急性淋巴细胞性白血病患儿巯嘌呤耐受性研究

目的 调查急性淋巴细胞性白血病(acute lymphoblastie leukemia,ALL)患儿,维持化疗期间巯嘌呤(6-mercaptopurine,6-MP)的耐受性,为进一步研究6-MP耐受性差异的原因提供依据.方法 选择规范应用北京儿童医院急性淋巴细胞性白血病2003年化疗方案(BCH-ALL-2003),随访至2008年9月30日的患儿.全部患儿处于骨髓缓解期,且维持化疗≥13个月.详细记录患儿6-MP服用情况,包括服用剂量以及恶心、呕吐、皮疹等用药反应,以调查6-MP的耐受性.所有患儿每周复查血常规,间隔4周复查肝功能,并根据检查结果进行6-MP毒性分级.记录6-MP停止时间和剂量减少程度.结果共133例,男81例,女52例,中位年龄67个月(18～188个月),中位缓解时间26个月(6～47个月).6-MP维持化疗(13.5±7.4)个月(3～25个月),其中6-MP标准剂量、全疗程者72例(54%),剂量46 ms/(m~2·d),白细胞(WBC)(3～4)×10~9/L,中性粒细胞(ANC)(1.5～2.0)×10~9/L,肝脏毒性小于Ⅱ级,4例(3%)患儿ANC持续在3×10~9/L以上,6-MP剂量增加为标准剂量125%.余61例患儿均为严重不耐受6-MP者,其中骨髓抑制48例(同时伴肝毒性9例),单纯肝脏功能异常12例,反复皮疹1例.平均毒性反应出现时间为2.5周.19例患儿平均停用6-MP 7 d,42例患儿平均6-MP实际剂量25～30 ms/(m~2·d).结论 ALL患儿个体间6-MP的耐受性差异很大,46%ALL患儿对6-MP的标准治疗剂量表现为明显的骨髓抑制和肝功能异常等不耐受反应,临床需要根据血常规不断调整6-MP的剂量,以避免较大的毒性反应的发生,而3%患儿给予标准剂量6-MP,表现为无轻度骨髓抑制等化疗反应,临床需要增加6-MP剂量以减少复发危险性.但如何更准确地进行6-MP剂量调整是临床研究的难题之一.选择6-MP严重不耐受患儿进行6-MP代谢酶活性和基因多态性研究,以明确ALL儿童6-MP耐受性差异的原因,为进一步进行个体化药物剂量的调整提供理论依据.

Tolerability of 6-mercaptopurine in children with acute lymphoblastic leukemia

Objective 6-Mercatopurine(6-MP)has been the backbone of maintenance chemotherapy for acute lymphoblaatic leukemia(ALL),the response to 6-MP is highly variable,adverse events leading to discontinuation or dose-reduction(children intolerant)of 6-MP occur in many children with ALL.The aim of this study was to investigate the tolerability of 6-MP and to optimize thiopurine use.Methods The authors evaluated in a prospective manner the tolerance of 6-MP in ALL children from Oct.1,2004 to Sept.30,2007 who were newly diagnosed in Beijing Children's Hospital,using BCH-ALL-2003 protocols,during the maintenance therapy and followed up to Sept.30,2008.All children had a treatment period of at least 3 months for maintenance therapy.Results Totally 133 children including 81 boys and 52 girls at median age of 67 months(18-188 months),100% of the patients went into complete remission(CR)on day 33 of induction chemotherapy,and the median time to CR was 26 months(6-47 months).All the children had maintenance therapy from 3 to 25 months(mean 13.5±7.4)and 72(54%) received 6-MP standard doses continuously for total courses,the median daily dose of 6-MP was 46 mg/(m~2·d) 6-MP,their WBC was(3-4)×10~9/L,ANC(1.5-2)×10~9/L,they had no severe liver toxicity.In 4 children the dose of 6-MP was increased to 125% because WBC was higher than 6×10~9/L,ANC higher than 3×10~9/L.Sixty one children(46%)had poor tolerability to 6-MP,they experienced adverse events that led to discontinuation(n=19) or dose reduction(n=42) of 6-MP,the actual mean dose for the 42 cases was 25-30 mg/(m~2·d) and the time to occurrence of toxic effects was 2.5 weeks.Reasons for discontinuation or dose reduction were severe myelotoxicity occurred in 48 children,hepatotoxicity in 12,and skin rash in one.Conclusions In this cohort of ALL children,the difference of tolerance to oral 6-MP was obvious,54% of the children well tolerated 6-MP during the whole course at oral standard dose,and severe granulocytopenia did not occur.However,46% developed severe granulopenia or hepatotoxicity,the dosage had to be reduced in order to decrease the probability of severe toxicity.It is suggested that standard dose of 6-MP is not always the maximum tolerant dose in some children and inadequate dose may be the cause of therapy failure.