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.

Giovanni Caocci,Sara Galimberti,Emilia Scalzulli,Francesco Albano,Luigiana Luciano,Giorgio La Nasa,Claudia Baratè,Francesca Pirillo,Alessandra Iurlo,Robin Foà,Chiara Elena,Luigi Scaffidi,Massimo Breccia,Elisabetta Abruzzese,Claudio Fozza,Malgorzata Monika Trawinska,Daniele Cattaneo,Immacolata Attolico,Fabio Stagno,Antonella Gozzini,Gianni Binotto,Patrizia Pregno,Gabriele Gugliotta,Fausto Castagnetti,Mario Annunziata,Nicola Sgherza,Massimiliano Bonifacio,Olga Mulas,F De Gregorio ,Ester Orlandi

doi:10.1002/hon.2606

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.

Highlights

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]
In the 5‐year follow‐up of the multinational phase II Ph + ALL and CML Evaluation (PACE) trial, the cumulative incidence rate of arterial occlusive events (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]
The cumulative incidence rate of AOEs reported by the 5‐year follow‐up of PACE trial was 31% in the chronic‐phase CML population; in this report, the higher cumulative incidence rate correlated with the longer duration of treatment with ponatinib.[2]

Summary

| INTRODUCTION

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]. 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]. 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

| RESULTS

Findings

| DISCUSSION