new anti leukemic treatments deserve a cardioncology approach · 2020. 8. 21. · cardiovascular...
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New Anti Leukemic treatments deserve a Cardioncology approach
Guido Gini
AOU «Ospedali Riuniti»
Università Politecnica delle Marche
Ancona
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1 2 3 4 5
6 7 8 10 11 9 12
13 14 15 16 17 18
19 20 21 22
X Y
CML Is Linked to a Single Cytogenetic Abnormality: The Philadelphia
Chromosome
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BCR-ABL Oncogene
Hybrid BCR-ABL gene encodes a continuously activated BCR-ABL
fusion protein
Drives leukemic transformation, causing CML
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NUCLEUS
Cell Cycle
BCR/ABL
ABL
4. Decreased normal ABL function
at nuclear level: genomic instability
Paxillin
F-actin
2. Changes in adhesion
to stromal layer
Pathways activated by BCR-ABL expression
3- Inhibition of
apoptosis
PIK3 -AKT
RAS
JAK-STAT
MYC
1. Signal transduction
alteration
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TKIs have changed the natural history of CML The Treatment Milestones in Ph+ CML Continue to Evolve: Earlier and
Deeper
5
IS, international scale; MCyR, major cytogenetic response; MR4,
molecular response ≥ 4-log reduction; MR4.5, molecular response ≥
4.5-log reduction; TKI, tyrosine kinase inhibitor.
Goal of Therapy
CHR CCyR MMR
Deeper molecular responses
1970 2000 1990 1980 1960 2010-2011
Leukemic Burden
Leukemic
Reduction
≤ 1% ≈ 2-log
≤ 10% ≈ 1-log
≤ 0.1%IS ≈ 3-log
BUSULFAN IFN IMATINIB NILOTINIB-DASATINIB……
≤ 0.0032%IS ≈ 4.5-log
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Evolution of CML treatment
1Baccarani M et al. Blood, 2006 2Baccarani M et al. J Clin Oncol, 2009
3Baccarani M et al. Blood, 2013 6
20061 20092 20133
1st LINE Imatinib 400 Imatinib 400
Dasatinib
Nilotinib
Imatinib 400-600-800
2nd LINE Imatinib 600-800
Allo-SCT
Dasatinib
Nilotinib
Allo-SCT
Dasatinib
Nilotinib
Bosutinib
Ponatinib
Allo-SCT
3rd LINE Palliation Palliation
Anyone of remaining
TKIs
Allo-SCT
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Cardiovascular toxicity in pts receiving imatinib
Steegmann et al, Leukemia 2016
Conclusions
- Cardiovascular mortality rate less than 1%
- Cardiotoxicity is uncommon event in the long term
- Incidence of CHF less than 1%
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Cardiovascular toxicity in pts receiving nilotinib
Moslehi and Deninger, JCO 2015
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Risk factors associated to ATE
Moslehi and Deninger, JCO 2015
Suggestion: we have to select pts from baseline or to identify pts who need
close monitoring of CV risk factors
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Holistic approach to appropriately select TKI
• Primary endpoint: antileukemic efficacy
“Patients related” drivers for selection : - Comorbidities (please apply CCI at baseline) - Clinical indexes: Sokal, Hasford and Eutos - Age (not as single selection criterion but as part of
multicomplex evaluation) - Social, psychological aspects (lifestyle, work, etc) - Patient expectation - Costs (only if required)
Breccia M and Alimena G, Expert Rev Hematol. 2015;8(1):5–7
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Comorbidity, Measured By The Charlson Index, Has No Negative
Impact On Remission In Patients With Chronic Myeloid Leukemia:
Results Of The Randomized CML-Study IV
1524 patients evaluable from German
Study IV.
Median follow-up time was 67.5 months.
Most common comorbidities were: - diabetes (n=106), - non-active cancer (n=102), - chronic pulmonary disease (n=74), - renal insufficiency (n=47), - myocardial infarction (n=38), - cerebrovascular disease (n=29), - congestive heart failure (n=28), - peripheral vascular disease (n=28).
No significant differences in remission
rates were found neither for CCRy nor
for time to MR3.
Significant differences for OS.
Saussele S, et al. Blood. 2015;126(1):42-9
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Age as criterion of selection at baseline
• Older pts: we have to prolong OS reducing risk of
progression. We can decide according to comorbidities.
We should consider improved tolerance of second
generation TKIs as compared to imatinib
• “Frail” older pts: consider only QoL
• Young pts: considering OS but with aiming to discontinue
• Young women: considering discontinuation for possible
pregnancy
• Pediatric pts: discontinuation
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Haematologists need specialist collaborations
Haematologist
Cardiologist (at baseline and
during Tx. Management of
concomitant drugs)
Diabetologist (if diabetic at baseline or during Tx)
Angiologist (only if
necessary)
Pulmonologist (only if
necessary)
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Specific safety profile related to different drug guide us to better tailored treatment
Drug Side effect Off target
Imatinib
-fluid retention, oedema
-muscle cramps
-GI effects
-skin rash
-skin fragility
-rare events (conjunctivitis, CV, etc)
Nilotinib
-skin rash
-headache
-biochemical toxicity
-pancreatitis
-hyperglycaemia
-hypercholesterolemia
-PAOD
-CV
Dasatinib
-headache
-GI effects
-haematological toxicity
-fluid retention, oedema
-bleedings
-pleural effusions
-PAH
-CV
-Infections
-Autoimmune disorders
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Features No. (%) Range
First line 42
Second line 40
Sex (M/F) 48/34
Age (median) 51 22-84
FG (median, mg/dl) 102 87-148
Total cholesterol (median, mg/dl) 199 92-350
Concomitant risk factors
- Diabetes
- Smoking
- Hypertension
- Dislipidemia
17 (20.7%)
23 (28%)
29 (35%)
15 (18%)
BMI
- Normal (
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What are the priorities?
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Remember the qualifiers and the targets
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SCORE chart: French experience
• 57 pts (51% male)
• 28% nilotinib 1° line 58% nilotinib 2° line after imatinib 14% nilotinib 2° line after im/das
Rea D Leukemia 2015; 29: 1206-1209
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Prevention of cardiac problems
Cardiac function monitoring (2 and 3 generation TKIs):
- Echocardiography has a low power to detect subclinical tox
- BNP has excellent negative predictive value for LV
dysfunction
- Check blood pressure
ECG monitoring:
- At baseline and frequent monitoring with 2 or 3 generation
TKIs for possible QTc prolongation: if QTc > 450 ms stop
TKI, if > 440 ms check weekly
- Consultation with cardiologist
- Check electrolytes
- Appropriate management of concomitant medications
Steegmann et al, Leukemia 2016
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Management of CV SAEs (in pts that required to continue with treatment)
Consider type of TKI
In pts with PAOD grade I/II:
- Optimize therapy of PAOD
- Careful consideration of CV risk factors
- Strict monitoring of metabolic and local conditions (ABI, ECD,
FG, HbA1C)
- Antiplatelets in prophilaxys
In pts with PAOD grade III/IV:
- Switch to other TKI (if MR is not deep)
- For stable MR4-4.5 possible discontinuation
- Elimination of CV risk factors
- Antiplatelets and/or anticoagulant Valent et al, Blood 2014; Steegmann et al, Leukemia 2016
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Modifiable Non modifiable
• Previous CV event
• Age
• Gender
• Family History
• (Chronic kidney disease)
• Smoking
• Dyslipidaemia
• Diabetes
• Hypertension
• Obesity
• Unhealthy diet
• Physical inactivity
• Psychosocial factors
Careful attention to “modifiable”cardiovascular risk factors at baseline
European Guidelines on cardiovascular disease prevention in clinical practice
Perk J, et al. Eur Heart J. 2012l;33(13):1635-701
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• In first line, randomized studies have shown that the incidence of
hyperglycaemia grade 3-4 with nilotinib is about 6%, vs 0% with
imatinib.
• In diabetic patients treated with nilotinib, 31% changed antidiabetic
treatment and 60% developed hyperglycaemia grade 3-4, but none
developed ketoacidosis, hyperosmolar events, or cardiovascular
complication
• In normoglycemic patients, excluding patients with diabetes at
baseline, 20.1% developed diabetes by 3 years with 2nd generation TKI
vs 8.9% with imatinib. In the whole series of patients, none had
discontinued due to this side effect and less than 2% started with
antidiabetic drugs
Larson RA, et al. Leukemia 2012; 26(10):2197-203; Saglio G, et al. ASH 2010, Abstract #3430; Rea et al, ASH 2012; Breccia M, et al. Leuk Res
2008;32(10):1626-8
Hyperglycaemia with TKIs
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Hypercholesterolemia
• Imatinib reduces total level of cholesterol and triglycerides
• Hypercholesterolemia was detected in 22% of patients treated with
nilotinib first line. No hypercholesterolemia grade 3-4 was
detected
• No evidences of this effect with dasatinib
• Is an early event: it is suggested to test lipidic profile at baseline and
regularly during treatment.
• It is not a contraindication for treatment. In case of sustained
hypercholesterolemia during nilotinib, add pravastatin or
rosuvastatin, in order to reduce the risk of CV events.
Larson et al, 2010; Rea D, et al Haematologica. 2014;99(7):1197-203
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FOLLOW-UP IN LOW-RISK PATIENTS
(IMATINIB, DASATINIB, BOSUTINIB)
baseline 3 months 6 months 9 months 1 year Every year
Medical history, physical
examination (smoke, physical
activity, weight, BMI..)
x x x
Edimburgh Questionnaire X x x
GIMEMA Questionnaire
Quality of life
X x x x x x
GIMEMA Questionnaire
Comorbidity
x
Comorbility index x
PT. PTT. Fibrinogen x x x x
Homocysteine x (x) x x
LDL,HDL, Tryglicerides,
Glicaemia, HbA1c
x x x x
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baseline 3 months 6 months 9 months 1 year Every 6
months
Amylase,Lipase x x x x
hs-CRP x x x
Lp (a) x x x
ACA, GPI, LAC, MTHFR
mutations
x*
AT, FV , FII, ACA,GPI, LAC,
C and S protein
x**
BNP, Troponin I x x x
EKG x x x
Echocardiography + Doppler x x x
Carotid Echo-Doppler x x x
* if previous arterial thrombosis ** if previous venous thrombosis
FOLLOW-UP IN LOW-RISK PATIENTS
(IMATINIB, DASATINIB, BOSUTINIB)
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FOLLOW-UP IN HIGH-RISK PATIENTS
(NILOTINIB AND PONATINIB)
baseline 3 months 6 months 9 months 1 year Every 6
months
Medical history, physical
examination (smoke, physical
activity, weight, BMI..)
x x x x x x
Edimburgh Questionnaire x x x x x x
GIMEMA Questionnaire
Quality of life
x x x x x x
GIMEMA Questionnaire
Comorbidity
x
Comorbility index x
PT. PTT. Fibrinogen x x x x x x
Homocysteine x x x x x x
LDL,HDL, Tryglicerides,
Glicaemia, HbA1c
x x x x x x
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FOLLOW-UP IN HIGH-RISK PATIENTS
(NILOTINIB AND PONATINIB)
baseline 3 months 6 months 9 months 1 year Every 6
months
Amylase,Lipase x x x x x x
hs-CRP x x x x x x
Lp (a) x x x x x x
ACA, GPI, LAC, MTHFR
mutations
x*
AT, FV , FII, ACA,GPI, LAC,
C and S protein
x**
BNP, Troponin I x x x x x x
EKG x x x x x
Echocardiography + Doppler x x x x x
Carotid Echo-Doppler x x x x x
* if previous arterial thrombosis ** if previous venous thrombosis
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Conclusions
• The choice of TKI for patients with Ph+ CML-CP should be
individualized based on a benefit/risk assessment
• Increased evidences of specific side effects related to
different TKIs: need for prognostic scores in order to
stratify pts according to comorbidities and other risk factors
• A proactive approach is important for all patients,
regardless of TKI:
• Minimizing the impact of adverse events that lead to treatment
interruptions, reductions and discontinuations
• Maximize the chance for deepest responses
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