Kushner B H, Heller G, Cheung N K, Wollner N, Kramer K, Bajorin D, Polyak T, Meyers P A
Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Clin Oncol. 1998 Sep;16(9):3016-20. doi: 10.1200/JCO.1998.16.9.3016.
To help fill the gap in knowledge about the risk of leukemia from repetitive high-dose use of alkylating agents and topoisomerase-II inhibitors in young patients with solid tumors.
Poor-risk solid tumors were treated with four courses of cyclophosphamide (4,200 mg/m2)/ doxorubicin (75 mg/m2), and three courses of ifosfamide (9,000 mg/m2)/etoposide (500 mg/m2). The cumulative incidence of treatment-related myelodysplasia/ leukemia (t-AML) was calculated using the method of competing risks. The expected number of leukemic events was calculated by applying national incidence rates to person-years classified by age and sex.
Among 86 patients (median age, 17 years) monitored for 6 to 88 months (median, 24), five cases of t-AML were detected at 10 to 37 months (median, 17). The expected number of leukemic events in this cohort was .001. Clinical and cytogenetic findings implicated prior alkylator therapy in three cases and prior treatment with topoisomerase-II inhibitors in two. At 40 months, the cumulative incidence of t-AML was 8% (SE 7%).
Repetitive high-dose use of alkylating agents given with topoisomerase-II inhibitors is strongly leukemogenic, even with modest cumulative doses of each drug. This finding is notable for the following reasons: (1) it undermines predictions that limited use of high-dose chemotherapy might be minimally leukemogenic, and (2) it contrasts strikingly with the previously reported low risk of t-AML following treatment of pediatric solid tumors with chemotherapy lacking the alkylator dose-intensity and prominence of etoposide that are hallmarks of current regimens.
填补关于实体瘤年轻患者重复高剂量使用烷化剂和拓扑异构酶-II抑制剂引发白血病风险的知识空白。
对预后不良的实体瘤患者采用四个疗程的环磷酰胺（4200mg/m²）/阿霉素（75mg/m²），以及三个疗程的异环磷酰胺（9000mg/m²）/依托泊苷（500mg/m²）进行治疗。使用竞争风险法计算治疗相关骨髓发育异常/白血病（t-AML）的累积发病率。通过将全国发病率应用于按年龄和性别分类的人年数来计算白血病事件的预期数量。
在86例患者（中位年龄17岁）中进行了6至88个月（中位时间24个月）的监测，在10至37个月（中位时间17个月）时检测到5例t-AML。该队列中白血病事件的预期数量为0.001。临床和细胞遗传学结果表明，3例与先前的烷化剂治疗有关，2例与先前的拓扑异构酶-II抑制剂治疗有关。在40个月时，t-AML的累积发病率为8%（标准误7%）。
烷化剂与拓扑异构酶-II抑制剂重复高剂量使用具有很强的致白血病性，即使每种药物的累积剂量适中。这一发现值得关注，原因如下：（1）它推翻了有限使用高剂量化疗可能致白血病风险极小的预测；（2）它与先前报道的小儿实体瘤化疗后t-AML低风险形成鲜明对比，先前化疗方案缺乏当前方案中作为标志的烷化剂剂量强度和依托泊苷的突出地位。
