Cardiovascular events in CML patients treated with Nilotinib: validation of the HFA-ICOS baseline risk score

Abstract

Background: The therapeutic landscape of chronic myeloid leukaemia (CML) has been transformed by tyrosine kinase inhibitors (TKI). Nilotinib, showed higher rates of major molecular response than imatinib, however associated with higher cardiovascular (CV) toxicity. We sought to describe the CV events associated with nilotinib in a real-world population and assess the predictive value of the HFA-ICOS risk score.

Methods: The HFA-ICOS baseline risk was calculated for patients with CML treated with nilotinib beween 2006 and 2021. The primary end point was the incidence of all CV events. The secondary end point was the incidence of ischaemic events. Survival analysis evaluated the risk (hazard ratio [HR]) of events stratified by baseline risk category, whilst on nilotinib therapy.

Results: Two hundred and twenty-nine eligible patients were included. The incidence of CV events was 20.9% (95% CI: 15.7-26.2%) following a median duration of treatment of 34.4 months. The secondary end point occurred in 12.7% (95% CI: 8.4-16.9%) of the population. Patients with higher HFA-ICOS baseline score had higher rates of CV events (low: 11.2%, medium: 28.2% [HR: 2.51, 95% CI: 1.17-5.66], high/very high: 32.4% [HR: 3.57, 95% CI: 1.77-7.20]) and ischaemic events (low: 5.20%, medium: 17.9% [HR: 2.19, 95% CI: 0.97-4.96], high/very high: 21.6% [HR: 3.9, 95% CI: 1.91-7.89]). In patients who did not have a CV event, the median total dose at last follow up or cessation of nilotinib therapy was lower when compared to the total daily median dose of nilotinib in patients who had a CV event (450 mg vs. 600 mg, p = 0.0074).

Conclusions: The HFA-ICOS risk stratification tool is an efficient discriminator at low, medium and high/very high risk of developing cardiovascular events, with an overall positive trend towards increasing cardiotoxicity rates with rising risk catergories. This study provides evidence to support the use of this predictive tool in nilotinib treated patients.

Keywords: CV toxicity; Chronic myeloid leukaemia; Nilotinib; Risk stratification; TKI.

Fig. 1

a. Risk factors and their corresponding score included in the baseline CV risk stratification proforma for BCR::ABL1 kinase inhibitors for chronic myeloid leukaemia including second and third generationTKI. BMI = Body mass index, CABG = Coronary artery bypass graft, IHD = Ischaemic heart disease, PCI = Percutaneous coronary intervention, PVD = Peripheral vascular disease, TIA = Transient ischaemic attack, LVSD = Left ventricular systolic dysfunction, CVD = Cardiovascular disease, AF = Atrial fibrillation, atrial flutter, ventricular tachycardia or ventricular fibrillation. b. Definition of each risk category according to the number of risk factors. RF = risk factor. Adapted from Eur J Heart Fail. 2020 Nov;22 (11):1945–1960. doi: 10.1002/ejhf.1920. Epub 2020 Aug 6. PMID: 32463967; PMCID: PMC8019326

Fig. 2

Frequency of cardiovascular events in CML patients receiving nilotinib. CVA = cerebrovascular accident. TIA = transient ischaemic accident. DVT/PE = deep vein thrombosis, pulmonary embolism

Fig. 3

a) List of CV events and incidence of end-points, per HFA-ICOS risk score. b) Barchart showing the percentage of patients with a CV event, an Ischaemic Event and a Second CV Event grouped by baseline CV risk score. CVA = cerebrovascular accident, TIA = transient ischaemic accident, HTN = hypertension, PVD, peripheral vascular disease, DVT = deep vein thrombosis, PE = pulmonary embolism, MACE = major adverse cardiovascular event, ACS = acute coronary syndrome, CV = cardiovascular

Fig. 4

Kaplan Meier curves showing the time to event according to each risk category. (A) All cardiovascular events, (B) Ischaemic events

Fig. 5

Receiver Operator Characteristic Curves to predict all CV events and Ischaemic events in patients on nilotinib using HFA-ICOS risk assessment tool. CV = cardiovascular