Cardiovascular Risk Management Recommendations for Patients with Chronic Myeloid Leukaemia who are Candidates for Ponatinib: Multidisciplinary Delphi Analysis

Steegmann JL; Zamorano JL; Paramo JA; Hernandez-Boluda JC; Perez R; Garcia-Gutierrez V; Gonzalez-Porras JR; de Haro J; Roa-Chamorro R; Pardo A; Alvarez-Larran A; Fernandez E; Lopez-Fernandez T

Review Article

Ann Hematol Oncol. 2021; 8(7): 1354.

Cardiovascular Risk Management Recommendations for Patients with Chronic Myeloid Leukaemia who are Candidates for Ponatinib: Multidisciplinary Delphi Analysis

Steegmann JL¹, Zamorano JL², Páramo JA³, Hernández-Boluda JC⁴, Pérez R⁵, García-Gutierrez V⁶, González-Porras JR⁷, de Haro J⁸, Roa-Chamorro R⁹, Pardo A¹⁰, álvarez-Larrán A¹¹, Fernández E¹², López-Fernández T¹³*

¹Haematology and Haematotherapy Department, La Princesa University Hospital, Madrid, Spain

²Head of Cardiology Department, Ramón y Cajal University Hospital, Madrid, Spain

³Haematology and Haemotherapy Department and Coordinator of the Vascular Medicine Area, University of Navarra Clinic, Pamplona, Spain

⁴Haematology Department of the Clinical University Hospital of Valencia, Spain

⁵Haematology and Haematotherapy Department of the Virgen de la Arrixaca Clinical University Hospital, Murcia, Spain

⁶Haematology and Haematotherapy Department of the Ramón y Cajal University Hospital, IRYCIS, Madrid, Spain

⁷Haematology Department of the Clinical University Hospital of Salamanca, Spain

⁸Angiology and Vascular Surgery Department of the University Hospital of Getafe, Spain

⁹9Internal Medicine Department of the Virgen de las Nieves University Hospital, Granada, Spain

¹⁰Cardiology Department, Ramón y Cajal University Hospital, Madrid, Spain

¹¹Clinical Haematology Department of the Clinical Hospital, IDIBAPS, Barcelona, Spain

¹²Hospital Pharmacy Department of the University Hospital Complex of A Coruña, Spain

¹³Cardiology Department at La Paz University Hospital, IdiPAZ, CIber CV, Madrid, Spain

*Corresponding author: López-Fernández T, Cardiology Department, La Paz University Hospital, IdiPAZ, CIber CV, Paseo de la Castellana 261, 28046, Madrid, Spain

Received: April 14, 2021; Accepted: May 20, 2021; Published: May 27, 2021

Abstract

Progress in the treatment of Chronic Myeloid Leukaemia (CML) has significantly improved the survival rates and prognosis of these patients. As a result, there is a growing awareness of the adverse effects that the treatments used can have on the Cardiovascular (CV) system. A high percentage of patients develop sequential resistance to CML treatments and, in these cases, ponatinib represents a good therapeutic option that has been associated with cardiovascular events. This required the development of recommendations for its management.

A Delphi analysis conducted by a multidisciplinary panel of experts developed and agreed on clinical practice recommendations to optimize cardiovascular risk control in CML patients requiring ponatinib treatment.

Keywords: Chronic myeloid leukaemia; Ponatinib; Recommendations; Cardiovascular risk; Delphi analysis; Multidisciplinary panel

Abbreviations

3D: 3-Dimensional; ASA: Acetylsalicylic Acid; DOACs: Direct- Acting Oral Anticoagulants; CVA: Cerebrovascular Accident; TIA: Transient Ischaemic Attack; ARA-II: Angiotensin II Receptor Antagonists; anti-Xa: Anti-Activated Factor X; GLP-1 RA: GLP- 1 Receptor Agonist; VKA: Vitamin K Antagonist; BCG: Bacillus Calmette-Guérin; BCRP: Breast Cancer Resistance Protein; BNP: Brain or B-type Natriuretic Peptide; CHA2DS2-VASc: Ischaemic Stroke Risk Assessment Scale; HDL-c: High Density Lipoprotein Cholesterol; LDL-c: Low Density Lipoprotein Cholesterol; CTRCD: Cancer Therapy-Related Cardiac Dysfunction; CV: Cardiovascular; CVRFs: Cardiovascular Risk Factors; SD: Standard Deviation; DM: Diabetes Mellitus; PAD: Peripheral Arterial Disease; ECG: Electrocardiogram; CVD: Cardiovascular Disease; ELN: European LeukaemiaNet; VTD: Venous Thromboembolic Disease; AF: Atrial Fibrillation; LVEF: Left Ventricular Ejection Fraction; FGFR: Fibroblastic Growth Factor Receptor; GELMC: Spanish Chronic Myeloid Leukaemia Group; GLS: Global Longitudinal Strain; HAS-BLED: Bleeding Risk Assessment Scale; HbA1c: Glycosylated Haemoglobin; LMWH: Low Molecular Weight Heparin; AHT: Arterial Hypertension; AMI: Acute Myocardial Infarction; CHF: Congestive Heart Failure; ACEI: Angiotensin-Converting Enzyme Inhibitor; BMI: Body Mass Index; INR: International Normalised Ratio; SGLT-2i: Sodium-Glucose Co-Transporter Type 2 Inhibitor; ABI: Ankle-Brachial Index; TKI: Tyrosine Kinase Inhibitor; CML: Chronic Myeloid Leukaemia; CP-CML: Chronic Phase Chronic Myeloid Leukaemia; NSTEMI: Non-ST Segment Elevation Myocardial Infarction; NT-proBNP: N-terminal pro-brain or B-type Natriuretic Peptide; BP: Blood Pressure; PDGFR: Platelet-Derived Growth Factor Receptor; Pgp: Permeability Glycoprotein; QTc: Corrected QT Interval; CCyR: Complete Cytogenetic Response; MCyR: Major Cytogenetic Response; CVR: Cardiovascular Risk; MMR: Major Molecular Response; RR: Relative Risk; STEMI: ST Elevation Myocardial Infarction; PTE: Pulmonary Thromboembolism; VTE: Venous Thromboembolism; TTE: Transthoracic Echocardiography; DVT: Deep Vein Thrombosis; VEGFR1-3: Vascular Endothelial Growth Factor Receptor

Introduction

The introduction of Tyrosine Kinase Inhibitors (TKIs) targeting the bcr-abl oncoprotein has revolutionized the management of patients with CML. Treatment with imatinib, the first BCR-ABL inhibitor, takes the 10-year survival rate to over 80%, significantly approaching that of the general population. However, the need for continued treatment and the adverse effects associated with the use of TKIs have a significant impact on patient quality of life and health systems [1]. Despite the significant therapeutic advancement provided by imatinib [1,2], a substantial proportion of patients develop resistance or intolerance to imatinib [3] and new TKIs are needed to maintain the therapeutic response [4-8]. New generations of TKIs are associated with an increased risk of cardiovascular complications and require the involvement of multidisciplinary cardio-onco-hematology teams for their early prevention and control [9-12].

Ponatinib is a third generation TKI specifically designed to overcome resistance to other TKIs and is the only one approved with clinical activity against the T315I mutation [13]. The use of ponatinib may be associated with an increased risk of cardiovascular complications, so it is essential to establish prevention strategies and specific management recommendations in patients who are candidates for ponatinib, in order to maximise its therapeutic benefits.

Objectives

The aim of the study was to obtain feedback from members of a multidisciplinary panel of experts on best clinical practices to reduce the risk of cardiovascular events and inappropriate treatment interruptions in patients with CML treated with ponatinib.

Participants and Methodology

This project was carried out by a multidisciplinary panel composed of three coordinators and ten specialist practitioners, using Delphi methodology. Appendix I describe the project phases, the methodology used and the characteristics of the participants.

Results

Section 1: Correlation between clinical trial data and actual practice

The difference between CV events in patients in the PACE study [14] and clinical practice records [15-18] was analyzed. Overall, clinical practice records appear to reflect a lower prevalence of adverse CV events of different grades, which appears to be associated with both younger ages and the more frequent use of ponatinib doses below 45mg. An important conclusion from clinical practice records is that the incidence of Cardiovascular Disease (CVD) increases with a longer follow-up period and in patients who have previously received more than two TKIs [15,18].

Section 2: Medical history and initial clinical evaluation

Initial assessment of the patient with CML makes it possible to establish an adequate CV monitoring and prevention protocol [20,21]. The main points that must be included in the initial medical history and physical examination are summarized in Table 1.

Table 1: Necessary parameters in the patient’s medical history and initial physical examination.




  
    Medical history 
    Chronic illness: DM, AHT,    dyslipidaemia [20,21]. 
  
  
    Personal and family history    of previous CV diseases [20,21]. 
  
  
    Unhealthy habits: smoking, alcohol,    diet, physical activity [20,21]. 
  
  
    Chronic treatments: due to    interactions with TKIs [22]. 
  
  
    Haemato-oncological history    and treatments received [23]. 
  
  
    Physical examination 
    Height, weight and BMI [24]. 
  
  
    Blood pressure and heart    rate [24]. 
  
  
    Determination of ABI [24]. 
  
  
    Cardiopulmonary auscultation    [24]. 
  
  
    Peripheral pulses [24]. 
  
  
    DM: Diabetes Mellitus;    AHT: Arterial Hypertension; BMI: Body Mass Index; ABI: Ankle-Brachial Index.



Table 1: Necessary parameters in the patient’s medical history and initial physical examination.

According to the latest recommendations issued by Spanish Chronic Myeloid Leukaemia Group, a multidisciplinary follow-up of patients treated with TKIs makes it possible to optimize prevention strategies. Baseline assessment helps stratify the risk of complications into low, intermediate, high or very high and establish patientspecific management indications [25,26]. In this multidisciplinary team it is essential to have the collaboration of specialists in hematology, cardiology, primary care, cardiovascular risk and clinical pharmacology [27].

Based on the available evidence, the panel makes the recommendations listed in Table 2.

Table 2: Consensus recommendations for the medical history and initial evaluation of patients who are candidates for ponatinib.

Recommendation
Level of consensus
Level of agreement*

The medical history of patients who are candidates for ponatinib must include the presence of chronic diseases, a personal and family history of cardiovascular disease, unhealthy habits and chronic treatments, in order to discuss possible interactions with ponatinib.
Consensus
Agreement

The essential physical examination must include height, weight, BMI, and cardiopulmonary auscultation.
Consensus
Agreement

The initial patient evaluation must be multidisciplinary, involving the haematologist, the cardiovascular specialist, the hospital pharmacist and the family doctor.
Consensus
Agreement

At the initial patient assessment, the haematologist must be responsible for collecting information from other practitioners and for choosing the most appropriate TKI.
Consensus
Agreement

At the initial patient assessment, the vascular specialist must be responsible for the initial risk assessment.
Consensus
Agreement

In the initial patient assessment, the pharmacist must be responsible for monitoring potential interactions.
No consensus**
Agreement

In the initial patient assessment the family practitioner must be involved because of his/her importance as a more patient accessible practitioner.
Consensus
Agreement

Patients with a history of CV disease, uncontrolled risk factors, or a lower than normal ejection fraction are considered high risk and require cardio-oncology management and follow-up.
Consensus
Agreement

*Based on a Likert scale assessment: disagreement 1 to 3, neither disagreement nor agreement 4 to 6 and agreement 7 to 9. **There is consensus that the panelists disagree.



Table 2: Consensus recommendations for the medical history and initial evaluation of patients who are candidates for ponatinib.

Section 3: Laboratory and imaging tests

There is not yet any evidence as to which tests need to be performed in normal clinical practice, since there are no clinical trials that have specifically evaluated this; so the suggestions collected are based on a compilation of retrospective analyses and expert recommendations (Table 3).

Table 3: Laboratory and imaging tests recommended in the literature regarding patients who are candidates for TKIs at the initial assessment.




  
    
    
    Recommended    in clinical practice 
    Recommended    in selected cases 
  
  
    Laboratory 

      tests 
    Creatinine and eGFR 
    X 
    
  
  
    Blood glucose and HbA1c:    [20,28,29]. 
    X 
    
  
  
    Lipid panel (total cholesterol,    triglycerides, HDL-c, LDL-c: [9]. 
    X 
    
  
  
    Blood count and clotting    tests: [9]. 
    X 
    
  
  
    Determination of    electrolytes, liver and pancreatic enzymes [9]. 
    X 
    
  
  
    Determination of BNP:    suspected congestive heart failure. 
    
    X 
  
  
    Additional tests 
    Chest X-ray: [2,28,29]. 
    
    X 
  
  
    ECG with determination of    the QT interval: [27,28]. 
    
    X 
  
  
    Baseline echocardiogram:    [20,28,29]. 
    
    X 
  
  
    ABI: [9,20.27,28]. 
    X 
    
  
  
    Carotid Doppler [23]. 
    X 
    
  
  
    BNP: Brain or B-type Natriuretic    Peptide; HDL-c: High Density Lipoprotein Cholesterol; LDL-c: Low Density Lipoprotein    Cholesterol; ECG: Electrocardiogram.



Table 3: Laboratory and imaging tests recommended in the literature regarding patients who are candidates for TKIs at the initial assessment.

With regard to the frequency of the aforementioned tests, a monthly evaluation of Blood Presure (BP) and Cardiovascular Risk (CVR) with an evaluation of glucose and lipid metabolism [28,29] is recommended, in addition to a quarterly evaluation of glucose and lipid metabolism and ABI, and a chest X-ray and ECG if necessary [20,28,29].

Based on the available evidence, the panel makes the recommendations included in Table 4.

Table 4: Consensus recommendations on laboratory and imaging tests to be performed on patients who are candidates for ponatinib and for its follow-up.

Recommendation
Level of consensus
Level of agreement*

For patients who are candidates for ponatinib, initial analytical monitoring should include blood count, clotting, liver and pancreatic enzymes, renal function monitoring (creatinine and eGFR), glucose metabolism (glycaemia and HbA1c), electrolytes and cholesterol metabolism (triglycerides, total cholesterol and HDL-c/LDL-c). In addition, BNP/pro-BNP levels will be determined for their prognostic value for congestive heart failure.
Consensus
Agreement

For patients who are candidates for ponatinib, blood pressure levels must first be determined and an ABI, ECG (with determination of the Fridericia QTc interval), echocardiogram and chest X-ray must be performed.
Consensus
Agreement

For moderate, high and very high risk patients** carotid Doppler ultrasound is also recommended and, in moderate CV risk patients, the measurement of coronary calcium.
Consensus
Agreement

During the follow-up of patients receiving ponatinib, blood pressure and cardiovascular risk monitoring is recommended on a weekly basis during the first month, monthly during the first quarter and quarterly thereafter.
Consensus
Agreement

During the follow-up of patients receiving ponatinib, monitoring of glucose and lipid metabolism and determination of ABI every 3, 6 and 12 months is recommended, reserving echocardiography according to clinical indication.
Consensus
Agreement

*Based on Likert scale assessment: disagreement 1 to 3, neither disagreement nor agreement 4 to 6 and agreement 7 to 9. **See definition of risk in Block 4. QTc: Corrected QT.



Table 4: Consensus recommendations on laboratory and imaging tests to be performed on patients who are candidates for ponatinib and for its follow-up.

Section 4: CVR evaluation and prophylaxis strategies

While there are no validated specific prospective scales to estimate CVD risk in patients with CML who are candidates for ponatinib, the use of available scales makes it possible to optimize control objectives and to standardize clinical practice in this patient profile.

Specifically, SCORE risk tables make it possible to estimate the risk of cardiovascular mortality at 10 years in patients without known cardiovascular disease, based on various risk factors: age, sex, systolic blood pressure, smoking and total cholesterol [23] (Table 5).

Table 5: Cardiovascular risk stratification groups established by SCORE.




  
    Risk 
    Interpretation 
  
  
    Very high 
    Documented CVD: AMI, ACS,    angina, stroke or TIA, peripheral arterial disease, coronary or arterial    revascularization.
  
  
    DM with target organ damage    (e.g. proteinuria), DM with 3 or more associated major CVRFs (smoking,    dyslipidaemia and hypertension), or type 1 DM of more than 20 years'    duration.
  
  
    Stage IV CKD (eGFR<    30mL/min/1.73 m2).
  
  
    SCORE calculated =10%.
  
  
    Family history of    hypercholesterolemia with CVD or 1 major associated CVRF.
  
  
    High 
    Very high major CVRF (i.e.    marked dyslipidaemia (Total Col >300, LDL >190) or severe hypertension    (180/110 mmHg)).
  
  
    DM with a major CVRF or of    longer than 10 years.
  
  
    CKD stage III (eGFR 30–59    mL/min/1.73 m2).
  
  
    SCORE calculated =5% and    <10%.
  
  
    Family history of    hypercholesterolemia without CVD or CVRF.
  
  
    Moderate 
    SCORE calculated =1% and <5%. 
  
  
    Low 
    SCORE <1%.
  
  
    TIA: Transient Ischaemic    Attack; CVRFs: Cardiovascular Risk Factors.



Table 5: Cardiovascular risk stratification groups established by SCORE.

It should be noted that in a small registry (n=85) patient with CML and a SCORE >5% have been observed to be at increased risk of occlusive arterial events during ponatinib treatment [19]. Likewise, real-life studies with ponatinib have shown that patients mostARA likely to develop treatment-derived CV complications are those ≥65 years of age (relative risk (RR): 1.8) and with a history of AHT (RR: 3.2), DM (RR: 2.5) or ischaemic heart disease (RR: 2,6) [30,31], so during treatment these factors must be closely monitored for adequate CVR assessment.

With regard to the prevention of cardiovascular toxicity due to ponatinib, there are currently no published clinical trials supporting the use of any drug as a prophylactic strategy. In the general population without clinical or subclinical cardiovascular disease, the use of Acetylsalicylic Acid (ASA) has not shown any benefit in primary prevention but an increased risk of bleeding [32], although the proportion of patients with CML without prior cardiovascular disease has been shown to be low in patients who are candidates for ponatinib [16]. There is also no data from clinical trials on the control of risk factors during prospective follow-up of the treatment, so the premise that strict control of CVR and adherence to clinical practice guidelines on the management of different heart diseases improves the overall prognosis of patients [33] is extended to patients who are candidates for ponatinib.

Based on the available evidence, the panel makes the recommendations included in Table 6.

Table 6: Consensus recommendations for the evaluation of CVR and prophylaxis strategies in the candidate patient for ponatinib or in its follow-up.




  
    Recommendation 
    Level of consensus 
    Level of agreement* 
  
  
    Cardiovascular risk must be    quantified with SCORE tables in all ponatinib candidates and vascular disease    must be actively ruled out. 
    Consensus 
    Agreement 
  
  
    High risk patients are those    with SCORE >5% or =65 years, with DM, moderate or severe chronic kidney    disease and/or previous clinical or subclinical cardiovascular disease.
    Consensus 
    Agreement 
  
  
    The administration of ASA    100 mg/day as a primary prophylaxis in low cardiovascular risk patients    treated with ponatinib is not recommended as there is no evidence of benefit    in this scenario. 
    Consensus 
    Agreement 
  
  
    *Based on a Likert scale assessment: disagreement 1 to 3, neither    disagreement nor agreement 4 to 6 and agreement 7 to 9.



Table 6: Consensus recommendations for the evaluation of CVR and prophylaxis strategies in the candidate patient for ponatinib or in its follow-up.

Section 5: Cardiovascular therapeutic goals in ponatinib candidates

In general, optimising the control of possible cardiovascular comorbidities must be adapted to clinical practice guidelines, favouring the use of drugs with a better CVR reduction profile.

Regarding AHT control, the latest update of the European guidelines recommends treating patients with BP levels >140/90 mmHg regardless of their cardiovascular risk. Thus, the objective to be achieved will be the reduction of BP <140/90 mmHg for all patients and, if treatment is well tolerated, ≤BP 130/80 mmHg values for the majority of patients [34]. Treatment must be based on lifestyle interventions and pharmacological treatment, and the initiation of treatment with angiotensin-converting enzyme inhibitor/ angiotensin II receptor antagonists (ACEI/ARA-II) and dihydropyridine calcium channel blockers is recommended [35].

Cholesterol target values vary depending on the CVR (Table 7), LDL-c control being the primary objective [36]. Pharmacological guidelines will be the same as in the general population, paying particular attention to interactions due to P450 CYP3A4 and binding to Permeability glycoprotein (Pgp) and Breast Cancer Resistance Protein (BCRP) transport proteins [37].

Table 7: LDL control targets in patients who are candidates for TKIs.




  
    Risk 
    Lipid Control Objectives    (LDL) 
  
  
    Very high risk 
    <55mg/dL and ↓ 50% from    baseline 
  
  
    High Risk 
    <70mg/dL and ↓ 50% from    baseline 
  
  
    Moderate risk 
    <100mg/dL 
  
  
    Low risk 
    <116mg/dL



Table 7: LDL control targets in patients who are candidates for TKIs.

The ADA/EASD consensus advocates an HbA1c target ≤7% except in frail patients or patients with multiple comorbidities where targets may be more lenient (8%) [38]. A patient-centred approach must be employed to guide the choice of pharmacological agents, prioritising the use of Sodium-Glucose Co-Transporter Type 2 inhibitor (SGLT-2) inhibitors or GLP-1 receptor agonist (GLP-1 RA); for patients with established CVD, given their demonstrated cardiovascular benefit [39].

Based on the available evidence, the panel makes the recommendations included in Table 8.

Table 8: 9 Consensus recommendations for the cardiovascular therapeutic objectives in patients who are candidates for ponatinib or for its follow-up.




  
    Recommendation 
    Level of consensus 
    Level of agreement 
  
  
    It is recommended that    treatment be given to all patients with BP values >140/90mmHg, regardless    of their cardiovascular risk, establishing as the first objective of    pharmacological treatment the achievement of BP values <140/90mmHg without    producing hypotension. 
    Consensus 
    Agreement 
  
  
    Antihypertensive treatment    must be based on lifestyle interventions and pharmacological treatment, it    being advisable to initiate treatment with ACEI/ARA-II and dihydropyridine    calcium channel blockers. 
    Consensus 
    Agreement 
  
  
    Target cholesterol values    vary depending on the patient’s cardiovascular risk, (Table 7). 
    Consensus 
    Agreement 
  
  
    With regard to    lipid-lowering treatment, the same guidelines must be followed as in the    general population, taking special care with P450 CYP3A4 drug interactions    and binding to Pgp and BCRP transport proteins, so the use of pitavastatin    and ezetimibe is recommended due to their lower risk of interactions. 
    Consensus 
    Agreement 
  
  
    The overall glycaemic    control target in ponatinib candidate patients is HbA1c <7% and    may be considered more strictly (HbA1c <6.5%) in a selected    population (short-duration or lifestyle treated DM or metformin only, long    life expectancy or without significant cardiovascular disease) and less    strict (HbA1c <8%) in frail patients. 
    Consensus 
    Agreement 
  
  
    A patient-centered approach    must be taken to guide the choice of pharmacological agents, the use of    SGLT-2i or GLP-1 RA being recommended in patients with DM2 and established    cardiovascular disease, due to their demonstrated benefit on cardiovascular    function. 
    Consensus 
    Agreement 
  
  
    *Based on a Likert scale assessment: disagreement 1 to 3, neither    disagreement nor agreement 4 to 6 and agreement 7 to 9.



Table 8: 9 Consensus recommendations for the cardiovascular therapeutic objectives in patients who are candidates for ponatinib or for its follow-up.

Section 6: Multidisciplinary approach and collaboration with other specialties

Clinical trials with ponatinib followed up over two years have shown a 6% incidence of venous thromboembolic disease (VTD), possibly related to the potent inhibition of tyrosine kinases and vascular endothelial growth factor receptor (VEGFR1-3), fibroblastic growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) receptors [29], leading to the definition of specific recommendations in this regard in the Summary of Product Characteristics [13].

Regarding the risk of VTD, ponatinib has not been shown to be a risk factor per se and therefore the routine use of antithrombotic prophylaxis is not recommended [40]. However, the association with another risk factor (e.g. hereditary predisposition, comorbidity associated with the tumour process, treatment with immunomodulators, etc.) will make it necessary to consider the benefit/risk ratio of this strategy, following the same guidelines as for any cancer patient [27]

Treatment of any VTD arising during treatment with ponatinib must be associated with an assessment of the possible discontinuation of treatment or dose optimisation to minimise vascular toxicity without compromising efficacy [20,29], as the cardiovascular toxicity of ponatinib has been shown to be dose-dependent [13]. In the event of the onset of VTD during treatment, it is recommended that ponatinib be suspended until resolution of the event and that the indications in Table 9 [27] be followed, prioritising the use of Low Molecular Weight Heparin (LMWH) or Direct-Acting Oral Anticoagulants; (DOACs) over vitamin K antagonists.

Table 9: VTD treatment strategies recommended in cancer patients.




  
    Full dose LMWH* 
    Duration of treatment    (long-term treatment phase): LMWH minimum 3 months (6 months desirable for    cancer), after which the possibility of extended treatment will be assessed. 
  
  
    Individualize    discontinuation of treatment: maintain LMWH until completion of curative    treatment or as long as risk factors for VTD recurrence persist. 
  
  
    If there is a recurrence of    VTD with LMWH: increase the dose and optimize anti-Xa control. Consider an    inferior vena cava filter for pulmonary embolism. 
  
  
    *If the patient has platelet levels >50,000 platelets/mm3,    as they have fewer thrombotic relapse rates than vitamin K antagonists.    Anti-Xa: Anti-Activated Factor X



Table 9: VTD treatment strategies recommended in cancer patients.

Conversely, ponatinib has been shown to act as a platelet antagonist, inducing thrombocytopenia and platelet dysfunction [41]. In a series of 80 patients, an incidence of 11% of bleeding events was reported; however, none of them compromised safety; caution is recommended in the management of patients with antithrombotic therapy or observed thrombocytopenia [42]. Taking these data into account, the concomitant use of ASA should be carefully evaluated, as well as the ponatinib regimen in both elective and emergency surgery, with platelet transfusion being evaluated in the latter case.

Given its increased CVR compared with its analogues, the indication of ponatinib should result in referral to a specialist in Angiology and Vascular Surgery and a Cardiologist or Onco- Cardiologist prior to initiation of treatment. These specialists must perform an adequate assessment of the CVR associated with the drug, as well as its possible management during treatment [9], through an adequate baseline assessment, the establishment of thromboembolic prophylaxis in the indicated cases, treatment for primary prevention in cases of the concurrence of one or more CVRFs and secondary prevention in cases of diagnosis of CV disease and adequate longterm patient follow-up.

Based on the available evidence, the panel makes the recommendations included in Table 10.

Table 10: Consensus recommendations for the prevention of VTD in candidate patients for ponatinib or in its follow-up.




  
    Recommendation 
    Level of consensus 
    Level of agreement 
  
  
    Routine prophylaxis with    anticoagulant therapy is not recommended in patients treated with ponatinib    with no other prothrombotic risk factors susceptible to prophylaxis for    associated VTD. 
    Consensus 
    Agreement 
  
  
    In case of elective surgery    ponatinib should be suspended 7 days before surgery and resumed when no    bleeding risk is envisaged (approximately 1-3 days). 
    Consensus 
    Agreement 
  
  
    Ponatinib must be suspended    in patients with venous thromboembolism until resolution of the event,    avoiding the administration of vitamin K antagonists due to the increased    risk of interactions, and preferably considering the use of    low-molecular-weight heparins or direct-acting oral anticoagulants    (rivaroxaban and edoxaban). 
    Consensus 
    Agreement 
  
  
    The concomitant use of ASA    in patients who are candidates for surgery must be assessed; therefore, in    those patients at low/moderate risk, interruption is recommended and ASA must    be restricted in high-risk patients to a maximum dose of 100mg/day. 
    Consensus 
    Agreement 
  
  
    It is recommended that all    patients being considered for ponatinib treatment be assessed by an    angiologist/vascular surgeon and an (onco) cardiologist prior to initiation    of the treatment. 
    Consensus 
    Agreement 
  
  
    During the subsequent    follow-up of patients who have previously presented with VTD, it is    recommended that limb Doppler scans be performed. 
    No consensus** 
    Agreement 
  
  
    During the subsequent follow-up    of patients who have previously had VTD, it is recommended that D-dimer    levels be determined at the end of treatment to assess the possible risk of    recurrence. 
    No consensus† 
    Indeterminate 
  
  
    *Based on a Likert scale assessment: disagreement 1 to 3, neither    disagreement nor agreement 4 to 6 and agreement 7 to 9. **There is    consensus that the panelists disagree. †There was no majority in    agreement or disagreement.



Table 10: Consensus recommendations for the prevention of VTD in candidate patients for ponatinib or in its follow-up.

Section 7: Management of pre-existing and emerging cardiovascular problems

CML and the Treatments Applied (TKIs) can affect cardiac function [43], so signs and symptoms of CV disease should be monitored and CVRFs actively sought, with a view to emphasising the importance of prevention. For this, in addition to the clinical interview, we have certain diagnostic tests that may be useful in the early identification of patients who will go on to develop cardiac dysfunction [11,20] (Table 11).

Table 11: Recommended function monitoring tests.




  
    Laboratory tests 
    Elevation of BNP may indicate    latent cardiac dysfunction, so baseline determination and repeat testing    during treatment is recommended [17]. 
  
  
    The role of troponin is not    well established, and is not therefore recommended as a routine test [20]. 
  
  
    Laboratory 

      tests 
    A baseline echocardiogram is    recommended, and quantification of 3D LVEF whenever this is available. If the    LVEF at follow-up falls more than 10% below baseline and below normal values,    the study will need to be repeated in 2-3 weeks and, if this is confirmed,    the patient must be referred to cardio-oncology [11]. 
  
  
    Left ventricular GLS is a    more sensitive and reproducible marker than LVEF for subclinical changes in    left ventricular function, so it can be useful in anticipating dysfunction. 
  
  
    If GLS decreases without    changes in the LVEF, it is recommended that the study be repeated at 2-3    weeks [11]. 
  
  
    The use of MRI is only    recommended if there is uncertainty in the echocardiographic examination    [11]. 
  
  
    3D: 3-Dimensional; LVEF: Left    Ventricular Ejection Fraction; GLS: Global Longitudinal Strain.



Table 11: Recommended function monitoring tests.

The approach with a patient who develops systolic dysfunction following ponatinib treatment is the treatment of systolic heart failure, i.e. initiating ACEI/ARA-II and beta-blockers as soon as possible, as well as the possible addition of potassium-sparing diuretics (e.g. eplerenone, spironolactone). If the patient develops decompensated heart failure, intravenous diuretic therapy should be initiated, resuming background therapy as soon as possible [11,27].

On the other hand, the European Cardio-Oncology guidelines indicate that the thrombotic-haemorrhagic risk balance could be modified in the presence of cancer [11]. However, at the moment there are no specific risk scales for cancer patients, so in practice the risk prediction scales CHA2DS2-VASc and HAS-BLED validated for the general population are used [44]. Similarly, the European clinical practice guidelines for the management of Atrial Fibrillation (AF) make no distinction in patients with concomitant oncological pathology, applying the same criteria as in the general population for the use of antithrombotic treatment [45]. As to which anticoagulant drug should be used in patients with AF and CML treated with ponatinib, the recommendations are not yet clear. Vitamin K antagonists do not seem to be an appropriate option, due to a possible alteration of International Normalized Ratio (INR) by interaction with treatment, so the use of LMWH is more frequent. In this regard, it is worth mentioning that in normal practice the use of DOACs is increasing in the general population, although the pivotal trials for their approval have not included patients with these characteristics [46-49]. However, it should be noted that in this last year the first randomised studies in cancer patients have begun to emerge, which will provide new evidence in the choice of treatment.

Also, it should be noted that TKIs produce Peripheral Arterial Disease (PAD) in up to 30% of cases, so it is recommended that determination of ABI and the control of CVRFs at baseline be carried out in all patients, as well as anti-aggregation and revascularisation in symptomatic patients if indicated [20].

Based on the available evidence, the panel makes the recommendations included in Table 12.

Table 12: Consensus recommendations for the management of pre-existing and emerging cardiovascular problems in patients who are candidates for ponatinib or in its follow-up.

Recommendation
Level of consensus
Level of agreement*

In patients with cardiac dysfunction it is not routinely recommended to perform troponin determination, as its role is not well established in this context.
No consensus
Agreement

Baseline echocardiogram is recommended in all patients. Echocardiogram follow-up at 3 months in high-risk patients and annual follow-up in all patients. If LVEF is below normal, even if the patient is asymptomatic, he/she must be referred to cardio-oncology and heart failure treatment must be initiated. The decision to interrupt ponatinib in the event of a reduction of LVEF must be individualised.
Consensus
Agreement

Magnetic resonance imaging is recommended for cardiac function assessment in patients not diagnosed with echocardiography (poor ultrasonic window or clinically inconsistent data).
Consensus
Agreement

The treatment of a patient who develops systolic dysfunction following ponatinib treatment must include the treatment of systolic heart failure, i.e. the administration of ACEI/ARA-II and beta-blockers as soon as practicable. If the patient develops decompensated heart failure, intravenous diuretic therapy (usually furosemide) to control symptoms and acute phase treatment must be initiated, resuming basic treatment as soon as possible.
Consensus
Agreement

In the patient with atrial fibrillation it is recommended that the same risk scores as in the general population be used, i.e. anticoagulate if patients have CHA2DS2-VASc=1 and consider high bleeding risk if HAS-BLED =3.
Consensus
Agreement

Given the risk of thrombocytopenia in cancer patients, anticoagulation is not recommended in patients with less than 50,000 platelets, despite being indicated by CHA2DS2-VASc.
Consensus
Agreement

In patients with atrial fibrillation it is recommended that the same antithrombotic treatment as before be continued; if INR control is difficult or the patient experiences embolic or bleeding events, it is recommended that direct-acting oral anticoagulants be initiated.
Consensus
Agreement

In patients with a history of STEMI, NSTEMI, coronary revascularisation surgery or an ischaemic cerebrovascular event, secondary prophylaxis with antiplatelet agents is recommended in accordance with the recommendations in the available clinical guidelines.
Consensus
Agreement

*Based on Likert scale assessment: disagreement 1 to 3, neither disagreement nor agreement 4 to 6 and agreement 7 to 9. STEMI: ST Elevation Myocardial Infarction; NSTEMI: Non-ST Segment Elevation Myocardial Infarction.



Table 12: Consensus recommendations for the management of pre-existing and emerging cardiovascular problems in patients who are candidates for ponatinib or in
its follow-up.

Section 8: Dose adjustment as approved by regulatory agencies

In 81% of patients chronic phase CML (CP-CML) included in the PACE trial it was necessary to reduce the dose due to the appearance of toxicity, however, after the dose reduction 96% of patients maintained major cytogenetic response [14]. A predictive model that took into account the influence of dose on the occurrence of thrombotic events demonstrated that every 15 mg/day of ponatinib dose reduction resulted in a 33% decrease in the risk of an arterial occlusive event [50]. These results indicate the need to act to reduce the incidence of thrombosis, especially arterial thrombosis, and several factors are recommended when selecting the starting dose (Table 13).

Table 13: Determining factors in ponatinib dose choice.




  
    Factors associated with a    greater likelihood of response 
    Chronic phase of disease. 
  
  
    Presence of T315I mutation. 
  
  
    Individual factors    associated with increased CVR
    Age > 60-65 years. 
  
  
    History of arterial    thrombosis (ischemic heart disease, cerebral vascular disease or peripheral    vascular disease). 
  
  
    Presence of CVRF (AHT, DM,    dyslipidaemia, etc.).



Table 13: Determining factors in ponatinib dose choice.

The European LeukemiaNet. guidelines available at the time of analysis conclude that there is no absolute contraindication to using any particular TKI, indicating that the use of ponatinib is not advisable in patients with any level of PAD and ponatinib should be used with caution in those with ischaemic heart disease or prior cerebral ischaemia, given its increased vascular risk [14]. However, these guidelines do not include the assessment of other specialists.

It must be borne in mind that in the PACE study patients with significant or active CVD were excluded, specifically mentioning congestive heart failure, acute myocardial infarction (AMI) or unstable angina in the previous 3 months. Likewise, 30% of patients with CP-CML developed arterial ischaemia of any type after 5 years, and the history of previous ischaemia was responsible for a 2.65 fold increase in the risk of an arterial event with ponatinib. Additionally, the probability of developing severe cardiac events at 5 years was 12%, and 10% and 11% for cerebral and peripheral events, respectively [14].

However, we do not have the actual mortality data for ponatinib patients treated in the PACE study with previous ischaemic artery disease, which means that we must rely on extrapolations.

Based on the available evidence, the panel makes the recommendations included in Table 14.

Table 14: Consensus recommendations for dose adjustment of ponatinib as approved by regulatory agencies.




  
    Recommendation 
    Level of consensus 
    Level of agreement* 
  
  
    When selecting the starting    dose for ponatinib, it is necessary to take account of both factors related    to an increased likelihood of response and the presence of patient risk    factors associated with increased cardiovascular toxicity (e.g. AHT,    dyslipidaemia). 
    Consensus 
    Agreement 
  
  
    To evaluate treatment    response it is recommended that the ELN criteria defining response to    second-line TKIs after failure with imatinib be applied; assessments will be    performed at 3, 6 and 12 months after the initiation of treatment, bearing in    mind that achieving a partial cytogenetic response may be a reasonable    objective in some patients in whom there is no other therapeutic alternative. 
    Consensus 
    Agreement 
  
  
    In general terms, a dose    reduction of 15 mg/day is recommended if an optimal response is obtained,    with the aim of reducing cardiovascular toxicity without compromising    efficacy; and dose maintenance in cases of concern or failure, if there has    been no toxicity. 
    Consensus 
    Agreement 
  
  
    In the event of a serious    cardiovascular event it is recommended that ponatinib treatment be    discontinued indefinitely; however, in this context it is necessary to    establish the concept of a serious event in terms of morbidity/mortality in    order to adequately assess the drug's benefit/risk ratio. 
    Consensus 
    Agreement 
  
  
    In patients with previous    vascular events it is necessary to consider the balance of the risk of both    the new ischemic event and the mortality associated with the antileukaemic    effect of ponatinib. 
    Consensus 
    Agreement 
  
  
    In patients who have had a    TIA, ponatinib treatment would not be contraindicated. 
    Consensus 
    Agreement 
  
  
    In patients who have had    ischaemic stroke, ponatinib treatment would be contraindicated. 
    Consensus 
    Agreement 
  
  
    In patients who have    suffered from non-atherothrombotic AMI, ponatinib treatment would be    contraindicated. 
    Consensus 
    Agreement 
  
  
    For patients with    symptomatic peripheral arterial disease, ponatinib treatment would be    contraindicated. 
    Consensus 
    Agreement 
  
  
    For patients with    asymptomatic peripheral arterial disease, ponatinib treatment would not be    contraindicated. 
    Consensus 
    Agreement 
  
  
    *Based on a Likert scale assessment: disagreement 1 to 3, neither    disagreement nor agreement 4 to 6 and agreement 7 to 9.



Table 14: Consensus recommendations for dose adjustment of ponatinib as approved by regulatory agencies.

Section 9: Management of drug-drug interactions

It has been observed that about 20-30% of adverse drug reactions are caused by drug-drug interactions, in addition to other interactions with food, nutritional supplements, medicinal plants, excipients or environmental factors [51]. In addition, although numerous studies reveal the high prescription of TKIs with drugs susceptible to interaction, which can increase toxicity by up to 74%, epidemiological data describing the clinical significance are very limited [52]. Although drug-drug interactions that affect the therapeutic effect of ponatinib are not expected, given the specificity of its binding site, those that affect its safety can be expected, the most relevant being those described in Table 15.

Table 15: Main pharmacodynamic interactions reported with ponatinib.




  
    Major pharmacodynamic    interactions 
    Concomitant use of    cladribine, deferiprone, dipyrone, clozapine, chlorpromazine or    levomepromazine is contraindicated due to the risk of myelosuppression and/or    agranulocytosis [53]. 
  
  
    Caution when used at the    same time as anticoagulant medicinal products. If association with vitamin K    antagonists cannot be avoided, closer monitoring of INR [54] must be carried    out. 
  
  
    The use of intravesical BCG    and live virus vaccines must be avoided as the immune response will be    limited [54]. 
  
  
    TKIs can produce    prolongation of the QT interval. However, cases of severe QTc prolongation    are explained by drug interaction or previous heart disease [55,56]. 
  
  
    Carefully assess possible    interactions that may aggravate other toxicities (e.g. be cautious when    combined with L-asparaginase because of the risk of hepatotoxicity) [54]. 
  
  
    BCG: Bacillus    Calmette-Guérin.



Table 15: Main pharmacodynamic interactions reported with ponatinib.

However, it is important to stress that they must be taken as a starting point, since the fact that an interaction is not described does not mean that it can be ruled out [54]. In this sense, oncohaematological pharmacists have the training and experience that allows the early identification of potentially harmful drug-drug interactions, and their inclusion in the clinical team plays a vital role in this field [57].

To reduce the potential for unexpected drug-drug interactions, the patient’s medical history must collect comprehensive and interactive information on all medications and supplements the patient receives and must be periodically updated. The patient must also be educated on the need to consult prior to the inclusion of any medicinal product, supplement or alternative therapy, in order not to compromise the efficacy and safety of ponatinib [58].

Based on the available evidence, the panel makes the recommendations included in Table 16.

Table 16: Consensus recommendations for management of drug interactions with ponatinib.




  
    Recommendation 
    Level of consensus 
    Level of agreement* 
  
  
    The patient's active    medication must be comprehensively recorded in the medical records and    periodically updated; and the patient must be educated on the need to consult    on the risk of interactions. 
    Consensus 
    Agreement 
  
  
    It is recommended that patients    with risk factors for potential interactions (e.g. impaired liver function,    age, and polymerization) be identified so that these interactions can be    minimized. 
    Consensus 
    Agreement 
  
  
    In the absence of scientific    evidence, theoretical pathways and mechanisms of interaction must be assessed    to anticipate possible side effects in the patient, and it is essential that    this involve collaboration with the hospital pharmacist. 
    Consensus 
    Agreement 
  
  
    *Based on a Likert scale assessment: disagreement 1 to 3, neither    disagreement nor agreement 4 to 6 and agreement 7 to 9.



Table 16: Consensus recommendations for management of drug interactions with ponatinib.

Section 10: Lifestyle and patient education

As already discussed, TKI therapy leads to an increase in intrinsic CVR, so non-pharmacological cardiotoxicity prevention measures need to be implemented in all patients, regardless of their treatment regimen. These measures must include the promotion of a healthy lifestyle, understood as observance of a balanced diet, regular exercise, adequate body weight control and cessation of smoking, as well as strict identification and control of CVRFs before, during and after treatment [25].

When it comes to dietary patterns, the available European guidelines agree that a Mediterranean diet is the most appropriate in our context [59]. With regard to physical activity, aerobic exercise is recommended, for 150 minutes/week if the exercise is of moderate intensity, or for 75 minutes/week in the case of more vigorous activity. However, shorter exercise sessions may also be appropriate for patients who are unable to meet these requirements [24], as may be the case for patients undergoing oncology therapy.

The timing of oncology diagnosis can be a good opportunity for encouraging patients to change their lifestyle and promote healthier habits, as fear of side effects from therapy or possible relapse greatly increases the patient’s willingness to listen to nutrition and lifestyle advice [60].

Based on the available evidence, the panel makes the recommendations included in Table 17.

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Citation: Steegmann JL, Zamorano JL, Páramo JA, Hernández-Boluda JC, Pérez R, García-Gutierrez V, et al. Cardiovascular Risk Management Recommendations for Patients with Chronic Myeloid Leukaemia who are Candidates for Ponatinib: Multidisciplinary Delphi Analysis. Ann Hematol Oncol. 2021; 8(7): 1354.

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Risk	Lipid Control Objectives (LDL)
Very high risk	<55mg/dL and ↓ 50% from baseline
High Risk	<70mg/dL and ↓ 50% from baseline
Moderate risk	<100mg/dL
Low risk	<116mg/dL

	Patients who are candidates for ponatinib	Patients treated with ponatinib
Medical history and initial clinical evaluation Table 1 and Table 2	Multidisciplinary evaluation (Table 2). Detailed clinical history. Initial physical examination: height, weight, BMI and cardiovascular and pulmonary auscultation.	Patients with a history of CV disease, uncontrolled risk factors or a lower than normal ejection fraction are considered high risk and require cardio-oncology management and follow-up.
Laboratory and imaging tests Table 3 and Table 4	Analytical monitoring: blood count, coagulation, liver and pancreatic enzymes, creatinine and eGFR, blood glucose and HbA1c, electrolytes, triglycerides, total cholesterol and HDL-c/LDL-c, BNP/pro-BNP levels. Blood pressure, ABI, ECG (QTc Fridericia), echocardiogram and chest X-ray. Carotid Doppler ultrasound in moderate, high and very high risk patients. Coronary calcium determination in moderate CV risk patients.	Weekly checking of blood pressure and cardiovascular risk during the first month, monthly during the first quarter and then quarterly. Monitoring of glucose and lipid metabolism, and determination of ABI every 3, 6 and 12 months. Echocardiogram follow-up at 3 months of high-risk patients and annual follow-up of all patients.
CVR evaluation and prophylaxis strategies Table 5 and Table 6	Cardiovascular risk must be quantified with SCORE tables in all ponatinib candidates and vascular disease must be actively ruled out.	ASA 100 mg/day is not recommended as the primary prophylaxis in low CV risk patients treated with ponatinib.
Cardiovascular treatment objectives Table 7 and Table 8	Set targets for blood pressure, lipid control and glycaemic control and the treatments necessary to achieve them (Table 8).	Review of blood pressure, lipid control and glycaemic control objectives and the treatments necessary to achieve them (Table 8).
Prevention of VTD Table 9 and Table 1	Routine prophylaxis with anticoagulant treatment: not routinely recommended in patients without other risk factors. Assessment, by an angiologist/vascular surgeon and an (onco)cardiologist, of all patients being considered for ponatinib treatment prior to initiation.	Elective surgery: suspend ponatinib 7 days before surgery and resume when no bleeding risk is envisaged (approximately 1-3 days). VTE patients: suspend ponatinib until resolution of the event, avoiding the administration of vitamin K antagonists and considering the use of LMWH and DOACs. ASA in surgery: in low-/moderate-risk patients interruption is recommended, and ASA restricted in high-risk patients to a maximum dose of 100mg/day.
Management of pre-existing and emerging CV issues Table 11 and Table 12	Optimization of treatment in accordance with clinical practice guidelines is recommended in patients with a history of CV risk factors or cardiovascular disease.	If LVEF < normal, refer to cardio-oncology and initiate HF treatment. The treatment of patients who develop systolic dysfunction following ponatinib treatment must include HF treatment as soon as possible. If the patient develops severe decompensate HF, ponatinib therapy must be interrupted and the decision on when and whether to resume ponatinib must be agreed by a multidisciplinary team, In patients with AF, CHA2DS2VASc is recommended for indicating the use of anticoagulation, prioritizing the use of OACs. Anticoagulation decision in patients with AF or VTD and less than 50,000 platelets must be agreed by the multidisciplinary team.
Adjustment of doses in accordance with approved indications. Table 13 and Table 14	Initial dose of ponatinib: consider factors related to a greater likelihood of response and the presence of CVRFs. Patients with previous events: assess the balance between the possibility of a new event and mortality associated with the antileukaemic effect of ponatinib. Ponatinib is indicated in patients who have had a TIA or have asymptomatic peripheral arterial disease. Ponatinib is contraindicated in patients who have had an ischaemic stroke, non-atherothrombotic AMI or have symptomatic peripheral arterial disease.	Apply ELN criteria that define the response to second-line TKIs: assessments will be performed at 3, 6 and 12 months after initiation of therapy. If an optimal response is achieved: it is recommended that the ponatinib dose be reduced by 15mg/day to reduce CVR. In case of concern or failure: if there has been no toxicity, dose maintenance is recommended. Onset of severe CVD: suspend treatment indefinitely; assess severity and morbidity/mortality.
Management of drug-drug interactions Table 15 and Table 16	Recording of patient medication: through the medical history records, with periodic updating. Educate the patient on the need to consult about the risk of interactions.

Cardiovascular Risk Management Recommendations for Patients with Chronic Myeloid Leukaemia who are Candidates for Ponatinib: Multidisciplinary Delphi Analysis

Abstract

Abbreviations

Introduction

Objectives

Participants and Methodology

Results

Section 1: Correlation between clinical trial data and actual practice

Section 2: Medical history and initial clinical evaluation

Section 3: Laboratory and imaging tests

Section 4: CVR evaluation and prophylaxis strategies

Section 5: Cardiovascular therapeutic goals in ponatinib candidates

Section 6: Multidisciplinary approach and collaboration with other specialties

Section 7: Management of pre-existing and emerging cardiovascular problems

Section 8: Dose adjustment as approved by regulatory agencies

Section 9: Management of drug-drug interactions

Section 10: Lifestyle and patient education

Discussion and Conclusions

Acknowledgements

References