Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation:: Study of pharmacokinetics and early clinical outcomes
Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation:: Study of pharmacokinetics and early clinical outcomes
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DOI：
10.1053/bbmt.2002.v8.pm12374451
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发表时间：
2002-01-01
影响因子：
4.3
通讯作者：
Andersson, BS
中科院分区：
文献类型：
--
作者：
Russell, JA;Tran, HT;Andersson, BS
白消安（Bu）的IV形式的可用性促使研究除了口服Bu通常使用的每日4次剂量之外的给药方案。我们研究了一种异基因干细胞移植（SCT）准备方案，包括氟达拉滨（FLU）50 mg/m2，第-6天至第-2天，加上WBu 3.2 mg/kg，每天3小时输注，第-5天至第-2天。70例年龄15 ~ 64岁（中位年龄41岁）的恶性血液病患者接受了该方案。36名患者（51%）有高风险恶性肿瘤，28名（40%）有无关或基因型不匹配的相关供体（替代供体[AD]），29名（41%）接受骨髓而不是血液作为干细胞来源。急性GVHD预防包括移植前3天内4.5 mg/kg抗胸腺细胞球蛋白，环孢素A和短期甲氨蝶呤与亚叶酸。肝毒性为一过性，无临床诊断的静脉闭塞性疾病。49例患者（70%）发生R级口腔炎，9例患者（13%）发生出血性膀胱炎。1例苯妥英钠水平低于治疗水平的患者在第3次IV Bu给药后8小时发生惊厥，但无其他明显神经毒性。H至IV级急性GVHD的发生率为8%，III-IV级的发生率为3%，无该原因导致的死亡。2年时慢性GVHD的精算发生率为38%。2例非亲缘供者BMT受体移植失败，其中1例经二次移植逆转。中位随访时间为16个月（范围，6-27个月），100天和2年时，匹配相关供体（MRD）SCT的移植相关死亡率分别为2%和5%，AD SCT为8%和19%（P =无显著性）。34例完全缓解的急性髓性白血病（AML）或慢性期慢性髓性白血病（低风险）患者的复发率为21%，19例高危AML患者的复发率为66%，17例其他活动性恶性肿瘤患者的复发率为18%。低风险疾病的2年无病生存率和总生存率分别为74%和88%，晚期AML为26%和37%，其他高风险疾病为65%和71%。使用第一次和第四次Bu给药的11份样本进行药代动力学研究。动力学呈线性，第一次和第四次给药的半衰期分别为2.60 +/- 0.44和2.57 +/- 0.36小时。清除率分别为106.77 +/- 16.68和106.86 +/- 21.57 mL/min/m2，峰浓度（Cmax）分别为3.92 +/- 0.31和3.96 +/- 0.28 mcg/mL，Bu和Bu的血浆浓度-时间曲线下面积（AUC）分别为4866.51 ± 771.42和4980 ± 882.80 μ M × min。Bu在24小时内完全清除，每例患者第4天的药代动力学值与第1天的药代动力学值非常相似。累积AUC与PO Bu确立的目标范围相当。这种方案纳入每日一次IV Bu是方便的，是相对良好的耐受性，提供可预测的血液水平，值得进一步研究的情况下，细胞减少以及免疫抑制是必要的。
The availability of an IV form of busulfan (Bu) has prompted investigation of administration schedules other than the 4-times-daily dosage commonly used with oral Bu. We have studied an allogeneic stem cell transplantation (SCT) preparative regimen comprising fludarabine (FLU) 50 mg/m(2) on days -6 to -2 plus W Bu 3.2 mg/kg daily in a 3-hour infusion on days -5 to -2. The regimen was given to 70 patients aged 15 to 64 years (median, 41 years) with hematologic malignancy. Thirty-six patients (51%) had high-risk malignancy, 28 (40%) had unrelated or genotypically mismatched related donors (alternate donors [AD]) and 29 (41%) received bone marrow rather than blood as stem cell source. Acute GVHD prevention comprised antithymocyte globulin 4.5 mg/kg over 3 days pretransplantation, cyclosporin A, and short-course methotrexate with folinic acid. Hepatic toxicity was transient and there was no clinically diagnosed veno-occlusive disease. Grade R stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 patients (13%). One patient with subtherapeutic phenytoin levels had a convulsion 8 hours after the third IV Bu dose, but no other neurotoxicity was apparent. Incidence of acute GVHD grades H to IV was 8% and incidence of grade III-IV was 3%, with no deaths from this cause. Actuarial incidence of chronic GVHD at 2 years is 38%. There were 2 cases of graft failure in unrelated donor BMT recipients, 1 of which was reversed by a second transplantation. With a median follow-up of 16 months (range, 6-27 months), transplantation-related mortality at 100 days and 2 years was 2% and 5% for matched related donor (MRD) SCT and 8% and 19% for AD SCT, respectively (P = not significant). Relapse rates were 21% for 34 patients with acute myeloid leukemia (AML) in complete remission or chronic myeloid leukemia in chronic phase (low-risk), 66% for 19 patients with high-risk AML, and 18% for 17 patients with other active malignancy. Projected disease-free and overall survival rates at 2 years were 74% and 88% for low-risk disease, 26% and 37% for advanced AML, and 65% and 71% for other high-risk disease, respectively. Pharmacokinetic studies were done using 11 samples with the first and fourth doses of Bu. Kinetics were linear, and for the first and fourth doses, the half-lives were 2.60 +/- 0.44 and 2.57 +/- 0.36 hours, respectively. Clearances were 106.77 +/- 16.68 and 106.86 +/- 21.57 mL/min per m(2), peak concentrations (Cmax) were 3.92 +/- 0.31 and 3.96 +/- 0.28 mcg/mL, and Bu areas under the plasma concentration versus time curve (AUC) were 4866.51 +/- 771.42 and 4980 +/- 882.80 muM x min, respectively. Bu was completely cleared within 24 hours and the day 4 pharmacokinetic values were very similar to those on day 1 for every patient. The cumulative AUC was comparable to the target range established for PO Bu. This regimen incorporating once-daily IV Bu is convenient to give, is relatively well tolerated, gives predictable blood levels, and deserves further study in circumstances in which cytoreduction as well as immune suppression is needed.