Abstract

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.

NIL 300 mg BID (n = 264)NIL 400 mg BID (n = 262)IM 400 mg QD (n = 267)
BL characteristics    
Median age, y 47.0 46.0 46.0 
Mean BMI, kg/m2 25.3 25.4 24.9 
Untreated prediabetes, n (%) 92 (34.9) 93 (35.5) 101 (37.8) 
Untreated diabetes, n (%) 16 (6.1) 16 (6.1) 9 (3.4) 
Median time on treatment, mo 36.6 36.6 35.4 
Glycemic status by 3 y, n (%)    
Hyperglycemia 111 (42.1) 116 (44.3) 57 (21.4) 
Prediabetes* 121 (48.8) 127 (51.6) 129 (50.0) 
Diabetes* 50 (20.2) 56 (22.8) 23 (8.9) 
Highest grade of hyperglycemiaby 3 y, n (%)    
Gr 0 133 (50.4) 116 (44.3) 163 (61.1) 
Gr 1 97 (36.7) 112 (42.8) 92 (34.5) 
Gr 2 27 (10.2) 26 (9.9) 11 (4.1) 
Gr 3 5 (1.9) 6 (2.3) 
Gr 4 1 (0.4) 1 (0.4) 
Median time to hyperglycemia, mo 27.9 16.6 NA 
Change in mean value from BL to 3 y    
BMI, kg/m2 1.0 1.3 1.2 
HbA1C#, % −0.05 −0.2 
Fasting insulin, mU/L 3.7 3.9 0.4 
Pts requiring antidiabetic medication by 3 y, n (%) 12 (4.6) 14 (5.3) 6 (2.3) 
NIL 300 mg BID (n = 264)NIL 400 mg BID (n = 262)IM 400 mg QD (n = 267)
BL characteristics    
Median age, y 47.0 46.0 46.0 
Mean BMI, kg/m2 25.3 25.4 24.9 
Untreated prediabetes, n (%) 92 (34.9) 93 (35.5) 101 (37.8) 
Untreated diabetes, n (%) 16 (6.1) 16 (6.1) 9 (3.4) 
Median time on treatment, mo 36.6 36.6 35.4 
Glycemic status by 3 y, n (%)    
Hyperglycemia 111 (42.1) 116 (44.3) 57 (21.4) 
Prediabetes* 121 (48.8) 127 (51.6) 129 (50.0) 
Diabetes* 50 (20.2) 56 (22.8) 23 (8.9) 
Highest grade of hyperglycemiaby 3 y, n (%)    
Gr 0 133 (50.4) 116 (44.3) 163 (61.1) 
Gr 1 97 (36.7) 112 (42.8) 92 (34.5) 
Gr 2 27 (10.2) 26 (9.9) 11 (4.1) 
Gr 3 5 (1.9) 6 (2.3) 
Gr 4 1 (0.4) 1 (0.4) 
Median time to hyperglycemia, mo 27.9 16.6 NA 
Change in mean value from BL to 3 y    
BMI, kg/m2 1.0 1.3 1.2 
HbA1C#, % −0.05 −0.2 
Fasting insulin, mU/L 3.7 3.9 0.4 
Pts requiring antidiabetic medication by 3 y, n (%) 12 (4.6) 14 (5.3) 6 (2.3) 

CTCAE, Common Terminology Criteria for Adverse Events; NA, not available due to the small number of pts with hyperglycemia.

*

In population excluding pts with diabetes at BL (n = 248, 246, and 258, respectively).

All hyperglycemia events according to CTCAE v3.0.

#

Reported as a ratio of HbA1C/Hb.

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.

Author notes

*

Asterisk with author names denotes non-ASH members.