Relling M V, Yanishevski Y, Nemec J, Evans W E, Boyett J M, Behm F G, Pui C H
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, and The University of Tennessee, Memphis 38105, USA.
Leukemia. 1998 Mar;12(3):346-52. doi: 10.1038/sj.leu.2400928.
Etoposide, an effective agent for acute lymphoblastic leukemia (ALL), can cause secondary acute myeloid leukemia (AML) in a subset of patients. Our objectives were to determine whether patients who develop secondary AML displayed altered etoposide pharmacokinetics or other pharmacologic characteristics compared to identically treated patients who did not develop AML. Children with newly diagnosed ALL were treated according to a protocol which included etoposide 300 mg/m2 given three times over 8 days during remission induction and once every 2-4 weeks during 120 weeks of continuation therapy. Characteristic 11q23 rearrangements were documented in seven of the eight patients with AML. Etoposide clearance, time that etoposide concentrations exceeded 10 microM, etoposide or etoposide catechol area-under-the-plasma-concentration vs time curve (AUC), serum albumin, and average methotrexate concentration did not differ significantly between the two groups; thiopurine methyltransferase (TPMT) activity tended to be lower in the eight children who did vs the 23 matched control children who did not develop AML (P=0.16). Further regression analyses likewise indicated that lower TPMT activity tended to be associated with shorter onset of secondary AML (P=0.11); it also tended to be lower among the eight index cases compared to the entire unmatched cohort of 105 identically treated children with ALL (P=0.10). We observed no statistically significant differences in etoposide disposition and antimetabolite pharmacology between patients who did and did not develop secondary AML.
依托泊苷是治疗急性淋巴细胞白血病（ALL）的有效药物，但在部分患者中可引发继发性急性髓系白血病（AML）。我们的目的是确定与未发生AML的同等治疗患者相比，发生继发性AML的患者是否表现出依托泊苷药代动力学或其他药理学特征的改变。新诊断的ALL患儿按照一项方案进行治疗，该方案包括在缓解诱导期8天内分3次给予依托泊苷300mg/m²，在120周的维持治疗期间每2 - 4周给药1次。在8例AML患者中的7例中记录到了特征性的11q23重排。两组之间依托泊苷清除率、依托泊苷浓度超过10μM的时间、依托泊苷或依托泊苷儿茶酚的血浆浓度-时间曲线下面积（AUC）、血清白蛋白以及甲氨蝶呤平均浓度均无显著差异；与23例匹配的未发生AML的对照患儿相比，8例发生AML的患儿的硫嘌呤甲基转移酶（TPMT）活性倾向于更低（P = 0.16）。进一步的回归分析同样表明，较低的TPMT活性倾向于与继发性AML的较短发病时间相关（P = 0.11）；与105例接受相同治疗的ALL患儿的整个非匹配队列相比，8例索引病例中的TPMT活性也倾向于更低（P = 0.10）。我们观察到发生和未发生继发性AML的患者在依托泊苷处置和抗代谢物药理学方面没有统计学上的显著差异。
