Cardiovascular Scoring and Age-Related Mutations Predict the Occurrence of Adverse Vascular Events in CML Patients during Nilotinib Therapy (2017)

Although otherwise considered a relatively safe drug, the BCR/ABL1 tyrosine kinase inhibitor nilotinib has recently been associated with the occurrence of progressive arterial occlusive disease (AOD). In most of the affected patients, cardiovascular risk factors have been identified. However, AOD may even occur in patients without known risk factors. The aim of this project was to identify clinical and molecular risk factors predicting AOD development in CML patients receiving nilotinib. A total number of 36 consecutive nilotinib-treated patients with Ph+ CML (median age: 49 years; m/f ratio: 1.25, all seen at our department between 2006-2013) were examined. With the exception of one case, none of these patients had developed an AOD before nilotinib-therapy. During nilotinib therapy, AOD events were found to accumulate over time. After 2.0 years, 29.4% of our patients had developed one or more AOD events. After 3.0 years, the frequency of AOD increased to 38.9%, and after 3.7 years, it reached 47.2%. After 3.7 years, a total number of 39 symptomatic AOD events were recorded, resulting in 32 AOD-events per 100 patient-years and a 1-year hazard ratio of 4.72 compared to the AOD-risk of healthy individuals (p 1%-44%). The allele burden of age-related mutations ranged between 2% and 68%. In one patient without AOD, low levels (1.6% allele-frequency) of JAK2 V617F were detected. In conclusion, multiple clinical and molecular risk factors predict the occurrence of AOD development in nilotinib-treated patients with CML. Based on our results the major recommended tool for prognostication is the ESC-SCORE. However, additional factors, like protein C and S, the blood group and age related mutations detected by NGS after debulking of the dominant BCR-ABL1+ sub-clones, should also be taken into account. Together with optimal metabolic control and co-medication, these recommendations may lead to optimal patient-selection and better control and management of vascular side-effects in nilotinib-treated patients with CML. Disclosures Hadzijusufovic: Novartis: Honoraria. Hoermann: Gilead: Honoraria, Research Funding; Ariad: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Sperr: Amgen: Consultancy, Honoraria, Research Funding; Meda: Research Funding; Celgene: Consultancy, Honoraria; Phadia: Research Funding; Teva: Honoraria; Novartis: Other: Register. Jilma: Biomed: Research Funding; Arsanis: Research Funding; Baxalta: Research Funding; Emcools: Research Funding; Bayer: Research Funding; Syntheract: Research Funding; Valneva: Research Funding; Boehringer Ingelheim: Research Funding; TrueNorth Therapeutics Inc.: Consultancy; Octapharma: Research Funding; Prediction Biosciences: Research Funding; Recardio: Research Funding; Themis: Research Funding; TrueNorth Therapeutics: Research Funding; Bioverativ: Research Funding; JHL: Research Funding; VitaerisBios: Research Funding. Schernthaner: Amgen: Honoraria; Astra Zeneca: Honoraria; Boehringer Ingelheim: Honoraria; BMS: Honoraria; Elli Lilly: Honoraria; Merck: Honoraria; Novo-Nordisk: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Sanofi-Aventis: Honoraria. Valent: Teva: Honoraria; Ariad: Honoraria, Research Funding; BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; Blueprint: Research Funding; Pfizer: Honoraria; Deciphera: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.