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Original Investigation
August 27, 2019

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

Author Affiliations
  • 1Department of Pediatrics, Seattle Children’s Hospital, Seattle, Washington
  • 2University of Washington, Seattle
  • 3Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina
  • 4Department of Pediatrics, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts
  • 5Department of Biostatistics, University of Florida, Children’s Oncology Group Statistics and Data Center, Gainesville
  • 6Department of Pediatrics, University of Chicago, Chicago, Illinois
  • 7Department of Pediatrics Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 8Department of Biostatistics, University of Florida, Children’s Oncology Group Statistics and Data Center, Gainesville
  • 9Department of Radiation Oncology, Dana Farber/Brigham and Women’s Cancer Center and Harvard Medical School, Boston, Massachusetts
  • 10Bone Marrow Transplant, Children's Hospital at Westmead, Sydney, Australia
  • 11Department of Pediatrics, Medical University of South Carolina, Charleston
  • 12Department of Pediatrics, Memorial Sloan Kettering Cancer Center, Manhattan, New York
  • 13Section of Pediatric Surgery, CS Mott Children’s Hospital, Michigan Medicine, Ann Arbor
  • 14Departments of Surgery and Pediatrics, UT Health San Antonio, San Antonio, Texas
  • 15Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA. 2019;322(8):746-755. doi:10.1001/jama.2019.11642
Visual Abstract.
Visual Abstract.
Tandem Autologous Stem Cell Transplant vs Single Transplant and Event-Free Survival in Neuroblastoma
Tandem Autologous Stem Cell Transplant vs Single Transplant and Event-Free Survival in Neuroblastoma
Key Points

Question  Does intensification of consolidation therapy using tandem autologous transplant improve event-free survival for patients with high-risk neuroblastoma?

Findings  In this randomized clinical trial that included 652 eligible patients with high-risk neuroblastoma, tandem autologous stem cell transplant vs single transplant resulted in 3-year event-free survival of 61.6% vs 48.4%, a difference that was statistically significant.

Meaning  Tandem autologous transplant after induction chemotherapy resulted in better event-free survival than single transplant, but, because of the low randomization rate, the findings may not be representative of all patients with high-risk neuroblastoma.

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

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