Allogeneic blood stem cell transplantation after a reduced-intensity, preparative regimen - A pilot study in patients with refractory malignancies
Allogeneic blood stem cell transplantation after a reduced-intensity, preparative regimen - A pilot study in patients with refractory malignancies
复制标题
DOI：
10.1002/cncr.10491.abs
复制
发表时间：
2002-05-01
期刊：
影响因子：
6.2
通讯作者：
Della Cuna, GR
中科院分区：
文献类型：
--
作者：
Pedrazzoli, P;Da Prada, GA;Della Cuna, GR
背景资料。免疫介导的移植物抗肿瘤(GVT)效应在接受异基因造血干细胞移植(HSCT)的恶性血液病患者的治疗中发挥着重要作用。最近，有报道称，在接受转移性肾癌移植的患者中也出现了GVT效应。作者在包括实体瘤在内的难治性恶性肿瘤患者中进行了降低强度、准备方案后的同种异体移植的试点试验。方法：17例无法接受常规治疗的TV期恶性肿瘤患者，其中肾细胞癌7例，肉瘤3例，乳腺癌2例，霍奇金病2例，卵巢癌1例，黑色素瘤1例，黑色素瘤合并肾细胞癌1例。患者年龄中位数为43岁(10-60岁)。东部合作肿瘤组评分(PS)0~1分11例，2~3分6例。准备治疗包括在人类白细胞抗原相合的同胞进行异基因造血干细胞移植之前使用氟达拉滨(每天30 mg/m(2)，连续4天)和环磷酰胺(30 mg/kg，每天30 mg/kg，连续2天)的低强度化疗。CD34+细胞输注的中位数为6.06×10(6)/kg(1.5~14.0×10(6)/kg)。移植物抗宿主病(GVHD)的预防包括环孢素A和短期甲氨蝶呤。结果：接受HSCT前PS为2~3的患者出现4级血液学毒性和大于或等于3级器官毒性，并在移植后100天内死于与治疗相关的并发症或疾病进展。相比之下，在接受HSCT前PS为0~1的11例患者中，有10例仅出现短期、小于或等于3级的中性粒细胞减少和血小板减少，没有器官毒性；10例患者中有1例在接受HSCT后+29天死于移植物衰竭。到+90天，所有既往有重度化疗病史的患者均出现了100%的供者嵌合体，而在进入HSCT计划之前仅接受过一次化疗和/或免疫治疗的4名患者中观察到了混合供者嵌合体。5例发生2~3级急性移植物抗宿主病。在随访100天的患者中，记录到2例完全缓解和3例一过性部分缓解。结论：在这种预适应方案中，只有接受过强化化疗的患者才能迅速实现供者完全嵌合。在部分难治性恶性肿瘤患者中，异基因移植导致肿瘤消退。这一新的治疗策略可能对PS较差和病情进展迅速的患者几乎没有好处。(C)2002年美国癌症协会。
BACKGROUND. The immune-mediated graft-versus-tumor (GVT) effect plays a therapeutic role in the treatment of patients with hematologic malignancies who undergo allogeneic hematopoietic stem cell transplantation (HSCT). More recently, it was reported that a GVT effect also occurred in patients who underwent transplantation for metastatic renal carcinoma. The authors carried out a pilot trial of allogeneic transplantation after a reduced-intensity, preparative regimen in patients with refractory malignancies, including solid tumors. The objectives of the current study were to evaluate the feasibility of this approach in terms of toxicity and engraftment and to document evidence of GVT effects.METHODS. Seventeen patients with Stage TV malignancies (7 patients with renal cell carcinoma, 3 patients with sarcoma, 2 patients with breast carcinoma, 2 patients with Hodgkin disease, 1 patient with ovarian carcinoma, 1 patient with melanoma, and 1 patient with both melanoma and renal cell carcinoma) that were not amenable to further conventional treatment were enrolled. The median patient age was 43 years (range, 10-60 years). The Eastern Cooperative Oncology Group performance status (PS) was 0-1 in 11 patients and 2-3 in 6 patients. Preparative treatment consisted of reduced-intensity chemotherapy with fludarabine (30 mg/m(2) per day for 4 consecutive days) and cyclophosphamide (30 mg/Kg per day for 2 consecutive days) prior to allogeneic HSCT from a human leukocyte antigen-identical sibling. The median number of CD34+ cells infused was 6.06 X 10(6)/kg (range, 1.5-14.0 X 10(6)/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin-A and short-term methotrexate.RESULTS. Patients who had a PS of 2-3 prior to undergoing HSCT experienced Grade 4 hematologic toxicities and Grade greater than or equal to 3 organ toxicities and died of either treatment-related complications or disease progression within 100 days from transplantation. By contrast, 10 of 11 patients who had a PS of 0-1 prior to undergoing HSCT experienced only short-lasting, Grade less than or equal to 3 neutropenia and thrombocytopenia and no organ toxicity; 1 of 10 patients died of graft failure on Day +29 after undergoing HSCT. By Day +90, 100% donor chimerism was documented in all patients with a past history of heavy chemotherapy, whereas mixed donor chimerism was observed in the 4 patients with a past history of only 1 line of chemotherapy and/or immunotherapy prior to entering the HSCT program. Grade 2-3 acute GVHD occurred in 5 patients. Among patients with a follow-up > 100 days, 2 complete responses and 3 transitory partial responses were recorded.CONCLUSIONS. With this conditioning regimen, full donor chimerism was achieved rapidly only in patients who had received previous intensive chemotherapy. In a proportion of patients with refractory malignancies, allogeneic transplantation resulted in tumor regression. This novel therapeutic strategy may provide little benefit in patients with poor PS and rapidly progressing disease. (C) 2002 American Cancer Society.