Schmiegelow Kjeld, Nersting Jacob, Nielsen Stine Nygaard, Heyman Mats, Wesenberg Finn, Kristinsson Jon, Vettenranta Kim, Schrøeder Henrik, Weinshilboum Richard, Jensen Katrine Lykke, Grell Kathrine, Rosthoej Susanne
Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark.
Faculty of Medicine, Institute of Clinical Medicine, University of Copenhagen, Denmark.
Pediatr Blood Cancer. 2016 Dec;63(12):2104-2111. doi: 10.1002/pbc.26139. Epub 2016 Jul 22.
6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines.
To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 10 /l.
After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 10 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, r = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model.
This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.
基于6-巯基嘌呤（6MP）和甲氨蝶呤（MTX）的维持治疗是儿童急性淋巴细胞白血病治疗的关键阶段。个体间药物处置存在广泛差异，需要频繁调整剂量，但在剂量调整指南方面缺乏国际共识。
为了确定复发预测因素，我们收集了28255组关于药物剂量和血细胞计数的数据（中位数：每位患者47组），并分析了532名接受MTX/6MP维持治疗且目标白细胞计数（WBC）为1.5 - 3.5×10⁹/L的儿童的9182份血样（中位数：每位患者14份血样）中细胞毒性6MP/MTX代谢物的红细胞（Ery）水平。
缓解期患者的中位随访时间为13.8年，逐步Cox回归分析未发现年龄、6MP和MTX的平均剂量、血红蛋白、绝对淋巴细胞计数、血小板计数或6 - 硫鸟嘌呤核苷酸或MTX（包括其多聚谷氨酸）的Ery水平是显著的复发预测因素。与复发风险显著相关的参数（N = 83）为男性（风险比[HR] 2.0 [1.3 - 3.1]，P = 0.003）、诊断时的WBC（每升高10×10⁹/L，HR = 1.04 [1.00 - 1.09]，P = 0.048）、绝对中性粒细胞计数（ANC；每升高10⁹/L，HR = 1.7 [1.3 - 2.4]，P = 0.0007）以及Ery硫嘌呤甲基转移酶活性（每升高1 IU/ml，HR = 2.7 [1.1 - 6.7]，P = 0.03）。WBC与ANC显著相关（Spearman相关系数，r = 0.77；P < 0.001），当在Cox模型中排除ANC时，WBC仅是复发的边缘显著风险因素（HR = 1.28 [95%置信区间：1.00 - 1.64]，P = 0.046）。
本研究表明，低中性粒细胞计数可能是维持治疗剂量调整的最佳血液学指标。
