Duke University Medical Center, Durham, NC, USA.
Lancet Oncol. 2013 Sep;14(10):999-1008. doi: 10.1016/S1470-2045(13)70309-7. Epub 2013 Jul 25.
Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma.
Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either non-purged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus meta-iodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188.
495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33-46) in the purged group versus 36% (30-42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43-56) in the purged group compared with 51% (44-57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged group and five of 243 in the non-purged group) and elevated creatinine (five of 242 in the purged group and six of 243 non-purged group) and during consolidation were sinusoidal obstructive syndrome (12 of 177 in the purged group and 17 of 191 in the non-purged group), acute vascular leak (11 of 177 in the purged group and nine of 191 in the non-purged group), and decreased cardiac function (one of 177 in the purged group and four of 191 in the non-purged group).
Immunomagnetic purging of PBSC for autologous stem-cell transplantation did not improve outcome, perhaps because of incomplete purging or residual tumour in patients. Non-purged PBSC are acceptable for support of myeloablative therapy of high-risk neuroblastoma.
对于高危神经母细胞瘤患者，大剂量化疗联合免疫磁珠清除的自体骨髓移植可改善预后。目前，在大剂量化疗后输注外周血造血干细胞（PBSC），但清除效果未知。我们在高危神经母细胞瘤患者的干细胞移植中进行了一项随机研究，比较了肿瘤选择性 PBSC 清除的效果。
2001 年 3 月 16 日至 2006 年 2 月 24 日，采用基于网络的系统（1:1 比例），按国际神经母细胞瘤分期系统（INSS）分期、年龄、MYCN 状态和国际神经母细胞瘤病理分类进行分层，对初诊的儿童和年轻成人（<30 岁）患者进行随机分组，分别接受非清除或免疫磁珠清除的 PBSC。患者和治疗医生均不了解治疗分组情况。所有患者均接受六个周期诱导化疗、大剂量化疗联合放疗，对原发肿瘤部位和大剂量化疗前出现的间碘苄胍阳性转移灶进行照射，随后口服异维 A 酸。在两个诱导周期后采集 PBSC。为了清除，将 PBSC 与羰基铁混合，用钐钴磁铁去除吞噬细胞。剩余的细胞与 5 种针对神经母细胞瘤细胞表面抗原的单克隆抗体制备的免疫磁珠混合，用钐钴磁铁去除结合的细胞。在六个周期诱导治疗后，根据随机分组接受 PBSC 进行自体干细胞移植。主要终点是无事件生存，采用意向治疗分析。该试验在 ClinicalTrials.gov 注册，编号为 NCT00004188。
共纳入 495 例患者，486 例患者随机分组治疗：243 例接受非清除 PBSC，243 例接受清除 PBSC。从清除组和非清除组中分别采集了 229 例和 236 例患者的 PBSC，180 例清除组和 192 例非清除组患者接受了移植。清除组 5 年无事件生存率为 40%（95%CI 33-46），非清除组为 36%（30-42）（p=0·77）；清除组 5 年总生存率为 50%（95%CI 43-56），非清除组为 51%（44-57）（p=0·81）。诱导期有 15 例患者发生毒性死亡（清除组 8 例，非清除组 7 例），巩固期有 12 例（清除组 8 例，非清除组 4 例）。最常见的不良事件是诱导期和巩固期均有 3 级或以上的口腔黏膜炎（清除组 242 例患者中有 87 例，非清除组 243 例患者中有 93 例）。诱导期有 3 级或以上的不良事件包括心功能下降（清除组 242 例患者中有 4 例，非清除组 243 例患者中有 5 例）和血肌酐升高（清除组 242 例患者中有 5 例，非清除组 243 例患者中有 6 例），巩固期有窦道阻塞综合征（清除组 177 例患者中有 12 例，非清除组 191 例患者中有 17 例）、急性血管渗漏（清除组 177 例患者中有 11 例，非清除组 191 例患者中有 9 例）和心功能下降（清除组 177 例患者中有 1 例，非清除组 191 例患者中有 4 例）。
自体干细胞移植中用免疫磁珠清除 PBSC 并不能改善预后，这可能是因为清除不彻底或患者体内仍有肿瘤。非清除的 PBSC 可用于支持高危神经母细胞瘤的大剂量化疗。
