Agrawal Neeraj R, Bukowski Ronald M, Rybicki Lisa A, Kurtzberg Joanne, Cohen Lewis J, Hussein Mohamad A
Cleveland Clinic Myeloma Research Program, Cleveland, Ohio 44195, USA.
Cancer. 2003 Jul 1;98(1):94-9. doi: 10.1002/cncr.11480.
Multiple myeloma remains an incurable disease. New agents are needed to improve therapy for patients with this disease. Previous investigators evaluated in vitro sensitivity of myeloma cells to polyethylene glycol-conjugated L-asparaginase (PEG-L-asparaginase) using the human tumor clonogenic assay. Of the 19 myeloma samples evaluated, 63% were inhibited at 0.075 IU/mL, and 74% were inhibited at 0.75 IU/mL. PEG-L-asparaginase is a form of Escherichia coli-derived L-asparaginase that is bound covalently to polyethylene glycol. Compared with the native form, it has a longer half-life and is less likely to cause allergic reactions.
The authors conducted a Phase I-II trial using PEG-L-asparaginase as a single agent in patients with recurrent and/or refractory multiple myeloma.
Twenty-two patients received a median of two doses of PEG-L-asparaginase. In the 17 patients who are evaluable for response, a complete response was observed in one patient after four doses, and stable disease was observed in eight patients. Progression of disease was the reason for termination from study in the remaining eight patients. The median survival was 31.7 months, with four patients who were alive at 72 months after the start of therapy. Grade 3-4 toxicity was noted by the PEG-L-asparaginase 2000 mg/m(2) level. Severe allergic reactions were noted only at the highest dose level.
Current data suggest that the maximal tolerated dose for single agent PEG-L-asparaginase in relapse/refractory multiple myeloma patients is 1000 mg/m(2) every 4 weeks. We could not identify any correlation between dose, plasma level and response. In this advanced group of patients we noted stable disease and/or response in 52% of evaluable patients. PEG-L-asparaginase has lower tolerance when used in the standard dosage as a single agent in this group of patients. We therefore recommend further studying of PEG-L-asparaginase dose of 1000 mg/m(2) on alternate weeks with steroids and/or other immune modulators.
多发性骨髓瘤仍然是一种无法治愈的疾病。需要新的药物来改善对这种疾病患者的治疗。先前的研究人员使用人肿瘤克隆形成试验评估了骨髓瘤细胞对聚乙二醇缀合的L-天冬酰胺酶（PEG-L-天冬酰胺酶）的体外敏感性。在评估的19个骨髓瘤样本中，63%在0.075 IU/mL时受到抑制，74%在0.75 IU/mL时受到抑制。PEG-L-天冬酰胺酶是一种源自大肠杆菌的L-天冬酰胺酶，它与聚乙二醇共价结合。与天然形式相比，它具有更长的半衰期，并且不太可能引起过敏反应。
作者进行了一项I-II期试验，使用PEG-L-天冬酰胺酶作为单一药物治疗复发和/或难治性多发性骨髓瘤患者。
22名患者接受了中位数为两剂的PEG-L-天冬酰胺酶治疗。在可评估反应的17名患者中，一名患者在接受四剂治疗后出现完全缓解，八名患者病情稳定。其余八名患者因疾病进展而退出研究。中位生存期为31.7个月，四名患者在治疗开始后72个月时仍存活。在PEG-L-天冬酰胺酶2000 mg/m²剂量水平时出现3-4级毒性。仅在最高剂量水平时观察到严重过敏反应。
目前的数据表明，复发/难治性多发性骨髓瘤患者单药使用PEG-L-天冬酰胺酶的最大耐受剂量为每4周1000 mg/m²。我们未能确定剂量、血浆水平与反应之间的任何相关性。在这组晚期患者中，我们注意到52%的可评估患者病情稳定和/或有反应。在这组患者中，PEG-L-天冬酰胺酶以标准剂量单药使用时耐受性较低。因此，我们建议进一步研究每两周一次1000 mg/m²的PEG-L-天冬酰胺酶剂量与类固醇和/或其他免疫调节剂联合使用的情况。
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