Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Cohn reported receiving grants from the National Cancer Institute (NCI) during the conduct of the study and equity ownership in United Therapeutics outside the submitted work. Dr Geiger reported being a founder of FlexDex Inc, a medical device company, outside the submitted work. Dr London reported receiving grants from the National Institutes of Health (NIH)/NCI/Cancer Therapy Evaluation Program during the conduct of the study; personal fees from United Therapeutics Corp, and personal fees from American Association for Cancer Research outside the submitted work. Dr Naranjo reported receiving grants from NIH/NCI (Children's Oncology Group Statistics & Data Center Grants U10 CA180899 and U10 CA98413) during the conduct of the study and personal fees from Novartis outside the submitted work. Dr Park reported receiving grants from the Children's Oncology Group during the conduct of the study and serving on an advisory committee for Bristol Myers Squibb outside the submitted work. Dr Tenney reported receiving grants from the NIH/NCI (Children's Oncology Group Statistics & Data Center grants U10 CA180899 and U10 CA98413) during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Enrollment and Randomization of Patients in a Study of the Effect of Tandem Transplant vs Single Transplant on Event-Free Survival in Patients With Neuroblastoma

aTwenty-seven patients with favorable characteristics were nonrandomly assigned to receive single transplant. Outcome for patients nonrandomly assigned to receive single transplant will be reportedly separately. bThirty patients (14 in the single transplant and 16 in the tandem transplant group) discontinued protocol therapy after receiving the allocated intervention.

Figure 2.. Estimates of Survival of Patients in a Study of the Effect of Tandem Transplant vs Single Transplant on Event-Free Survival in Patients With Neuroblastoma

P values were calculated using a 1-sided log-rank test for the primary analysis and a 2-sided log-rank test for the post hoc analyses. A, Median (interquartile range [IQR]) duration of follow-up after randomization for patients without an event was 5.6 (4.9-6.8) years and 3.9 (1.0 to 5.7) years for all patients. The bars represent the 95% CIs for event-free survival at 3 years. B, Median (IQR) duration of follow-up after randomization for patients still alive at the final follow-up was 5.4 (4.9-6.8) years and 4.8 (2.1-6.0) years for all patients. C, Median (IQR) duration of follow-up after initiating immunotherapy for patients without an event was 5.1 (4.6-6.4) years and 4.4 (1.2-5.5) years for all patients. D, Median (IQR) duration of follow-up after initiating immunotherapy for patients still alive was 5.0 years [IQR, 4.6 to 6.4 years] and 4.7 years [IQR, 3.1 to 5.7 years] for all patients.