450mg/m2
- Incidence of congestive heart failure in the two trastuzumab-containing regimens was higher in the group receiving AC-T plus trastuzumab (2.0%) than in the AC-T group (0.7%) or the TCH group (0.4%) In addition, a significant difference in sustained, subclinical loss of mean LVEF (defined as >10% relative loss) was observed in the group receiving AC-T plus trastuzumab, as compared with the TCH group (18.6% vs. 9.4%, P<0.001), with a rate of 11.2% in the AC-T group.
- <1-27% depending on trial and arm for trastuzumab Concurrent anthracycline vs delay. 90days for HERA. Only 0.6 developed class 3 or 4 heart failure
- Oncogenic signalling in a breast cancer cell can be mediated by members of the epidermal growth factor receptor (EGFR) family. Amplification of the gene encoding ERBB2 (also known as HER2/neu) tyrosine kinase is crucial for the progression of some forms of human breast cancer. ERBB2–ERBB3 kinase then activates the Ras–extracellular signal-regulated kinase (ERK) pathway and the phosphatidylinositol 3-kinase (PI3K)–AKT pathway. AKT has a central oncogenic role, partially through inhibiting B cell lymphoma 2 (BCL-2) and antagonist of cell death (BAD). Trastuzumab (Herceptin; Genentech) binds to the extracellular domain of ERBB2 and inhibits the proliferation and survival of ERBB2-dependent breast cancer cells. Trastuzumab also reverses inhibition of BAD, which leads to BCL-2-associated X protein (BAX) oligomerization at the mitochondrial membrane, release of cytochrome c (Cyt c), and caspase activation to cause apoptosis of tumour cells. In addition to inhibiting ERBB2 signalling, trastuzumab might also exert effects through antibody-dependent cell-mediated cytotoxicity (not shown).b | Signalling in cardiomyocytes through ERBB2–ERBB4 heterodimers is essential for cardiomyocyte proliferation during cardiac growth and development, and for contractile function in the adult. Although several of the same signalling pathways (such as Ras–ERK and PI3K–AKT) are activated in cardiomyocytes and in breast cancer cells, an increase in the ratio of BCL-Xs to BCL-XL induced by ERBB2-specific antibodies might trigger BAX oligomerization, mitochondrial membrane depolarization, ATP depletion and contractile dysfunction. In addition, antibody-dependent cell-mediated cytotoxicity might contribute to trastuzumab cardiotoxicity. Trastuzumab also blocks neuregulin 1 (NRG1)-mediated activation of Src and focal adhesion kinase (FAK), and this appears to worsen left ventricular dysfunction. GRB2, growth factor receptor-bound protein 2; PIP3, phosphatidylinositol triphosphate. Adapted from Refs 152, 159.
- Likely that ERBB2/4 pathways is chronically activated in many CV disease states. Blocking can make these disease states more prominent promoting fibrosis and apoptosis. These findings confirm that trastuzumab toxicity is not always reversible
- Forest plot of relative risk (RR) of all- and high-grade congestive heart failure (CHF) events associated with sunitinib versus control. RR of all- and high-grade CHF was calculated using fixed-effects model; size of squares is directly proportional to amount of data in each trial. RR of all grade 1.81 RR of high grade 3.3
- Cardiovascular complications include any cardiac 22%, hypertension (14%), cardiac failure (7% -- includes pulmonary edema and reduced EF) More recent single center data In the phase III ASPIRE trial comparing the efficacy of carfilzomib, lenalidomide, and dexamethasone to lenalidomide and dexamethasone, the carfilzomib arm demonstrated higher rates of cardiovascular complications including CHF (6.4% vs 4.1%), ischemic heart disease (5.9% vs. 4.6%), hypertension (14.3% vs. 6.9%) and VTE (10.2% vs. 6.2%) Carfilzomib irreversible binding which may explain more consistent cardiotoxicity findings however no studies directly comparing bortez and carfilz proteosome inhibition in cardiac myocytes.
- 2D echo is now preferred over muga. Less radiation. Greater than 15 change from baseline is significant Why no muga – less radiation, current gamma cameras have large field of view 2 head system which has less reproducibility compared to past due to patient positioning. Also cant give additional info.
- Possibility of early addition of cardioprotective medications
- Risk up to 3.5% among women with BC who receive XRT Conduction abnormalities mainly RBBB or AV block including CHB No clear screening guidelines
- Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray with no apparent threshold Increase started within the first 5 years of XRT and continued for 30 years after therapy 2 Gy 10%; 2-4 Gy 30%; 5-9 Gy 40%; >10 Gy 116% (% increase in rate of MACE compared to those without XRT)
- Asymptomatic carotid stenosis in the general population has a reported prevalence of up to 3.1% in the general population. The endothelium and the vasa vasorum are particularly vulnerable to radiation damage. Also to accelerated atherosclerosis. Studies have shown that IMT was significantly increased in nasopharyngeal cancer patients who received prior neck XRT with carotid plaque detected in 36% of patient at least 42.5 months post exposure. They found that those patients had significantly higher rates of carotid disease compared to controls (78.9% vs. 22%). Severe disuse (>70%) only in the post XRT group. It had previously been thought that radiation induced vascular disease did not occur for more than 10 years post exposure however several studies have suggested the development of significant disease can occur as early as 5 years post exposure Significant risk factors for carotid plaques included age, duration after radiotherapy, and HbA1c levels. Age, duration after radiotherapy, hs-CRP, HbA1c, and platelet count positively correlated with IMT. The cut-off value of age and duration after radiotherapy for the presence of plaque was 52.5 years and 42.5 months, respectively. After adjustments for age, gender and platelet counts, IMT increased in a linear manner with duration after radiotherapy.
- Initially a second line agent, nilotinib was approved for patients with newly diagnosed CML based on higher 12 months major molecular response rates and reduced progression compared to imatinib in the ENESTnd trial. Serial echocardiograms during the trial revealed no evidence of cardiomyopathy. 36% of patients on nilotinib 300bid experienced hyperglycemia compared to 20% on imatinib. Grade ¾ (glucose >250) 6% vs 0 Also associated with hyperlipidemia.
- Several recent studies have demonstrated vascular toxicity with nilotinib. May aggravate a pre-exisiting atherosclerotic condition. Meta-analysis of IRIS, TOPS and ENESTnd trials: PAOD 1.3% with nilotinib, 0.6% with no TKI, 0.2% with imatinib (PAOD). At 6 year follow up from ENESTnd trial, the number of vascular events is striking. Included ischemic heart disease, cerebrovascular disease, and PAD. Suggest toxicity occurs in the arterial bed. Shortcoming is the various definitions. PAOD not used in cardiology. And it is not a specific CTCAE category – peripheral arterial ischemia is a category but vague definitions. In the meta-analysis, cardiac and cerebral events were not included in analysis.
- Ponatinib designed to inhibit BCR-ABL T315I Median of 28 months of follow up cumulative cardiovascular, cerebrovascular and peripheral AE: 10%, 7%, 7%. 14% arterial and 3 % venous serous AE. 26% of patients develop hypertension which is expected given VEGFR2 inhibition. Traditional atherosclerotic risk factors such as age, hypertension or diabetes and especially 2 or more RF predisposed to serious vascular AE Exact pathophys is unclear. Accelerated Atherosclerosis or embolic or vasospasm. Possible endothelial dysfunction
- Patient we saw receiving 5FU for head and neck cancer. Receiving it as an infusion which increases risk of cardiotoxicity. Developed chest pain, rapid AF and ST elevations. Cath lab activated but prior to going degenerated into VT/VF requiring cardioversion. Cath showed clean cor. Possible vasospasm but not clear as challenges with ergonovine don’t always cause vasospasm. Mechanism is not entirely clear – possibly myocarditis. Role for ICD or not???
- Older age Bradycardia Female Electrolytes drugs
- TKIs: 9 have either standard or black box warnings Sunitinib: QT prolongation was only observed with high concentrations of the drug, however no clinical events were reported. The mean increase in the QTc using the Fridericia formula was 15.4ms (90% confidence interval 8.4 to 22.4ms). Other clinical studies with sunitinib failed to show any impact on the QT interval. Vandetanib (thyroid cancer) – up to 18%. Most asymptomatic. At least 1 TdP. Black Box. Nilotinib – Under 3% but 0.3% SCD (attributed to TdP but not proven). Nonetheless, Black box warning. Histone deacetylase inhibitors (HDI) are group of molecularly targeted pharmaceuticals which modulate the post transcriptional activity of proteins by inactivating histone deacetylase enzymes. ,
- There is increased prevalence of AF in cancer. Most evidence has been in lifethreatening patients in the post op settting. Non life threatening, not on theapy. Still elevated risk. Multivariate analysis adjusting for socioeconmic and CV risk factors, cancer still more likely to have AF (OR 1.19, 95% CI).
- First reported with Sunitinib and Sorafenib. Also nilotinib. Ibrutinib is a TKI that targets BTK (bruton’s tyrosine kinase inhibitor) and TEC protein kinase. Used to treat CLL, Mantle Cell and Waldenstroms. Rate of AF up to 10%. In Resonate, 10 fold increase in AF. Incidence of AF (or other SVT) was 12% (n = 9) among the entire study cohort. Indications for ibrutinib use were primarily chronic lymphocytic leukemia (71%) and mantle cell lymphoma (22%). There were 69 pts without prior history of AF or antiarrhythmic drug use who were further analyzed for arrhythmia risk factors. In all incident cases, arrhythmias were managed by temporary cessation of ibrutinib with resumption after achieving adequate heart rate control. Comparing the pts that developed AF to those that did not, there were no significant differences in age, gender, body mass index, race, prior cardiovascular disease, hypertension, diabetes mellitus, tobacco use, or ibrutinib dose. Median ejection fraction (EF) among pts with AF was 65%, and the median left atrial (LA) size was 3.0cm. In those pts without AF, median EF was 62% and the median LA size was 3.5cm. There was no significant difference between groups (p = 0.96 for EF; p = 0.46 for LA size). Conclusions: The incidence of AF in our study was higher than in the original ibrutinib trials. There was no difference in echocardiographic parameters or traditional risk factors for the development of AF between groups, suggesting that ibrutinib may be intrinsically associated with AF. A case control study is ongoing to evaluate ibrutinib as an independent risk factor for AF. Soon to be presented data suggests that ibrutinib may also have effects on cardiac repolarization. A recently published meta-analysis of ibrutinib studies reported the relative risk of ibrutinib-associated AF was 3.9 (2.0-7.5, p=0.0001) and the pooled rate of AF among participants exposed to ibrutinib was 3.3 per 100 person-years.21 Despite these data, none of the studies have reported their methods for identifying AF and other arrhythmias leading to a lack of consistency and perhaps substantial under-ascertainment in the reported data.
- Grade 2-4 hypertension (SBP >140 with need to initiate hypertensive therapy) Grade 3-4 up to 18% of patients. Greatest increase is usually during first cycle of treatment. Some people argue that hypertension is a marker for response to therapy. Pre-exisiting hypertension, BMI and age are risk factors for VEGF hypertension
- Multiple VEGF isoforms – A-D. 3 VEGFR – 1 and 2 predom in endothelial cells. Major angiogensis is VEGFA to VEGFR-2 This activates eNOS (NO synthase) resulting in up to a 5 Fold increase in NO production. Inhibition of VEGF leads to decreased NO and vasoconstriction. Other theories: Activation of the plasma enothelin system – study in Sunitinib showed 2 fold increase in endothelin 1 and giving endothelin receptor blocker improved hypertension. Also abnormalities in RAA system. Treatment is usually with traditional agents (ACE/ARB, CCB (except nondihydropyridines like dilt/verap with sorafenib given interaction with CYP3A4) and BB). There may be a role in adding NO donating medications early – long acting nitrate, phosdiesterase inhibitors like sildenafil or nebivolol which has NO donating properties. RCTs need to be conducted.
- During a median follow-up of 13.4 years (range 2 to 39 years), ≥ mild valvular disease was present in 61.2% of HL survivors with MRT (n = 30), compared with 31.0% of HL survivors without MRT Severe valvular disease was present in 24.5% of HL survivors with MRT compared with 3.4% without MRT (p = 0.016). This finding was most striking for AR; >20 years after MRT, 75% of patients showed at least a mild severity of AR
- Immunotherapy is revolutionizing the current treatment for many cancers including lung and melanoma. Immune-checkpoint blocking antibodies including anti-CTLA-4 and anti-PD1 can induce tumor responses in various tumor types including melanoma, non-small cell lung cancer (NSCLC), renal cell cancer (RCC), and Hodgkin disease. The anti-CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have been approved The primary effector cells of the adaptive immune response against cancer are the T lymphocytes that include helper T cells and cytotoxic T lymphocytes (CTLs). Helper T cells play an important role in propagating the antitumor immune response, and CTLs have direct tumor cell–killing capacity. The functions of both cell types require recognition of tumor antigens presented in the context of major histocompatibility complex (MHC) receptors. This process of T-cell priming and activation occurs through interactions of T-cell receptors (TCRs) and antigen/MHC complexes on antigen-presenting cells (APCs).[9] Importantly, T-cell priming/activation is tightly regulated by costimulatory or coinhibitory signals known as immune checkpoints (Figure 1). When TCR and antigen/MHC binding is accompanied by engagement of costimulatory receptors, this results in priming and activation of T cells toward that specific antigen. In contrast, when TCR and antigen/MHC binding is accompanied by engagement of coinhibitory receptors, such as cytotoxic lymphocyte–associated protein 4 (CTLA-4), this results in T-cell inhibition.[10] The CTLA-4 receptor is overexpressed in many cancers, and activation of this receptor leads to inhibition of naive and memory T-cell function, contributing to the development of cancer antigen tolerance in T cells.[10] After priming/activation, CTLs migrate to tumors, where they exert their killing activity on tumor cells. This is also tightly regulated by immune checkpoints such as the programmed cell death protein 1 (PD-1) receptor that is expressed on T cells.[10] The known ligands are PD-L1 and PD-L2, which are expressed on many types of cancer cells and APCs. Binding of the coinhibitory PD-1 receptor to its ligand results in T-cell apoptosis and anergy, and it downregulates cytokine production, leading to suppression of the antitumor immune response.[9] Under normal physiologic conditions, the immune checkpoints serve to inhibit immune responses against self-antigens, thereby preventing unwanted autoimmunity.[10] However, these inhibitory pathways are upregulated in many cancers, and immune checkpoints play critical roles in cancer-associated immune suppression and immune evasion.
- Ventricular arrhythmias likely secondary to immune effects from inhibiting these receptors on myocytes leading to CHF and myocarditis. Dilation and impaired movement of hearts from PD-1−/-mice as revealed by transthoracic echocardiography. (A) Echocardiographic analyses of heart from PD-1+/+ (upper) and PD-1−/− (lower) mice. Representative images of 2D (left) and M-mode (right) analyses are shown (11). Bars in M-mode images indicate left ventricular end-diastolic (left) and end-systolic (right) dimensions. IVS, interventricular septum; LV, left ventricle; RV, right ventricle; LVPW, left ventricular posterior wall. (B) Indices of heart movement based on the echocardiographic analysis of PD-1+/+ (n = 5) and PD-1−/−(n = 4) mice. LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; and %FS, percent fraction shortening. Statistical significance (P value) was evaluated by Student's t test. 6 person case series of cardiotoxicity with different PD1 and CTLA4 inhibitors -- myocarditis and CHF most common with superimposed arrhythmias. At least 2 fulminant cases leading to patient death with associated arrhythmias. Histologic presentation of case 5. a H&E stain of the endomyocardial biopsy shows patchy lymphohistiocytic infiltrates associated with myocyte damage, diagnostic for lymphocytic myocarditis. b IHC stain for CD3 highlights in brown T cells within the inflammatory infiltrate (c) IHC stain for CD8 highlights in brown T cells within the inflammatory infiltrate (d) IHC stain for CD68 shows many histiocytes/macrophages within the myocardial inflammation
- NOTES: LVEF decline usually does not occur until a significant amount of myocardial damage has occurred. Diastolic dysfunction may precede LVEF decline . Strain - measurement of myocardial deformation – subclinical changes in cardiac function even before a decrease in LVEF is seen – A 10-15% early decrease in peak systolic global longitudinal strain most useful parameter in early detection of cardiotoxicity. Normal more -18%. Troponins – proteins within myocardium released when myocyte damage occurs, can increase within hours after cardiac damage. Can detect cardiotoxicity in its earliest phase before LVEF reduction seen. BNP/NT-proBNP – biomarkers of hemodynamic overload and increased wall stress
- NOTES: LVEF decline usually does not occur until a significant amount of myocardial damage has occurred. Diastolic dysfunction may precede LVEF decline . Strain measurement of myocardial deformation – subclinical changes in cardiac function even before a decrease in LVEF is seen – A 10-15% early decrease in peak systolic global longitudinal strain most useful parameter in early detection of cardiotoxicity. Normal more -18%. Troponins – proteins within myocardium released when myocyte damage occurs, can increase within hours after cardiac damage. Can detect cardiotoxicity in its earliest phase before LVEF reduction seen. BNP/NT-proBNP – biomarkers of hemodynamic overload and increased wall stress
- NOTES: Early detection via cardiac biomarkers, echocardiogram, MRI If LVEF <50%, refer to cardiology – Discuss prognosis while weighing in risks vs benefits of withholding cancer therapy Slower infusions duration of 6 hrs or longer showed a lower rate of clinical HF Beta blockers and ACEi – cardioprotective - mitigate oxidative stress One observational study showed normalization of LVEF 42% patients with early institution. No improvement noted when tx was started > 6 mos post chemo completion. Every effort should be made to optimize GDMT so that chemotherapy can be resumed Early detection and early institution of GDMT, even anthracycline-induced cardiotoxicity may be reversible.
- NOTES: Early detection via cardiac biomarkers, echocardiogram, MRI If LVEF <50%, refer to cardiology – Discuss prognosis while weighing in risks vs benefits of withholding cancer therapy Slower infusions duration of 6 hrs or longer showed a lower rate of clinical HF Beta blockers and ACEi – cardioprotective - mitigate oxidative stress One observational study showed normalization of LVEF 42% patients with early institution. No improvement noted when tx was started > 6 mos post chemo completion. Every effort should be made to optimize GDMT so that chemotherapy can be resumed Early detection and early institution of GDMT, even anthracycline-induced cardiotoxicity may be reversible.