Long G D, Chao N J, Hu W W, Negrin R S, Wong R M, Blume K G
Department of Medicine, Stanford University Medical Center, California 94305, USA.
Cancer. 1996 Dec 15;78(12):2502-9. doi: 10.1002/(sici)1097-0142(19961215)78:12<2502::aid-cncr9>3.0.co;2-l.
A number of studies have demonstrated that high dose chemotherapy, with or without radiotherapy, with autologous marrow and/or peripheral blood progenitor cell support can result in improved overall and complete response rates in patients with multiple myeloma, and a minority of patients become long term survivors. Based on their favorable experience with high dose etoposide-based regimens in patients with Hodgkin's disease and non-Hodgkin's lymphoma, the authors explored the use of these regimens prior to autologous progenitor cell rescue in patients with multiple myeloma.
Thirty-four patients (median age, 49 years; range, 38-65) with multiple myeloma who were responsive to standard chemotherapy were enrolled in this study. Blood progenitor cells were collected after treatment with cyclophosphamide at a dose of 4 g/m2 followed by granulocyte-colony stimulating factor (G-CSF) at a dose of approximately 10 micrograms/kg/day subcutaneously, and the collection continued daily until the target number of mononuclear cells had been obtained. The preparative regimen consisted of fractionated total body irradiation (FTBI) of 1200 centigray in 10 fractions on Day -8 to Day -5, etoposide 60 mg/kg intravenously (i.v.) on Day -4, and cyclophosphamide 100 mg/kg i.v. on Day -2. Day 0 was the day of progenitor cell infusion. Patients who were older than 50 years or had received prior radiation therapy that precluded FTBI received carmustine 15 mg/kg i.v. or lomustine 15 mg/kg orally on Day -6 rather than FTBI. G-CSF (5 micrograms/kg/day) was begun the day after progenitor cell infusion and continued until engraftment.
Recovery of granulocytes to 500/microL occurred at a median of 9 days (range, 7-13), and platelet recovery to 20,000/microL occurred without transfusion at 9 days (range, 6-88) after progenitor cell infusion. Thirty-two patients were evaluable for response. Eleven patients (34%) achieved a complete remission, 17 (53%) achieved a partial remission, and 4 (13%) had stable disease following high dose therapy and progenitor cell rescue. The actuarial event free survival at 4 years for the entire group was 26%, and overall survival was 36%. The median time to progression of disease was 13 months (range, 2-42). Two patients died of regimen-related toxicity, one of venoocclusive disease of the liver and the other of multiorgan failure. In a multivariate analysis, only the extent of prior therapy was a significant prognostic factor for event free survival, and no significant factors were identified for overall survival.
High dose etoposide-based myeloablative regimens followed by autologous blood progenitor cell rescue are relatively well tolerated and effective for the treatment of multiple myeloma, and a minority of patients become long term disease free survivors.
多项研究表明，高剂量化疗，无论是否联合放疗，联合自体骨髓和/或外周血祖细胞支持，可提高多发性骨髓瘤患者的总缓解率和完全缓解率，少数患者成为长期存活者。基于在霍奇金病和非霍奇金淋巴瘤患者中使用以高剂量依托泊苷为基础的方案的良好经验，作者探讨了在多发性骨髓瘤患者自体祖细胞救援前使用这些方案。
34例对标准化疗有反应的多发性骨髓瘤患者（中位年龄49岁；范围38 - 65岁）纳入本研究。在用4 g/m²环磷酰胺治疗后，接着皮下注射剂量约为10微克/千克/天的粒细胞集落刺激因子（G-CSF），采集血液祖细胞，每天持续采集直至获得目标数量的单个核细胞。预处理方案包括在第-8天至第-5天分10次给予1200厘戈瑞的分次全身照射（FTBI），在第-4天静脉注射60 mg/kg依托泊苷，在第-2天静脉注射100 mg/kg环磷酰胺。第0天为祖细胞输注日。年龄大于50岁或之前接受过放疗而不能进行FTBI的患者，在第-6天接受15 mg/kg静脉注射卡莫司汀或15 mg/kg口服洛莫司汀，而非FTBI。祖细胞输注后次日开始使用G-CSF（5微克/千克/天），持续至植入。
祖细胞输注后，粒细胞恢复至500/微升的中位时间为9天（范围7 - 13天），血小板恢复至20,000/微升且无需输血的时间为9天（范围6 - 88天）。32例患者可评估疗效。11例患者（34%）达到完全缓解，17例（53%）达到部分缓解，4例（13%）在高剂量治疗和祖细胞救援后病情稳定。整个组4年的无事件生存率为26%，总生存率为36%。疾病进展的中位时间为13个月（范围2 - 42个月）。2例患者死于与方案相关的毒性，1例死于肝静脉闭塞病，另1例死于多器官功能衰竭。在多变量分析中，仅先前治疗的程度是无事件生存的显著预后因素，未发现总生存的显著因素。
以高剂量依托泊苷为基础的清髓性方案联合自体血祖细胞救援对多发性骨髓瘤的治疗耐受性相对良好且有效，少数患者成为长期无病生存者。
