New Anti Leukemic treatments deserve a Cardioncology approach. Guido Gini AOU «Ospedali Riuniti» Università Politecnica delle Marche Ancona

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1 New Anti Leukemic treatments deserve a Cardioncology approach Guido Gini AOU «Ospedali Riuniti» Università Politecnica delle Marche Ancona

2 CML Is Linked to a Single Cytogenetic Abnormality: The Philadelphia Chromosome X Y

3 BCR-ABL Oncogene Hybrid BCR-ABL gene encodes a continuously activated BCR-ABL fusion protein Drives leukemic transformation, causing CML

4 Pathways activated by BCR-ABL expression RAS JAK-STAT BCR/ABL MYC 1. Signal transduction alteration F-actin NUCLEUS Paxillin 2. Changes in adhesion to stromal layer PIK3 -AKT ABL Cell Cycle 3- Inhibition of apoptosis 4. Decreased normal ABL function at nuclear level: genomic instability

5 TKIs have changed the natural history of CML The Treatment Milestones in Ph+ CML Continue to Evolve: Earlier and Deeper BUSULFAN IFN IMATINIB NILOTINIB-DASATINIB Goal of Therapy CHR CCyR MMR molecular Deeper responses Leukemic Reduction 10% 1-log 1% 2-log 0.1% IS 3-log % IS 4.5-log Leukemic Burden 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.

6 Evolution of CML treatment st LINE Imatinib 400 Imatinib 400 Dasatinib Nilotinib Imatinib nd LINE Imatinib Allo-SCT Dasatinib Nilotinib Allo-SCT Dasatinib Nilotinib Bosutinib Ponatinib Allo-SCT 3rd LINE Palliation Palliation Anyone of remaining TKIs Allo-SCT 6 1 Baccarani M et al. Blood, Baccarani M et al. J Clin Oncol, Baccarani M et al. Blood, 2013

7 Cardiovascular toxicity in pts receiving imatinib Conclusions - Cardiovascular mortality rate less than 1% - Cardiotoxicity is uncommon event in the long term - Incidence of CHF less than 1% Steegmann et al, Leukemia 2016

8 Cardiovascular toxicity in pts receiving nilotinib Moslehi and Deninger, JCO 2015

9 Risk factors associated to ATE Suggestion: we have to select pts from baseline or to identify pts who need close monitoring of CV risk factors Moslehi and Deninger, JCO 2015

10 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

11 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

12 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

13 Haematologists need specialist collaborations Cardiologist (at baseline and during Tx. Management of concomitant drugs) Pulmonologist (only if necessary) Haematologist Diabetologist (if diabetic at baseline or during Tx) Angiologist (only if necessary)

14 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

15 Features No. (%) Range First line 42 Second line 40 Sex (M/F) 48/34 Age (median) FG (median, mg/dl) Total cholesterol (median, mg/dl) Concomitant risk factors - Diabetes - Smoking - Hypertension - Dislipidemia BMI - Normal (<25%) - Overweight (26-<30%) - Obese (>30%) 17 (20.7%) 23 (28%) 29 (35%) 15 (18%) 42 (51%) 26 (32%) 14 (17%)

16 What are the priorities?

17 Remember the qualifiers and the targets

18 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:

19 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

20 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

21 Careful attention to modifiable cardiovascular risk factors at baseline Modifiable Smoking Dyslipidaemia Diabetes Hypertension Obesity Non modifiable Previous CV event Age Gender Family History (Chronic kidney disease) Unhealthy diet Physical inactivity Psychosocial factors European Guidelines on cardiovascular disease prevention in clinical practice Perk J, et al. Eur Heart J. 2012l;33(13):

22 Hyperglycaemia with TKIs 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 2 nd 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): ; Saglio G, et al. ASH 2010, Abstract #3430; Rea et al, ASH 2012; Breccia M, et al. Leuk Res 2008;32(10):1626-8

23 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):

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25 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 GIMEMA Questionnaire Comorbidity Comorbility index X x x x x x x x PT. PTT. Fibrinogen x x x x Homocysteine x (x) x x LDL,HDL, Tryglicerides, Glicaemia, HbA1c x x x x

26 FOLLOW-UP IN LOW-RISK PATIENTS (IMATINIB, DASATINIB, BOSUTINIB) 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 AT, FV, FII, ACA,GPI, LAC, C and S protein x* 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

27 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 GIMEMA Questionnaire Comorbidity Comorbility index x x x x x x x 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

28 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 AT, FV, FII, ACA,GPI, LAC, C and S protein x* 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

29 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