PDF(Pubmed)
Abstract：
Patients with high-risk neuroblastoma (HR-NB) who are unable to achieve a complete response (CR) to induction therapy have worse outcomes. We investigated the combination of humanized anti-GD2 mAb naxitamab (Hu3F8), irinotecan (I), temozolomide (T), and sargramostim (GM-CSF)-HITS-against primary resistant HR-NB. Eligibility criteria included having a measurable chemo-resistant disease at the end of induction (EOI) treatment. Patients were excluded if they had progressive disease (PD) during induction. Prior anti-GD2 mAb and/or I/T therapy was permitted. Each cycle, administered four weeks apart, comprised Irinotecan 50 mg/m2/day intravenously (IV) plus Temozolomide 150 mg/m2/day orally (days 1-5); naxitamab 2.25 mg/kg/day IV on days 2, 4, 8 and 10, (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously was used (days 6-10). Toxicity was measured using CTCAE v4.0 and responses through the modified International Neuroblastoma Response Criteria (INRC). Thirty-four patients (median age at treatment initiation, 4.9 years) received 164 (median 4; 1-12) HITS cycles. Toxicities included myelosuppression and diarrhea, which was expected with I/T, and pain and hypertension, expected with naxitamab. Grade ≥3-related toxicities occurred in 29 (85%) of the 34 patients; treatment was outpatient. The best responses were CR = 29% (n = 10); PR = 3% (n = 1); SD = 53% (n = 18); PD = 5% (n = 5). For cohort 1 (early treatment), the best responses were CR = 47% (n = 8) and SD = 53% (n = 9). In cohort 2 (late treatment), the best responses were CR = 12% (n = 2); PR = 6% (n = 1); SD = 53% (n = 9); and PD = 29% (n = 5). Cohort 1 had a 3-year OS of 84.8% and EFS 54.4%, which are statistically significant improvements (EFS p = 0.0041 and OS p = 0.0037) compared to cohort 2. In conclusion, naxitamab-based chemo-immunotherapy is effective against primary chemo-resistant HR-NB, increasing long-term outcomes when administered early during the course of treatment.
摘要：
对诱导治疗不能达到完全反应(CR)的高风险神经母细胞瘤(HR-NB)患者的预后较差。我们研究了人源化抗GD2单克隆抗体纳西他单抗（Hu3F8）的组合，伊立替康(I),替莫唑胺（T），和sargamostim（GM-CSF）-HITS-对抗原发性耐药HR-NB。合格标准包括在诱导(EOI)治疗结束时具有可测量的化学抗性疾病。如果患者在诱导期间患有进行性疾病（PD），则将其排除在外。允许先前的抗GD2mAb和/或I/T疗法。每个周期,间隔四周服用，包括伊立替康50mg/m2/天，静脉注射（IV）加替莫唑胺150mg/m2/天，口服（第1-5天）；在第2、4、8和10天，naxitamab2.25mg/kg/天，（每个周期总计9mg/kg或270mg/m2），和GM-CSF皮下使用250mg/m2/天(第6-10天)。使用CTCAEv4.0测量毒性，并通过改良的国际神经母细胞瘤反应标准（INRC）测量反应。34例患者（治疗开始时的中位年龄，4.9年）收到164个（中位数4；1-12个）HITS周期。毒性包括骨髓抑制和腹泻，这是I/T所期望的，疼痛和高血压，纳西他单抗预期。34例患者中有29例（85％）发生≥3级相关毒性；门诊治疗。最佳响应是CR=29%(n=10);PR=3%(n=1);SD=53%(n=18);PD=5%(n=5)。对于队列1（早期治疗），最佳反应是CR=47％（n=8）和SD=53％（n=9）。在队列2（晚期治疗）中，最佳反应为CR=12%(n=2);PR=6%(n=1);SD=53%(n=9);PD=29%(n=5).队列1的3年OS为84.8%，EFS为54.4%，与队列2相比，有统计学意义的改善(EFSp=0.0041和OSp=0.0037)。总之,基于naxitamab的化学免疫疗法对原发性化学耐药性HR-NB有效，在治疗过程中早期给药会增加长期结局。
