CHICAGO -- Significantly more children with high-risk cancer of the nervous system remained alive and cancer free at 3 years if they received a dual rather than single stem-cell transplant, results of a practice-changing study showed.
Three years after treatment for neuroblastoma, 61.4% of patients who received the dual autologous stem-cell transplants (ASCT) were alive without cancer compared with 48.4% of those who received a single transplant, the current standard of care.
Dual, or tandem, transplant did not add toxicity, and the benefits persisted, and appeared to increase, in a subgroup of children who received immunotherapy after transplant, as reported here at the American Society of Clinical Oncology meeting.
"Tandem transplant consolidation improves outcome in patients with high-risk neuroblastoma, with the important caveat that this is in children who survive induction with disease progression or severe induction-related toxicity," said , of the University of Washington and Seattle Children's Hospital. "Toxicity or regimen-related mortality is not increased by tandem transplant.
"This will change the way we treat children with high-risk neuroblastoma in North America," she added.
The study offers yet another example of how progress in the treatment of childhood cancers often has occurred only after researchers and clinicians learned how to optimize the use of potent therapies in children, said ASCO spokesperson , of the University of Pennsylvania and Children's Hospital of Philadelphia. Although the improvement in event-free survival (EFS) is impressive, longer follow-up is needed to determine whether the aggressive treatment confers long-term morbidity that might detract from the benefits, he added.
Arising in tissue of the sympathetic nervous system, neuroblastoma occurs in young children and is the most common extracranial nervous system cancer in children. Historically, the disease has had a poor prognosis, associated with a 5-year survival of less than 50%.
Previous studies have shown that more intense treatment, including autologous hematopoietic stem cell transplant improves outcome in neuroblastoma. A few small pilot studies have suggested that tandem transplant may add to the survival advantage. Other studies have shown that post-consolidation may further improve outcomes.
Investigators in the Children's Oncology Group collaborated in a multicenter trial to test the hypothesis that dual transplant improves survival in high-risk neuroblastoma compared with a single transplant. The trial also continued the evaluation of dose-intensified chemotherapy post-consolidation immunotherapy.
From 2007 to 2012 investigators enrolled 665 children with newly diagnosed neuroblastoma, associated with one or more high-risk characteristic: age >18 months, advanced-stage disease, tumor MYCN amplification, poorly differentiated or undifferentiated tumor histology, and tumor diploid DNA content.
Historical data suggested a 40% dropout rate from such trials. The 665 patients enrolled in the trial ensured that at least 332 patients would be randomized, and 355 patients subsequently were randomized.
The study population had a median age of 3.1 years, 88% had stage IV disease, and almost 40% had MYCN amplification.
All patients began treatment with six cycles of induction chemotherapy, the first two cycles being dose-intensified cyclophosphamide/topotecan, followed by harvesting of peripheral blood stem-cell. After surgery the patients were randomized to single or tandem ASCT.
Patients randomized to a single transplant received additional chemotherapy, followed 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 post-transplant consolidation treatment with the immunotherapeutic agent anti-ganglioside GD2 antibody (dinutuximab, Unituxin) plus cytokines and isotretinoin.
The primary endpoint was 3-year event-free survival (EFS). 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=0.0081). The 3-year overall survival favored tandem transplant (74.0% versus 69.1%), but the difference did not attain statistical significance (P=01850).
Park said the patients would have to be followed considerably longer to determine whether tandem transplant improved overall survival. She also noted that an inability to account fully for additional treatment that patients might have received after transplant would complicate any analysis of overall survival.
Patients in both transplant groups had better EFS and overall survival when they also received anti-GD2, but an advantage still persisted for dual transplant. Among patients randomized to anti-GD2, the 3-year EFS was 73.7% with dual transplant and 56.0% with a single transplant (P=0.0033). The difference in overall survival attained statistical significance (83.7% versus 73.4%, P=0.0322).
Disclosures
The study was sponsored by the Children's Oncology Group and the National Cancer Institute.
Park disclosed a relationship with Roche.
Primary Source
American Society of Clinical Oncology
Park JR, et al "Tandem myeloablative autologous stem-cell transplant as consolidation therapy for high-risk neuroblastoma" ASCO 2016; Abstract LBA3.