Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study
Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study
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DOI：
10.1182/blood-2008-11-187880
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发表时间：
2009-06-11
期刊：
影响因子：
20.3
通讯作者：
Weinshilboum, Richard
中科院分区：
文献类型：
--
作者：
Schmiegelow, Kjeld;Al-Modhwahi, Ibrahim;Weinshilboum, Richard
在1614名接受北欧儿童血液与肿瘤学学会(NOPHO)ALL-92方案治疗的儿童急性淋巴细胞性白血病(ALL)患者中，20名患者在确诊后12年内发生第二恶性肿瘤(SMN)，累积风险为1.6%。16例急性髓系白血病或骨髓增生异常综合征中有9例存在7号单体或2号染色体7q缺失。在COX多因素分析中，口服6-巯基嘌呤(6MP)/甲氨蝶呤(MTX)维持治疗时间较长(P=0.02；对于标准风险患者最长)和存在高二倍体(P=0.07)与SMN的风险增加相关。硫代嘌呤甲基转移酶(TPMT)使6MP及其代谢物甲基化，从而降低细胞毒性6-硫鸟嘌呤核苷酸的水平。在524例接受红细胞TPMT活性检测的患者中，9例发生SMN的患者的TPMT活性中位数显著低于515例未发生SMN的患者(中位数分别为12.1和18.1 IU/mL；P=0.02)。在登记了6MP剂量的427名TPMT野生型患者中，出现SMN的患者的平均6MP剂量高于其余患者(69.7vs60.4 mg/m(2)；P=0.03)。本研究提示6MP/MTX儿童ALL维持治疗的持续时间和强度可能影响儿童ALL发生SMN的风险。(血。2009；113：6077-6084)
Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m(2); P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL. (Blood. 2009; 113: 6077-6084)