Arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real‐life practice are predicted by the Systematic Coronary Risk Evaluation (SCORE) chart

Abstract Arterial occlusive events (AOEs) represent emerging complications in chronic myeloid leukemia (CML) patients treated with ponatinib. We identified 85 consecutive CML adult patients who were treated with ponatinib in 17 Italian centers. Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 60‐month cumulative incidence rate of AOEs excluding hypertension was 25.7%. Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28 months (range, 3‐69 months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P < 0.001). Patients aged ≥60 years showed a significantly higher incidence rate of AOEs (51.5% vs 16.9%, P = 0.008). In multivariate analysis, no association was found between AOEs and positive history of CV disease, age, dose of ponatinib, previous exposure to nilotinib, and comorbidities. Only the SCORE risk was confirmed as a significant predictive factor (P = 0.01; HR = 10.9; 95% C.I. = 1.7‐67.8). Patients aged ≥60 years who were treated with aspirin had a lower incidence rate of AOEs (33.3% vs 61.8%). Among the 14 reported AOEs, 78.6% of them showed grade 3 to 4 toxicity. This real‐life study confirmed the increased incidence of AOEs in CML patients treated with ponatinib, with high to very high SCORE risk. We suggest that patients aged ≥60 years who were treated with ponatinib should undergo prophylaxis with 100 mg/day of aspirin. Our findings emphasize personalized prevention strategies based on CV risk factors.

stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels.
The 60-month cumulative incidence rate of AOEs excluding hypertension was 25.7%.
Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28 months (range, 3-69 months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P < 0.001).
Patients aged ≥60 years showed a significantly higher incidence rate of AOEs (51.5% vs 16.9%, P = 0.008). In multivariate analysis, no association was found between AOEs and positive history of CV disease, age, dose of ponatinib, previous exposure to nilotinib, and comorbidities. Only the SCORE risk was confirmed as a significant predictive factor (P = 0.01; HR = 10.9; 95% C.I. = 1.7-67.8). Patients aged ≥60 years who were treated with aspirin had a lower incidence rate of AOEs (33.3% vs 61.8%). Among the 14 reported AOEs, 78.6% of them showed grade 3 to 4 toxicity. This real-life study confirmed the increased incidence of AOEs in CML patients treated with ponatinib, with high to very high SCORE risk. We suggest that patients aged ≥60 years who were treated with ponatinib should undergo prophylaxis with 100 mg/day of aspirin. Our findings emphasize personalized prevention strategies based on CV risk factors. KEYWORDS arterial occlusive event, chronic myeloid leukemia, ponatinib, prophylaxis Ponatinib is a third-generation tyrosine kinase inhibitor (TKI), active against native and mutated BCR-ABL1, indicated for the treatment of chronic myeloid leukemia (CML) patients in every phase of the disease, resistant and/or intolerant to dasatinib and nilotinib, with or without T315I mutation. 1 Unfortunately, ponatinib treatment may induce cardiovascular adverse events (CVAEs) and, in particular, arterial occlusive events (AOEs).
In the 5-year follow-up of the multinational phase II Ph + ALL and CML Evaluation (PACE) trial, the cumulative incidence rate of AOEs was 31% in the chronic-phase CML population; the cumulative incidence rate of AOEs continued to increase over time, but the exposure-adjusted incidence of newly occurring AOEs remained relatively constant throughout the study, due to the reduction of the dose since October 2013. 2 The incidence rate of AOEs following ponatinib treatment in real life was reported only in a few small patient cohorts followed up for short periods, showing variable outcomes. [3][4][5][6] Risk factors associated with the development of AOEs have been identified in basal CV risk factors and/or may include the following: a history of previous ischemic disease, 2 dose intensity and age at starting ponatinib, 7 male sex, previous history of AOEs, and previous exposure to nilotinib. 5 The usefulness of the Systematic Coronary Risk Evaluation (SCORE) risk assessment at disease baseline, a 10-year risk estimation of fatal CV disease based on sex, age, smoking, systolic pressure, and total cholesterol level, to identify patients with increased risk of occurrence of AOEs during ponatinib treatment has been suggested. 8,9 Given the growing interest on the occurrence of AOEs in CML patients as off-target effects in the long term and the emergence of a new interdisciplinary specialty of "cardio-oncology" focusing on the proper stratification of CV risk in CML patients and management of complications, ad hoc expert opinions in this field have been published. 9,10 Overall, the recommendations agree on the importance of the CV risk stratification at baseline and suggest that certain TKIs should be used with caution in patients with preexisting CV risk factors, highlighting the need for a careful monitoring prior to the administration of the drug and during treatment.
Moreover, in CML patients treated with ponatinib, a preventing strategy with primary prophylaxis based on aspirin is still under discussion: the use of an antiplatelet agent in CML is not supported by literature data or by guidelines and is so far based on medical decision on an individual basis.
We therefore reported a large real-life cohort of Italian CML patients treated with ponatinib outside clinical trials. The primary endpoint was to establish the incidence of AOEs and the association with the SCORE assessment and baseline CV risk factors. Secondary endpoints were to evaluate the role of primary prophylaxis in preventing AOEs and to report the management of AOE complications in the clinical practice.

| METHODS
We identified 85 consecutive nonselected adult CML patients who were treated with ponatinib outside clinical trials between January 2012 and December 2017 in 17 Italian centers. Information on CV risk factors before starting ponatinib was retrospectively collected from the review of medical charts. To estimate the SCORE risk, all patients were evaluated at diagnosis for age, gender, tobacco use, systolic pressure, and total cholesterol serum level; patients were stratified into low to moderate (SCORE ≤ 5%) or high to very high (SCORE risk >5%) CV risk. Additional risk factors were as follows: presence of diabetes, body mass index >24.5 kg/m 2 , mild or severe renal insufficiency, and dyslipidemia.
Patients were also evaluated for comorbidities and a positive anamnesis of CV diseases, including myocardial infarction, heart failure, cardiomyopathy, angina, stroke, arterial hypertension, valvular heart disease, heart arrhythmia, aortic aneurysms, peripheral artery disease, ischemic cerebrovascular events, venous thrombosis, and thromboembolic disease. The probability of the cumulative incidence rate of AOEs was estimated after administering ponatinib. The cumulative incidence rate of MR 4 was evaluated from the start of ponatinib treatment. The log-rank test was used to compare two or more groups of stratified patients.
We evaluated the impact of the following variables on the incidence of AOEs: positive anamnesis for CV disease, age ≥ 60 years, ponatinib dose, previous exposure to nilotinib, comorbidities, primary prophylaxis, and SCORE risk. Multivariate analyses were performed using the Cox proportional hazards regression model. A P-value <0.05 was considered statistically significant. Data analysis was performed using a standard statistical package (SPSS for Macintosh, Version 21, Chicago, IL). Patients with a high to very high SCORE risk showed a significantly higher incidence of AOEs (74.3 ± 19.7% vs 15.2 ± 6.2%, P < 0.001) ( Figure 1). Patients aged ≥60 years showed a significantly higher incidence of AOEs (51.5 ± 16.6% vs 16.92 ± 6.9, P = 0.008).

| Role of primary prophylaxis
Overall, 19 patients were treated with 100 mg/day of aspirin as a primary prophylaxis before starting the administration of ponatinib.
In these patients, the 25-year overall survival rate was 94.  Figure 2. A higher drug dose was not associated to AOEs.      4 Other recent studies from real life reported a variable incidence rate of CVAEs from 23% to 56%, suggesting that male sex, previous history of AOEs, and previous exposure to nilotinib are considered risk factors. 5,6 Overall, these observations suggested the need to customize treatment approaches, considering the appropriate TKI selection according to baseline CV risk factors.
We evaluated a retrospective large cohort of 85 consecutive CML patients managed in Italy and treated with ponatinib in subsequent lines of treatment and found a 5-year AOE (excluding hypertension) cumulative incidence rate of 25.7%, similar to the PACE trial (31%), which included hypertension as one of the AOEs. Our study showed that patients aged ≥60 years represented a risk factor in a univariate analysis. Age was found to be associated to AOEs also in the published multivariate analysis including 671 ponatinib-treated patients. 7 Moreover, we confirmed for the first time that the SCORE risk chart, based on sex, age, smoking, systolic pressure, and total cholesterol level, in the setting of ponatinib-treated patients has an independent predictive value; indeed, patients with a high to very high risk score reported a significantly higher incidence of AOEs (74.3% vs 15.2%, P < 0.001), and this risk factor remained significant also in multivariate analysis ( Figure 1) were performed in three patients (Table 2). Ideally, management and treatment of these patients should be carried out in close collaboration with cardiologists, angiologists, and vascular surgeons.
Notably, primary prophylaxis with 100 mg/day of aspirin may represent an option for this category of patients, aiming at reducing the incidence of atherothrombotic events.
Although the role of aspirin is still a matter of debate and no data have thus far been published, we observed a lower, although not statistically significant, incidence rate of AOEs (16.9% vs 51.5%) in patients aged ≥60 years who were treated with 100 mg/day of aspirin.
Future prospective studies are needed to further corroborate our preliminary findings.
Given the long-term (often lifelong) TKI treatment required by the majority of CML patients, who nowadays can expect a survival similar to that of their peers from the general population, 16 a personalized treatment approach, based not only on disease-free survival but also on safety and quality of life, is needed. [17][18][19] This aim requires the availability of a cardio-oncology facility, with cardio-oncology a discipline based on the collaboration between cardiologists, hematologists, and other medical specialists with the aim of preventing, monitoring, diagnosing, and treating AOEs before, during, and after treatment. Several steps to prevent AOEs in CML patients treated withTKIs have been suggested. 20 Besides the management of modifiable CV risk factors, primary prophylaxis with aspirin has been proposed for "selected" patients.
In conclusion, this study confirms the increased risk of AOEs in CML patients treated with ponatinib in real life, harboring a high to very high SCORE risk. Our findings emphasize the need of personalized prevention strategies based on CV risk factors in close collaboration with cardio-oncologists, angiologists, and vascular surgeons. We suggest that patients aged ≥60 years treated with ponatinib should undergo a prophylaxis with 100 mg/day of aspirin. Data on the efficacy of the primary prophylaxis need to be confirmed in larger cohorts of patients and in prospective randomized trials.