Gandhi Varsha, Tam Constantine, O'Brien Susan, Jewell Roxanne C, Rodriguez Carlos O, Lerner Susan, Plunkett William, Keating Michael J
Department of Experimental Therapeutics, Box 71, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
J Clin Oncol. 2008 Mar 1;26(7):1098-105. doi: 10.1200/JCO.2007.14.1986.
To test whether nelarabine is an effective agent for indolent leukemias and to evaluate whether there is a relationship between cellular pharmacokinetics of the analog triphosphate and clinical responses.
Thirty-five patients with relapsed/refractory leukemias (n = 24, B-cell chronic lymphocytic leukemia and n = 11, T-cell prolymphocytic leukemia) were entered onto three different protocols. For schedule A, patient received nelarabine daily for 5 days, whereas for schedule B, nelarabine was administered on days 1, 3, and 5. Schedule C was similar to schedule B except that fludarabine was also infused. Plasma and cellular pharmacokinetics were studied during the first cycle.
Responses were achieved in 20%, 15%, and 63% of patients receiving schedule A, B, and C, respectively. Histologic category, number of prior therapies, and fludarabine refractoriness did not influence the response rate. The most common nonhematologic toxicity was peripheral neuropathy. Grade 4 neutropenia and thrombocytopenia complicated 23% and 26% of courses respectively, and were significantly more frequent among patients with pre-existing marrow failure. Pharmacokinetics of plasma nelarabine and arabinosylguanine (ara-G) and of cellular ara-G triphosphate (ara-GTP) were similar in the two groups of diagnoses, and the elimination of ara-GTP from leukemia cells was slow (median, > 24 hours). The median peak intracellular concentrations of ara-GTP were significantly different (P = .0003) between responders (440 micromol/L; range, 35 to 1,438 micromol/L; n = 10) and nonresponders (50 micromol/L; range, 22 to 178 micromol/L; n = 15).
Nelarabine is an effective regimen against indolent leukemias, and combining it with fludarabine was most promising. Determination of tumor cell ara-GTP levels may provide a predictive test for response to nelarabine.
测试奈拉滨是否为惰性白血病的有效药物，并评估类似物三磷酸的细胞药代动力学与临床反应之间是否存在关联。
35例复发/难治性白血病患者（24例B细胞慢性淋巴细胞白血病和11例T细胞原淋巴细胞白血病）进入三种不同方案。方案A中，患者每日接受奈拉滨治疗5天；方案B中，奈拉滨在第1、3和5天给药。方案C与方案B相似，但同时也输注氟达拉滨。在第一个周期中研究血浆和细胞药代动力学。
接受方案A、B和C的患者的缓解率分别为20%、15%和63%。组织学类别、既往治疗次数和氟达拉滨难治性均不影响缓解率。最常见的非血液学毒性是周围神经病变。4级中性粒细胞减少和血小板减少分别使23%和26%的疗程复杂化，并且在已有骨髓衰竭的患者中明显更常见。两组诊断中血浆奈拉滨和阿糖鸟苷（ara-G）以及细胞阿糖鸟苷三磷酸（ara-GTP）的药代动力学相似，并且白血病细胞中ara-GTP的消除缓慢（中位数，>24小时）。缓解者（440微摩尔/升；范围，35至1438微摩尔/升；n = 10）和未缓解者（50微摩尔/升；范围，22至178微摩尔/升；n = 15）之间细胞内ara-GTP的中位数峰值浓度有显著差异（P = .0003）。
奈拉滨是治疗惰性白血病的有效方案，将其与氟达拉滨联合最有前景。肿瘤细胞ara-GTP水平的测定可为奈拉滨反应提供预测性检测。
