click to edit master title style cardiovascular...
TRANSCRIPT
![Page 1: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/1.jpg)
Click to edit Master title style
Cardiovascular Considerations in Malignant HematologyMargot Davis, MD MSc FRCP(C)Clinical Assistant Professor, UBC Division of CardiologyDirector, UBC Cardio-Oncology Program
![Page 2: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/2.jpg)
Click to edit Master title styleDisclosures
• Consultancy/speaking fees: Janssen, Novartis, Boehringer-Ingelheim, Takeda, Pfizer, Akcea, Alnylam, Amgen, Ferring, TerSera
• Grant funding: Pfizer
![Page 3: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/3.jpg)
Click to edit Master title style• Review cardiovascular toxicities and prevention
strategies associated with the treatment of common hematologic malignancies, including
– Chronic lymphocytic leukemia (CLL)
– Chronic myelogenous leukemia (CML)
– Multiple myeloma
…In 15 minutes…
Objectives
![Page 4: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/4.jpg)
Click to edit Master title style
CLLIbrutinib & arrhythmias
![Page 5: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/5.jpg)
Click to edit Master title styleRisk of AF with Ibrutinib: Systematic review and meta-analysis
5
Relative risk of AF ibrutinib vs. comparator
Leong D, et al. Blood 2016. doi: https://doi.org/10.1182/blood-2016-05-712828.
![Page 6: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/6.jpg)
Click to edit Master title styleAF and bleeding in patients treated with ibrutinib
Grade 3/4 AF
All AF All Bleeding
Major Bleeding
Clinical Lymphoma, Myeloma & Leukemia, Vol. 17, No. 1, 31-7
![Page 7: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/7.jpg)
Click to edit Master title styleBleeding Events (> 3%) by AE Grade - RESONATE
• The most common bleeding
AEs were grade 1 petechiae
(13%) and contusion (11%)
(RESONATE™)
• Bleeding AEs led to
discontinuation of ibrutinib in
1 patient in the
RESONATE™ ibrutinib
arm), due to major bleeding
7Jones et al. ASH 2014; Abstract 1990.
![Page 8: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/8.jpg)
Click to edit Master title style• Bleeding AEs in 48% of
patients, majority grade 1
(40%), with grade 2 reported
in 6%, grade 3 (2%), and
grade 4 (1%)
• Grade ≥ 3 bleeding events
included grade 3 epistaxis (n
= 1), grade 3 spontaneous
hematoma (n = 1), and
grade 4 subdural hematoma
(n = 1)
• No grade 5 events
• Median time on treatment
was 16 months
Bleeding Events (> 3%) Over Time - RESONATE
8
Bleeding Events by Time to New Event
Onset in RESONATE™ (Ibrutinib Arm)*
Brown et al. ASH 2014; Abstract 3331; Jones et al. ASH 2014; Abstract 1990.
*Median follow-up 9.6 months
![Page 9: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/9.jpg)
Click to edit Master title styleIbrutinib strategies after new AF
British Journal of Haematology, 2016, 175, 462–466
First episode AF
Ibrutinibstopped
N=22
Resolved
N=11
Permanent D/C
N=8
Rechallenged
N=3
Recurred/ ongoing
N=11
Permanent D/C
N=10
Rechallenged
N=1
Dose reduced
N=13
Resolved
N=5
Continued
N=5
Recurred/ ongoing
N=8
Discontinued
N=1
Continued
N=7
Continued full dose
N=21
Resolved
N=8
Continued
N=8
Recurred/ ongoing
N=13
Discontinued
N=3
Continued
N=10
No AF,Ibrutinib
AF, Ibrutinib
AF, NoIbrutinib
No AF, NoIbrutinib
Stopped
Dose reduced
Continued
![Page 10: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/10.jpg)
Click to edit Master title styleIbrutinib strategies: AF in follow-up
British Journal of Haematology, 2016, 175, 462–466
First episode AF
Ibrutinibstopped
N=22
Resolved
N=11
Permanent D/C
N=8
Rechallenged
N=3
Recurred/ ongoing
N=11
Permanent D/C
N=10
Rechallenged
N=1
Dose reduced
N=13
Resolved
N=5
Continued
N=5
Recurred/ ongoing
N=8
Discontinued
N=1
Continued
N=7
Continued full dose
N=21
Resolved
N=8
Continued
N=8
Recurred/ ongoing
N=13
Discontinued
N=3
Continued
N=10
No AF,Ibrutinib
AF, Ibrutinib
AF, NoIbrutinib
No AF, NoIbrutinib
Stopped
Dose reduced
Continued
![Page 11: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/11.jpg)
Click to edit Master title styleIbrutinib strategies: continued ibrutinib
British Journal of Haematology, 2016, 175, 462–466
First episode AF
Ibrutinibstopped
N=22
Resolved
N=11
Permanent D/C
N=8
Rechallenged
N=3
Recurred/ ongoing
N=11
Permanent D/C
N=10
Rechallenged
N=1
Dose reduced
N=13
Resolved
N=5
Continued
N=5
Recurred/ ongoing
N=8
Discontinued
N=1
Continued
N=7
Continued full dose
N=21
Resolved
N=8
Continued
N=8
Recurred/ ongoing
N=13
Discontinued
N=3
Continued
N=10
No AF,Ibrutinib
AF, Ibrutinib
AF, NoIbrutinib
No AF, NoIbrutinib
Stopped
Dose reduced
Continued
![Page 12: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/12.jpg)
Click to edit Master title stylePFS in patients with and without AF in ibrutinib trials
Haematologica 2017;102(10):1796-1805
![Page 13: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/13.jpg)
Click to edit Master title style• Consider contributing causes
– TSH– Echo– Sleep study if appropriate
• Anticoagulation if indicated by CCS guidelines– CHADS2 ≥1 or age >65
• Consider bleeding risk, as in general AF patients– Avoid warfarin
• Excluded from clinical trials– NOACs preferred
• Evaluate rate control and symptom burden– Most patients easily rate-controlled with BB– Avoid drugs that interact with Ibrutinib: CCB, amiodarone, digoxin
• No evidence that Ibrutinib dose reduction changes AF burden
Approach to AF with Ibrutinib
![Page 14: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/14.jpg)
Click to edit Master title style
• Review of FDA AERS Nov 2013-May 2017
• 33 cases VA reported
• “Probably” causative in 8 cases; “possibly” in 25 cases
• Resulted in 5 deaths, 11 life-threatening events, and 21 hospitalizations
• No QTc prolongation or CAD in any “probable” cases, normal LVEF in 7/8
Ventricular arrhythmias in ibrutinib-treated patients
J Emerg Med (2016). doi:10.1016/j.jemermed.2016.10.019Leukemia & Lymphoma, (2018) 59:12, 3016-3017
![Page 15: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/15.jpg)
Click to edit Master title style
CMLTyrosine kinase inhibitors & vascular toxicity
![Page 16: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/16.jpg)
Click to edit Master title styleMulti-target kinase inhibition by TKIs
![Page 17: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/17.jpg)
Click to edit Master title styleImatinib• Early reports of imatinib-induced LV dysfunction in CML patients
and mice and of myocyte toxicity in culture prompted concern re: safety
– Mitochondrial toxicity, possibly mediated by c-Abl inhibition
• A prospective study of cardiac function in 59 CML patients receiving imatinib showed no evidence of toxicity
• Clinical trials and institutional data suggest <1% risk of CHF at usual doses of imatinib, comparable to general population
• Potential CV benefits of imatinib:
– Reduced risk of CV events compared to nilotinib and untreated controls
– PAH treatment?
Nat. Med. 12, 908–916 (2006).
Leukemia Research 35 (2011) 49–51
![Page 18: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/18.jpg)
Click to edit Master title styleDasatinib• Pleural and pericardial effusions in up to 44%
– May be associated with improved treatment response– Risk factors:
• Dasatinib dose and dosing schedule, duration of Rx• Duration of CML, CML phase• Age >55, Charlson score• Pre-existing CVD, HTN, hypercholesterolemia• Autoimmune disease
• PAH– Initial estimate of 0.45%, based on French PH registry– 3% incidence after 36 month follow-up in DASISION trial
• Vascular events?
![Page 19: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/19.jpg)
Click to edit Master title styleNilotinib• QT prolongation; no ventricular arrhythmias
reported• Metabolic abnormalities: hyperglycemia,
hyperlipidemia• Vascular events
– PAD – may be severe, require revascularization and/or amputation
– CAD, cerebrovascular disease– Increased risk in those with CV risk factors– Dose related
![Page 20: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/20.jpg)
Click to edit Master title styleNilotinib
![Page 21: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/21.jpg)
Click to edit Master title stylePonatinib • PACE trial – 28 month follow-up
– 10% coronary events– 7% cerebrovascular events– 7% peripheral vascular events– 26% hypertension
• Increased risk in patients with CV risk factors and/or established disease
• Dose-dependent– Role for dose reduction in patients with cytogenetic
response?
• Effect of CV risk modification?
![Page 22: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/22.jpg)
Click to edit Master title styleMeta-analysis: Vascular events with BCR-ABL inhibitors
JAMA Oncol. 2016;2(5):625-632
![Page 23: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/23.jpg)
Click to edit Master title styleAssociation of CV events with baseline CV risk during nilotinib Tx
Leukemia (2015) 29, 1206–1209
![Page 24: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/24.jpg)
Click to edit Master title styleBaseline CV risk profile of patients receiving nilotinib
Risk factor Baseline prevalence
Male 51%
Age >55 (M) or >65 (F) 32%
Smoking in past year 16%
HTN 21%
DM2 18%
Obesity 16%
Established atherosclerosis or CVD 16%
High/very high risk groups 26%
Leukemia (2015) 29, 1206–1209
![Page 25: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/25.jpg)
Click to edit Master title styleCardiovascular risk management
![Page 26: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/26.jpg)
Click to edit Master title style
MULTIPLE MYELOMAProteasome inhibitors & cardiotoxicity
![Page 27: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/27.jpg)
Click to edit Master title styleRisk factors for cardiovascular complications in MM patients
Patient factors Disease factors Treatment factors
AgePre-existing CV diseaseHypertensionSmokingDyslipidemiaDiabetesObesity
AmyloidosisHyperviscosityHigh-output stateAnemiaRenal dysfunction
AnthracyclinesSteroidsAlkylating agentsImmunomodulatory agentsProteasome inhibitorsStem cell transplantSupportive therapy
Adapted from: Clin Lymphoma Myeloma Leuk 17, 89–96.e3 (2017).
![Page 28: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/28.jpg)
Click to edit Master title styleCardiovascular comorbidities are more common in MM patients than age matched controls
Clin Lymphoma Myeloma Leuk 17, 89–96.e3 (2017).
![Page 29: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/29.jpg)
Click to edit Master title styleRisk of cardiovascular events in MM patients
60.1%
43.1%
29.1%
4.1% 5.4%
15.1% 14.3%
54.6%
49.4%
13.1%
2.7% 2.0%5.3%
15.7%
0%
10%
20%
30%
40%
50%
60%
70%
Any cardiac event Hypertensive/arterial Cardiac dysrhythmias Conduction disorders Cardiomyopathy CHF IHD
Multiple myeloma
No multiple myeloma
Clin Lymphoma Myeloma Leuk 17, 89–96.e3 (2017).
![Page 30: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/30.jpg)
Click to edit Master title styleRisk of cardiotoxicity with bortezomib vs. control
PLoS ONE. 2014;9(1):e87671.
![Page 31: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/31.jpg)
Click to edit Master title styleCardiovascular adverse events in carfilzomib trials
JAMA Oncol. 2018;4(3):e174519.
![Page 32: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/32.jpg)
Click to edit Master title styleSafety profile of single-agent carfilzomib
22.1%
13.3%
7.2%
3.4%1.7%
9.5%
2.3%
5.7%
1.3% 0.6%
7.8%
2.1%
4.9%
1.0% 0.4%
0%
5%
10%
15%
20%
25%
Any cardiac AE Arrhythmia Cardiac failure Ischemic heartdisease
Cardiomyopathy
Any AE ≥Grade 3 SAE73.6% had history of
CV event
70.0% had baseline CV risk factors
Haematologica. 2013;98(11):1753-1761.
![Page 33: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/33.jpg)
Click to edit Master title styleCardiovascular toxicity with ixazomib in RRMM
N Engl J Med 2016;374:1621-34.
![Page 34: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/34.jpg)
Click to edit Master title styleRecommendations for cardiovascular risk assessment in MM patients
JAMA Oncol. 2017;3(7):980-988.
![Page 35: Click to edit Master title style Cardiovascular …cardiaconcology.ca/wp-content/uploads/20.-Margot-Davis...Click to edit Master title style Ibrutinib strategies after new AF British](https://reader033.vdocuments.mx/reader033/viewer/2022042806/5f76f610ea3afc7c365913a4/html5/thumbnails/35.jpg)
Click to edit Master title style
Thank You.