Arterial Thrombotic Complications Are Uncommon in Patients without Cardiovascular Risk Factors and Occur at Equivalent Rates in Chronic Myeloid Leukemia (CML) Patients Treated with Imatinib and Nilotinib
Authors: Hekmatjou Hesam , Roboz Gail J. , Ritchie Ellen K. , Lee Sangmin , Desai Pinkal , Scandura Joseph M. , Allen-Bard Sandra , Christos Paul , Silver Richard T. , Feldman Eric J. 
Published: October 2019

Abstract
Arterial thrombosis (AT), including ischemic heart disease, stroke, and peripheral artery occlusive disease (PAOD), have been observed in several studies of CML patients treated with tyrosine kinase inhibitors (TKI’s), most often in patients treated with ponatinib. Reports of AT in patients treated with other TKI’s are based on anecdotal observations and/or studies with relatively short follow-up times and limited data on underlying risk factors. From 1999 to 2014, 408 patients with CML were seen at Weill-Cornell/New York Presbyterian Hospital. Of these, a cohort of 224 patients in chronic phase received ongoing therapy with TKI’s with continuous clinical observation with a median follow-up of 7 years (range 1-15 years). There were 124 (55.4%) men and 100 (44.6%) women with a median age of 52 years (range 21-75 years). Initial therapy with a TKI occurred in 86% whereas 14% had received prior therapy with interferon-alpha and 2% had a prior allogeneic transplant. The initial TKI therapy was imatinib in 82%, nilotinib in 14% and dasatinib in 4%. 49% of patients were treated with only 1 TKI, 21% with 2 TKI’s and 30% with > 2 TKI’s. Over the course of therapy, overall 82% of patients were exposed to imatinib, 33.9% to nilotinib, 25% to dasatinib and 2.2% to ponatinib. Information on pre-treatment cardiovascular risk factors which included; a history of a prior AT, diabetes, hyperlipidemia, hypertension and smoking, were available on all patients. Prior AT occurred in 7.5%; 25% had 1 risk factor and 20.6% had 2 or more risk factors. Overall AT was observed in 7.1% (95% CI = 3.8%, 10.5%) of all patients and there were no deaths associated with AT. Ischemic heart disease occurred in 4.9%, a stroke in 0.4% and PAOD in 1.8%. The median time from start of TKI therapy to development of AT was 7 years (range 4-14). The median age of patients who developed AT was 68 years (range 47-80). AT occurred predominantly in patients with pre-existing risk factors; the incidence was 14.6% in patients with prior risk factors whereas only 1.6% of patients without risk factors developed this complication (p<0.0001). In 16 /224 patients, 17 AT’s occurred; 10 while on treatment with imatinib, 5 on nilotinib, 1 on dasatinib and 2 on ponatinib. By overall TKI exposure, AT occurred in 5.4 % of patients exposed to imatinib 6.6% exposed to nilotinib and 1.8% exposed to dasatinib (p=not significant). Apart from ponatinib, neither the initial TKI used, the overall exposure or length of exposure to TKI’s, or the number of TKI’s administered were associated with an increased risk of AT. These data would suggest that the development of AT is uncommon in patients without prior risk factors and occurs with equal frequency in patients exposed to either imatinib or nilotinib. Additional data are needed to conclusively determine whether treatment with a TKI (excluding ponatinib) is an independent risk factor for the development of AT in CML patients. Importantly, identification of the mechanism(s) associated with TKI-related AT in CML patients are needed to plan preventive measures, particularly in patients with preexisting risk factors.

Disclosures
Roboz: Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Novartis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Allen-Bard:Novartis: Speakers Bureau. Feldman:Novartis: Honoraria, Research Funding, Speakers Bureau; Ariad: Honoraria, Speakers Bureau.