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Background Nilotinib is approved for use in pts with CML after failure of imatinib and in newly diagnosed CP-CML. In the ENESTnd trial, 1st line nilotinib was associated with a higher frequency of hypercholesterolemia than imatinib. Moreover, several studies reported a nilotinib-associated risk of artery occlusive disease (AOD). In ENESTnd, pre-existing treatment for dyslipidemia did not preclude pts from enrolment. To avoid this pitfall and to determine which cholesterol fractions are affected and whether triglycerides (TG) are modified, we prospectively studied the plasma lipid profile of nilotinib-treated pts without drug treatment for dyslipidemia. Methods Pts (n=25) in our center with CP-CML either newly diagnosed or after failure of imatinib were proposed 1st or 2nd line nilotinib provided that neither very high risk for fatal cardiovascular disease (CVD) nor nilotinib-resistant ABL kinase domain mutation were present at baseline. Pts with drug treatment for dyslipidemia at baseline were excluded from this study. Total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and TG were measured prior to the start of nilotinib and at 3, 6, 9 and 12 months. Fasting glucose (FG) and glycosylated hemoglobin (HbA1C) were also measured. Results are shown as medians (min-max). ESC/EAS 2012 guidelines were used to determine CVD risk categories and for the management of dyslipidemias. Results Median age at nilotinib initiation was 52 years (19-69), 13 were males (52%). Sokal risk group was low in 11 pts (44%), intermediate in 11 (44%) and high in 3 (12%). Nilotinib was given upfront in 20 pts (80%) and after 1st line imatinib in 5 pts (20%). Median time from diagnosis was 0.8 month (0.4-4.3) in the former and 15.7 months (2.5-47.9) in the latter. Initial nilotinib dosing regimen was 300mg BID in 22 pts (88%) and 400mg BID in 3 pts (12%). Baseline CVD risk factors included age ≥ 45 years in men and ≥ 55 years in women in 33 pts (52%), active smoking or ceased during the previous year in 6 pts (24%), body mass index (BMI) ≥ 25 kg/m2in 14 pts (56%), hypertension in 1 pt (4%), type 2 diabetes mellitus (DM) in 1 pt (4%). Two pts were discovered pre DM. The CVD risk was low in 12 pts (48%), moderate in 11 pts (44%) and high in 2 pts (8%). At baseline, no pt required drug intervention by lipid lowering agents based on LDL-C, 11 pts (44%) had low HDL-C (≤0.4g/L) and 7 (28%) had high TG (≥1.5g/L). Median FG and HBA1C were 0.88g/L (0.63-1.26) and 5.5% (4.7-6.5), respectively. All pts were given lifestyle medical advice. At M3, TC, LDL-C and HDL-C had increased by a mean of 26.9%, 31.8% and 36.3%, respectively. Median TC at baseline and M3 was 1.84g/L (1.17-2.74) and 2.27g/L (1.08-3.62) (p Three pts (12%) required statins during the first year of nilotinib therapy: 2 pts with a moderate CVD risk at baseline and in whom LDL-C rose above 1.9g/L and 1 pt with a moderate CVD risk at baseline who developed peripheral artery disease (PAD) at M12, leading to nilotinib discontinuation. By M12, the CVD risk changed from low to high in 1 pt due do to the onset of DM and from moderate to very high in the pt with PAD. Conclusions Nilotinib is associated with a significant and early increase in TC, LDL-C and HDL-C. In contrast, a decrease in TG occurs but this may be due to lifestyle medical advice given to our patients. All patients considered for nilotinib therapy should have an evaluation of blood lipids at baseline and early after the start of therapy. Requirement for lifestyle modifications and lipid lowering treatment by statins should be determined at baseline and throughout therapy according to TC, LDL-C and CVD risk category. The role of nilotinib-induced high LDL-C in the onset of AOD needs to be investigated. Disclosures: Rea: Novartis: Honoraria; BMS: Honoraria; Teva: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Gautier:Novartis: Honoraria. Messas:Novartis: Honoraria. Dombret:Novartis: Research Funding.

Abstract 1686 Background: ENESTnd established the superior efficacy of frontline NIL vs IM in pts with CML-CP. An association between NIL treatment and hyperglycemia has been previously reported. NIL-mediated increases in fasting plasma glucose levels (FGLs) have been shown to be reversible, with levels returning to normal on treatment discontinuation; in contrast, IM has been shown to decrease FGLs in pts with diabetes (Breccia M, Alimena G. Leuk Res. 2009;33:871–875). Here, we report the incidence of hyperglycemia and related glycemic outcomes with NIL and IM by 3 y in ENESTnd. Methods: Pts were randomized to receive NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). This analysis included randomized pts who had ≥1 dose of study drug and no drug treatment for diabetes mellitus /prediabetes at baseline (BL; 264, 262, and 267 pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively); pts with treated diabetes at BL (15, 15, and 13 pts, respectively) were excluded. Hyperglycemia was defined as FGL ≥1.1 g/L, prediabetes as FGL ≥1.1 g/L to < 1.26 g/L or glycated hemoglobin (HbA1C) ≥5.7% to < 6.5%, and diabetes as FGL ≥1.26 g/L or HbA1C ≥6.5%. These criteria represent a combination of World Health Organization and American Diabetes Association guidelines. Results: At BL, median age and mean body mass index (BMI) were similar across the 3 arms (Table). In the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively, 34.9%, 35.5%, and 37.8% of pts had untreated prediabetes at BL, and 6.1%, 6.1%, and 3.4% of pts had untreated diabetes at BL. Median time on treatment in the 3 arms was similar (≈ 3 y). Cumulative incidence of hyperglycemia by 3 y was higher with NIL vs IM (Table). By 3 y, grade 3/4 hyperglycemia was reported in 6 (2.3%), 7 (2.7%), and 0 pts on NIL 300 mg BID, NIL 400 mg BID, and IM, respectively; no pt discontinued due to hyperglycemia. Median time to hyperglycemia was longer with NIL 300 mg BID than with NIL 400 mg BID. From BL to 3 y, there were minimal changes in mean BMI and mean HbA1C in all 3 arms; greater increases in mean fasting insulin were observed with NIL vs IM. Excluding pts with diabetes at BL, 20.1%, 22.8%, and 8.9% of pts developed diabetes by 3 y, and 48.8%, 51.6%, and 50.0% developed prediabetes by 3 y (NIL 300 mg BID, NIL 400 mg BID, and IM, respectively). Relatively few pts required antidiabetic medication by 3 y. Based on a multivariate analysis, prediabetes at BL was a risk factor for development of hyperglycemia in all 3 treatment arms (P =.0252.0004, and.0296 [NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively]). Age > 60 y at BL was a risk factor for NIL 300 mg BID (P =.0183) and IM (P =.0010) but was not a risk factor for NIL 400 mg BID (P =.6001). Dyslipidemia (P =.0455) at BL was identified as an additional risk factor for development of hyperglycemia on IM in the multivariate analysis. Conclusions: In ENESTnd, the incidence of hyperglycemia by 3 y was higher with NIL vs IM. However, most events were low grade, HbA1C levels remained stable over time, and few pts required antidiabetic medication. The underlying mechanism of action driving NIL-mediated hyperglycemia is unknown, but the increases in fasting insulin observed suggest NIL therapy is associated with insulin resistance. NIL-treated pts with CML-CP and BL risk factors for diabetes should be monitored closely. Disclosures: Delphine: Novartis: Honoraria; BMS: Honoraria; Teva: Honoraria. Gautier:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Gao:Novartis: Employment. Piccolo:Novartis Pharma AG: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.