Terapie Oncologiche e Cardiotossicità Il rischio di

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Terapie Oncologiche e Cardiotossicità

Patrizia PregnoSC Ematologia

A.O.U. Città della Salute e della Scienza di TorinoTorino

Torino, 21 settembre 2015

Il rischio di tossicità riguardo a:Terapie Ematologiche

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L’ematologo deve tener conto di molti fattori

?

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Quale paziente?

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Quale terapia per quale malattia?

Linfomi: terapia breve a cicli (3-6 mesi) a diversa intensità (chemioterapia a dosi standard / ad alte dosi con autotrapianto di midollo); possibile associazione con Radioterapia

Leucemie acute: terapia a medio termine con durata di mesi (anche > un anno) a dosi elevate con o senza allotrapianto di midollo)

Leucemie croniche (es LMC): terapia cronica per molti anni

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Chemioterapia e CardiotossicitàANTRACICLINE: daunorubicina, doxorubicinaS i intercalano tra le catene del DNA compromettendone la funzionalità e provocandone la rottura. S ono in grado di formare forme attivate dell’Oss igeno (ROS )

Effetti toss ici:Mielosoppress ione, reazioni anafilattiche, alopecia, dis turbi gas trointestinaliPotenziale mutagenicità/carcinogenicità

30/09/15 Bhave M et al, Oncology, 2014;28(6):482-90.

Cardiovascular toxicity of biologic agents for cancer therapy

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Probability of CCR ( GMALL )

Hoelzer D et al. Blood. 1988; 71:123 – 131

Leucemia acuta linfoblastica

> 50 aa

< 20 aa

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Trapianto allogenico: cas is tica Ematologia

ANNI AlloBMT AutoBMT

2000-2013 750 2000

2013 52 (32 MUD) 131

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Diffuse Large B-Cell Lymphoma

§ Most common NHL: 31%– Peak incidence in sixth decade– Incidence increased by 50-90%

(depending on race, gender)

Distribution by age: 53% of pts are ≥60

Prognostic factors for survivalIPI risk factors Relative risk

Age: ≤60 yrs vs. > 60yrs 1.96Serum LDH: normal vs. above normal 1.85ECOG PS: 0,1 vs: ≥ 2 1.80Extranodal involvement: ≤ 1 vs. ≥ 2 sites 1.48Ann Arbor Stage: I/II vs. III or IV 1.47

Distribution by IPI score: 34% of patients are IPI 3-5

Shipp, Blood 1994

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GELA-LNH 98.5: R-CHOP21aaIPI 2-3 DLBCL patients

Coiffier B et al, Blood 2010.

RCHOP vs CHOP: 10-yrs PFS 37% vs 20%

Diffuse Large B-Cell Lymphoma

Cardiotossicità nei linfomi

Nousiainen T et al. Br J Canc 2002

Decremento mediano della LVEF in 28 pazienti con linfoma non–Hodgkin’s trattati con CHOP

35%

40%

45%

50%

55%

60%

LV EF

58%

52.5%50.4%

49.6%

p < 0.05 p < 0.01 p < 0.001

Basale 200 mg/m² 400 mg/m² 500 mg/m²

10% 14% 15%

36% dei pts ha avuto un abbattimento nel valore di LVEF tale da condurlo a valori finali inferiori al 50%

Studio retrospettivo su 135 pazienti affetti da NHL aggressivi trattati con CHOP

Una dose di Doxorubicina > 200 mg/m2 e l’età > 50 anni sono risultati dei fattori di rischio indipendenti

Cardiotossicità nei linfomi

Limat S. et al Ann Oncol 2003

20% ptscardiotossicit

à

50% hanno avuto CHF 50% hanno avuto una riduzione di LVEF

Johnson SA, Sem Oncol 2006

nella probabilità di sviluppare CHF

Significativa riduzione dei valori di LVEF già a

dosi di 200 mg/m2

Influenza della dose cumulativa di doxorubicina

Decessi tardivi correlati al trattamento con antracicline nei pazienti lungo-sopravviventi

Aviles A et al. Leuk Lymphoma 2001

Linfomi non HodgkinStudio retrospettivo su 714 pazienti

(Dose cumulativa di Doxorubicina: 365 mg/m2)

Le morti per evento cardiaco sono state la PRIMA causa di mortalità

Il numero di decessi per evento cardiotossico è aumentato di 26.4 rispetto alla popolazione generale. (p<0.001)

Kilickap S et al, Med Oncol 2008

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First line treatment

FIT patients UNFIT patients

Comprehensive geriatric assessment

Tucci A et al, Cancer 2009.

Doxorubicina liposomiale nei linfomi - razionale

• Rispetto alla doxorubicina convenzionale:

captazione nel fegato, milza, linfonodi captazione nel miocardio e nella mucosa gastrointestinale Non tossicità aggiuntive

• Liposomi raggiungono concentrazioni elevate nel sistema reticolo-endoteliale

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R-COMP – HEART01 trialAge > 60 years, if age > 70 years:

ADL = 6; IADL = > 4; No more than two grade 2 extracardiac comorbidities and absence of grade 3 extracardiac comorbidities;

Absence of geriatric syndromes “Cardiopathy” (doxorubicin not allowed)

DLBCL: new options

S ignaling pathway inhibition§ Immunomodulators: lenalidomide§ Proteasome inhibitors: bortezomib § mTOR inhibitors: everolimus§ HDACs inhibitors § BCR inhibitors (BTKI: PCI-32765)§ Inhibitors of Syk in B-cell signaling pathway: tamatinib§ PKCβ-selective inhibitors: enzastaurin § Pro-apoptotic ABT-263 Bcl-2 family; AT-101 Bcl-2 family

Bortezomib Lenalidomide BTKI PCI-32765

Fare clic per modificare lo stile del sottotitolo dello schema

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LEUCEMIA MIELOIDE CRONICASOSPETTO DIAGNOSTICO

-leucocitosi con neutrofilia (soprattutto se GB > 20.000 /l) - presenza di cellule immature circolanti (mieloblasti, metamielociti)- aumento di basofili e talora eosinofili- piastrinosi (30%)-Splenomegalia

-Età mediana 45-55 aa e 30% > 60 aa-Spesso asintomatica alla diagnosi

CROMOSOMA Ph+• traslocazione bilanciata reciproca tra le braccia lunghe dei cromosomi 9 e 22, t(9;22)(q34;q11). • Sono coinvolti l’oncogene ABL, sul cr.9, ed il gene BCR, Breakpoint Cluster Region sul cr.22

ASPETTI PATOGENETICI

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Chronic Phase

B lastic Phase

After Fabian et al. Nature Biotech.

2005;23:329

IC50

< 10 nM

10-50 nM

50-250 nM

250-1000 nM

Kinase selectivity profiles of nilotinib and dasatinib

Dasatinib15 targets

Imatinib

4 targets

Nilotinib

4 targets 50 X

325 XIMA

16 XNILO

27

P

PP PATP

SIGNALINGTKI

Bcr-abl

1. Savage DG et al. N Engl J Med. 2002;346:683-693.2. Scheijen B et al. Oncogene. 2002;21:3314-3333.

Azione degli inibitori delle tirosin-chinasi

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Cytogenetic Responses Molecular Responses2009 2013 2009 2013

Optimal

3 mo ≥ MinorCyR (Ph+ ≤ 65%) Ph+ ≤ 35% NA BCR-ABL ≤ 10%

6 mo ≥ PCyR (Ph+ ≤ 35%) Ph+ 0% NA BCR-ABL < 1%12 mo CCyR (Ph+ 0%) NA NA BCR-ABL ≤ 0.1%

18 mo NA NAMMR(BCR-ABL ≤ 0.1%) NA

At any time NA NA ≥ MMR BCR-ABL ≤ 0.1% Cytogenetic Responses Molecular Responses2009 2013 2009 2013

Failure3 mo < CHR Ph+ > 95% NA NA6 mo No CyR (Ph+ > 95%) Ph+ > 35% NA BCR-ABL > 10%12 mo < PCyR (Ph+ > 35%) Ph+ > 0 NA BCR-ABL > 1%18 mo < CCyR NA NA NA

At any time Loss of CCyR; CCA/Ph+ Loss of CCyR; CCA/Ph+

Mutations Confirmed loss of MMR; mutations

ELN 2013 recommendation: response definition, optimal and failure

Baccarani M, et al. Blood. 2013;122(6):872-884

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Eventi nello s tudio IRIS : importanza del monitoraggio nei primi anni di

terapia

Year

% W

ith E

vent

EventLoss of CHR,Loss of MCR,

AP/BC,Death during treatmentAP/BC

3.3

7.5

4.8

1.7

1.5

2.8 1

.6

0.9

0.8

0.3

0.5

0

2.0

0.4

• KM estimated EFS at 8 years = 81% (3 events)• KM estimated rate without AP/BC at 8 years = 92%

*Total events (n=3) including 1 progression and 2 deaths (unrelated to CML).

Deininger et al. ASH 2009

0.4

1.3

% W

ith E

vent

87

6

5

4

3

2

1

01 2 3 4 5 6 7 8

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Elevato score di comorbidità

Elevato rischio di sviluppare tossicità ematologica e/o extraematologica

Maggiore necessità di aggiustamenti di dose

(interruzioni o riduzione)

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IssuesQTc

prolongation

Cardiac failurePleural effusion

Diabetes

PAOD

PAH

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• ABL: protection from oxidative s tress• KIT: remodelling after miocardial infarction• FAK1: phys iologic cardiac hypertrophy• RAF1: protection from oxidative s tress and

arterial hypertens ion• JAK/S TAT: anti-apoptotic effect, regulation of

miocardial capillarity dens ity • RS K: anti-apoptotic effect• mTOR: upregulation of HIF (hypoxia inducible

factors ), including VEGFR

Heart - Tyrosine-Kinase Proteins

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• The European Guidelines for the management of hypertension identify as drugs of choice for the treatment of hypertension:

– thiazide diuretics (TD)– angiotensin II receptor blockers (ARBs)– angiotensin-converting enzyme inhibitors (ACEIs), – b-blockers (BBs), – calcium channel blockers (CCBs)Drug-drug interactions to occur with these treatments and second-generation TKIs

should be carefully considered.

Arterial Hypertension

Risk of cardiovascular events

Risk of pleural effusion

E. Abruzzese, M. Breccia, R. Latagliata, BioDrugs 2013

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Ipertensione e TKIs


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Ipertensione e TKIs


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TKIs and QTc prolongation

1. Saglio et al. N Engl J Med (2010) 362:2251-2259. 2. Kantarjian et al. N Engl J Med (2010) 362:2260-2270.3. Cortes et al. J Clin Oncol (2012) 30:3486-3492.

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7.88.380

2.24.070

0.71.360

0.10.850

0.10.240FemaleMale

CHF 5-Year Risk,* %Age, Yrs

Data From Framingham Heart Study

Imatinib and cardiac failure

9.376-85 (4/43)

2.366-75 (5/211)

2.056-65 (6/291)

0.345-55 (1/322)

0< 45 (0/409)

Incidence of CHF,* %Age, Yrs (n/N)

Patients Exposed to Imatinib

Atallah et al, Blood 2006;108(11):abs#2146.

Incidence of cardiac failure in patients exposed to Imatinib compared with cardiac failure incidence in general population

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How we can measure the CV risk?

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Identification of pts at risk of CV events in routine clinical setting

75 patients treated with Nilotinib front-line or after imatinib failuremedian age 51 years (range 19-76), 54.7% males

Ø CVD risk estimation according to ESC 2012: high/very high risk (pre-existing CVD, diabetes, severe hypertension, familial dyslipidemia, SCORE risk >5%) or low/moderate risk

Ø CV events occurred in 12 patients:- Myocardial Infarction or CHD (3)- Cerebrovascular events (3)- PAOD (6)

Rea et al. ASH annual meeting abstracts (2013) abs.#2726.

Low/moderate risk(n=55)

High/Very high risk(n=20)

Cumulative incidence of CV events at 48 months

15.47%(95% CI: 5.8-41.27)

77.73%(95%CI: 49.59-100)

High/Very High risktreated with Imatinib/Dasatinib

(n=28)

High/Very high risktreated with Nilotinib

(n=16)

CV events 3(10.7%)

7 (43.8%)

Median TKI duration at CV event, months (range)

31 (27-92) 28 (9-41)

Cumulative incidence of CV events at 48 months

20.47%(95% CI: 7.17-58.19)

77.73%(95%CI: 49.59-100)

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Risk factors for PAOD

European Guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal 2012;33:1635–1701.

• PAOD is characterized by the presence of a stenosis or occlusion in the arteries of the limbs and is usually caused by atherosclerosis, which is a systemic disease.

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PAOD e TKIs

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Ankle-Brachial Index

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S elected cardiovascular events by 5 years(all causes , all grades)

§ Due to the discontinuation rate, patients had longer exposure to nilotinib than imatinib

§ Approximately 85% of patients with a cardiovascular event had at least 1 risk factor and were not optimally managed for hyperglycemia and hypercholesterolemia

*All cause indicates all events, not only those deemed study drug-related by the investigator.IHD, ischemic heart disease; ICVE, ischemic cerebrovascular events; PAD, peripheral arterial disease.

Patients With an Event, n

Imatinib400 mg QD

n = 280

Nilotinib300 mg B ID

n = 279

Nilotinib400 mg B ID

n = 277

Total, n Y1-4, n Y5,

nTotal,

n Y1-4, n Y5, n

Total, n

Y1-4, n

Y5, n

IHD 5 3 2 11 11 0 21 14 7

ICVE 1 1 0 4 3 1 8 5 3

PAOD 0 0 0 4 4 0 6 5 1

Saglio G, et al. Blood. 2013:[abstract 92].

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Results of PAD S creening

• The relative risk for pathological ABI on frontline nilotinib vs frontline imatinib was 10.3 (95% CI, 2.3-61.5)• The relative risk for pathological duplex ultrasonography results with or without a PAOD event on frontline nilotinib

vs frontline imatinib was 13.2 (95% CI, 1.1-692.5)

All

N = 159

Frontline imatinib

n = 54

Frontline nilotinib

n = 33

Second-line nilotinibn = 33

Post-nilotinib

n = 25

Nilotinib-naive

n = 14

Median duration of CML, months (range)

74(4-269)

102(16-250)

30* (7-62)

78(27-240)

116(10-269)

14.5** (4-248)

Pathological ABI, n (% )

31/129 (24)

3/48 (6.3)

7/27 (26)

10/28 (35.7)

3/18(16.6)

1/8 (12.5)

P vs frontline imatinib 0.0297 0.0029 ND ND

Pathological duplex sonography, n (% )

8/30 (26.7)

1 2 2 3 0

S AE, n (% ) 5/159 (3.1)

0/54 (0)

1/33 (3)

3/33 (9.1)

1/25 (4)

0/14 (0)

Pathological duplex sonography or S AE, n (% )

13/159 (8.2)

1/54 (1.9)

3/33 (9.1)

5/33 (15.2)

4/25 (16)

0/14 (0)

P vs frontline imatinib 0.1507 0.0276 0.0327 ND

Kim TD, et al. Leukemia. March 5, 2013;

30/09/15 a4 events in 3 imatinib patients. bMedDRA preferred terms: myocardial infarction, acute myocardial infarction, and silent myocardial infarction.cMedDRA preferred terms: angina pectoris and unstable angina.

Dasatinib (n=259) Imatinib (n=260)

Adverse event Grade1/2

Grade 3/4

Grade 5

Totaln (% )

Grade 1/2

Grade 3/4

Grade 5

Totaln (% )

Cardiac ischemia 10(3.9% )

3a(1.2% )

Myocardial infarctionb 1 2 2 5 (1.9% ) 0 1 1 2

(0.8% )

Anginac 2 1 0 3 (1.2% ) 1 0 0 1

(0.4% )Coronary artery disease, myocardial ischemia 2 0 0 2

(0.8% ) 1 0 0 1 (0.4% )

Peripheral arterial occlus ive disease 0 0 0 0 0 0 0 0

Arterial Occlusive Events of Interest (Any Cause)

n Patients with a history of cardiac disease were included in DASISION, except those who had angina within 3 months, myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation

n 9 of 10 dasatinib and 2 of 3 imatinib patients with cardiac ischemia had at least 1 baseline risk factor for cardiovascular disease (eg, diabetes, hypertension, hyperlipidemia, left ventricular dysfunction, coronary artery disease)

PAOD e TKIs

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• Chronic pulmonary diseases comprise different conditions affecting the lungs and the respiratory system, such as chronic bronchitis, pleural effusions, emphysema and chronic obstructive pulmonary disease;

• Pleural effusions are the most common extra-haematological toxicity observed during dasatinib treatment;

• The aetiology of pleural effusions is unclear: dasatinib-induced inhibition of PDGF receptor or an immune-mediated mechanism may be implicated;

• In the DASISION study, the 3-year all-grade incidence of pleural effusions was 17.5% in dasatinib recipients compared with 0.4% in imatinib recipients.

• However, pleural effusions were generally manageable with temporary drug interruption and it did not affect the efficacy of the drug.

Chronic Pulmonary diseases

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• QTc prolongation is approximately one third that of imatinib;

• At 24 months, DASISION data showed pulmonary hypertension rate of 1.2 %, while drug-related cardiovascular adverse events of all WHO grades occurred in 6.6 % of dasatinib recipients, compared with 5.4 % of imatinib recipients. Postmarketing reports of dasatinib treatment have also reported incidences of pulmonary hypertension in patients receiving dasatinib, particularly in those patients receiving concomitant medications or who have comorbidities. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib therapy

• However, to reflect the risk observed with other TKIs, the SmPC for dasatinib states that patients at risk of developing prolonged QTc should be carefully monitored

Dasatinib and Cardiovascular disease

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Pulmonary Arterial Hypertens ion (PAH)

• PAH is defined by the European Cardiology Society as the elevation of the mean pulmonary artery pressure (mPAP) 25 mmHg at rest, or ≥

30 mmHg with exercise (≥ normal mPAP is 14±3 mmHg).

• PAH may be suspected if the right ventricular systolic pressure (RVSP), which is equal to the PA systolic pressure in the absence of pulmonary outflow obstruction, is >35 mmHg measured by Doppler transthoracic echocardiography.

• Definite diagnosis of PAH requires right-heart catheterization.

• Dyspnoea, nausea, fatigue and oedema - unspecific yet classical symptoms found in PH - are among the most frequently observed unwanted dasatinib effects.

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PAH is associated with pleural effus ion

Quintas-Cardama et al. J Clin Oncol 2007;25:3908-14.

Ø All patients except one had a normal Left Ventricular Ejection Fraction (LVEF).Ø All these events were suspected and not confirmed by catheterization.

Right Ventricular Systolic Pressure (RSVP), mmHg

p = .0014

(n=18)

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Dasatinib and PAH: conclusions

• Uncommon adverse event, maybe underestimated (but few confirmed diagnoses).

• Comorbidities do not have a significant predictive value (age?).

• Unknown mechanism, maybe off-target effect of SRC inhibition (probably not caused by PDGFR inhibition).

• Improvement in haemodynamics in the majority of cases at dasatinib discontinuation.

• An echocardiogram should be performed in patients with pre-existing cardiac diseases.

• Patients developing dyspnea or fatigue during treatment with dasatinib should be evaluated for common etiologies (such as pleural effusion, pulmonary edema, anemia). During this evaluation it is recommended to reduce or temporarily discontinue dasatinib treatment.

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Based on the clinical evidence of nilotinib and dasatinib, it is important to evaluate the following to determine the most appropriate 2GTKI treatment for each patient

Summary of comorbidities and 2G TKIs suitability

Abruzzese E. et al, Biodrugs 2013 modified

Disease Dasatinib NilotinibHypertension Possibly Suitable Possibly suitableQTc prolungation* Possibly suitable Possibly suitableCardiovascular disease Possibly suitable Possibly suitableSevere Diabetes mellitus** Suitable Not suitable

Chronic pulmonary diseaseNot suitable Suitable

Liver or endocrine disease Suitable Not suitable

Prior Pancreatitis Suitable Not suitableAutoimmune disease Possible suitable SuitablePrior gastrointest bleeding Not suitable Suitable

* QTc prolungation: ECG baseline and close monitoring of K+, Mg++** severe diabete : glycosilated haemoglobil >7%, high insulin requirement, organ damage

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Ipertens ione arteriosa: • Cautela con Nilotinib (> rischio interazioni e PAOD)

• Cautela con Dasatinib (> rischio di versamento pleurico)

• Cautela con Ponatinib (> rischio PAOD)

S . del QTc lungo: molta cautela con Dasatinib e Nilotinib (esclus ione dai protocolli regis trativi) ed Imatinib

Miocardiopatia: molta cautela con Imatinib (potenzialmente miocitotoss ico) con Dasatinib (ipertens ione polmonare? )

Patologia Cardiovascolare e TKIs

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Conclus ioni • Importante un corretto inquadramento alla diagnos i

– S tile di vita– Comorbidità (CCI)

• Trattamento puntuale delle comorbidità

• Buona conoscenza degli eventi avvers i

• Educazione del paziente ad un corretto s tile di vita

• Attenzione alla poss ibile interferenza di farmaci concomitanti

• Necessario il monitoraggio cardiovascolare dei pazienti con fattori di rischio e la collaborazione con il cardiologo e con altri specialis ti (diabetologo, pneumologo… )

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La gestione della cardiotoss icità nel paziente ematologico


Patrizia Pregno

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Terapie Oncologiche e Cardiotossicità Il rischio di