Anticuerpos monoclonales, inhibidores de kinasas e inhibidores de proteasomas #COH18

Toxicidad cardiovascular secundaria a tratamientos onco-hematológicos: mecanismos y estrategias de prevención en onco-hematología
Módulo I-2
Anticuerpos monoclonales,
inhibidores de kinasas e
inhibidores de proteasomas
Ramón García Sanz
Hospital Universitario de Salamanca

Andrea K. Ng. Blood 2014 124:3373-3379
Linfoma de Hodgkin:
Mortalidad acumulada según su causa

Positioning Papers

Chemotherapy agents Incidence (%)
Anthracyclines (dose dependent)
Doxorubicin (Adriamycin)
• 400 mg/m2
• 550 mg/m2
• 700 mg/m2
3–5
7–26
18–48
Idarubicin (>90 mg/m2) 5–18
Epirubicin (>900 mg/m2) 0.9–11.4
Mitoxantrone >120 mg/m2 2.6
Liposomal anthracyclines (>900) 2
Alkylating agents
Cyclophosphamide 7–28
Ifosfamide
• <10 g/m2
• 12.5–16 g/m2
0.5
17
Antimetabolites
Clofarabine 27
Antimicrotubule agents
Docetaxel 2.3–13
Paclitaxel <1
Chemotherapy agents Incidence (%)
Monoclonal antibodies
Trastuzumab 1.7–20.128a
Bevacizumab 1.6–414b
Pertuzumab 0.7–1.2
Small molecule tyrosine kinase inhibitors
Sunitinib 2.7–19
Pazopanib 7–11
Sorafenib 4–8
Dasatinib 2–4
Imatinib mesylate 0.2–2.7
Lapatinib 0.2–1.5
Nilotinib 1
Proteasome inhibitors
Carfilzomib 11–25
Bortezomib 2–5
Miscellanous
Everolimus <1
Temsirolimus <1
Zamorano et al, European Heart Journal (2016) 37, 2768-2801
Incidence of Left Ventricular dysfunction with chemotherapy drugs

Inhibidores de Tirosín Kinasas
• Anti BCR-ABL: LMC, LLA Ph’ positiva
– Imatinib
– Dasatinib
– Nilotinib
– Ponatinib
– Bosutinib
• Anti BTK:
– Ibrutinib
– Acalabrutinib
– Zanubrutinib
• Anti PI3K

Logros de Imatinib
Bjorkholm M. JCO 2011 Jun 20;29(18):2514-20
Leucemia Mieloide Crónica

Hochaus et al, N Engl J Med 2017; 376:917-27
Only 6.8% of patients had discontinued imatinib as a
result of AEs, whereas the projected overall survival
was at an unprecedented 83.3%, establishing imatinib
as an efficacy and safety benchmark.
Kaplan–Meier Estimated Overall Survival Rates at 10
Years in the Intention-to-Treat Population

• Protein TKs catalyze the transfer of
phosphate from ATP to tyrosine residues on
specific protein.1
• TKs also play a critical role in cardiovascular
system, including vascular, metabolic, and
myocardial physiology.21. Bellinger et al. Circulation 2015; 132:2248
2. D’Agostino et al. Circulation. 2008;117:743
Mecanismo de acción de los ITKs

Activity of approved ABL1 tyrosine
kinase inhibitors
Moslehi & Deininger, J Clin Oncol. 2015, 33:4210-4218

CVE with TKI in CML
Imatinib Nilotinib Dasatinib Bosutinib Ponatinib
CHF 0.2% - 0.1% - 0.4%
LVEF ↓ No - - - -
PAH 0 0.4% 0.45% - -
PAD 0 6.2% - - 23%
Liquid retention* 20% 15% 28% 19%** -
Hypertension 4% 9% - 0% 26%
CVE Global 4.8% 6.5% 1.1% 10% 27%
CVE: Cardio Vascular Event; CHF Congestive Heart Failure; CVD: Cardio Vascular Disease; LVEF: Left Ventricular Ejection
Fraction; PAH : Pulmonary Arterial Hypertension; PAD: Peripheral Arterial Disease; AMI: Acute Myocardial Infarction.
*Mostly non-cardiogenic; **pleural effusion

Koji Sasaki, MD; Elias J. Jabbour, MD
Cancer 2016; American Cancer Society.
Conclusions:
The clinical outcome of patients treated with HCVAD plus ponatinib appears to be superior to that
of patients treated with HCVAD plus dasatinib among individuals with Ph+ALL.
Hyper-CVAD Plus Ponatinib Vs Hyper-CVAD
Plus Dasatinib as Frontline Therapy for
Patients with Ph+ALL: A Propensity Analysis

Assessment Imatinib Nilotinib Dasatinib Bosutinib Ponatinib
Baseline Follow SOC
• Clinical cardiovascular assessment,
incl. blood pressure
REC REC REC REC
• Fasting glucose REC ACI ACI REC
• Fasting lipid panel REC ACI ACI REC
• Echocardiogram ACI ACI ACI ACI
• ECG REC† REC ACI ACI
• Ankle-brachial index REC ACI ACI REC
1-month follow-up
• Clinical cardiovascular assessment. REC REC ACI REC
• Blood pressure check ACI ACI ACI REC
3- to 6-month follow-up
• Clinical cardiovascular assessment REC REC REC REC
• Blood pressure check REC ACI ACI REC
• Fasting glucose REC ACI ACI ACI
• Fasting lipid panel REC ACI ACI REC
• Echocardiogram ACI ACI ACI ACI
• ECG ACI† ACI ACI ACI
• Ankle-brachial index REC ACI ACI REC
NOTE. Practice guidelines regarding prevention of cardiovascular toxicity should be followed, including tobacco cessation counseling. In symptomatic
patients or those with high cardiovascular risk, consider referral to cardiologist.
Abbreviations: ACI, as clinically indicated; ECG, electrocardiogram; REC, recommended; TKI, tyrosine kinase inhibitor.
Low threshold for an echocardiogram in patient considered for treatment or being treated with dasatinib who has cardiopulmonary symptoms.
†ECG prior to starting, after 7 days after starting, and after each dose change (package insert).
Recommendations for Cardiovascular Follow-Up in patients receiving BCR-ABL1 TKIs
Moslehi & Deininger, J Clin Oncol. 2015, 33:4210-4218

• Subcomité de Linfoma de Hodgkin
• Subcomité de Linfomas agresivos
• Subcomité de Linfomas indolentes
– Linfoma del Manto
– Linfoma Folicular
– Linfoma de la Zona Marginal
– Linfoma Linfoplasmocítico
– Linfoma linfocítico de célula pequeña / LLC
– Otros
Linfoma

Vía patogénica de BTK
Ibrutinib
Acalabrutinib
Zanubrutinib

Progression-free and Overall Survival
Ibrutinib vs. Ofatumumab
PHES/IBR/0317/0004(1)aBurger JA. N Engl J Med. 2015 Dec 17;373(25):2425-37
OverallSurvival(%)

PFS PFS
PFS OS
Dimopoulos et al, Lancet Oncol. 2017 Feb;18(2):241-250
iNNOVATE (Arm C): Survival

Overall survival: RESONATE-2 study
Burguer et al, N Engl J Med 2015;373:2425-37

Higher level term, n (%) Ibrutinib (n=756) Comparator (n=749) P
Hypertension 71 (9.4) 26 (3.5) <0.0001
Congestive heart failure 151 (20.0) 163 (21.8) 0.7118
Ischemic cardiac disease 17 (2.2) 17 (2.3) 0.4802
Ischemic CNS vascular conditions 10 (1.3) 6 (0.8) 0.3044
Arrhythmia 55 (7.3) 46 (6.1) 0.1148
Characterization of
Atrial Fibrillation
adverse events
reported in ibrutinib
randomized controlled
registration trials
Brown et al, Haematologica
2017, 102:1796-1805

Vrontikis et al.
Oncology (WP).
2016; 30:970-4

Survival in Multiple myeloma

Carfilzomib
Pomalidomide
Melphalan
(1958, Blokhin)
Ann NY Acad Sci
Combination chemo
Vincristine
Doxorubicin
Dexamethasone
Melphalan
Glucocorticoids
(1969)
Mr.
McBean
1844
HD
Melphalan
ASCT
IMiDs
Thalidomide
(1999)
PIs
Bortezomib
Lenalidomide
Targeted Therapy EraChemotherapy Era
Rituximab
(NHL) 1997
Gleevec
(CML) 2001
Herceptin
(Breast) 1998
Panobinostat
Elotuzumab
Ixazomib
Daratumumab
Treatment of Multiple Myeloma
Isatuximab
Selinexor
Venetoclax
CAR-T cells
BiTe
1844 1960 19801970 1990 2000 2003 2013 2015 2017

Inhibidores del Proteasoma
• Bortezomib
• Carfilzomib
• Ixazomib
• Oprozomib
• Marizomib
– Mieloma múltiple
– Linfoma del Manto
– Linfoma difuso de célula grande

Cardiovascular Disease in Multiple Myeloma
AE, adverse event; A–V, arteriovenous; CV, cardiovascular; IMiD, immunomodulatory drug; PI, proteasome inhibitor; SCT, stem cell transplantation.
1. Kistler K, et al. ASH 2012: Abstract 2916;
2. SEER Cancer Statistics Factsheets: Myeloma. National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed 11 March 2015;
3. Wang M, Cheng J. Oncology 2013;27(Suppl. 3):24–30.
Disease-related1,3
Pathogenesis & progression:
•Amyloid infiltration
•Hyperviscosity
•A–V shunting
•Chronic anemia
Treatment-related3
Treatments for MM are
associated with increased
CV risk, e.g.
anthracyclines, alkylating
agents, IMiDs, PIs, and
SCT
High incidence of cardiac comorbidities and cardiac events in
MM patients were seen regardless of relapse status and type
of anti-myeloma treatment1
Age-related2
Most patients are
diagnosed between 65–74
years of age,
with a median age at
diagnosis of 69 years
Elderly population and/or
history of CV events are
associated with occurrence
of cardiac AEs1,3
Over 60% of patients with MM have cardiac comorbidities at diagnosis1

Cardiovascular Disease in Multiple Myeloma:
Hypothesized Mechanisms of Proteasome Inhibitor-
Induced Cardiac Adverse Events
Increased apoptosis of endothelial
progenitor cells1
Impaired endothelial nitric
oxide synthase activity1
Functional and structural
abnormalities in
cardiomyocytes due to
protein accumulation
(decreased proteasomal
protein degradation)2,3
Potentiation of
cardiomyocyte cytoxicity from
other agents (melphalan, doxorubicin)2
Left ventricular contractile dysfunction2
mitochondrial cardiac
function dysruption2
Induction of ER stress
in cardiomyoblasts2
Myocardial
scarring and fibrosis4
Suppression of adaptive,
cytoprotective ubiquitin-proteasome system
activity in the setting of baseline cardiomyopathy5
1. Takamatsu H, et al. Int J Hematol. 2010; 91:903‐906; 2. Nowis D, et al. Am J Pathol. 2010;
176:2658‐2668; 3. Hacihanefioglu A, et al. Int J Hematol. 2008; 88:219‐222; 4. Foley P, et al. J
Cardiovasc Med. 2010; 11:386‐388; 5. Voortman J, et al. BMC Cancer. 2006; 6:129‐132

All-Grade Adverse Events Grade ≥3 Adverse Events
Outcome
No. Of
Studies % (95% CI)
P
Value I2
I2 P
Value
No. Of
Studies % (95% CI) P Value I2
I2 P
Value
All events 22 18.1 <.001 87.4 <.001 24 8.2 <.001 71.6 <.001
(13.5-23.3) (5.9-10.7)
Congestive 17 4.1 <.001 65.2 <.001 23 2.5 <.001 49.2 .004
heart failure (2.3-6.2) (1.5-3.8)
Hypertension 16 12.2 <.001 54.1 .004 17 4.3 <.001 60.3 .001
(9.8-14.9) (2.6-6.4)
Arrhythmia 13 2.4 .004 84.4 <.001 17 0.8 <.001 0 .86
(0.4-5.6) (0.3-1.4)
Ischemia 13 1.8 <.001 38.0 .08 18 0.8 <.001 0 .78
(0.8-3.0) (0.4-1.4)
Cardiac arrest NA NA NA NA 24 0.0 >.99 0 .98
(0.0-0.1)
Dyspnea 17 23.9 <.001 88.4 <.001 18 3.2 <.001 29.5 .11
(18.4-29.9) (2.2-4.3)
Edema 12 24.7 <.001 64.2 .001 12 0.4 <.001 0 .61
(21.0-28.6) (0.1-0.9)
Summary Estimates of Carfilzomib
Cardiovascular Adverse Events
Waxman et al, JAMA Oncol. 2017 Dec 28:e174519. [Epub ahead of print]

Cardiac AEs in ASPIRE/ENDEAVOR
Updated analyses
Grade ≥3 AE rates, % KRd Rd
Hypertension 5.9 2.1
Cardiac failure 3.9 1.8
Peripheral neuropathy 2.8 3.1
ASPIRE update: median follow-up of 37.8 (KRd) and 37.0 months (Rd)1
Kd (n = 463) Vd (n = 456)
All grade Grade ≥ 3 All grade Grade ≥ 3
AE, %
Acute renal failure* 10.4 5.6 6.1 3.3
Hypertension 32.2 14.5 9.9 3.3
Dyspnea 32.2 6.3 13.6 2.2
Cardiac failure* 10.8 5.8 3.3 2.0
Peripheral neuropathy* 21.0 2.4 54.6 9.6
Ischemic heart disease* 3.9 2.6 2.0 1.5
*Grouped term
1. Siegel DS, et al. Poster presented at IMW 2017.
2. Dimopoulos MA, et al. Lancet Oncol. 2017 Oct;18(10):1327-1337
ENDEAVOR update: median follow-up of 37.5 (Kd) and 36.9 months (Vd)2

Primary End Point: Progression-Free Survival
Intent-to-Treat Population (N=929)
1.0
0.8
0.6
0.4
0.2
0
ProportionSurvivingWithoutProgression
0
Months Since Randomization
Kd
Vd
Kd
(n=464)
171 (37)
18.7
Vd
(n=465)
243 (52)
9.4
0.53 (0.44–0.65)
1-sided P<0.0001
Disease progression or death – n (%)
Median PFS – months
HR for Kd vs Vd (95% CI)
Median follow-up: 11.2 months
6 12 18 24 30
Dimopoulos MA, et al.: 16th International Myeloma Workshop; March 1-4, 2017; New Delhi, India.

Afectos cardiovasculares adversos
(CVAEs) Prevención y control (I)
1. Kyprolis Summary of Product Characteristics (SmPC). Amgen. 2. Mikhael, J. Clinical Lymphoma, Myeloma & Leukemia. 2016;16:241-5. 3. American Heart Association. Get With The
Guidelines® ‐ Heart Failure. June 2011.
1
ANTES
Consideraciones previas al tratamiento
Identificar y determinar el riesgo
potencial de EA cardíacos en
pacientes1:
• Edad avanzada: ≥75 años
• Fallo cardíaco previo (Clase NYHA III &
IV)
• Infarto de miocardio reciente (4 meses1)
• Anomalías de conducciòn
• Angina
• Arritmia no controlada
farmacológicamente
Medidas para mitigar el riesgo
• Control de hipertensión y/o fallo
cardíaco previos previa y considerar
la consulta previa al cardiólogo antes
de empezar tratamiento con
carfilzomib1,2
Control de fluidos:
• Establicer el peso basal del paciente
• Oral: 30 mL/kg/day de líquidos al
menos 48 h antes del Ciclo 1, Día 11,2
• IV: 250-500 mL de líquidos antes de la
cada dosis del 1er Ciclo1,2
• Considerar reducir el volumen de fluido
en pacientes con mayor riesgo
cardíaco1,2
1

Efectos Cardiovasculares Adversos
(CVAEs) Prevención y control (II)
Monitorizar TA y CVAEs:
• Medición regular de la TA en todos
los pacientes1
• Monitorización de signos y síntomas
de fallo cardíaco activo1:
• Disnea3
• Tos/sibilancias3
• Edema3
• Dolor torácico4
• Fatiga/debilidad3
• Confusión/aletargamiento4
• Naúseas/anorexia3
• Ritmo cardíaco acelerado3
• Cambios bruscos en el peso3
Monitorización y adaptación de
hidratación :
• Monitorizar signos de sobrecarga
de volumen y ajustar
apropiadamente la hidratación,
especialmente en pacientes con
riesgo de fallo cardíaco1,2
DURANTE
Consideraciones durante el tratamiento2

Efectos Cardiovasculares Adversos
(CVAEs) Prevención y control (III)
DESPUÉS
Cuando el Efecto Cardíaco Adverso ya se ha producido
Suspender carfilzomib1,2:
• En caso de CVAE Grado 3 o 4
(incluyendo disnea) hasta que se
resuelva o retorne a la situación
previa
• En caso de hipertensión pulmonar
hasta que se resuelva o retorne a
la situación previa
• En caso de crisis hipertensiva
hasta que se resuelva o retorne a
la situación previa1
Reducir la dosis de carfilzomib1:
• En caso de hipertensión no
controlable
3
Considerar reiniciar carfilzomib en
un nivel de dosis basado en una
evaluación riesgo/beneficio1,2
Consultar a cardiología2

Conclusiones
• La terapia dirigida en hematología tiene poca toxicidad cardíaca
• La mayoría de los inhibidores de tirosín kinasa ABL tienen
escasa repercusión cardíaca y se puede controlar con cambio del
fármaco, a excepción de Ponatinib, cuya mayor toxicidad podría
tener que ser aceptada en el balance riesgo-beneficio.
• Los inhibidores de la Tirosín Kinasa de Bruton son seguros,
aunque producen Fibrilación Auricular. Salvo excepciones, la regla
es tratar la FA y continuar tratamiento con ibrutinib sin
modificaciones
• Los inhibidores del proteasoma apenas producen cardiotoxicidad,
con excepción del Carfilzomib, cuya menor neurotoxicidad se
acompaña de efectos cardiovasculares adversos que requieren
atención específica

Anticuerpos monoclonales, inhibidores de kinasas e inhibidores de proteasomas #COH18

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