Toporski Jacek, Garkavij Michael, Tennvall Jan, Ora Ingrid, Gleisner Katarina Sjögreen, Dykes Josefina H, Lenhoff Stig, Juliusson Gunnar, Scheding Stefan, Turkiewicz Dominik, Békássy Albert N
Department of Pediatric Oncology, University Hospital, Lund, Sweden.
Biol Blood Marrow Transplant. 2009 Sep;15(9):1077-85. doi: 10.1016/j.bbmt.2009.05.007. Epub 2009 Jul 8.
We evaluated the feasibility and efficacy of using high-dose iodine-131-metaiodobenzylguanidine ((131)I-MIBG) followed by reduced-intensity conditioning (RIC) and transplantation of T cell-depleted haploidentical peripheral blood stem cells (designated haplo-SCT) to treat relapsing/refractory neuroblastoma (RRNB). Five RRNB patients were enrolled: 4 with relapse (3 after autologous SCT) and 1 with induction therapy failure. The preparative regimen included high-dose (131)I-MIBG on day -20, followed by fludarabine (Flu), thiotepa, and melphalan (Mel) from day -8 to -1. Granulocyte-colony stimulating factor (G-CSF)-mobilized, T cell-depleted haploidentical paternal stem cells were infused on day 0 together with cultured donor mesenchymal stem cells. A single dose of rituximab was given on day +1. After cessation of short immunosuppression (mycophenolate, OKT3), 4 children received donor lymphocyte infusion (DLI). (131)I-MIBG infusion and RIC were well tolerated. All patients engrafted. No primary acute graft-versus-host disease (aGVHD) was observed. Four children developed aGVHD after DLI and were successfully treated. Analysis of immunologic recovery showed fast reappearance of potentially immunocompetent natural killer (NK) and T cells, which might have acted as effector cells responsible for the graft-versus-tumor (GVT) effect. Two children are alive and well, with no evidence of disease 40 and 42 months after transplantation. One patient experienced late progression with new bone lesions (sternum) 38 months after haplo-SCT, and is being treated with local irradiation and reinstituted DLI. One patient rejected the graft, was rescued with autologous backup, and died of progressive disease 5 months after transplantation. Another child relapsed 7 months after transplantation and died 5 months later. High-dose (131)I-MIBG followed by RIC and haplo-SCT for RRNB is feasible and promising, because 2 of 5 children on that regimen achieved long-lasting remission. Further studies are needed to evaluate targeted therapy and immune-mediated tumor control in high-risk neuroblastoma.
我们评估了使用高剂量碘-131-间碘苄胍（（131）I-MIBG），随后进行减低剂量预处理（RIC）以及输注去除T细胞的单倍体相合外周血干细胞（即单倍体造血干细胞移植）来治疗复发/难治性神经母细胞瘤（RRNB）的可行性和疗效。纳入了5例RRNB患者：4例复发（3例在自体造血干细胞移植后复发），1例诱导治疗失败。预处理方案包括在第-20天给予高剂量（131）I-MIBG，随后在第-8天至-1天给予氟达拉滨（Flu）、塞替派和马法兰（Mel）。在第0天输注粒细胞集落刺激因子（G-CSF）动员的、去除T细胞的单倍体相合父源干细胞，同时输注培养的供体间充质干细胞。在第+1天给予单剂量利妥昔单抗。在短期免疫抑制（霉酚酸酯、OKT3）停止后，4名儿童接受了供体淋巴细胞输注（DLI）。（131）I-MIBG输注和RIC耐受性良好。所有患者均实现造血重建。未观察到原发性急性移植物抗宿主病（aGVHD）。4名儿童在DLI后发生aGVHD并成功治愈。免疫恢复分析显示，具有潜在免疫活性的自然杀伤（NK）细胞和T细胞快速重新出现，它们可能是发挥移植物抗肿瘤（GVT）效应的效应细胞。2名儿童存活且状况良好，移植后40和42个月无疾病证据。1例患者在单倍体造血干细胞移植后38个月出现新的骨病变（胸骨）晚期进展，正在接受局部放疗并重新进行DLI治疗。1例患者发生移植物排斥反应，通过自体备用方案挽救，移植后5个月死于疾病进展。另1名儿童在移植后7个月复发，5个月后死亡。高剂量（131）I-MIBG联合RIC和单倍体造血干细胞移植治疗RRNB是可行且有前景的，因为采用该方案的5名儿童中有2名实现了长期缓解。需要进一步研究来评估高危神经母细胞瘤的靶向治疗和免疫介导的肿瘤控制。
