大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的安全性与疗效分析

An Analysis of Safety and Efficacy in High-dose Methotrexate Treatment for Children with Acute Lymphoblastic Leukemia

目的:研究《儿童急性淋巴细胞白血病诊疗建议(第三次修订草案)》(简称:04方案)中大剂量甲氨蝶呤(HD-MTX)治疗儿童急性淋巴细胞白血病(ALL)的疗效与安全性及血浆甲氨蝶呤浓度监测的临床意义。方法:2004年10月～2008年4月72例ALL患儿共接受309例次HD-MTX(3g/m2)治疗,从第42h起监测血浆MTX浓度,据此调整甲酰四氢叶酸钙(CF)解救的次数,观察化疗后毒副反应,并随访复发及死亡等情况至2009年12月。所有数据分析均由SPSS13.0完成。结果:42h血浆MTX浓度为(0.45±0.77)(0～6.85)μmol/L,48h血浆MTX浓度为(0.32±0.53)(0.02～3.87)μmol/L。42h血浆MTX浓度(C42h)与48h血浆MTX浓度(C48h)呈明显相关(r=0.893,P<0.01),其回归方程为:C48h=-0.04+0.59×C42h。82.7%的患儿48h血浆MTX浓度<0.25μmol/L,4.3%的患儿48h血浆MTX浓度≥1μmol/L。83.8%的患儿无需行6次CF解救,需解救6～8次的为11.9%,1.5%的患儿需超过8次的CF解救。不良反应以骨髓抑制(69.6%)、消化道症状(38.2%)、感染(24.9%)较多见,经血浆MTX浓度监测,患儿多治疗顺利,无严重及致死性不良反应发生。A、B两组间骨髓抑制发生率差异有统计学意义,且骨髓抑制程度差异也有统计学意义,两组间其余不良反应(除皮疹外)差异也有统计学意义。04方案中HD-MTX治疗儿童ALL的总体复发率为13.89%,中枢神经系统白血病的发生率为4.17%,5年无事件生存率(EFS)为62.6%。结论:HD-MTX(3g/m2)治疗儿童ALL疗效肯定,在血浆MTX浓度监测下,实施个体化CF解救,毒副反应多轻微。

Objective：To study the safety and efficacy of high-dose methotrexate （HD-MTX） in treatment of children with acute lymphoblastic leukemia,and the clinical significance of plasma concentration monitoring. Methods：Seventy two children with acute lymphoblastic leukemia received a total of 309 cases of HD-MTX （3 g/m2） treatment and the patients＇ plasma concentration of methotrexate （MTX） was monitored beginning at the 42nd hour. Reasonable times for calcium folinate （CF） rescue was adjusted according to the plasma methotrexate concentration. Adverse effects of post-chemotherapy were recorded,and the patients were also followed up for the recurrence or death by regular visiting till the end of December 2009. The data analysis was completed with SPSS13.0. Results：The plasma MTX concentration at the 42nd hour was （0.45±0.77） （0～6.85） μmol/L,and （0.32±0.53） （0.02～3.87） μmol/L at the 48 th hour. The plasma MTX concentration of 42 h was significantly related to that of 48 h. The regression equation was as follows：C48 h=-0.04＋0.59×C42 h. The pediatric patients whose plasma MTX concentration fell below 0.25 μmol/L in the 48 th hour accounted for 82.7%,and 4.3% with a concentration higher than or equal to 1 μmol/L. We found that 1.5% of the pediatric patients needed CF rescue for more than eight times,and 11.9% needed CF rescue for six to eight times,while,83.8% only needed CF rescues fewer than six times. Bone marrow suppression （69.6%）,gastrointestinal symptoms （38.2%） and infections （24.9%） were the common adverse effects,and we did not observe serious and fatal adverse effects of chemotherapy. There were significant differences in both incidence and degree of bone marrow suppression between group A and B. The same result was obtained in other adverse effects excluding erythra. The five-year event-free survival of HD-MTX treatment in 04 protocol for children with ALL was 62.6%,the overall recurrence rate was 13.89%,and the ALL relapse rate in central nervous system was 4.17%. Conclusions：The efficacy of HD-MTX （3 g/m2） treatment for children with ALL is positive. Providing reliable monitoring of the plasma concentration of MTX is performanced,the implementation of the individual CF rescue strategy will only cause slight adverse effects for most patients.