Genetic risk of prediabetes and diabetes development in chronic myeloid leukemia patients treated with nilotinib

Abstract

Impaired fasting glucose and type 2 diabetes represent adverse events in patients with chronic myeloid leukemia (CML) treated with the second generation tyrosine kinase inhibitor nilotinib. An unweighted genetic risk score (uGRS) for the prediction of insulin resistance, consisting of 10 multiple single-nucleotide polymorphisms, has been proposed. We evaluated uGRS predictivity in 61 CML patients treated with nilotinib. Patients were genotyped for IRS1, GRB14, ARL15, PPARG, PEPD, ANKRD55/MAP3K1, PDGFC, LYPLAL1, RSPO3, and FAM13A1 genes. The uGRS was based on the sum of the risk alleles within the set of selected single-nucleotide polymorphisms. Molecular response (MR)^3.0 and MR^4.0 were achieved in 90% and 79% of patients, respectively. Before treatment, none of the patients had abnormal blood glucose. During treatment and subsequent follow-up at 80.2 months (range: 1-298), seven patients (11.5%) had developed diabetes that required oral treatment, a median of 14 months (range: 3-98) after starting nilotinib treatment. Twelve patients (19.7%) had developed prediabetes. Prediabetes/diabetes-free survival was significantly higher in patients with a uGRS <10 than in those with higher scores (100% vs. 22.8 ± 12.4%, p <0.001). Each increment of one unit in the uGRS caused a 42% increase in the prediabetes/diabetes risk (hazard ratio = 1.42, confidence interval: 1.04-1.94, p = 0.026). The presence of more than 10 allelic variants associated with insulin secretion, processing, sensitivity, and clearance is predictive of prediabetes/diabetes development in CML patients treated with nilotinib. In clinical practice, uGRS could help tailor the best tyrosine kinase inhibitor therapy.