Tandem ASCT for neuroblastoma comes with caveat
Photo by Chad McNeeley
CHICAGO—A phase 3 study of tandem autologous stem cell transplant (ASCT) for children with high-risk neuroblastoma has shown that tandem transplant as consolidation significantly improved event-free survival (EFS).
Nevertheless, the improvement comes “with an important caveat,” according to Julie R. Park, MD, “that this is in children who survive induction without disease progression after induction or severe induction-related toxicity.”
Of note, the tandem transplant did not increase toxicity or regimen-related mortality.
Dr Park, of the Seattle Children’s Hospital and University of Washington, presented the study data on behalf of the Children’s Oncology Group and the COG ANBL0532 Study Committee during the plenary session at the 2016 ASCO Annual Meeting (LBA3*).
Neuroblastoma, Dr Park explained, is a disease that occurs in young children and is the most common extracranial tumor of childhood. Patients with high-risk neuroblastoma account for 50% of all children diagnosed with the disease, and neuroblastoma accounts for more than 10% of all childhood cancer mortality.
The outcome for high-risk neuroblastoma patients is dismal: fewer than 50% survive following current multi-agent, aggressive therapy, she said.
Randomized clinical trials performed over the last 25 years “have taught us that dose intensification of therapy is important,” Dr Park said, “and the treatment of minimal residual disease with non-cross resistant therapies is equally important.”
Pilot studies of tandem ASCT demonstrated tolerable toxicity and suggested efficacy, and clinical trials demonstrated that collecting peripheral blood stem cells in small children with neuroblastoma was feasible.
So the investigators undertook the current study to improve 3-year EFS of high-risk neuroblastoma patients using a strategy of tandem transplant consolidation.
Eligibility
Patients with newly diagnosed high-risk neuroblastoma were eligible. They had to have metastatic disease (INSS stage 4) and be older than 18 months to be eligible for the trial.
They could be any age if they had INSS stage 2, 3, or 4 with MYCN amplification.
“Our prior studies had identified that the group with regional disease and toddlers with MYCN non-amplified metastatic disease had a better outcome compared to other children with high-risk neuroblastoma,” Dr Park commented.
“Therefore, these children were non-randomly assigned to single transplant and are not included in the randomization results provided today,” she explained.
All children had to have normal cardiac, liver, and renal function.
Trial design: Induction
Induction therapy consisted of 6 cycles of chemotherapy—2 cycles of cyclophosphamide/topotecan, followed by 4 alternating cycles of cisplatin/etoposide and cyclophosphamide/vincristine/doxorubicin.
Peripheral blood stem cells (PBSCs) were harvested after the first 2 cycles of dose intensive cyclophosphamide and topotecan.
Patients had surgery on the primary tumor after 5 cycles of induction.
Trial design: Consolidation
Following completion of induction therapy, patients were assessed for eligibility for consolidation. These criteria included sufficient PBSC harvest, adequate organ function, no evidence of disease progression, and consent for post induction therapy.
Children eligible for consolidation were randomized to either the standard transplant with carboplatin, etoposide, melphalan or tandem transplant with cyclophosphamide and thiotepa followed 6 – 8 weeks later by the second transplant with carboplatin, etoposide, and melphalan.
Patients in both arms received radiotherapy to their primary tumor site.
Trial Design: Post-consolidation
Patients then went on for post consolidation chemotherapy with isotretinoin.
“During the conduct of ANBL0532,” Dr Park pointed out, “there was an additional trial running within the Children’s Oncology Group for which patients were eligible to enroll.”
So from 2007 – 2009, the additional trial (ANBL0032) randomized patients to their then standard of isotretinoin or isotretinoin plus the anti-GD2 antibody dinutuximab and cytokines.
