Elevated Risk of Peripheral Artery Occlusive Disease (PAOD) in Nilotinib Treated Chronic Phase Chronic Myeloid Leukemia (CML) Patients Assessed by Ankle-Brachial-Index (ABI) and Duplex Ultrasonography
Authors: Schwarz Michaela , Kim Theo D. , Mirault Tristan , Grille Peggy , Rea Delphine , Lindhorst Ruhdja , Dombret Herve , Buschmann Ivo , Haverkamp Wilhelm , Doerken Bernd , le Coutre Philipp 
Published: October 2019

Abstract
Abstract 914
In bcr-abl-positive CML first-line therapy with the second generation tyrosine kinase inhibitors (TKI) nilotinib or dasatinib results in superior response rates and prevention of transformation as compared to imatinib. Generally, these TKIs are associated with mild and reversible toxicities but recent reports have indicated an elevated risk of PAOD in patients (pts) treated with nilotinib (Aichberger et al. 2011, Tefferi et al. 2011, le Coutre et al. 2011, Quintás-Cardama et al. 2012). We therefore screened all 153 chronic phase CML pts at our center for PAOD by sequentially determining ABI, followed by duplex ultrasonography when indicated. Cardiovascular risk factors were assessed with a specific questionnaire and biochemical parameters associated with PAOD were analyzed. We here present a first interim analysis.
Overall, 146 of 153 pts were evaluable and categorized into five groups: (I) first-line imatinib (n = 53); (II) first-line nilotinib (n= 31); (III) second-line nilotinib (n = 32); (IV) previously exposed to nilotinib (n = 23) and (V) never treated with nilotinib and currently not on imatinib (n = 7).
A pathological ABI, defined as <0.9, occurred in 24/116 (21 %) of all examined patients, but was more frequent in pts on first-line (7/26; 27 %, p=0.0181) and second-line nilotinib (10/24; 42 %, p=0.0004) as compared to pts on first-line imatinib (3/45; 7 %) despite a significantly longer treatment on first-line imatinib (median 80.25 months, range 4 – 137) than on first-line nilotinib (median 25.48 months, range 5 – 49, p<0.001). Newly diagnosed PAOD defined as a peripheral vascular occlusive event or pathological duplex ultrasonography was observed in 13/146 (8.9 %) of all pts and was more frequent in pts on first-line nilotinib (3/31; 9.6%, p=0.1057), second-line nilotinib (5/32, 15.6 %, p=0.0166) or pts previously exposed to nilotinib (4/23; 17.4 %, p=0.0123) as compared to pts on first-line imatinib (1/53; 1.9 %). No substantial differences between the five groups with respect to clinical cardiovascular risk factors were observed. However, biochemical risk factor assessment showed significantly higher levels of cholesterol and LDL in pts receiving first-line (218.0 mg/dl, p< 0.001, and 135.5 mg/dl, p< 0.01) and second-line nilotinib (219.9 mg/dl, p < 0.001, and 138.9 mg/dl, p < 0.01) as compared to pts on first-line imatinib (167.2 mg/dl and 97.8 mg/dl).
Of 16 pts with PAOD under or after nilotinib treatment, including three additional patients from a second center, 4 pts received nilotinib as first-line, 10 pts as second-line and 2 pts as third-line treatment. Median age was 62.4 years (range, 38–76) and median duration of CML was 103.1 months (range: 22–209). Best responses observed in this group of patients were CMR or MMR in 10/16 (62.5 %) and CCyR or MCyR in 6/16 (37.5 %) of patients. Major cardiovascular risk factors such as hypertension (13/15; 87), diabetes mellitus (5/14; 36 %), nicotine abuse (11/15; 73 %), cholesterol (5/12; 42 %) or LDL (6/13; 46 %) elevation were detectable in the majority. Vascular lesions affected the lower limb in 15/16 (94 %) and the eye in 1/16 pts (6 %). Cardiovascular interventions included percutaneous transluminal angioplasty (PTA) (7/16; 44 %), stent-implantation (5/16; 31 %) and/or surgery, including amputation (5/16; 31 %). Nilotinib was discontinued in 10/16 pts (63 %), dose-reduced in 5/16 pts (32 %) and continued in 1/16 pts (6 %).

Conclusions:
Prospective monitoring of pts with CML in chronic phase by sequential evaluation of ABI and duplex ultrasonography revealed a significantly higher frequency of PAOD in pts on nilotinib than in pts on imatinib. Mechanisms leading to the development of PAOD under nilotinib treatment remain unknown. Aside from elevation of cholesterol and glucose levels not yet fully understood mechanisms such as inhibition of targets involved in vascular cell homeostasis (i.e. DDR1, KIT or PDGFR) must be considered. More prospective data is needed to determine the cardiovascular risk attributable to nilotinib. But at present, caution is advised in pts with ≥ 2 major risk factors or a known history of arteriopathy.

Disclosures:
Rea: Bristol Myers-Squibb, Novartis, and Teva: Honoraria. le Coutre:Novartis: Research Funding, Speakers Bureau; BMS: Honoraria; Pfizer: Honoraria.