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Cardiovascular Considerations in Malignant HematologyMargot Davis, MD MSc FRCP(C)Clinical Assistant Professor, UBC Division of CardiologyDirector, UBC Cardio-Oncology Program
Click to edit Master title styleDisclosures
• Consultancy/speaking fees: Janssen, Novartis, Boehringer-Ingelheim, Takeda, Pfizer, Akcea, Alnylam, Amgen, Ferring, TerSera
• Grant funding: Pfizer
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
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CLLIbrutinib & arrhythmias
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.
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
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.
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
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
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
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
Click to edit Master title stylePFS in patients with and without AF in ibrutinib trials
Haematologica 2017;102(10):1796-1805
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
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• 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
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CMLTyrosine kinase inhibitors & vascular toxicity
Click to edit Master title styleMulti-target kinase inhibition by TKIs
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
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?
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
Click to edit Master title styleNilotinib
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?
Click to edit Master title styleMeta-analysis: Vascular events with BCR-ABL inhibitors
JAMA Oncol. 2016;2(5):625-632
Click to edit Master title styleAssociation of CV events with baseline CV risk during nilotinib Tx
Leukemia (2015) 29, 1206–1209
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
Click to edit Master title styleCardiovascular risk management
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MULTIPLE MYELOMAProteasome inhibitors & cardiotoxicity
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).
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).
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).
Click to edit Master title styleRisk of cardiotoxicity with bortezomib vs. control
PLoS ONE. 2014;9(1):e87671.
Click to edit Master title styleCardiovascular adverse events in carfilzomib trials
JAMA Oncol. 2018;4(3):e174519.
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.
Click to edit Master title styleCardiovascular toxicity with ixazomib in RRMM
N Engl J Med 2016;374:1621-34.
Click to edit Master title styleRecommendations for cardiovascular risk assessment in MM patients
JAMA Oncol. 2017;3(7):980-988.
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Thank You.