Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2 immunotherapy and isotretinoin: a prospective Phase II study
Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2 immunotherapy and isotretinoin: a prospective Phase II study
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DOI：
10.1080/2162402x.2015.1016704
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发表时间：
2015-01-01
期刊：
影响因子：
7.2
通讯作者：
Cheung, Nai-Kong V.
中科院分区：
文献类型：
--
作者：
Kushner, Brian H.;Ostrovnaya, Irina;Cheung, Nai-Kong V.
高危神经母细胞瘤（HR - NB）复发被认为必死无疑，但越来越多的HR - NB患者实现了第二次完全缓解/非常好的部分缓解（CR/VGPR），因此迫切需要找到一种成功的巩固治疗方法。然而，在无评估疾病的患者中确定疗效是有问题的。我们报道了第一项为这组预后不良的患者提供结果数据的研究。为防止再次复发，在第二次或之后达到CR/VGPR的HR - NB患者在一项II期试验中接受了抗GD2鼠抗体3F8加粒细胞 - 巨噬细胞集落刺激因子加异维甲酸治疗。在最初的33名患者队列中达到无进展生存期（PFS）的目标后，试验进行了修订，允许产生人抗鼠抗体（HAMA）的患者接受利妥昔单抗以清除HAMA，同时可选择是否进行低剂量维持化疗，直至免疫治疗能够恢复。在总共101名研究患者中，5年PFS率和总生存率（OS）分别为33%±5%和48%±5%。在33名长期无进展生存者中，19名有MYCN扩增，19名先前接受过抗GD2免疫治疗加异维甲酸（作为一线治疗），15名从未接受过维持化疗。在对预后因素的多变量分析中，只有在2个周期的免疫治疗后且在开始异维甲酸或抗HAMA治疗前骨髓中无微小残留疾病对PFS和OS均显著有利。因此，对于至少达到第二次CR/VGPR并接受包括抗GD2免疫治疗加异维甲酸的巩固治疗的HR - NB患者，长期PFS是可能的，即使患者在复发前接受过这些生物治疗。这项前瞻性研究的结果将有助于为这一不断增长的超高危患者群体开展未来的II期研究。
Relapse of high-risk neuroblastoma (HR-NB) is deemed invariably fatal yet increasing numbers of HR-NB patients achieve a second complete/very good partial remission (CR/VGPR), hence the urgency to find a successful consolidative therapy. Identifying efficacy in patients without assessable disease, however, is problematic. We report the first study providing outcome data for this group of patients with poor prognosis. To prevent another relapse, HR-NB patients in second or later CR/VGPR received the anti-G(D2) murine antibody 3F8 plus granulocyte-macrophage colony-stimulating factor plus isotretinoin in a Phase II trial. Upon meeting the target aim for progression-free survival (PFS) in the initial cohort of 33 patients, the trial was amended to allow patients who developed human anti-mouse antibody (HAMA) to receive rituximab to ablate HAMA with or without low-dose maintenance chemotherapy until immunotherapy could resume. For the total of 101 study patients, 5-year PFS and overall survival (OS) rates were 33% +/- 5% and 48% +/- 5%, respectively. Among the 33 long-term progression-free survivors, 19 had MYCN amplification, 19 had previously received anti-G(D2) immunotherapy plus isotretinoin (as first-line therapy), and 15 never received maintenance chemotherapy. In a multivariate analysis of prognostic factors, only absence of minimal residual disease in bone marrow after 2 cycles of immunotherapy and before initiation of isotretinoin or anti-HAMA therapy was significantly favorable for both PFS and OS. Therefore, long-term PFS is possible for HR-NB patients who achieve at least a second CR/VGPR and receive consolidation that includes anti-G(D2) immunotherapy plus isotretinoin, even if the patients received these biological treatments before relapse. Results from this prospective study will aid in the development of future Phase II studies for this growing ultra high-risk patient population.