Horton Terzah M, Thompson Patrick A, Berg Stacey L, Adamson Peter C, Ingle Ashish M, Dolan M Eileen, Delaney Shannon M, Hedge Madhuri, Weiss Heidi L, Wu Meng-Fen, Blaney Susan M
Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX 77030, USA.
J Clin Oncol. 2007 Nov 1;25(31):4922-8. doi: 10.1200/JCO.2007.12.0667.
To determine the tolerability, pharmacokinetics, and mechanisms of temozolomide resistance in children with relapsed or refractory leukemia.
Cohorts of three to six patients received 200 or 260 mg/m2/d of temozolomide by mouth daily for 5 days every 28 days. Toxicities, clinical response, and pharmacokinetics were evaluated. Pretreatment leukemia cell O6-methylguanine-DNA methyltransferase (MGMT) activity, tumor and plasma MGMT promoter methylation, and microsatellite instability (MSI) were examined in 14 of 16 study patients and in tissue bank samples from children with acute leukemia not treated with temozolomide (MGMT, n = 67; MSI, n = 65).
Sixteen patients (nine female, seven male; acute lymphoblastic leukemia [ALL], n = 8; acute myeloid leukemia [AML], n = 8), median age 11 years (range, 1 to 19 years), received either 200 mg/m2/d (nine enrolled, three assessable for toxicity) or 260 mg/m2/d (seven enrolled, three assessable for toxicity) of temozolomide. Temozolomide was well tolerated and no dose-limiting toxicities occurred. The mean clearance of temozolomide was 107 mL/min/m2, with a volume of distribution of 20 L/m2 and half-life of 109 minutes. MGMT activity in leukemia cells was quite variable and was highest in patients with relapsed ALL. Only one patient had MSI. Two patients had a partial response. Both of these patients had no detectable MGMT activity; both also had methylated MGMT promoters and were MSI stable.
Temozolomide was well tolerated at doses as high as 260 mg/m2/d for 5 days in children with relapsed or refractory leukemia. Increased MGMT activity may account for the temozolomide resistance in children with relapsed leukemia. Leukemia cell MGMT activity was higher in pediatric ALL than AML (P < .0001).
确定复发或难治性白血病患儿对替莫唑胺的耐受性、药代动力学及耐药机制。
每28天为一组，每组3至6名患者，每天口服替莫唑胺200或260mg/m²，共5天。评估毒性、临床反应及药代动力学。对16例研究患者中的14例以及未接受替莫唑胺治疗的急性白血病患儿的组织库样本（MGMT，n = 67；微卫星不稳定性[MSI]，n = 65）检测预处理白血病细胞O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）活性、肿瘤及血浆MGMT启动子甲基化和微卫星不稳定性（MSI）。
16例患者（9例女性，7例男性；急性淋巴细胞白血病[ALL]，n = 8；急性髓细胞白血病[AML]，n = 8），中位年龄11岁（范围1至19岁），接受200mg/m²/d（9例入组，3例可评估毒性）或260mg/m²/d（7例入组，3例可评估毒性）的替莫唑胺治疗。替莫唑胺耐受性良好，未发生剂量限制性毒性。替莫唑胺的平均清除率为107mL/min/m²，分布容积为20L/m²，半衰期为109分钟。白血病细胞中的MGMT活性差异很大，在复发ALL患者中最高。仅1例患者存在MSI。2例患者有部分缓解。这2例患者均未检测到MGMT活性；二者也均有甲基化的MGMT启动子且MSI稳定。
复发或难治性白血病患儿接受高达260mg/m²/d剂量的替莫唑胺治疗5天时耐受性良好。MGMT活性增加可能是复发白血病患儿对替莫唑胺耐药的原因。小儿ALL中白血病细胞MGMT活性高于AML（P < .0001）。
