Wolff S N, Herzig R, Lynch J, Ericson S G, Greer J P, Stein R, Goodman S, Benyunes M C, Ashby M, Jones D V, Fay J
Bone Marrow Transplant Program, Vanderbilt University, Nashville, TN 37232-5505, USA.
Bone Marrow Transplant. 2001 Feb;27(3):261-8. doi: 10.1038/sj.bmt.1702772.
Thrombocytopenia following myelotoxic therapy is a common problem and when severe (<20,000/microl) can lead to severe morbidity and mortality. Thrombopoietin (TPO) is a naturally occurring glycosylated peptide which stimulates the differentiation of bone marrow stem cells into megakaryocyte progenitor cells, induces the expression of megakaryocyte differentiation markers, promotes megakaryocyte proliferation, polyploidization and, ultimately, the formation of increased numbers of platelets in the circulation. TPO has now been produced by recombinant technology and has entered clinical trials. This open label phase I study was designed to determine the safety, tolerance and pharmacokinetics of recombinant thrombopoietin (rhTPO) when administered to patients after undergoing high-dose chemotherapy followed by autologous bone marrow transplantation. rhTPO was administered intravenously by bolus injection at doses ranging from 0.3 to 4.8 microg/kg/day every 3 days to 30 patients and 0.6 microg/kg daily to three patients. rhTPO was begun the day after marrow infusion and continued until platelet recovery to >20,000/microl. G-CSF was concomitantly administered to promote myeloid recovery. Serious adverse events or neutralizing antibodies to rhTPO were not observed during the study. Median platelet recovery after ABMT was 19 days (range, 11-41). Neither the dose nor the schedule of rhTPO appeared to have any impact upon the time course of platelet recovery. In this phase I study, rhTPO was found to be well tolerated without the development of neutralizing antibodies and without compromising neutrophil recovery. Platelet recovery was similar for all doses studied warranting further evaluation in phase II and III trials designed to test for platelet recovery efficacy.
骨髓毒性治疗后出现的血小板减少是一个常见问题，严重时（<20,000/微升）可导致严重的发病率和死亡率。血小板生成素（TPO）是一种天然存在的糖基化肽，它刺激骨髓干细胞分化为巨核细胞祖细胞，诱导巨核细胞分化标志物的表达，促进巨核细胞增殖、多倍体化，并最终在循环中形成数量增加的血小板。TPO现已通过重组技术生产并进入临床试验阶段。这项开放性I期研究旨在确定重组血小板生成素（rhTPO）在大剂量化疗后接受自体骨髓移植的患者中给药时的安全性、耐受性和药代动力学。rhTPO以0.3至4.8微克/千克/天的剂量通过静脉推注每3天给药一次，共给药30例患者，另有3例患者每天给予0.6微克/千克。rhTPO在骨髓输注后第二天开始给药，持续至血小板恢复至>20,000/微升。同时给予粒细胞集落刺激因子（G-CSF）以促进骨髓恢复。研究期间未观察到严重不良事件或针对rhTPO的中和抗体。自体骨髓移植后血小板恢复的中位时间为19天（范围11 - 41天）。rhTPO的剂量和给药方案似乎均未对血小板恢复的时间进程产生任何影响。在这项I期研究中，发现rhTPO耐受性良好，未产生中和抗体，也未影响中性粒细胞的恢复。所有研究剂量的血小板恢复情况相似，这使得有必要在旨在测试血小板恢复疗效的II期和III期试验中进行进一步评估。
