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Cardio-Oncology in the Service of CML Patient
Zaza Iakobishvili, MD, PhD
Department of Cardiology, Rabin Medical Center,
Petah Tikva, Israel
September 7, 2017
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Urban Myths and Reality C
ardio
nco
logy Service - R
MC
Experie
nce, D
r. Zaza Iakob
ishvili
2
“For cancer patients, cardiovascular outcomes do not matter as much”
Dr. B., 63y, oncologist
“When I got the news that I had heart failure, I was devastated having just survived breast cancer”
Ms. R, 51y, breast cancer survivor
“Cardiovascular surveillance in cancer survivors – not sure this is cost-effective, and who is going to pay for this anyway?”
Dr. L., 67y, hematologist
“I had no idea that cardiovascular disease could be/could have such a profound long-term impact”
Mr. A., 45y, Hodgkins lymphoma survivor
Source: Dr. Joerg Herrmann, USA
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Communication Breakdown C
ardio
nco
logy Service - R
MC
Experie
nce, D
r. Zaza Iakob
ishvili
3
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Patient Centered Approach
Card
ion
colo
gy Service - RM
C Exp
erien
ce, Dr. Zaza
Iakob
ishvili
4
Cancer Patient
Team Leader
Medical Oncologist
Consulting Services (Cardio-
oncology, Neuro-oncology,
etc.)
Nurses
Physiothe-rapists
Dietitian
Social Workers
Medical Imaging
Hospice Care
Laboratory Services
Palliative Care
Survivorship Clinic
Dedicated Hospital
beds
Radio-oncology Services
Surgical Team
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Rates of Vascular Events for Patients With Chronic Myeloid Leukemia (CML) and Matched Non-cancer Patients
Lang et al, Clinical Lymphoma, Myeloma & Leukemia, 2016
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Rask-Andersen Trends Pharmacol Sci 2014;35
Wu et al. Trends Pharmacol Sci 2015;36
T. Mirault, IMCO 2017
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Chronic Myeloid Leukemia and TKI
2001 Imatinib
2007 Nilotinib
2006 Dasatinib
1st generation 2nd generation 3rd generation
2012 Ponatinib
2012 Bosutinib
UK 2013
714 new cases
(0.2% of cancers)
prevalence < 1%
median age: 65 years old
www.cancerresearchuk.org
Deeper molecular response - More CV side Effect
T. Mirault, IMCO 2017
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Cardiovascular Toxicity of BCR-ABL1 Inhibitors
The numbers represent percent inhibition of kinase activity at 1 mmol/L of inhibitor. Reported values less than 0 were set to 0. Red indicates 96% to 100% inhibition; gold indicates 51% to 95% inhibition; and blue indicates 0% to 50% inhibition.
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Rea D,et al Haematologica; 2014;99:1197–203. IMC
O 2
017
tris
tan.m
irault@
aphp.fr
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Lipid profile during nilotinib therapy
Fig. 1A: TC
M0 M3 M6 M9 M12 0
1
2
3
4
Months since nilotinib
g/L
Fig. 1B: LDL-C
M0 M3 M6 M9 M12 0
1
2
3
Months since nilotinib
g/L
Fig. 1C: HDL-C
M0 M3 M6 M9 M12 0.0
0.5
1.0
1.5
Months since nilotinib
g/L
Fig. 1D: TG
M0 M3 M6 M9 M12 0
1
2
3
4
5
Months since nilotinib
g/L
p<0.0001 p<0.0001
P=0.0004 p<0.0001
IMC
O 2
017
tris
tan.m
irault@
aphp.fr
IMC
O 2
017
tris
tan.m
irault@
aphp.fr
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Lipid profile during other TKIs: Ponatinib
Fig. 2A: TC
Baseline M3 0
1
2
3
4 g/L
ns Fig. 2B: LDL-C
Baseline M3 0
1
2
3
g/L
ns
Fig. 2D: TG
Baseline M3 0
1
2
3
4
5
g/L
ns
Fig. 2C: HDL-C
Baseline M3 0.0
0.5
1.0
1.5
g/L
ns
IMC
O 2
017
tris
tan.m
irault@
aphp.fr
IMC
O 2
017
tris
tan.m
irault@
aphp.fr
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Need for lipid-lowering drugs when using nilotinib
• At baseline 4/27 (15%) pts had LDL-C levels above target thresholds for lifestyle intervention and/or drug intervention
• At 3 months proportion increased up to 11/27 (41%) .
• In 2 pts, nilotinib was discontinued because of symptomatic (PAD n=1) or primary resistance with onset of a T315I mutation (n=1). These 2 pts respectively received imatinib or Ponatinib.
• In all patients, both TC and LDL-C rapidly decreased below target LDL-C thresholds after statin initiation.
IMC
O 2
017
tris
tan
.mira
ult@
ap
hp
.fr
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Glycemia increase
Racil Z, et al. Haematologica; 2013;98:e124–6.
10 patients under nilotinib
IMC
O 2
017
tris
tan.m
irault@
aphp.fr
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Nilotinib (European Medicines Agency Recommendations):
• Close cardiovascular monitoring;
• Fasting blood glucose before treatment and than as clinically indicated;
• Fasting blood lipids at baseline, 3, 6, 12 months and than yearly.
Javid J. Moslehi and Michael Deininger, JCO, 2015
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Ponatinib
Javid J. Moslehi and Michael Deininger, JCO, 2015
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Ponatinib
Javid J. Moslehi and Michael Deininger, JCO, 2015
הסיכון עולה במטופלים שיש להם גורמי סיכון למחלות לב וכלי דם
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Vascular Occlusive Events in Patients with Ph+ Leukemia Treated with New-Generation TKIs vs Imatinib
Beilinson hospital Beilinson hospital
Douxfils et al, JAMA Oncology, 2016
10 RCTs N=3043 pts
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Pulmonary hypertension
N- 105 CML patients, Imatinib – 37 Nilotinib- 30 Dasatinib -38 A TRPG > 31 mmHg- in 9 of 105 (8.6%) patients: one (2·7%) treated with imatinib, three (10·0%) with nilotinib five (13·2%) with dasatinib. 3- complained of dyspnea 6- asymptomatic
TRPG – tricuspid regurgitation peak gradient, >31 mm Hg suspicious for Pulmonary hypertension
Minami et al, British J of Hematology, 2017
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Pulmonary hypertension
N- 105 CML patients, Imatinib – 37 Nilotinib- 30 Dasatinib -38 A TRPG > 31 mmHg- in 9 of 105 (8.6%) patients: one (2·7%) treated with imatinib, three (10·0%) with nilotinib five (13·2%) with dasatinib. 3- complained of dyspnea 6- asymptomatic
TRPG – tricuspid regurgitation peak gradient, >31 mm Hg suspicious for Pulmonary hypertension
Minami et al, British J of Hematology, 2017
התופעה היא נדירה וחולפת לאחר הפסקת הטיפול בתרופה שגרמה לה
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איך יודעים אם אני בסיכון או לא לתופעות לוואי של ?התרופה
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SCORE risk chart
Perk et al. Eur Heart J 2012; 33: 1635-1701.
SCORE: Systematic Coronary Risk Evaluation (http://www.escardio.org/Guidelines-&-Education/Practice-tools/CVD-prevention-toolbox/SCORE-Risk-Charts).
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יכול לעשות אם אני ( יחד עם הרופא שלי)מה אני ?בקבוצת סיכון
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Javid J. Moslehi and Michael Deininger, JCO, 2015
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Pasvolsky et al, Cardio-oncology, 2015
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ABCDE Steps to Prevent Cardiovascular Disease in Patients with CML treated with a TKI
Javid J. Moslehi and Michael Deininger, JCO, 2015
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Incident CVD in ARIC (JACC, 2011)
Patients with cancer in the Community Southern Cohort
had a median of 3 healthy behaviors with only 0.9%
achieving 6-7, compared with 1.7% in controls without
cancer (p < 0.001).
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Benefit of Adherence to Life’s Simple 7
• Extends beyond cardiovascular risk reduction
• May decrease the incidence of cancer
• Cancer and cardiovascular disease are not necessarily competing risks but are both driven by common risk factors
• Modifying these shared risk factors may jointly attenuate the top two causes of death in Western society.
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Cardio-Oncology Service – Rabin Medical Center Experience
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Referral Criteria • Patients with decreased EF and in need of cancer therapy.
• Cancer patients planned for potentially cardiotoxic agents and at increased risk of cardiotoxicity as perceived by the medical oncologist.
• Hemato-oncologic patients with cardiovascular involvement (CML, amyloidosis, malignant infiltrative diseases of the heart, before and after bone marrow transplantation).
• Childhood cancer survivors (more than 10 years after chemotherapy and chest radiotherapy).
• Patients with cardiac tumors.
• Cancer patients with heart rhythm disturbances.
• Patients with malignancies and pericardial effusion.
Cardioncology Service - RMC Experience, Dr. Zaza Iakobishvili 44
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Investigations provided:
• Anamnesis with careful review of oncologic treatment
• Physical examination (incl BP/HR/weight/BMI)
• ECG with thorough monitoring of QT interval
• V-Scan ™(GE) – useful extension to physical examination Stethoscope vs stethophone
• 6 minute walk test for heart failure patients
• Non-invasive hemodynamic assessment (cardiac output, peripheral resistance, cardiac power index, fluid status) and follow-up at each visit (NiCAS™)
• Ankle-brachial index measurement
• Ischemia testing Cardioncology Service - RMC Experience, Dr. Zaza Iakobishvili 45
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Investigations provided
• 2D echocardiography (serial) with increasing implementation of speckle tracking
• Troponin and BNP testing for ongoing chemotherapy patients
• MRI for cardiac amyloidosis or unclear cases of cardiotoxicity (different kinetics of LGE)
• Blood lipids, glucose, kidney functions, CBC, etc.
• Nurse-led follow-up clinic for cardiac drug titration and patient education
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Cardioncology Service - RMC Experience, Dr. Zaza Iakobishvili 47 Incremental Use of Speckle Tracking > 200
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Card
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Cardioncology Service in Numbers
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ishvili
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Rabin Cardio-Oncology Clinic
0
200
400
600
800
1000
1200
2013 2014 2015 2016
unique IDs Visits
N-571 Mean Age(SD) – 66.2(12.8) Male N(%) – 290(51.9)
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ishvili
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Distribution of Patients According to the Cancer Diagnosis
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Reasons for Referral to Cardio-Oncology Clinic
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Cancer-Related Treatment
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Cardiac Risk Factors and Medications
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Conclusions
• CML is associated with increased cardiovascular problems
• New generation TKIs improve CML prognosis
• TKIs increased use leads to off-target cardiovascular effects
• Management of cardiovascular risk should be made by close collaboration between hemato-oncologists and cardiologists at the specialized cardio-oncology clinics
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“
” Can two walk together, except they be agreed?
AMOS 3:3
Cardioncology Service - RMC Experience, Dr. Zaza Iakobishvili 56