Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia
Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia
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DOI：
10.1182/blood-2010-10-311969
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发表时间：
2011-02-24
期刊：
影响因子：
20.3
通讯作者：
Relling, Mary V.
中科院分区：
文献类型：
--
作者：
Kawedia, Jitesh D.;Kaste, Sue C.;Relling, Mary V.
骨坏死是急性淋巴细胞白血病治疗中糖皮质激素引起的严重并发症。无论症状如何，我们前瞻性地对儿童（n = 364）进行髋关节和膝关节磁共振成像筛查；任何（1-4级）和症状性（2-4级）骨坏死的累积发生率分别为71.8%和17.6%。我们调查了年龄、种族、性别、急性淋巴细胞白血病治疗组、体重、血脂、白蛋白和皮质醇水平、地塞米松药代动力学和全基因组种系遗传多态性是否与症状性骨坏死相关。年龄大于10岁（优势比为4.85,95%可信区间为2.5 ~ 9.2,P = 0.00001）和强化治疗（优势比为2.5,95%可信区间为1.2 ~ 4.9,P = 0.011）是危险因素，并作为协变量纳入所有分析。低白蛋白（P = 0.05）和高胆固醇（P = 0.02）与症状性骨坏死相关，严重（3级或4级）骨坏死与地塞米松清除率低相关（P = 0.0005）。调整临床特征，ACP1多态性(如rs12714403， P = 1.9 × 10(-6)，优势比= 5.6；95%可信区间（2.7-11.3），调节脂质水平和成骨细胞分化，与骨坏死风险以及低白蛋白和高胆固醇相关。总体而言，年龄较大、白蛋白水平较低、脂质水平较高和地塞米松暴露与骨坏死有关，并可能与遗传基因组变异有关。(血。2011;117 (8):2340 - 2347)
Osteonecrosis is a severe glucocorticoid-induced complication of acute lymphoblastic leukemia treatment. We prospectively screened children (n = 364) with magnetic resonance imaging of hips and knees, regardless of symptoms; the cumulative incidence of any (grade 1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. We investigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms were associated with symptomatic osteonecrosis. Age more than 10 years (odds ratio, = 4.85; 95% confidence interval, 2.5-9.2; P = .00001) and more intensive treatment (odds ratio = 2.5; 95% confidence interval, 1.2-4.9; P = .011) were risk factors and included as covariates in all analyses. Lower albumin (P = .05) and elevated cholesterol (P = .02) associated with symptomatic osteonecrosis, and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P = .0005). Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P = 1.9 x 10(-6), odds ratio = 5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, were associated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, older age, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosis and may be linked by inherited genomic variation. (Blood. 2011;117(8):2340-2347)