血药浓度监测在大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病中的应用

Application of blood concentration monitoring in childhood acute lymphoblastic leukemia treated with high-dose Methotrexate

目的探讨大剂量甲氨蝶呤(MTX)治疗儿童急性淋巴细胞白血病(ALL)中排泄延迟与MTX剂量的关系。方法 30例103例次ALL患儿采用大剂量MTX治疗〔按MTX剂量分为A组(2～3 g/m2)组和B组(3.1～5 g/m2)组〕,后1、24、36、42、48、54、96 h进行药物浓度检测,根据血药浓度调整四氢叶酸钙(CF)解救次数及剂量,比较其不同时段血药浓度的分布及排泄延迟的发生率、不良反应及CF的用量。结果①B组较A组MTX稳态血药浓度(24 h血药浓度)高,两组在24 h内浓度下降幅度明显,而24 h以后个体差异很大。两组1 h及24 h血药浓度差异有统计学意义(P<0.05),36～96 h差异无统计学意义(P>0.05);②103例次血浆MTX浓度监测显示,61.2%的患儿48 h血浆MTX浓度<0.25μmol/L,75.8%的患儿<0.5μmol/L,仅12.6%的患儿≥1μmol/L;约65.8%的患儿CF解救次数不超过3次,需解救6～8次的为11.9%,1.5%的患儿需解救超过8次;③有排泄延迟的患儿骨髓抑制、消化道症状、黏膜损害及感染较无排泄延迟时增加(P<0.05),CF解救剂量明显增加(P<0.05)。A组和B组排泄延迟发生率分别为4%和20.8%,两组比较差异有统计学意义(P<0.05)。结论在血药浓度监测下使用大剂量MTX安全可行。大剂量较低剂量稳态血药浓度高,但更易出现排泄延迟。大剂量MTX排泄延迟情况下不良反应增加,CF用量增加。MTX个体化用药可以减少排泄延迟的发生。

Objective To discuss the relationship between the Methotrexate dosage and excretion delay in childhood acute lymphoblastic leukemia（ALL） treated with the high dose Methotrexate（HDMTX） therapy. Methods 103 episodes of HDMTX infusion happened in 30 cases were analysed in this study.The MTX concentration at 1,24,36,42,48,54 and 96 h after infusion was measured.Reasonable frequency for Calcium Folinate（CF） was adjusted according to the plasma Methotrexate concentration.We compared the drug concentration at different times,the incidence of excretion delay,the adverse effects（2～3 g/ m2vs 3～5 g/ m2）,and the dosage of CF among groups. Results The MTX concentration in Group B was higher than that in Group A,that at 1 and 24 h was significantly different between the two groups（P 0.05）,and that during the periods 36～96 hours was not significantly different between the two groups（P 0.05）.The plasma MTX concentration of 61.2% pediatric patients was less than 0.25 μmol/L in the 48th hour,that of 75.8% was less than 0.5 μmol/L and that of 12.6% was not less than 1 μmol/L.We found that 1.5% of the pediatric patients needed CF for more than 8 times,and 11.9% needed for 6 to 8 times,while 65.8% only needed for not more than 3 times.Children with excretion delay had higher incidence of myelosuppression,gastrointestinal disturbance,and mucosal injuries and infection than those without excretion delay（P 0.05）,and needed higher CF dosage（P 0.05）.There was significant difference in the incidence of excretion delay between the high dose group and the low dose group（P 0.05）. Conclusions The HDMTX therapy is safe and feasible under blood concentration monitoring.The plateau concentration is higher in the high dose group,which results in higher incidence of excretion delay and more adverse drug reactions,and needs higher CF dosage.Personalized MTX dosage may decrease the incidence of excretion delay.