Seidel H, Nygaard R, Moe P J, Jacobsen G, Lindqvist B, Slørdal L
Department of Paediatrics, Norwegian University of Science and Technology, Trondheim, Norway.
Leuk Res. 1997 May;21(5):429-34. doi: 10.1016/s0145-2126(96)00127-0.
The prognostic value of systemic methotrexate clearance (ClMTX) during high-dose therapy was evaluated in a cohort of 42 children with acute lymphocytic leukemia (ALL). As part of an extensive chemotherapy protocol, they had received a total of 293 methotrexate (MTX) infusions in the 6-8 g/m2 dose range. At the termination of the study, when they had all been followed up for 3.5 years or more, 26 of these patients were still in continuous complete remission, whereas 16 had suffered relapse. The intrapatient variability in ClMTX during the eight courses was up to six-fold. In 67% of the patients, the maximum level of ClMTX reached at least twice the minimum value. The coefficients of variation for the intra- and interindividual variability in ClMTX were 9-57% and 26-41%, respectively. The cumulative probability of relapse, estimated by the Kaplan-Meier procedure, was increased for patients with a high ClMTX during the initial treatment course, but the difference was not significant on a 5% level. There was no significant relationship between high individual median ClMTX and subsequent relapse of ALL. However, ClMTX during the initial infusion, the time-dependent mean for ClMTX, and the individual patient's median ClMTX, were significant predictors for event-free survival in a Cox proportional hazards regression analysis. The present study demonstrates gross pharmacokinetic variability and unpredictable values of ClMTX in subsequent courses after standardized administration of MTX to paediatric patients with ALL. In spite of the association between ClMTX and prognosis shown by some of the analyses, estimates of ClMTX rates may not necessarily be related to disease outcome in a way that can be exploited to the benefit of the individual patient.
在42名急性淋巴细胞白血病（ALL）儿童队列中评估了高剂量治疗期间全身甲氨蝶呤清除率（ClMTX）的预后价值。作为广泛化疗方案的一部分，他们总共接受了293次剂量范围为6 - 8 g/m²的甲氨蝶呤（MTX）输注。在研究结束时，当所有患者均已随访3.5年或更长时间时，其中26例患者仍处于持续完全缓解状态，而16例患者复发。在八个疗程中，患者体内ClMTX的变异性高达六倍。67%的患者中，ClMTX的最高水平至少达到最低值的两倍。ClMTX个体内和个体间变异的变异系数分别为9 - 57%和26 - 41%。通过Kaplan - Meier法估计，初始治疗疗程中ClMTX较高的患者复发累积概率增加，但在5%水平上差异不显著。个体ClMTX中位数较高与ALL随后复发之间无显著关系。然而，在Cox比例风险回归分析中，初始输注时的ClMTX、ClMTX的时间依赖性均值以及个体患者的ClMTX中位数是无事件生存的显著预测因素。本研究表明，对患有ALL的儿科患者标准化给予MTX后，后续疗程中ClMTX存在总体药代动力学变异性且值不可预测。尽管一些分析显示ClMTX与预后相关，但ClMTX速率的估计不一定与疾病结局相关，无法以此方式为个体患者带来益处。
