Le Terapie

(1)

Le Terapie

Ematologiche oggi

Evento residenziale

TERAPIE ONCOLOGICHE E CARDIOTOSSICITA’: IL RUOLO

DEL TERRITORIO

DATE

Ed.1: 20 novembre 2015

ORARIO

Dalle 9.30 alle 16.30

SEDE DEL CORSO

Via Rosmini 6 – piano terra

Torino, 20 novembre 2015

Patrizia Pregno

SC Ematologia

Città della Salute e della Scienza di Torino

Torino

(2)

L’ematologo deve tener conto di

molti fattori

(3)

Quale paziente?

(4)

Quale terapia per quale malattia?

Linfomi: terapia breve a cicli (3-6 mesi) ad 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

(5)

Chemioterapia e Cardiotossicità

ANTRACICLINE: daunorubicina, doxorubicina

Si intercalano tra le catene del DNA compromettendone la funzionalità e provocandone la rottura.

Sono in grado di formare forme attivate dell’Ossigeno (ROS)

Effetti tossici:

Mielosoppressione, reazioni anafilattiche, alopecia, disturbi gastrointestinali

Potenziale mutagenicità/carcinogenicità

(6)

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

Cardiovascular toxicity of biologic agents for cancer therapy

(7)

Probability of CCR ( GMALL )

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

Leucemia acuta linfoblastica

> 50 aa

< 20 aa

(8)

(9)

Trapianto allogenico: casistica Ematologia

ANNI AlloBMT AutoBMT

2000-2013 750 2000

2013 52 (32 MUD) 131

(10)

Trapianto allogenico: casistica Ematologia

(11)

GELA-LNH 98.5: R-CHOP21 aaIPI 2-3 DLBCL patients

Coiffier B et al, Blood 2010.

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

Diffuse Large B-Cell Lymphoma

(12)

Studio retrospettivo su 135 pazienti

affetti da NHL aggressivi trattati con CHOP

Una dose di Doxorubicina > 200 mg/m

²

e l’età > 50 anni sono risultati dei fattori di rischio indipendenti

Cardiotossicità nei linfomi

Limat S. et al Ann Oncol 2003

20% pts

cardiotossicità

50% hanno avuto CHF 50% hanno avuto una riduzione

di LVEF

(13)

Johnson SA, Sem Oncol 2006

nella probabilità di sviluppare CHF

Significativa riduzione dei valori di LVEF già a

dosi di 200 mg/m

²

Influenza della dose cumulativa di

doxorubicina

(14)

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

Aviles A et al. Leuk Lymphoma 2001

Linfomi non Hodgkin

Studio retrospettivo su 714 pazienti

(Dose cumulativa di Doxorubicina: 365 mg/m

²

)

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)

(15)

First line treatment

FIT patients UNFIT patients

(16)

Comprehensive geriatric assessment

Tucci A et al, Cancer 2009.

(17)

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

(18)

R-COMP – HEART01 trial

Age > 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)

(19)

LEUCEMIA MIELOIDE CRONICA SOSPETTO 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

(20)

Chronic Phase Blastic Phase

(21)

(22)

(23)

Issues

QTc

prolongation

Cardiac failure Pleural effusion

Diabetes PAOD

PAH

(24)

• ABL: protection from oxidative stress

• KIT: remodelling after miocardial infarction

• FAK1: physiologic cardiac hypertrophy

• RAF1: protection from oxidative stress and arterial hypertension

• JAK/STAT: anti-apoptotic effect, regulation of miocardial capillarity density

• RSK: anti-apoptotic effect

• mTOR: upregulation of HIF (hypoxia inducible factors), including VEGFR

Heart - Tyrosine-Kinase Proteins

(25)

• 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

(26)

Ipertensione e TKIs

(27)

Ipertensione e TKIs

(28)

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.

(29)

7.8 8.3

80

2.2 4.0

70

0.7 1.3

60

0.1 0.8

50

0.1 0.2

40

Female Male

CHF 5-Year Risk,* % Age, Yrs

Data From Framingham Heart Study

Imatinib and cardiac failure

9.3 76-85 (4/43)

2.3 66-75 (5/211)

2.0 56-65 (6/291)

45-55 (1/322) 0.3

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

(30)

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

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

 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

 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 risk

treated with Imatinib/Dasatinib (n=28)

High/Very high risk treated 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)

(31)

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.

(32)

PAOD e TKIs

(33)

Selected 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

Imatinib 400 mg QD

n = 280

Nilotinib 300 mg BID

n = 279

Nilotinib 400 mg BID

n = 277 Total,

n Y1-4,

n Y5,

n Total,

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].

(34)

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 Grade

1/2

Grade 3/4

Grade 5

Total n (%)

Grade 1/2

Grade 3/4

Grade 5

Total n (%)

Cardiac ischemia 10

(3.9%)

3^a (1.2%)

Myocardial infarction^b 1 2 2 5

(1.9%) 0 1 1 2

(0.8%)

Angina^c 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 occlusive

disease 0 0 0 0 0 0 0 0

Arterial Occlusive Events of Interest (Any Cause)

 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

 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)

(35)

PAOD e TKIs

(36)

• 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

(37)

• 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

• The selection criteria for DASISION were less restrictive;

• 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

(38)

PAH is associated with pleural effusion

Quintas-Cardama et al. J Clin Oncol2007;25:3908-14.

 All patients except one had a normal Left Ventricular Ejection Fraction (LVEF).

 All these events were suspected and not confirmed by catheterization.

Right VentricularSystolicPressure (RSVP), mmHg

p = .0014

(n=18)

(39)

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.

(40)