Pui C H, Relling M V, Behm F G, Hancock M L, Boyett J M, Raimondi S C, Krance R A, Mahmoud H H, Ribeiro R C, Sandlund J T
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Leukemia. 1995 Oct;9(10):1680-4.
The risk for induction of epipodophyllotoxin-related acute myeloid leukemia (AML) depends largely on the schedule of drug administration and, to a lesser degree, the cumulative dose. Concomitant use of other genotoxic drugs, such as alkylating agents and cisplatin, can increase the hazard further. We have treated 154 consecutive higher-risk cases of acute lymphoblastic leukemia in our recent Total Therapy Study XIII with an intensive post-remission regimen of chemotherapy that included etoposide given every other week or less often-a schedule associated with a relatively low cumulative incidence of secondary AML in our Study XI. Unexpectedly, four patients have developed secondary AML at 12 to 23 months from the start of treatment (median, 16 months). The 2-year cumulative risk estimate significantly exceeds that for 185 historical controls in Study XI whose continuation regimen included epipodophyllotoxins every other week: 5.4% (95% confidence interval, 0-11%) compared with 1.1% (0-2.6%), P = 0.046. Compared to patients treated in Study XI, those enrolled in Study XIII receive fewer scheduled doses of epipodophyllotoxin (48 (all etoposide) vs 63 (30 etoposide, 33 teniposide)) but 16 to 19 additional doses of L-asparaginase and eight additional doses of high-dose methotrexate, all within the week preceding etoposide treatment. We attribute the apparently increased rate of secondary AML in Study XIII to the use of L-asparaginase immediately before etoposide administration. On this schedule, the enzyme could increase systemic exposure to etoposide or its catechol metabolites and reduce the ability of cells to repair DNA damage.
表鬼臼毒素相关急性髓系白血病（AML）的诱发风险很大程度上取决于给药方案，在较小程度上还取决于累积剂量。同时使用其他具有基因毒性的药物，如烷化剂和顺铂，会进一步增加风险。在我们最近的全疗法研究 XIII 中，我们采用了强化缓解后化疗方案治疗了 154 例连续的高危急性淋巴细胞白血病病例，该方案包括每两周或更不频繁使用依托泊苷——在我们的研究 XI 中，这种方案与继发性 AML 的相对低累积发生率相关。出乎意料的是，4 例患者在治疗开始后的 12 至 23 个月（中位时间为 16 个月）发生了继发性 AML。2 年累积风险估计值显著超过研究 XI 中 185 例历史对照的风险估计值，其维持方案为每两周使用表鬼臼毒素：分别为 5.4%（95%置信区间，0 - 11%）和 1.1%（0 - 2.6%），P = 0.046。与研究 XI 中治疗的患者相比，参与研究 XIII 的患者接受的表鬼臼毒素计划剂量更少（48 剂（均为依托泊苷）对 63 剂（30 剂依托泊苷，33 剂替尼泊苷）），但在依托泊苷治疗前一周内额外接受了 16 至 19 剂 L - 天冬酰胺酶和 8 剂高剂量甲氨蝶呤。我们将研究 XIII 中继发性 AML 发生率明显增加归因于在依托泊苷给药前立即使用 L - 天冬酰胺酶。按照这种方案，该酶可能会增加全身对依托泊苷或其儿茶酚代谢物的暴露，并降低细胞修复 DNA 损伤的能力。
