Buckstein R, Imrie K, Spaner D, Potichnyj A, Robinson J B, Nanji S, Pennel N, Reis M, Pinkerton P, Dubé I, Hewitt K, Berinstein N L
Advanced Therapeutics Program, Toronto Sunnybrook Regional Cancer Center, Sunnybrook Health Sciences Centre, University of Toronto, Ontario.
Semin Oncol. 1999 Oct;26(5 Suppl 14):115-22.
The chimeric anti-CD20 monoclonal antibody rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA) has recently been approved by the US Food and Drug Administration as single-agent treatment of relapsed/refractory low-grade or follicular non-Hodgkin's lymphoma. Initial results from the pivotal clinical trial revealed that response rates to rituximab were higher in patients who previously had high-dose therapy and autologous stem cell transplantation. We have initiated a clinical trial that combines the use of rituximab with high-dose chemotherapy followed by autologous stem cell transplantation for patients with chemosensitive relapsed follicular small cleaved or mantle cell lymphoma. A unique feature of this study is that in addition to eight maintenance infusions of rituximab after autologous stem cell transplantation, patients also received rituximab 375 mg/m2 2 days before a granulocyte colony-stimulating factor-mobilized stem cell collection as "in vivo purge." We report on preliminary results demonstrating the safety and efficacy of the in vivo purge on 10 patients undergoing stem cell mobilization, nine of whom have already undergone transplantation. The peripheral blood CD34+ counts were 14.92 and 20 x 10(6)/L on day 4 and day 5, respectively, of the stem cell mobilization with granulocyte colony-stimulating factor. This compares with 11.7 and 11.8 x 10(6)/L, respectively, for the control population. The median CD34 stem cell yield in the graft collection was 3.7 x 10(6)/kg in patients receiving rituximab in vivo purge compared with 3.1 x 10(6)/kg in the control population. The target stem cell collection was successfully collected in six of 10 patients in a 1-day single large-volume leukapheresis collection, while two patients required 2 days and the last two patients required 3 days. Functional assays revealed the stem cell colony-forming unit-granulocyte monocyte and burst-forming unit-erythrocyte to be 55 and 44 colonies per plate, respectively, for the patients receiving the in vivo rituximab purge. This compares favorably with 37 and 38.5 colonies per plate, respectively, for the control population. Neutrophil engraftment took a median of 11 days for both cohorts; platelet independence was achieved in 8 days compared with 10 days for the control population. The median number of platelet transfusions was two for patients receiving rituximab and 2.5 for the control group. Assessment of serum cytokines immediately before the rituximab infusion during the stem cell mobilization and immediately after revealed a twofold to sevenfold increase in interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6. The polymerase chain reaction analysis for minimal residual disease in stem cell collections and in peripheral blood and bone marrow samples of these patients will help to determine the efficacy of rituximab in vivo purge on disease progression.
嵌合抗CD20单克隆抗体利妥昔单抗(美罗华;IDEC制药公司,加利福尼亚州圣地亚哥,以及基因泰克公司,加利福尼亚州旧金山)最近已获美国食品药品监督管理局批准,作为复发/难治性低度或滤泡性非霍奇金淋巴瘤的单药治疗药物。关键临床试验的初步结果显示,先前接受过高剂量治疗和自体干细胞移植的患者对利妥昔单抗的反应率更高。我们已启动一项临床试验,将利妥昔单抗与大剂量化疗联合应用,随后对化疗敏感的复发滤泡性小裂细胞或套细胞淋巴瘤患者进行自体干细胞移植。本研究的一个独特之处在于,除了在自体干细胞移植后进行8次利妥昔单抗维持输注外,患者还在粒细胞集落刺激因子动员干细胞采集前2天接受375 mg/m2的利妥昔单抗作为“体内净化”。我们报告了关于10例接受干细胞动员患者的初步结果,证明了体内净化的安全性和有效性,其中9例患者已经接受了移植。在使用粒细胞集落刺激因子进行干细胞动员的第4天和第5天,外周血CD34+细胞计数分别为14.92和20×10(6)/L。对照组的这一数值分别为11.7和11.8×10(6)/L。接受利妥昔单抗体内净化的患者移植物采集中CD34干细胞的中位产量为3.7×10(6)/kg,而对照组为3.1×10(6)/kg。在10例患者中,有6例通过1天的单次大容量白细胞分离术成功采集到目标干细胞,2例患者需要2天,最后2例患者需要3天。功能分析显示,接受利妥昔单抗体内净化的患者干细胞集落形成单位-粒细胞单核细胞和爆式红细胞集落形成单位分别为每平板55和44个集落。相比之下,对照组分别为每平板37和38.5个集落。两个队列中性粒细胞植入的中位时间均为11天;血小板自主恢复时间为8天,而对照组为10天。接受利妥昔单抗治疗的患者血小板输注的中位数为2次,对照组为2.5次。在干细胞动员期间利妥昔单抗输注前和输注后立即对血清细胞因子进行评估,结果显示白细胞介素-1β、肿瘤坏死因子-α和白细胞介素-6增加了2至7倍。对这些患者的干细胞采集物以及外周血和骨髓样本进行微小残留病的聚合酶链反应分析,将有助于确定利妥昔单抗体内净化对疾病进展的疗效。