New Anti Leukemic treatments deserve a Cardioncology approach

Guido Gini

AOU «Ospedali Riuniti»

Università Politecnica delle Marche

Ancona

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CML Is Linked to a Single Cytogenetic Abnormality: The Philadelphia

Chromosome

BCR-ABL Oncogene

Hybrid BCR-ABL gene encodes a continuously activated BCR-ABL

fusion protein

Drives leukemic transformation, causing CML

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

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

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

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%

Cardiovascular toxicity in pts receiving nilotinib

Moslehi and Deninger, JCO 2015

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

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

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

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

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)

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

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 (

What are the priorities?

Remember the qualifiers and the targets

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

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

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

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

• 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

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

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

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)

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

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

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