Tandem Transplant in Neuroblastoma Leads to Significant Survival Advantage

Julie R. Park, MD

Julie R. Park, MD

Dual autologous stem-cell transplant (ASCT) led to a 13% absolute increase in 3-year event-free survival (EFS) for children with high-risk neuroblastoma as compared with a single transplant, a large randomized trial showed.

Intensive myeloablative chemotherapy followed by dual, or tandem, ASCT resulted in a 3-year EFS of 61.4%. That compared with 48.4% who underwent myeloablative chemotherapy and a single transplant, the usual practice for patients who qualify for ASCT. Overall survival (OS) favored tandem transplant, but the difference did not attain statistical significance, Julie R. Park, MD, professor of pediatrics at the University of Washington in Seattle, reported at the 2016 ASCO Annual Meeting in Chicago.

The addition of posttransplant immunotherapy appeared to augment the effects of single and tandem ASCT, resulting in a statistically significant improvement in 3-year OS for patients who underwent dual ASCT.

Tandem transplant did not add toxicity or risk of treatment-related death. In addition, the benefits of tandem transplant persisted, and appeared increased, in a subgroup of children who received immunotherapy after transplant, as reported at the ASCO presentation.

“Tandem transplant consolidation therapy improves outcome in patients with high-risk neuroblastoma,” said Dr. Park. “These results apply to children who survive induction without disease progression or severe induction-related toxicity. We found that tandem transplant did not increase toxicity.”

“This study will change the way we treat children with high-risk neuroblastoma in North America,” she added.

Neuroblastoma occurs in young children and is the most common extracranial nervous system cancer in children. Historically, the disease has had a poor prognosis, as fewer than half of patients are alive at 5 years.

Previous studies have shown that more intense treatment, including ASCT, improves outcome in neuroblastoma. A few small pilot studies have suggested that tandem transplant may add to the survival advantage. Still other studies have shown that post-consolidation immunotherapy may further improve outcomes.

To test the hypothesis that tandem transplant would improve survival in high-risk neuroblastoma patients, investigators in the Children’s Oncology Group performed a randomized trial. The trial design incorporated secondary randomization to post-consolidation immunotherapy.

The trial involved 652 children with newly diagnosed neuroblastoma and 1 or more high-risk characteristics: age >18 months, advanced-stage disease, tumorMYCNamplification, poorly differentiated or undifferentiated tumor histology, and tumor diploid DNA content. After screening the patients, investigators subsequently randomized 355 for the trial.

The study population had a median age of 3.1 years, 88% had stage IV disease, and almost 40% hadMYCNamplification.

All patients were given 6 cycles of induction chemotherapy, followed by peripheral stem-cell harvesting. After surgery the patients were randomized to either single or tandem ASCT.

Patients randomized to a single transplant received additional chemotherapy and radiation therapy. The tandem-transplant group received intensified chemotherapy and radiotherapy prior to ASCT. The second ASCT was performed 6 to 8 weeks after the first.

Within each treatment group, patients were further randomized to posttransplant consolidation with the immunotherapeutic agent anti-GD2 (dinutuximab, Unituxin) plus cytokines and isotretinoin.

The primary endpoint was 3-year event-free survival. Investigators defined an event as either worsening or recurrence of neuroblastoma.

The data showed a statistically significant 3-year EFS advantage for tandem transplant(P= .0081). The 3-year OS also favored tandem transplant (74.0% vs 69.1%), but the difference did not attain statistical significance (P= .1850).

Dr. Park said that substantially longer follow-up would be required to determine whether tandem transplant improves overall survival. She also noted an inability to fully account for additional treatments that patients might have received after transplant would complicate any analysis of overall survival.

Patients in both transplant groups had better EFS and OS with anti-GD2 immunotherapy, but tandem transplant maintained a significant advantage over single transplant. Among patients randomized to anti-GD2, the 3-year EFS was 73.7% with dual transplant and 56% with a single transplant (P= .0033). The difference in OS improved in both groups, but a larger difference in favor of tandem transplant attained statistical significance (83.7% vs 73.4%;P= .0322).

Park JR, Kreissman SG, London WB, et al. A phase III 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.J Clin Oncol34, 2016 (suppl; abstr LBA3).