A pilot induction regimen incorporating dinutuximab and sargramostim for the treatment of newly diagnosed high-risk neuroblastoma: A report from the Children's Oncology Group.
A pilot induction regimen incorporating dinutuximab and sargramostim for the treatment of newly diagnosed high-risk neuroblastoma: A report from the Children's Oncology Group.
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结合 dinutuximab 和 sargramostim 用于治疗新诊断的高危神经母细胞瘤的试点诱导方案：来自儿童肿瘤学组的报告。
DOI：
10.1200/jco.2022.40.16_suppl.10003
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发表时间：
2022
影响因子：
45.3
通讯作者：
S. Shusterman
中科院分区：
文献类型：
--
作者：
Sara M. Federico;A. Naranjo;Fan F. Zhang;A. Marachelian;A. Desai;H. Shimada;S. Braunstein;C. Tinkle;G. Yanik;S. Asgharzadeh;P. Sondel;A. Yu;Michael Acord;M. Parisi;B. Shulkin;S. DuBois;R. Bagatell;Julie R. Park;W. Furman;S. Shusterman
10003背景：在巩固治疗后增加dinutuximab（DIN）可提高高危神经母细胞瘤患者的无事件生存率。化学免疫疗法包括伊立替康、替莫唑胺、DIN和沙格司亭（GM-CSF）在复发性或难治性神经母细胞瘤患者中可获得稳健的客观临床缓解。评估新诊断的高危神经母细胞瘤（HR-NBL）患者的诱导环境中的化学免疫治疗值得调查。研究方法：儿童肿瘤组（COG）ANBL 17 P1是一项前瞻性、单臂、有限机构的初步研究，旨在评估DIN（17.5 mg/m2/剂，IV第2-5天）和GM-CSF（250 mcg/m2/剂，皮下第6天-计数恢复期）联合COG诱导化疗周期3-5治疗新诊断的高危神经母细胞瘤患者的耐受性和可行性。耐受性的主要终点包括诱导周期3-5期间毒性死亡的数量和发生预定义的不可接受毒性的患者数量。不可接受的毒性包括：需要升压剂的低血压> 24小时，需要呼吸支持的呼吸毒性> 24小时，在下一个周期之前未消退的4级神经病变，以及到第35天ANC未能恢复至> 750 mm 3。可行性被评估为能够在诱导周期3-5期间接受> 75%的计划DIN剂量。使用修订的国际神经母细胞瘤缓解标准（INRC）评估诱导结束（EOI）缓解。结果如下：2019年1月14日至2020年6月4日，在8家研究中心入组了42例符合条件且可评价的新诊断高风险神经母细胞瘤患者（22例[52.4%]男性;诊断时中位年龄3.3岁）。在诱导周期3-5期间观察到的最常见的DIN相关的>3级毒性包括发热（31.0%）和疼痛（9.5%）。在诱导周期3-5期间，无患者发生毒性死亡或不可接受的毒性。因此，认为该方案可耐受。患者在诱导周期3-5接受了预期总DIN剂量的97.4% - 101.8%。因此，认为该方案可行。42例患者中有38例完成了EOI评价，包括11例完全缓解，22例部分缓解，0例轻微缓解，3例疾病稳定，2例疾病进展。EOI总体客观缓解率（CR+PR+MR）为86.8%。结论：新诊断的高危神经母细胞瘤患者在COG诱导周期3-5给予DIN和GM-CSF是可耐受和可行的。意向书的客观答复率似乎令人鼓舞。该治疗方案将在一项随机III期试验中进行研究，以进一步评估诱导期化学免疫治疗对高危神经母细胞瘤的疗效。临床试验信息：NCT 03786783。
10003 Background: The addition of dinutuximab (DIN) in the post-consolidation setting led to improved event-free survival rates for patients with high-risk neuroblastoma. Chemoimmunotherapy including irinotecan, temozolomide, DIN and sargramostim (GM-CSF) in patients with recurrent or refractory neuroblastoma results in robust objective clinical responses. Evaluation of chemoimmunotherapy in the induction setting for patients with newly-diagnosed high-risk neuroblastoma (HR-NBL) warrants investigation. Methods: Children’s Oncology Group (COG) ANBL17P1 is a prospective, single arm, limited institution pilot study to assess the tolerability and feasibility of administering DIN (17.5mg/m2/dose, IV Days 2-5) and GM-CSF (250mcg/m2/dose, subcutaneous Days 6-count recovery) with COG Induction chemotherapy Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma. The primary endpoint of tolerability included the number of toxic deaths and number of patients experiencing predefined unacceptable toxicities during Induction Cycles 3-5. Unacceptable toxicities included: hypotension requiring pressors > 24 hours, respiratory toxicity requiring ventilatory support > 24 hours, Grade 4 neuropathy that did not resolve prior to the next cycle, and failure to recover the ANC to > 750 mm3 by day 35. Feasibility was assessed as being able to receive > 75% of planned DIN doses administered during Induction Cycles 3-5. Revised International Neuroblastoma Response Criteria (INRC) were used to assess end of Induction (EOI) response. Results: Forty-two eligible and evaluable patients with newly-diagnosed high-risk neuroblastoma enrolled at 8 sites (22 [52.4%] males; median age 3.3 years at diagnosis) from January 14, 2019 to June 4, 2020. The most common DIN related Grade >3 toxicities observed during Induction Cycles 3-5 included fever (31.0%) and pain (9.5%). None of the patients experienced a toxic death or unacceptable toxicity during Induction Cycles 3-5. Thus, the regimen was deemed tolerable. Patients received 97.4% - 101.8% of the total DIN dose expected to be administered during Induction Cycles 3-5. Therefore, the regimen was deemed feasible. Thirty-eight of 42 patients completed the EOI evaluations, including 11 with complete response, 22 with partial response, 0 with minor response, 3 with stable disease and 2 with progressive disease. The overall EOI objective response rate (CR+PR+MR) was 86.8%. Conclusions: The administration of DIN and GM-CSF to COG Induction Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma was tolerable and feasible. The objective response rate at EOI appears encouraging. This therapeutic regimen will be studied in a randomized phase 3 trial to further evaluate the efficacy of Induction phase chemoimmunotherapy for high-risk neuroblastoma. Clinical trial information: NCT03786783.