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

Impaired fasting glucose (IFG) and type 2 diabetes (T2D) represents adverse events in Chronic Myeloid Leukemia (CML) patients treated with the second-generation tyrosine kinase inhibitor (TKI) nilotinib. A genetic risk score (uGRS) for the prediction of insulin resistance, consisting of 10 multiple single-nucleotide polymorphisms (SNPs), has been proposed. We evaluated the 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 SNPs. Molecular response (MR)(3.0) and MR(4.0) were achieved in 90% and 79% of the patients, respectively. Before treatment, none of the patients had abnormal blood glucose. During treatment and subsequently follow-up of 80.2 months (range 1-298), 7 patients (11.5%) developed diabetes requiring oral treatment, after a median of 14 months (range 3-98) since nilotinib. Twelve patients (19.7%) developed prediabetes. Prediabetes/diabetes-free survival was significantly higher in patients with an uGRS below 10 compared to higher scores (100% vs 22.8±12.4%, p<0.001). Each increment of 1 unit on the uGRS caused a 42% increase in the prediabetes/diabetes risk (HR=1.42; CI: 1.04-1.94; p=0.026). The presence of more than 10 allelic variants associated to insulin secretion, processing, sensitivity and clearance is predictive of prediabetes/diabetes developing in CML patients treated with nilotinib. In clinical practice uGRS could help tailor the best TKI therapy.