Michael J. Mauro, MDLeader, Myeloproliferative Neoplasms Program
Memorial Sloan Kettering Cancer Center, New York, NY
Cardiotoxicities of Tyrosine Kinase Inhibitors to Treat CML and CLL: Heart Attacks, Strokes, and Atrial Fibrillation Oh My!
PresenterPresentation NotesPatients with BCR-ABL1 values >10% at 3 months had better outcomes if the BCR-ABL1 halving time was ≤76 days. Among the 95 patients with BCR-ABL1 values >10%, the 74 patients with a halving time of ≤76 days had significantly superior (A) OS, (B) PFS, (C) FFS, and (D) MMR compared with the 21 patients with a halving time of >76 days. For some of the patients with an assigned halving time of >76 days, their BCR-ABL1 value did not halve at any time or increased. The outcome for patients with BCR-ABL1 values ≤10% at 3 months are also plotted.
Disclosures:
• Consultant, Advisory Board Member:– Novartis, Bristol Myers Squibb, Takeda, Pfizer
• Clinical Trial Steering Committee:– Novartis, Bristol Myers Squibb, Takeda
• Clinical Trial Funding (to Institution, MSKCC):– Novartis, Bristol Myers Squibb, Sun Pharma
PresenterPresentation NotesPatients with BCR-ABL1 values >10% at 3 months had better outcomes if the BCR-ABL1 halving time was ≤76 days. Among the 95 patients with BCR-ABL1 values >10%, the 74 patients with a halving time of ≤76 days had significantly superior (A) OS, (B) PFS, (C) FFS, and (D) MMR compared with the 21 patients with a halving time of >76 days. For some of the patients with an assigned halving time of >76 days, their BCR-ABL1 value did not halve at any time or increased. The outcome for patients with BCR-ABL1 values ≤10% at 3 months are also plotted.
Targeted Therapy in Oncologyand the Problem of ‘Late Cardiovascular Events’
• CLL: Ibrutinib– Atrial Fibrillation, Ventricular Arrhythmias, Bleeding
• CML: Tyrosine Kinase Inhibitors– Vascular Occlusive Events; Pulmonary Arterial Hypertension
• Others likely to develop as targeted therapy continues to quickly expand
• CLL, the most common leukemia, previously was a disease treated expectantly, and ‘best’ (young/fit) with chemotherapy; now high risk pts better treated and ?cure
• CML has set the paradigm for targeted therapy and is highly treatable and (potentially) functionally curable for all patients– Imatinib and Herceptin development contemporaneous
Novel Agents for CLLBCR-associated Kinase and BCL-2 Inhibitors
Adapted from Niiro H. Nat Rev Immunol 2:945
• Syk (spleen tyrosine kinase):1. fostamatinib (R935788) 2. entospletinib (GS-9973)
• Btk (Bruton’s tyrosine kinase):1. ibrutinib (PCI-32765)2. acalabrutinib (ACP-196)3. tirabrutinib (GS-4059)
• PI3K (phosphatidylinositol 3-kinase):1. idelalisib (GS-1101)2. duvelisib (IPI-145)3. umbralisib (TG-1202)
mitochondria
X
• BCL-2:1. venetoclax (ABT-199)
Cumulative Incidence of Discontinuation of Ibrutinib in CLL by Cause
Woyach J. JCO. 2017; 35:1347.
Cumulative Incidence 2 Yrs 3 Yrs 4 Yrs
CLL Progression 5.0% 10.8% 19.1%
Transformation 7.3% 9.1% 9.6%
Other Event 18.7% 23.9% 25.0%
CMLAt present, five oral kinase inhibitors approved in the US for Ph+ Leukemia:
a ‘spoil of riches’; more on the way?
1st Gen. TKI
2nd Gen. TKIs
3rd Gen. TKI
2001Novartis(1st line)
2007/2010BMS
(1st, 2nd line)
2012/2015 IL-YANG:
(1st, 2nd line)
2012Pfizer
(1st, 2nd, 3rd line)
2012Ariad
(2nd?/3rd line)
2007/2010Novartis
(1st, 2nd line)
Radotinib (IY5511)
Imatinib (STI571)
Dasatinib (BMS354825) Nilotinib (AMN107)
Bosutinib (SKI606)
Ponatinib (AP24534)
4th Gen. TKI (allosteric): ABL001
South Koreaonly
Huang et al, Cancer 118:3123-3127, 2012.Bower H et al, J Clin Oncol 34:2851-57, 2016.
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
• Incidence 4700 per year• Age-matched mortality ratio vs
normal population = 1.50
• Accounts for increased US population to 410 million in 2050
Year
Num
ber o
f Cas
es 10x greatersteady state number
of CML patients in USby 2050
CML is an increasingly
prevalent and survivable cancer
lifespan
prevalence
Ready for prime time:
‘treatment free remission’
(TKI cessation for patients in
deep molecular remission)
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Months from discontinuation of TKI
EURO-SKI: Survival without loss of MMRn=200; MR4 or greater, >2y (inclusion)Relapses, n=86Relapses within 6 months , n=77
Saussele S, et al. EHA. 2014: [abstract LB-6214]
Relapsemol-free survival at 6 months : 61% (54-68)
Rel
apse
free
sur
viva
l
Cum
ulat
ive
inci
denc
e o
f MR
Months since stop of imatinib
• Median time to molecular recurrence: 2.5 mo. (range,0.8 to 22.2)
• 57 out of the 61 pts restarted TKI (imatinib, n=56; dasatinib , n=1) and 55 achieved 2nd CMR at a median of 4.2 months
• Median follow-up of 63 mo. : - None of the MR patients have CML progression event
Treatment Free Remission in the label for Nilotinibas of 12/22/17
Front-line nilotinib in CML: CVEs over time(5y data- ENESTnd)
Larson RA, et al. J Clin Oncol. 2014;32:5s (suppl; abstr 7073).
CLL
New agents, new problems
Ibrutinib in CLL
• Front-line CLL• Relapsed CLL• Mantle cell lymphoma• Waldenströms
• Effective in P53mutated disease(high risk)
Ibrutinib-associated bleeding
• Irreversibly binds BTK and TEC kinasesGPVIcollagen / CRP dep’dactivation abolished
• CLEC-2 signaling inhibited (mediates thrombus stability after platelet adhesion to damaged endothelium)
• Inhibits GPIb-VWF interaction (tethers plts to injured vessel wall)• Inhibits αIIbβ3 signaling (Fibrinogen-integrin αIIbβ3 induced
platelet activation)
Current understanding of bleeding with ibrutinib use:a systematic review and meta-analysis
• 22 manuscripts, 4 randomized trials, 2152 pts• Pooled rate of major bleeding- 17 studies: 2.76 per 100 person-
years (vs 1.9 per 100 for non-ibrutinib therapy)• RESONATE: ibrutinib = 44% vs. ofatumumab = 12%• HELIOS: ibrutinib = 31% vs. placebo = 15%• Acalabrutinib: all grades = 34%; grade >3 = 0%
Caron F et al, Blood Advances 1:772-78, 2017
major bleeding
Potential Mechanism of AF:AP and APD perturbation by overlapping pathways
Alexandre J et al Pharmacology and Therapeutics 189 89-103, 2018
Ibrutinib AF and Hypertension
Atrial fibrillation• Ibrutinib = 5% vs. ofatumumab = 1%• Possibly due to ibrutinib metabolism• HELIOS: I + BRi = 7.7% vs. P + BR = 2.4%• RESONATE2: ibrutinib = 7.4% vs chlorambucil = 1%• Acalabrutinib = 3%
Hypertension• HELIOS: ibrutinib = 10% vs. placebo = 5%• RESONATE2: ibrutinib = 14% vs. chlorambucil = 0%• Acalabrutinib: not reported
The risk of atrial fibrillation with ibrutinib use:a systematic review and meta-analysis
• 20 manuscripts, 4 randomized trials
• Pooled rate of AF- all studies, 26mo follow-up: 3.3 per 100 person-years (vs 0.84 per 100 for non-ibrutinib therapy)
• Framingham data: age 65-74, 1-2/100 person yearsLeong DP et al, Blood 128:138-40, 2016
: R/R MCL, IB vs temsirolimus
: HELIOS: BR +/- IB in CLL
: RESONATE: IB vs Ofatumumab in CLL
: RESONATE-2: IB vs Chlorambucilin CLL
Surveillance methods? Case definitions? Underestimate? Unmasking preexisting AF?
Ventricular Arrhythmias and Sudden Death in Patients Taking Ibrutinib
• Index cases-> FAERS data for 2y after approval date
• 13 additional cases (VA) with 6 sudden death– 10/13 no CV history; median age = 61; median 65d after ibrutinib start
• Clinical trial experience (n~1000): incidence rate 788 events per 100,000 person-years– HELIOS trial: bendamustine/rituximab +/- ibrutinib: 7 vs 0 >Gr3 VA,
cardiac arrest, sudden death-> 1991 vs 0 per 100,000 person years
Lampson BL et al Blood 129:2581-84, 2017
Honigberg LA. PNAS 2010; 107:13075.
Activity of Ibrutinib on Other Kinases;Acalabrutinib vs Ibrutinib
Irreversible Reversible
Kinase IC50 (nM) Kinase IC50 (nM)BTK 0.46 FGR 2.31
BLK 0.52 CSK 2.30
BMX/ETK 0.76 Brk 3.34
EGFR 5.55 HCK 3.67
ErbB2 9.40 YES 6.50
ITK 10.70 FRK 29.20
JAK3 16.13 LCK 33.24
TEC 77.76 RET 36.5
FLT3 73.0
ABL 86.12
FYN 96.0
KinaseACP-196IC50(nM)
IbrutinibIC50(nM)
Btk 1.2 0.43
Tec 29 1.8
Bmx 39 0.87
Itk >1000 168
Txk 291 2.0
EGFR >1000 5.0
ErbB2 912 6.2
ErbB4 13.2 2.7
Blk >1000 0.10
Jak3 >1000 48
CML
Trying to avoid collateral damagewhilst headed for functional cure
Cardiomyopathy associated with
imatinib
Decreased EFMyocyte injury
Myocyte apoptosis
Injury via endoplasmicreticulum stress response
Mediated via c-JunN-terminal kinase
Kerkela R et al. Nat Med 2006; 12(8):908-16.
PAD associated with nilotinib:biochemical and ABI changes
Kim TD et al. Leukemia 2013; 27:1316-21.
PAD associated with nilotinib: clinical impact
Kim TD et al. Leukemia 2013; 27:1316-21.
Summary of VOEs:ponatinib phase I and phase II (PACE) trials
Treatment-EmergentAdverse Events
Treatment-EmergentSerious Adverse Events
All, n/N (%)
Treatment-Related, n /N (%)
All, n/N (%)
Treatment-Related, n/N (%)
Phase IAll patients (N=81)
37/81 (46) 7/81 (9) 16/81 (20) 5/81 (6)
Phase ICML and Ph+ ALL(N=65)
31/65 (48) 7/65 (11) 14/65 (22) 5/65 (8)
Phase II (PACE)All patients (N=449)
109/449 (24) 45/449 (10) 67/449 (15) 27/449 (6)
27%Dec 2013
USPI
Phase I Data as of 26 Sep 2013; PACE Data as of 03 Sept 2013
Meta-analysis:imatinib versus subsequent generation TKIs, VOEs
Douxfils J et al, Lancet Oncology, 2016
Montani et al. Circulation. 2012 May 1;125(17):2128-37
Data from French PH Registry 2006-2010
Incidence:13/2900 (0.45%)
8:1 female:male
Median interval:34 mths (8-48)
Characterization of PAH with dasatinib:
Clinical, functional, and hemodynamic parameters after dasatinibdiscontinuation
Montani et al. Circulation. 2012 May 1;125(17):2128-37
•All but 1 pt improved after withdrawal of dasatinib
•Symptomatic and functional improvement seen but did not return to normal hemodynamics
•2 pts died from RV failure and SCD
Other cases reported:• Dumitrescu et al. Eur Respir J. 2011 Jul;38(1):218-20• Rasheed et al. Leuk Res. 2009 Jun;33(6):861-4• Mattei et al. Bone Marrow Transplant. 2009 Jun;43(12):967-8• Hennigs et al. BMC Pulm Med. 2011 May 23;11:30zz
PresenterPresentation NotesMuestra la evolucion clinica funcional y parametros hemodinamicos luego de discontinuado DASATINIB. A muestra la evolucion clinica. Luego de una media de 15 meses de discontinuado la droga los pts mejoraron per en tres continuaban con sintomas y 2 fallecieron. B evaluacion de la caminta de 6 minutos. Cy D: evaluacion hemodinamica invasiva: La mayoría de los pacientes mejoró después de parar el dasatinib pero ninguno regresó completamente a la normalidad
Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site
• pro-atherogenic and anti-angiogenic effects in vivo– aortic root plaque– hind limb ischemia – BM microvessel density (n.b. may be treatment effect)
Hadzijusufovic E et al, Leukemia 2017 epub 9/8/2017
Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site
Hadzijusufovic E et al, Leukemia 2017 epub 9/8/2017
Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension
• serum markers EC injury/dysfunction in vitro, in pt samples
Healthy ControlCML, no PAH, at DX CML, no PAH, on DAS
CML, no PAH, on IM
Guignabert C E et al, J Clin Inv 126(9), 3207-18, 2016
Dasatinib induces lung vascular toxicity and predisposes to
pulmonary hypertension• exaggerated response to
monocrotaline and chronic hypoxia• Induced apoptosis of pulmonary EC
Guignabert C E et al,J Clin Inv 126(9), 3207-18, 2016
Ponatinib exerts anti-angiogenic effects in the zebrafish and human umbilical vein endothelial cells
via blocking VEGFR signaling pathway
• antiangiogenic effect of PON demonstrated by reduction/elimination of intersegmental and subintestinalvessels (ISV / SIV)
Ai N, et al, Oncotarget 9:62, 31958-70, 2018
First it was pastrami, now ponatinib too?
Ponatinib exerts anti-angiogenic effects in the zebrafish and human umbilical vein endothelial cells
via blocking VEGFR signaling pathway
Ai N, et al, Oncotarget 9:62, 31958-70, 2018
Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation
• In cultured human aortic ECs (HAECs) treated with ponatinib– NF-kB/p65 phosphorylation and NF-kB activity– inflammatory gene expression, cell permeability, cell apoptosis– extracellular signal-regulated
kinase 5 (ERK5) transcriptionalactivity
– KLF2/4, eNOS– ERK5 SUMOylationtranscriptional activity
Paez-Mayorga J et al, Front. Cardiovasc Med 06 Sept 2018 (ePUB)Figure adapted from SpringerLink Encyclopedia of Signaling Molecule, 2018 edition
Dasatinib reversibly disrupts endothelial vascular integrity by increasing non-muscle myosin II contractility in a ROCK-dependent manner
• Dasatinib may active ROCK kinase as an off target effect-> EC dysregulation, permeability-> pleural effusions, PAH?
• Ponatinib potentially thought to have similar effect?
Kreutzman A et al, Clin Can Res 23(21), 6697-6707, 2017
Aphosphoproteomic
signature in endothelial cells predicts vascular
toxicity of tyrosine kinase inhibitors
used in CML
• HUVEC ‘toxicity’ assessed with in vitro exposure
Leukocyte Adhesion
Wound Healing
Cell Survival Gopal A et al, Blood Advances 2(14) 1680-84, 2018
A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase
inhibitors used in CML
• Mass spec study of 96 sentinel phosphopeptides validated to be representative of cellular states in response to drug perturbations
Gopal A et al, Blood Advances 2(14) 1680-84, 2018
What to do?
a call to action (slow march?)
Monitoring on TKI trials:minimal imaging, biochemical assessments
Entry criteria related to CV/vascular disease:PACE Phase II trial
Monitoring Schedule:PACE Phase II trial
Cortes JC, et al, N Engl J Med 2013; 369:1783-1796 (Supplemental Materials)
Guidelines at present for management of CV risk:
work-in-progress
‘ABCDE’ Step Approach to CV InterventionA: Awareness of cardiovascular disease signs and symptoms
A: Aspirin (in select patients)
A: Ankle-brachial index measurement at baseline and follow-up to document peripheral arterial disease
B: Blood pressure control
C: Cigarette/tobacco cessation
C: Cholesterol (regular monitoring and treatment if indicated)
D: Diabetes mellitus (regular monitoring, dose of radiation/chemotherapy, and treatment if indicated)
D: Diet and weight management
E: Exercise (echocardiogram)
= Recommended = As clinically indicated Imatinib Bosutinib Dasatinib Nilotinib Ponatinib
Baseline Assessment Cardiovascular assessment
Blood pressure check Fasting glucose
Fasting lipid panel Echocardiogram
* Electrocardiogram
Ankle-brachial index 1-month follow up
Cardiovascular assessment Blood pressure check
3- to 6-month follow-up Cardiovascular assessment
Blood pressure check Fasting glucose
Fasting lipid panel Echocardiogram
* Electrocardiogram
Ankle-brachial index *Patients treated with dasatinib should be considered for echocardiogram if cardiopulmonary symptoms are present.
‘Complete MolecularRemission’
‘Treatment FreeRemission’
MICVAPADDyslipidemiaDM/Glu Intol
Barber M, Mauro M and Moslehi J, Blood 2017
• Extraction of medical records• Biomarkers: Fasting lipid panel, Homocysteine,
Insulin, c-peptide, hsTNT, hs-CRP, NT-proBNP, sST2, GD-15, HbA1c, glucose, LOX-1 sequencing
• Urine for albuminuria• ECG
• Ankle-brachial Index (ABI)• Coronary calcium scoring• Echocardiography• Cytogenetic and molecular assessments
Dasatinib cohort
Imatinib cohort
Nilotinib cohort
Newly diagnosed patients with Ph+
CML-CP aged ≥18 years (N = 200)
Δ in CV riskΔ in metabolic risk
CV AEsCML response
Data Collection
Cardiovascular (CV) and Metabolic Risk in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Receiving First-line BCR-ABL Tyrosine Kinase Inhibitors (TKIs) in the United States (CA180-653)
CA180-653 (NCT03045120) is a prospective cohort study intended to characterize the impact of imatinib, dasatinib, and nilotinib on CV and metabolic risk factors in patients with newly diagnosed CML-CP in the United States
‘dealer’s choice’ of therapy
during SOC visits
CA180-653 Study Design
Hypertension observed on Ponatinib: warrants monitoring for and intervention…
PFA and aggregation studies demonstrate inhibition with
dasatinib and ponatinib
Quintas-Cardama A, et al. Blood 2009; 114(2):261-63Neelakantan P et al. Haematologica 2012; 97(9):1444
Retrospective analysis of known and novel biomarkers of risk
• MVA showed cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism associated with CV events
• IVS4-14 G/G LOX-1 polymorphism strongest predictive factor for a higher incidence of CV events in nilotinib patients
• unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients Boccia M et al, Oncotarget, 2016
Role of additional markers of clonal hematopoiesis
Jaiswal S et al, NEJM 371: 2488-98, 2014; Hadzijusufovic E et al, Leukemia 2017 epub 9/8/2017
Coronary Artery Disease:Traditional RF and ARCH mutations
ARCH mutations in NIL patients:Association with AOD?
Role of additional markers of clonal hematopoiesis
Jaiswal S et al, NEJM 371: 2488-98, 2014; Hadzijusufovic E et al, Leukemia 2017 epub 9/8/2017
ARCH mutations in NIL patients:Association with AOD?
Questions/Future: ‘Good Problems’
• Using CML as an example-> ‘functional curable’ cancer but ~5-6y therapy needed (new paradigm), potentially indefinite for many– How to risk stratify, risk mitigate, track AE development?
• Needed:– Prospective evaluation, rapid engagement for collaboration,
MOA based research and intervention
• Cardio-Oncology collaboration will be essential for our success in oncology!
Thank you for the kind [email protected]
212-639-3107
mailto:[email protected]
Slide Number 1Slide Number 2Targeted Therapy in Oncology�and the Problem of ‘Late Cardiovascular Events’Slide Number 4Cumulative Incidence of Discontinuation of Ibrutinib in CLL by Cause CML�At present, five oral kinase inhibitors approved in the US for Ph+ Leukemia:�a ‘spoil of riches’; more on the way?CML is an increasingly prevalent and survivable cancerReady for prime time:��‘treatment free remission’��(TKI cessation for patients in deep molecular remission)Treatment Free Remission in the label for Nilotinib as of 12/22/17Front-line nilotinib in CML: CVEs over time�(5y data- ENESTnd)CLLIbrutinib in CLLIbrutinib-associated bleedingCurrent understanding of bleeding with ibrutinib use:�a systematic review and meta-analysisPotential Mechanism of AF:�AP and APD perturbation by overlapping pathwaysIbrutinib AF and HypertensionThe risk of atrial fibrillation with ibrutinib use:�a systematic review and meta-analysisVentricular Arrhythmias and Sudden Death in Patients Taking IbrutinibSlide Number 19CMLCardiomyopathy associated with imatinibPAD associated with nilotinib:�biochemical and ABI changesPAD associated with nilotinib: clinical impactSummary of VOEs:�ponatinib phase I and phase II (PACE) trialsMeta-analysis:�imatinib versus subsequent generation TKIs, VOEs Characterization of PAH with dasatinib:Clinical, functional, and hemodynamic parameters after dasatinib discontinuation �Slide Number 28Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target siteNilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target siteDasatinib induces lung vascular toxicity and predisposes to pulmonary hypertensionDasatinib induces lung vascular toxicity and predisposes to pulmonary hypertensionPonatinib exerts anti-angiogenic effects in the zebrafish and human umbilical vein endothelial cells via blocking VEGFR signaling pathwayPonatinib exerts anti-angiogenic effects in the zebrafish and human umbilical vein endothelial cells via blocking VEGFR signaling pathwayPonatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation�Dasatinib reversibly disrupts endothelial vascular integrity by increasing non-muscle myosin II contractility in a ROCK-dependent mannerA�phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CMLA phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CMLWhat to do?Monitoring on TKI trials:�minimal imaging, biochemical assessmentsGuidelines at present for management of CV risk:��work-in-progressCardiovascular (CV) and Metabolic Risk in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Receiving First-line BCR-ABL Tyrosine Kinase Inhibitors (TKIs) in the United States (CA180-653)Hypertension observed on Ponatinib: �warrants monitoring for and intervention…PFA and aggregation studies demonstrate inhibition with dasatinib and ponatinibRetrospective analysis of known and novel biomarkers of riskRole of additional markers of clonal hematopoiesisRole of additional markers of clonal hematopoiesisQuestions/Future: ‘Good Problems’Slide Number 49
