Toxicité cardiaque des chimiothérapies Journée de l AIH 24 ...cluster013.ovh.net/~aihemato/AIH/documents/JournéesAIH2016... · Kittiwarawut, 2013 NT pro BNP BC /ATC FS Not available

saint antoine

Toxicité cardiaque des chimiothérapies

Journée de l’AIH

24 Septembre 2016

Dr Stéphane Ederhy

Service de Cardiologie Hôpital Saint Antoine

Hôpitaux Universitaire Est Parisien

saint antoine Mr M, 62 ans

Vous recevez en consultation Mr M, 62 ans, que vous suivez pour un myélome multiple Il a bénéficié d’une chimiothérapie d’induction comportant 2 cycles ( Bortézomib , Dexamethasone et Thalidomide), en attente du 3 eme cycle ATCD médicaux : 0 ATCD chirurgicaux : 0 FDRCV : Dyslipidémie traitée, HTA traitée Traitement : Atorvastatine, Amlodipine Il se plaint depuis 1 semaine d’une dyspnée d’effort croissante et d’épisode de chute à répétitions survenant au lever

saint antoine

L’examen clinique retrouve : PA : 92 / 58 mm Hg ; FR = 25 /mn, Sat = 94 % en AA BDC irréguliers avec un SS 3/6 FA Crépitants aux bases OMI , RHJ , THJ

saint antoine Cardiotoxicity in Hematology

Peripheral Artery disease

Pulmonary Hypertension

saint antoine

Cancer Therapeutics regimens associated with type I and type II Cancer therapeutics related cardiac dysfunction or heart Failure

Cancer

Cancer Therapeutics

Regimen potentially associated with Type 1

Toxicity

Doxorubicin Epirubicin Idarubicin

Mitoxantrone


Toxicity

Trastuzumab Lapatinib

Pertuzumab Sorafenib Sunitinib

Bevacizumab

Plana J Am Soc Echocardiogr 2014;27:911-39

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Ewer et al. J Clin Oncol 2005;23,2900-2902

Characteristic Type I Myocardial Damage

Type II Myocardial Dysfunction

Agent Doxorubicin Trastuzumab

Clinical course Permananent damage and irreversible

High likelihood of recovery in 2-4 months

Dose Effects Cumulative, dose related Not dose related

Mechanism Free Radical formation Oxidative stress/damage

Blocker ErbB2 signaling

Ultrastructure Necrosis No ultra structural abnormalities

Non invasive cardiac testing

Decreased EF Decreased EF

Effect of rechallenge High probabilty of recurence

Relative safety of rechallenge

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Cancer Therapeutics regimens associated with type I and type II Cancer therapeutics related cardiac dysfunction

Cancer

Chemotherapy


Toxicity

Doxorubicin Epirubicin Idarubicin

Mitoxantrone

De plana J Am Soc Echocardiogr 2014;27:911-39

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Swain et al. Cancer 2003; 97:2872

Incidence of Heart Failure with Doxorubicin

Cumulative dose of doxorubicin in mg/m2

Inci

de

nce

of

HF

in %

9 to 30 % of Asm LVEF dysfunction

saint antoine Underlying causes and long term survival in patients

with initially unexplained cardiomyopathy

Felker et al. N Engl J Med 2000; 342:1077

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Cardinale et al. J Am Coll Cardiol 2010; 3 :210

Delay in months between LVEF dysfunction and ACE i treatment

% re

sp

on

de

rs

Anthracycline and LVEF dysfunction Reversibility under ACE i treatment

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Left ventricular dysfunction after Chemotherapy

Yoon et al. J Am Coll Cardiol 2010; 20 :1644

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Cardinale et al. Circulation 2015;9,Epub

Early detection of ATC cardiotoxicity and improvemetnt with heart failure 2625 pts, Echo, ACE i + BB

9 % LVEF drop > 10 % unit + LVEF < 50 %

98 % in the first year

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Pre-existing Risk Factors for

Cardiac Damages

Angina pectoris

Arterial hypertension

Valvulopathy

Radiotherapy < 6 months

Ethnicity

Age < 15 years ; Age > 70 years

Cumulative Dose

Combination with vincristine,

cyclophosphamide, mitomycin,

mithramycin, trastuzumab

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Detecting cardiotoxicity

LVEF Other Echo tools ? TDI , STE

Biomarkers

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Detecting cardiotoxicity

LVEF Other Echo tools ? TDI , STE

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LVEF to Predict Early

Anthracycline-Induced Cardiotoxicity

Echocardiography, 65 pts, mean age 50 y, cardiotoxicity 26%, TEI

index*, LVEF

Variability : 4,79 %

Belham et al. European Journal of Heart Failure 2007;9,409-414 * TEI=Myocardial performance index

Baseline After low dose anthracyclines

After completion of anthracyclines

64 62

59

EF

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Tissue Doppler Imaging (TDI)

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P=NS

Belham et al. European Journal of Heart Failure 2007;9,409-414

Echocardiography, 65 pts, mean age 50 y, cardiotoxicity 26%,

TEI index, LVEF

LVEF to Predict Early

Anthracycline-Induced Cardiotoxicity

0

2

4

6

8

10

12

14

Tei

Baseline After low dose anthracycline

After completion of anthracycline

Sa Ea E/Ea E/A

saint antoine DTI and Cardiotoxicity

Studies Cumulative dose (mg/m2)

Early and late deterioration

Jurcut 180 SR,E’

Dodos 230 Early FE,TEI

Mantovani 200-400 E’/A’, late S’

Nagy 300 E/A,E’/A’

Belham 300 EF,Tei Index

Mercuro 200-400 Early SR, lateE’,E’/A’

Tassan-Mangina 210 Early E/A,E’,late EF, S’

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Atrium Atrium

Ventricle

BNP

ANP**

N-terminal

ANP

Vasodilatation, urinary excretion of sodium

of stretching and cavitary volume

leads to increased release of natriuretic

peptides

Determinants and Consequences of the Secretion of BNP*

*BNP= Brain natriuretic peptide; **ANP=Atrial natriuretic peptide

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Natriuretic peptides in the monitoring of

anthracycline induced reduction in LVEF.

Daugaard et al. Eur J Heart Fail 2005;7:87

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Author, year Marker Tumor /

Chemo

Asym LVSD Symp LVSD

Mercuro, 2007 BNP Various/ATC No association No association

Dodes, 2008 NTpro BNP No association No association

Feola, 2011 BNP Associated

Romano, 2011 NT proBNP, NHDC LVEFdysfunction

Fallah-Rad,2011 Nt pro BNP BC/ATC, TZM No elevation

Sawaya, 2012 NT pro BNP BC/ATC, TZM Not associated

Kittiwarawut, 2013 NT pro BNP BC /ATC FS Not available

Drafts, 2013 BNP BC, NHL, A ML No association No Association



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Left Ventricular Dysfunction Predicted By

Early Troponin I Release

Cardinale et al. J Am Coll Cardiol 2000;36:517-522

204 pts, 32 % Tp > 0,4 ng/ml

0 1 2 3 4 7

Months

LVEF

(%

)

50

55

60

65

70

*

§ * § * § *

cTnI−

cTnI+

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TnI and Prediction of

Cardiovascular Events 703 patients, TnI > 0,08 ng/ml, after chemo and M1

Cardinale et al. Circulation 2004;109:2749-54

SD, sudden death; CD, cardiac death; APE, acute pulmonary edema; CHF, congestive heart failure;

ASM LVD, asymptomatic left ventricular dysfunction;

70 % 9 % 21 %

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Prevention of Cardiotoxicity with

ACE Inhibitors

114 pts (Tp+) Randomized

Cardinale et al. Circulation 2006;114:2472

CVE

P< 0.01 2%

ACE I

51%

Controls ACE I Controls

62.4

48.3

LVEF

CVE=Cardiovascular event

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Author,year Method, Cut off Tumors /

Chemo

% Tp > cut off Main result

Cardinale, 2000 TnI, >0.4ng/ml Various/ ATC 32 % LVSD

Cardinale, 2002 TnI, >0.5ng/ml BC/ATC 33% LVSD

Sandri, 2003 TnI, 0.08micro/l Various /ATC 32% LVSD

Auner, 2003 TnT, ≥ 0.03ng/ml Hemato /ATC 15 % LVSD

Cardinale,2004 TnI,, >0.08ng/ml HDC/ATC 30 % Cardiac events

Kilickap, 2005 TnT, >0.1ng/ml /ATC 34 % DD

Horacek, 2008 TnI or T, > 0.4ug/l AL/ATC 17.4% LVSD, HF

Nistico, 2007 TnT, BC/ATC 0% No association with LVSD

Dodes, 2008 TnT ATC 0 % No association with LVSD

Cardinale, 2010 TnI, BC/ATC,TZM 17% LVSD

Fallah-rad,2011 Tnt, >0,01ug/l BC/ATC, TZM No elevation No association with LVSD

Sawaya, 2012 TnUS, >30pg/ml BC/ATC, TZM 33% LVSD

Mornos, 2013 TnT, NHL,HL/ATC NA No association with LVSD

Kittiwarawut,2013 TnT, BC/ATC NA No association with LVSD

Drafts, 2013 TnI, >0.6ng/ml BC/AL, Lymp 26 % No association with LVSD

Romano,2012 TnI N HDC 0% No association with LVSD

TnI and Prediction of LVSD

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N = (L2-L1)/L1 [%]

Strain Rate

1,3cm

1,0cm 0,7cm

L2

L1

1,0cm

time

1,0cm 0,7cm

2s 1s

time

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Sawaya Circ Cardiovasc Imaging. 2012;5:596-603

Strain, biomarkers and cardiotoxicty 81 pts, 26 pts cardiotoxicity

Longitudinal strain < 19 % remained the only independent predictor of cardiotoxicity in multivariate analysis

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Initiation of regiment potentially associated with type I toxicity

Baseline LVEF 3DE (prefered) / 2 DE (consider contrast)

GLS, Troponin

LVEF < 53 % GLS < LLN

+ Troponins > 0

LVEF > 53 % GLS > LLN

+ Troponins < 0

F/U at completion and 6

months later Cardiology

Consultation

Consider CMR


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Baseline evaluation of LVEF 3DE prefered / 2D (consider contrast)

Tn I at each cycle

TnI positive Tn I

Negative

Echo 6 months after completion of therapy

Cardiology Consultation


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Drop of 10 points to LVEF < 53 %

Relative drop of GLS as compared to baseline

Δ < 8 % Δ > 15 %

Subclinical LV dysfunction

No evidence of subclinical LV dysfunction

plana J Am Soc Echocardiogr 2014;27:911-39

Cardiotoxicity

Yes No

1- GLS consider Vendor, Gender, Age, loading conditions 2- The abnormal GLS value should be confirmed by a repeat study performed 2 to 3 weeks after the initial abnormal study

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Cancer

Cancer Therapeutics


Toxicity

Trastuzumab Lapatinib

Pertuzumab Sorafenib Sunitinib

Bevacizumab


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Cancer

Cancer Therapeutics


Toxicity

Dasatinib, Imatinib, nilotinib

Bortezomib, Carfilzomib

No Guidelines

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Left Ventricular systolic dysfunction and molecular targeted agents

Chemotherapy Incidence (%)

Antibody

Bevacizumab 1,7 to 3%

Trastuzumab 2 to 28 %

Proteasome Inhibitors

Bortezomib 2 to 5 %

Carfilzomib 1 to 5 %

Tyrosine kinase Inhibitors

Dasatinib 2 to 4 %

Imatinib 0,5 to 1,7 %

Lapatinib (Tykerb) 1,5 to 2,2 %

Sunitinib (Sutent) 2,7 to 11 %

Yeh et al. J Am Coll Cardiol 2009;24,2231-2247

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Ewer et al. J Clin Oncol 2005;23,2900-2902

Characteristic Type I Myocardial Damage

Type II Myocardial Dysfunction

Agent Doxorubicin Trastuzumab

Clinical course Permananent damage and irreversible

High likelihood of recovery in 2-4 months

Dose Effects Cumulative, dose related Not dose related

Mechanism Free Radical formation Oxidative stress/damage

Blocker ErbB2 signaling

Ultrastructure Necrosis No ultra structural abnormalities

Non invasive cardiac testing

Decreased EF Decreased EF

Effect of rechallenge High probabilty of recurence

Relative safety of rechallenge

saint antoine

Initiation of regiment potentially associated with type II toxicity


GLS, Troponin


+ Troponins > 0


+ Troponins < 0

Echo every 3 months Cardiology

Consultation

Consider CMR


saint antoine

Initiation of trastuzumab


GLS, Troponin


+ Troponins


+ Troponins

F/U every 3 months later Cardiology

Consultation

Consider CMR


saint antoine

Left Ventricular systolic dysfunction and molecular targeted agents


Anticorps

Bevacizumab 1,7 to 3%

Trastuzumab 2 to 28 %

Proteasome

Bortezomib 2 to 5 %

Carfilzomib 1 to 5 %

Inhibiteur des tyrosine kinase

Dasatinib 2 to 4 %

Imatinib 0,5 to 1,7 %

Lapatinib (Tykerb) 1,5 to 2,2 %

Sunitinib (Sutent) 2,7 to 11 %


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Kerkela et al. Nature Medecine 2006;12,908-914

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Heart Failure and Imatinib

1276 pts

Incidence according to age

Atallah et al. Blood 2007;110,1233-1237

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Heart failure and Imatinib

1276 pts

Cardiovascular risk factors

saint antoine Heart failure

Comparison Phase III trial vs Framingham

Ins Card + Imatinib Framingham heart study

Age, y No CHF Age,y 5-year risk of CHF

Men Women

< 45 409 0(0) 40 0,2 0,1

45-55 322 1 (0,3) 50 0,8 0,1

56-65 291 5 (1,7) 60 1,3 0,7

66-75 211 6 (2,8) 70 4 2,2

76-85 43 4 (9,3) 80 8,3 7,8


saint antoine Heart Failure and Imatinib

Management


22 pts with HF

50 % 11 pts : Imatinib poursuivi

50 % dose reduction 50 % dose reduction + Furosemide + ACE i

50 % 11 pts Imatinib

Stopped

saint antoine Integrated safety profiles of carfilzomib

experience from 526 patients enrolled in 4 phase II clinical studies

Theurer. Haematologica 2013;98,1753

saint antoine

Patterns of cardiac toxicity associated with irreversible

proteasome inhibition in the treatment of multiple

myeloma

Grandin Journal of cardiac failure 2015 ; 21 : 2

saint antoine Incidence and risk of cardiotoxicity associated with bortezomib in the

treatment of cancer : meta-analyis

Xiao Y PLOS 2014 ; 9 : 1

saint antoine TKI / IP

1.Prise en charge : Réversible et sensible au TTT par IEC + Diurétique

2.Indentification rapide des signes et symptômes d’IC = > Echographie

cardiaque

3.Echographie cardiaque ne peut être proposée en pré traitement

4.Echographie cardiaque : pas de monitoring systématique

5.Myelome et atteinte cardiaque


saint antoine Molecular targeted agents and QT prolongation



HDAC inhibitors

Vorinostat (Zolinza) 3,5 to 6 %

Tyrosine kinase Inhibitors

Dasatinib (Sprycel) < 1-3 %

Lapatinib (Tykerb) 16 %

Nilotinib (Tasigna) 1 to 10 %

saint antoine Torsades de pointes - ECG

saint antoine QT mesure vs QT corrige

Strevel et al. J Clin Oncol, 2007; 25 : 3362

Feature Formula

Bazett QTc=QT(HR/60)1/2

Fridericia QTc=QT(HR/60)1/3

Framingham QTc=QT+0,154 (1-RR)

Hodges QT+105(1/RR-1)

saint antoine Facteurs associes a une

prolongation du QT

Strevel et al. J Clin Oncol, 2007; 25 : 3362

Cause

Congenital : Syndrome du QT long

Cardiopathie : HVG, Dysfonction VG, cardiopathie ischémique, Trouble conductif

Métabolique : HypoK+,HypoMG, HypoCA+, Hypothyroidie

Psychotropes : amitriptyline,haloperidol

Antibiotiques : Clarithromycin, Quinilone

Antihistaminiques : Terfenadine

Autre : Domperidone, Cisapride, droperidol, Tacrolimus , Tamox 5 hybdroxy trytamine antagonist

saint antoine Initiation traitement

Examen clinique : Asymptomatique ? HTA ?, ICA ?, DT ?

Ordonnance ? Inhibiteur CYP3A4 ? ECG : QT m / QTc F

metabolisme : K+ / Mg 2+ Fonction hépatique

Suivi Examen clinique : Asymptomatique ?

ECG : D7, periodique, apres changement dose surveillance K+ / Mg 2 +

Stop Nilotinib Si Symptomatique If QTc > 450 msec

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QTcF Posologie Nilotinib Action

> 480 msec Stop Nilotinib Vérifier et corriger K+,Mg2+

Vérifier interaction médicamenteuse

Vérifier Interaction CYP

< 450 msec Reprendre Nilotinib Dose Initiale

ECG a chaque changement de dose

Si 450 < QtcF < 480 msec

Diminuer Posologie 400 mg/j

ECG a chaque changement de dose

Prise en charge


Peripheral Artery disease

saint antoine Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid

leukemia in chronic phase: 5-year update of the randomized ENESTnd trial

Leukemia 2016 ; 30 : 1044 – 1054

Nilotinib 300 mg x 2 N=279 N(%)

Nilotinib 400 mg x 2 N=277 N(%)

Imatinib 400 mg N=280 N(%)

Any grade

Grade 3/4

Any grade

Grade 3/4

Any grade

Grade 3/4

HTN 29 (10,4) 4 (1,4) 23 (8,3) 3 (1,1) 12 (4,3) 1 (0,4)

Symp QTc prolongation

5 (1,8) 2 (0,7) 7 (2,5) 2 (0,7) 8 (2,9) 4 (1,4)

Ischemic heart disease

11 (3,9) 6 (2,2) 24 (8,7) 17 (6,1) 5 (1,8) 4 (1,4)

Cardiovascular events

4 (1,4) 3 (1,1) 9 (3,2) 6 (2,2) 1 (0,4) 1 (0,4)

Peripheral artery disease

7 (2,5) 4 (1,4) 7 (2,5) 3 (1,1) 0 0

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Rea Bull Cancer 2016 ; 103 : 180 - 189

Gestion du risque d’evenements cardiovasculaires sous nilotinib

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Ponatinib et évènement cardio

vasculaire

Ponatinib

SCA

12%

AVC

6 %

AOMI

8 %

MVTE

5 %


Pulmonary Hypertension

saint antoine Conclusions

1- Anthracycline : Stratégie de depistage et de prevention 2- Thérapies moléculaires ciblées : Reversibilite, Modulation de la posologie 3- Toxicités emergentes : AOMI, HTP

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A vos boitiers ! 4 questions

saint antoine Pulmonary Hypertension and Dasatinib

Montani et al. Circulation 2012;125,2128-2137

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AFFSAPS / ANSM 2011

Hypertension pulmonaire et Dasatinib

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Variability of global left ventricular deformation analysis using vendor dependent and independent two dimensional speckle

tracking software in adults

Risum J Am Soc Echocardiogr 2012;25:1195-203

saint antoine Effect of vendor and gender on GLS


Age

Vendor 0-19 20-29 30-39 40-49 50-59 >60 p

Overall 22.1 ± 2.4 21.2 ± 1.9 21.1 ± 2.1 21.4 ± 2 21 ± 2.2 20.3 ± 1.9 0.218

male - 21.7 ± 3.1 20.9 ± 1.9 20.6 ± 1.9 20.9 ± 1.8 21 ± 1.9 19.7 ± 1.4 0.1982

Female -22.4 ± 1.6 22.3 ± 1.6 22.6 ± 1.8 22.6 ± 2.1 23.3 ± 1.9 20.9 ± 2.1 0.0348

P(m vs f) 0.42 0.0316 <0.001 0.0178 0.0029 0.13

V 2

Overall 19.9±2.5 19±2.1 19.5± 18.2±2.5 17.6±2.5 16.7 ± 2.1 < 0.0001

Male 19.4 ± 2.7 18.8 ± 2 19.1 ± 2.3 17.9 ± 2.8 16.9 ± 2.3 15.8 ± 1.4 0.0019

Female 20.5 ± 2.2 20.6 ± 2.3 20.2 ± 2 19.3 ± 0.9 20.4 ± 1.5 17.3 ± 2.3 0.0002

P(m vs f) 0.13 0.0248 0.10 0.43 0.0294 0.0928

V 3

Overall 21.4 ± 1.7 20.2 ± 2.1 20.4 ± 2.3 19.4 ± 2.2 18.5 ± 2.6 17.6 ± 2.8 <0.0001

Male 21.6 ± 2 20.2 ± 2 20.4 ± 2.2 19.8 ± 2.3 18.7 ± 2.6 16.3 ± 3.1 <0.0001

Female 21.2 ± 1.5 20.2 ± 2.4 20.4 ± 2.8 18.7 ± 1.8 18.3 ± 2.8 18.6 ± 2.3 0.0141

P(m vs f) 0.60 0.97 0.92 0.14 0.73 0.068

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95 % CI p

Age -0,01 (-0,14 to 0,12) 0,85

Male Gender -0,01 (-0,02 to 0,01) 0,33

Body Mass Index -0,56 (-1,56 to 0,44) 0,17

Systolic Blood Pressure

0,43 (-0,18 to 0,69) 0,01

Frame Rate -0,04 (-0,15 to 0,07) 0,37

Vendor (non GE) -2,82 (-6,26 to 0,62) 0,08

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Yang et al. Journal of the american society of echocardiography 2015;E pub

Improvement in strain concordance between vendors

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Cancer patient / Chemotherapy

Cardiotoxicity

Detection of early myocardial change

during cancer chemotherapy

Detection of late subclinical consequences of cancer therapy

Prognostic value of echo parameters to detect

cardiotoxicity

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Author, year Marker Tumor /

Chemo

Asym LVSD Symp LVSD

Nousiainen, 1998 BNP AML/ATC DD No association

Nousiainen, 1999 ANP, BNP NHL/ATC No association No association

Okumura, 2000 ANP, BNP AL/ATC No association Association

Meinardi, 2001 BNP BC/ATC No association No association

Nouisiainen, 2002 BNP Hemato/ATC DD

Daugaard, 2005 ANP, BNP Various /ATC No association No Association

Sandri, 2005 Nt pro BNP Various Association

Horacek, 2005 Nt pro BNP AML No association No association

Pichon, 2005 BNP BC No association Association



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Algorithm for management of cardiotoxicity in pts receiving anthracyclines

Curigliano et al. Annals of Oncology 2012;23:1156

Baseline cardiologic evaluation, Echo

TnI evaluation at each cycle

TnI not evaluated during ChT

No LVD

Echo 3 Months

Echo at end ChT

No LVD

No LVD

Echo 9 Months

Echo 6 months

LVD

ACE + BB

No LVD

Echo 12 Months

Tn NEG Tn POS

Enalapril for 1 year

Echo end 3,6,9,12 months

Echo every 6 months for 5 years

Echo 12 months

Echo every year

saint antoine Management of cardiac health in Trastuzumab-treated patients with breast cancer

UK national Cancer Research Institute recommendations for monitoring Patient assessment

Jones et al. British Journal of Cancer 2009;100,684-692

LVEF value

LVEF decrease

Signs or symptoms

Trastuzumab Start ACEi

cardiologist monitoring

> LLN < 0,10 NONE Continue YES REFER 6 to 8 w

≤ LLN > 40 %

≥ 0,10 NONE Continue Yes REFER 6 to 8 w

≤ 40 % - ANY STOP YES REFER 6 to 8 w

Documents

Toxicité cardiaque des chimiothérapies Journée de l AIH 24 ...cluster013.ovh.net/~aihemato/AIH/documents/JournéesAIH2016... · Kittiwarawut, 2013 NT pro BNP BC /ATC FS Not available