Martino Bruno, Mammì Corrado, Labate Claudia, Rodi Silvia, Ielo Domenica, Priolo Manuela, Postorino Maurizio, Tripepi Giovanni, Ronco Francesca, Laganà Carmelo, Musolino Caterina, Greco Marianna, La Nasa Giorgio, Caocci Giovanni
Operative Unit of Hematology, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.
Operative Unit of Medical Genetics, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.
Exp Hematol. 2017 Nov;55:71-75. doi: 10.1016/j.exphem.2017.07.007. Epub 2017 Jul 28.
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) and MR 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.
空腹血糖受损和2型糖尿病是接受第二代酪氨酸激酶抑制剂尼罗替尼治疗的慢性髓性白血病（CML）患者的不良事件。有人提出了一种用于预测胰岛素抵抗的非加权遗传风险评分（uGRS），它由10个多个单核苷酸多态性组成。我们评估了uGRS在61例接受尼罗替尼治疗的CML患者中的预测性。对患者的IRS1、GRB14、ARL15、PPARG、PEPD、ANKRD55/MAP3K1、PDGFC、LYPLAL1、RSPO3和FAM13A1基因进行基因分型。uGRS基于所选单核苷酸多态性集合内风险等位基因的总和。分别有90%和79%的患者实现了分子反应（MR）和主要分子反应（MMR）。治疗前，所有患者的血糖均无异常。在治疗期间及随后80.2个月（范围：1 - 298个月）的随访中，7例患者（11.5%）发生了需要口服治疗的糖尿病，开始尼罗替尼治疗后中位时间为14个月（范围：3 - 98个月）。12例患者（19.7%）发生了糖尿病前期。uGRS <10的患者无糖尿病前期/糖尿病生存率显著高于评分较高的患者（100%对22.8±12.4%，p <0.001）。uGRS每增加一个单位，糖尿病前期/糖尿病风险增加42%（风险比 = 1.42，置信区间：1.04 - 1.94，p = 0.026）。存在超过10个与胰岛素分泌、加工、敏感性和清除相关的等位基因变异可预测接受尼罗替尼治疗的CML患者发生糖尿病前期/糖尿病。在临床实践中，uGRS有助于制定最佳的酪氨酸激酶抑制剂治疗方案。
