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

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


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


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


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.


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.


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.