click to edit master title style cardiovascular...

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

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


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


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


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


• 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


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


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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