Oral Presentation Advances in Neuroblastoma Research Congress 2016

A Phase 3 randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): A Children’s Oncology Group (COG) study (#90)

Julie R Park 1 , Susan G Kreissman 2 , Wendy B London 3 , Arlene Naranjo 4 , Susan L Cohn 5 , Michael D Hogarty 6 , Sheena C Teeney 4 , Daphne Haas-Kogan 3 , Peter J Shaw 7 , John Doski 8 , James Geiger 9 , Sandra W Gorges 10 , Gheetika Khanna 11 , Stephan Voss 3 , John M Maris 6 , Lisa Diller 3 , Stephan Grupp 6
  1. University of Washington, Seattle Children's Hospital, Seattle, WA, United States
  2. Duke University, Durnham, North Carolina, USA
  3. Dana-Farber/Boston Children’s Cancer and Blood Disorder Center, Harvard Medical School, Boston, MA, USA
  4. Children’s Oncology Group, University of Florida, Gainesville, Florida, USA
  5. University of Chicago, Chicago, Illinois, USA
  6. Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  7. The Children’s Hospital at Westmead, Sydney, Australia
  8. University of Texas Health Center at San Antonio, San Antonio, Texas, USA
  9. C.S. Mott Children’s Hospital, Ann Arbor, Michigan, USA
  10. University of California, Davis, Sacromento, California, USA
  11. Washington University School of Medicine, St. Louis, Missouri, USA

Background: ASCT improves event-free survival (EFS) for HR-NB. Pilot studies suggest that intensification of myeloablative therapy using tandem ASCT further improves outcome for HR-NB. We conducted a multicenter RCT comparing tandem vs. single consolidation in patients with HR-NB.

Methods: Between 11/2007 and 2/2012, 652 eligible patients (pts) with newly diagnosed HR-NB received induction therapy: 6 cycles of chemotherapy including initial 2 cycles of dose-intensive cyclophosphamide/topotecan followed by PBSC collection. Randomization occurred at end induction to single ASCT with carboplatin-etoposide-melphalan (CEM) or tandem ASCT with thiotepa–cyclophosphamide ASCT followed by a modified CEM (TC:CEM). HR pts with non-MYCN amplified Stage 3 (age>18mos) or Stage 4 (age 12-18 mos) tumors were non-randomly assigned to single ASCT (CEM). EFS and overall survival (OS) were analyzed as intent-to-treat.

Results: Median age at study entry was 3.1 yrs, 88% (n=574 pts) had Stage 4 disease and 38.2% (n=249 tumors) had MYCN amplification. A total of 355 pts were randomized (CEM n=179 pts; TC:CEM n=176 pts) and 27 patients were non-randomly assigned to CEM. Of randomized pts, 249 patients received post-consolidation immunotherapy on COG trials. Treatment-related mortality was 2.6% (Induction n=7 [1%]; Consolidation n=10 [2.8%; n=8 CEM, n=2 TC:CEM]). Rates of severe mucosal, infectious or liver toxicities were similar between arms. 3-year EFS and OS from diagnosis were 51.1±2.0% and 68.2±1.9%, respectively. EFS and OS for randomized cohort are noted in the Table.

Cohorts

N

3-yr EFS

+/- SE (%)

2-sided

p-value

3-yr OS

+/- SE (%)

2-sided

p-value

CEM

179

48.8 ± 4.0

 

69.0 ± 3.6

 

TC:CEM

176

61.8 ± 4.1

0.0082

73.8 ± 3.7

0.2563

Immunotherapy

 

 

 

 

 

CEM

129

55.4 ± 4.6

 

75.7 ± 3.9

 

TC:CEM

120

73.7 ± 4.4

0.0009

86.3 ± 3.4

0.0158

 

Conclusions: Tandem myeloablative consolidation therapy improves survival probability in patients with high-risk neuroblastoma, especially in the setting in post-consolidative immunotherapy.