Kantarjian H M, Estey E H, Plunkett W, Keating M J, Walters R S, Iacoboni S, McCredie K B, Freireich E J
Am J Med. 1986 Sep;81(3):387-94. doi: 10.1016/0002-9343(86)90287-1.
Sixty-four patients with refractory acute leukemia were treated with high-dose cytosine arabinoside given at a dosage of 3 g/m2 intravenously over two hours every 12 hours for four to 12 doses, repeated at two- to three-week intervals. Complete remissions were observed in 16 patients (25 percent), and the median duration of remission was three months (range, one to 10 months). Remission rates were similar for patients with acute myelogenous and acute lymphocytic leukemia (24 and 27 percent, respectively). Response rates were significantly higher in patients with initial remission durations of more than six months than in those with shorter remissions or those in whom there was no response to front-line therapy (41 and 9 percent; p less than 0.01). Similarly, patients with disease sensitive to conventional cytosine arabinoside had higher response rates than did those with resistant disease (54 and 17 percent; p = 0.03). Serial in vivo measurements of intracellular concentrations of the active metabolite of cytosine arabinoside in peripheral blasts following the initial dose demonstrated considerable individual variation. Favorable intracellular pharmacology of this active metabolite, manifested by its higher intracellular concentrations 12 hours after the first dose, by longer half-lives of active metabolite levels, and by higher values of the measured area under the curve of its accumulation and retention, was associated with higher response rates. Central nervous system toxicity occurred in 24 percent of patients, and pulmonary toxicity occurred in 22 percent; both were dose-limiting and dose-related. Other toxicities included nausea, vomiting, diarrhea, conjunctivitis, photophobia, cytosine arabinoside fever, skin rashes, and hepatic dysfunction. Response rates were similar for schedules utilizing four to six doses at two-week intervals or nine doses at three-week intervals (27 percent versus 25 percent). The schedule of 12 doses had a more rapid antileukemic effect but resulted in significantly higher toxicity and mortality rates during therapy with a similar overall response rate (21 percent). Thus, high-dose cytosine arabinoside is an effective regimen with substantial toxicity in patients with acute leukemia.
64例难治性急性白血病患者接受了大剂量阿糖胞苷治疗，剂量为3g/m²，每12小时静脉滴注2小时，共4至12剂，每隔2至3周重复一次。16例患者（25%）达到完全缓解，缓解期的中位数为3个月（范围1至10个月）。急性髓性白血病和急性淋巴细胞白血病患者的缓解率相似（分别为24%和27%）。初始缓解期超过6个月的患者的缓解率显著高于缓解期较短或对一线治疗无反应的患者（41%和9%；P<0.01）。同样，对传统阿糖胞苷敏感的疾病患者的缓解率高于耐药疾病患者（54%和17%；P = 0.03）。首次给药后对外周血母细胞中阿糖胞苷活性代谢产物的细胞内浓度进行的系列体内测量显示出相当大的个体差异。这种活性代谢产物良好的细胞内药理学表现为首次给药后12小时其细胞内浓度较高、活性代谢产物水平的半衰期较长以及其积累和保留曲线下测量面积的较高值，与较高的缓解率相关。24%的患者发生中枢神经系统毒性，22%的患者发生肺部毒性；两者均为剂量限制性且与剂量相关。其他毒性包括恶心、呕吐、腹泻、结膜炎、畏光、阿糖胞苷热、皮疹和肝功能障碍。每两周使用4至6剂或每三周使用9剂的方案的缓解率相似（分别为27%和25%）。12剂的方案具有更快的抗白血病作用，但在治疗期间导致显著更高的毒性和死亡率，总体缓解率相似（21%）。因此，大剂量阿糖胞苷是治疗急性白血病患者的一种有效方案，但毒性较大。
