Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma,JAMA

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Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma
JAMA ( IF 63.1 ) Pub Date : 2019-08-27 , DOI: 10.1001/jama.2019.11642
Julie R Park _{1,

2} , Susan G Kreissman ₃ , Wendy B London ₄ , Arlene Naranjo ₅ , Susan Lerner Cohn ₆ , Michael D Hogarty ₇ , Sheena C Tenney ₅ , Daphne Haas-Kogan ₈ , Peter John Shaw ₉ , Jacqueline M Kraveka ₁₀ , Stephen S Roberts ₁₁ , James Duncan Geiger ₁₂ , John J Doski ₁₃ , Stephan D Voss ₁₄ , John M Maris ₇ , Stephan A Grupp ₇ , Lisa Diller ₄

Affiliation

Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington.
University of Washington, Seattle.
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina.
Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.
Department of Biostatistics, University of Florida, Children's Oncology Group Statistics and Data Center, Gainesville.
Department of Pediatrics, University of Chicago, Chicago, Illinois.
Department of Pediatrics Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
Department of Radiation Oncology, Dana Farber/Brigham and Women's Cancer Center and Harvard Medical School, Boston, Massachusetts.
Bone Marrow Transplant, Children's Hospital at Westmead, Sydney, Australia.
Department of Pediatrics, Medical University of South Carolina, Charleston.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, Manhattan, New York.
Section of Pediatric Surgery, CS Mott Children's Hospital, Michigan Medicine, Ann Arbor.
Departments of Surgery and Pediatrics, UT Health San Antonio, San Antonio, Texas.
Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance Induction chemotherapy followed by high-dose therapy with autologous stem cell transplant and subsequent antidisialoganglioside antibody immunotherapy is standard of care for patients with high-risk neuroblastoma, but survival rate among these patients remains low. Objective To determine if tandem autologous transplant improves event-free survival (EFS) compared with single transplant. Design, Setting, and Participants Patients were enrolled in this randomized clinical trial from November 2007 to February 2012 at 142 Children's Oncology Group centers in the United States, Canada, Switzerland, Australia, and New Zealand. A total of 652 eligible patients aged 30 years or younger with protocol-defined high-risk neuroblastoma were enrolled and 355 were randomized. The final date of follow-up was June 29, 2017, and the data analyses cut-off date was June 30, 2017. Interventions Patients were randomized to receive tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan (n = 176) or single transplant with carboplatin/etoposide/melphalan (n = 179). Main Outcomes and Measures The primary outcome was EFS from randomization to the occurrence of the first event (relapse, progression, secondary malignancy, or death from any cause). The study was designed to test the 1-sided hypothesis of superiority of tandem transplant compared with single transplant. Results Among the 652 eligible patients enrolled, 297 did not undergo randomization because they were nonrandomly assigned (n = 27), ineligible for randomization (n = 62), had no therapy (n = 1), or because of physician/parent preference (n = 207). Among 355 patients randomized (median diagnosis age, 36.1 months; 152 [42.8%] female), 297 patients (83.7%) completed the study and 21 (5.9%) were lost to follow-up after completing protocol therapy. Three-year EFS from the time of randomization was 61.6% (95% CI, 54.3%-68.9%) in the tandem transplant group and 48.4% (95% CI, 41.0%-55.7%) in the single transplant group (1-sided log-rank P=.006). The median (range) duration of follow-up after randomization for 181 patients without an event was 5.6 (0.6-8.9) years. The most common significant toxicities following tandem vs single transplant were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%). Conclusions and Relevance Among patients aged 30 years or younger with high-risk neuroblastoma, tandem transplant resulted in a significantly better EFS than single transplant. However, because of the low randomization rate, the findings may not be representative of all patients with high-risk neuroblastoma. Trial Registration ClinicalTrials.gov Identifier: NCT00567567.

中文翻译：

串联自体干细胞移植与单次移植对高危神经母细胞瘤患者无事件生存率的影响

重要性诱导化疗后高剂量自体干细胞移植治疗和随后的抗双唾液酸神经节苷脂抗体免疫治疗是高危神经母细胞瘤患者的标准治疗，但这些患者的生存率仍然很低。目的确定串联自体移植与单次移植相比是否能提高无事件生存 (EFS)。设计、设置和参与者患者于 2007 年 11 月至 2012 年 2 月在美国、加拿大、瑞士、澳大利亚和新西兰的 142 个儿童肿瘤组中心参加了这项随机临床试验。共有 652 名年龄在 30 岁或以下的符合方案定义的高危神经母细胞瘤符合条件的患者入选，其中 355 名被随机分组。末次随访日期为2017年6月29日，数据分析截止日期为 2017 年 6 月 30 日。干预措施患者随机接受噻替哌/环磷酰胺串联移植，随后接受减量卡铂/依托泊苷/美法仑（n = 176）或卡铂/依托泊苷/美法仑单次移植(n = 179)。主要结果和测量主要结果是从随机化到第一次事件（复发、进展、继发性恶性肿瘤或全因死亡）发生的 EFS。该研究旨在检验串联移植与单次移植相比优势的单方面假设。结果在纳入的 652 名符合条件的患者中，297 名未进行随机化，因为他们是非随机分配的（n = 27）、不符合随机化的条件（n = 62）、未接受治疗（n = 1）或由于医生/父母的偏好（ n = 207）。在随机分组的 355 名患者（中位诊断年龄，36.1 个月；152 名 [42.8%] 女性）中，297 名患者 (83.7%) 完成了研究，21 名 (5.9%) 在完成方案治疗后失访。从随机化开始的三年 EFS，串联移植组为 61.6%（95% CI，54.3%-68.9%），单次移植组为 48.4%（95% CI，41.0%-55.7%）（1-侧对数秩 P=.006）。181 名无事件患者随机分组后的中位（范围）随访时间为 5.6 (0.6-8.9) 年。串联移植与单次移植后最常见的显着毒性是粘膜（11.7% 对 15.4%）和感染性（17.9% 对 18.3%）。结论和相关性在 30 岁或更年轻的高危神经母细胞瘤患者中，串联移植的 EFS 显着优于单次移植。然而，由于随机化率低，研究结果可能无法代表所有高危神经母细胞瘤患者。试验注册 ClinicalTrials.gov 标识符：NCT00567567。

更新日期：2019-08-27

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