Schmiegelow K, Bretton-Meyer U
The Laboratory for Pediatric Oncology, The Pediatric Clinic II, The Juliane Marie Centre, The National University Hospital, Rigshospitalet, Copenhagen, Denmark.
Leukemia. 2001 Jan;15(1):74-9. doi: 10.1038/sj.leu.2401986.
Through inhibition of purine de novo synthesis and enhancement of 6-mercaptopurine (6MP) bioavailability high-dose methotrexate (HDM) may increase the incorporation into DNA of 6-thioguanine nucleotides (6TGN), the cytoxic metabolites of 6MP. Thus, coadministration of 6MP could increase myelotoxicity following HDM. Twenty-one children with standard risk (SR) and 25 with intermediate risk (IR) acute lymphoblastic leukemia (ALL) were studied. During consolidation therapy they received either three courses of HDM at 2 week intervals without concurrent oral 6MP (SR-ALL) or four courses of HDM given at 2 week intervals with 25 mg/m2 of oral 6MP daily (IR-ALL). During the first year of maintenance with oral 6MP (75 mg/m2/day) and oral MTX (20 mg/m2/week) they all received five courses of HDM at 8 week intervals. In all cases, HDM consisted of 5,000 mg of MTX/m2 given over 24 h with intraspinal MTX and leucovorin rescue. Erythrocyte levels of 6TGN (E-6TGN) and methotrexate (E-MTX) were, on average, measured every second week during maintenance therapy. When SR consolidation (6MP: 0 mg), IR consolidation (6MP: 25 mg/m2), and SR/IR maintenance therapy (6MP: 75 mg/m2) were compared, white cell and absolute neutrophil count (ANC) nadir, lymphocyte count nadir, thrombocyte count nadir, and hemoglobin nadir after HDM decreased significantly with increasing doses of oral 6MP. Three percent of the HDM courses given without oral 6MP (SR consolidation) were followed by an ANC nadir <0.5 x 10(9)/l compared to 50% of the HDM courses given during SR/IR maintenance therapy. Similarly, only 13% of the HDM courses given as SR-ALL consolidation induced a thrombocyte count nadir <100 x 10(9)/l compared to 58% of the HDM courses given during maintenance therapy. The best-fit model to predict the ANC nadir following HDM during maintenance therapy included the dose of 6MP prior to HDM (beta = -0.017, P= 0.001), the average ANC level during maintenance therapy (beta = 0.82, P = 0.004), and E-6TGN (beta = -0.0029, P= 0.02). The best-fit model to predict the thrombocyte nadir following HDM during maintenance therapy included only mPLATE (beta = 0.0057, P = 0.046). In conclusion, the study indicates that reductions of the dose of concurrently given oral 6MP could be one way of reducing the risk of significant myelotoxicity following HDM during maintenance therapy of childhood ALL.
通过抑制嘌呤从头合成并提高6-巯基嘌呤（6MP）的生物利用度，大剂量甲氨蝶呤（HDM）可能会增加6-硫鸟嘌呤核苷酸（6TGN）掺入DNA的量，6TGN是6MP的细胞毒性代谢产物。因此，联合使用6MP可能会增加HDM后的骨髓毒性。对21例标准风险（SR）和25例中度风险（IR）的急性淋巴细胞白血病（ALL）患儿进行了研究。在巩固治疗期间，他们要么每隔2周接受3个疗程的HDM，不同时口服6MP（SR-ALL），要么每隔2周接受4个疗程的HDM，并每天口服25mg/m²的6MP（IR-ALL）。在口服6MP（7mg/m²/天）和口服甲氨蝶呤（20mg/m²/周）维持治疗的第一年，他们都每隔8周接受5个疗程的HDM。在所有病例中，HDM包括在24小时内给予5000mg甲氨蝶呤/m²，并进行鞘内注射甲氨蝶呤和亚叶酸解救。在维持治疗期间，平均每隔一周测量一次红细胞中的6TGN（E-6TGN）和甲氨蝶呤（E-MTX）水平。当比较SR巩固治疗（6MP：0mg）、IR巩固治疗（6MP：25mg/m²）和SR/IR维持治疗（6MP：75mg/m²）时，随着口服6MP剂量的增加，HDM后的白细胞和绝对中性粒细胞计数（ANC）最低点、淋巴细胞计数最低点、血小板计数最低点和血红蛋白最低点均显著下降。在没有口服6MP的HDM疗程（SR巩固治疗）中，3%的疗程后ANC最低点<0.5×10⁹/L，而在SR/IR维持治疗期间给予的HDM疗程中这一比例为50%。同样，作为SR-ALL巩固治疗给予的HDM疗程中，只有13%导致血小板计数最低点<100×10⁹/L，而在维持治疗期间给予的HDM疗程中这一比例为58%。预测维持治疗期间HDM后ANC最低点的最佳拟合模型包括HDM前的6MP剂量（β=-0.017，P=0.001）、维持治疗期间的平均ANC水平（β=0.82，P=0.004）和E-6TGN（β=-0.0029，P=0.02）。预测维持治疗期间HDM后血小板最低点的最佳拟合模型仅包括mPLATE（β=0.0057，P=0.046）。总之，该研究表明，在儿童ALL维持治疗期间，降低同时给予的口服6MP剂量可能是降低HDM后严重骨髓毒性风险的一种方法。
