Stem cells for transplant
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.

“In 2009, results of that study were released and the dinutuximab arm was superior,” she noted, so patients were no longer randomized to isotretinoin only.

Prior studies indicated that 40% of patients went off trial at the end of induction therapy, so the investigators enrolled 665 patients to ensure a randomization of at least 332 patients.

Data cut-off for the presentation was March 31, 2016.

Patient demographics

Of the 665 patients accrued, 13 were ineligible. Twenty-seven patients with favorable prognosis were non-randomly assigned to single ASCT.

Forty percent (229 patients) went off protocol therapy prior to randomization. The main reasons for this were death (8 patients), progressive disease (48 patients), and physician and patient discretion (206 patients).

Investigators randomized 355 patients, 179 to single ASCT and 176 to tandem ASCT.

Patients were a median age of 37.2 months, 38.2% had MYCN amplification, and 88% were INSS stage 4.

The randomized cohorts of patients were similar to the overall patient cohort in terms of age, MYCN amplification, and stage 4 disease.

The randomizations were also well balanced in terms of MYCN amplifications, stage 4 disease, and response to induction chemotherapy.

The investigators retrospectively reviewed the patient characteristics, including age at diagnosis, early response to induction, and assignment to receive immunotherapy, “and there was no statistically significant difference between the randomized cohorts for these characteristics,” Dr Park said.

Safety

The most commonly observed grade 3 or greater non-hematologic toxicities in the single and tandem arms included infection (18.3% and 17.9%, respectively), mucosal toxicities (17.2% and 13.6%, respectively), and hepatic toxicities, including sinusoidal obstructive disorder (6.5% and 6.2%, respectively).

The investigators observed no significant differences between the arms in regard to the rate of these toxicities. In addition, they observed no difference between the arms in the rate of regimen-related mortality, 4.1% in the single arm, and 1.2% in the tandem arm.

Efficacy

For all patients (n=652) from time of enrollment, the 3-year EFS was 51.0% and the 3-year OS was 68.3%.

In randomized patients (n=355), from the time of randomization, the 3-year EFS was 54.8% and the 3-year OS, 71.5%, with a median survival time of 4.6 years.

There was a statistically significant improvement in EFS for those patients assigned to tandem transplant, with a 3-year EFS of 61.4% as compared to those assigned to single transplant, who had a 3-year EFS of 48.4% (P=0.0081).

There was not a statistically significant difference in OS. However, Dr Park pointed out that the trial was not powered to detect a difference in overall survival.

When looking at the cohort of stage 4 patients who were older than 18 months, investigators again saw a statistically significant improvement in EFS. The 3-year EFS was 59%.1 for tandem transplants vs 45.5% for single transplants, P=0.0083.

Again, there was no difference in OS in the INSS stage 4 patients older than 18 months.

“And finally, when we analyzed the outcome for children who were assigned to receive immunotherapy,” Dr Park pointed out, “from the time of start of immunotherapy, there was a statistically significant improvement in both event-free survival and overall survival for those children who received tandem transplants.”

The 3-year EFS for patients who received a tandem transplant and immunotherapy was 73.7% compared to the 3-year EFS of 56.0% for patients who received a single transplant and immunotherapy (P=0.0033).

The 3-year overall survival was also significantly improved for patients who received tandem transplants and immunotherapy (83.7%) compared to those who received a single transplant and immunotherapy (74.4%) (P=0.0322).

Conclusions

“Tandem transplant consolidation improves outcome in patients with high-risk neuroblastoma,” Dr Park said, with the important caveat mentioned earlier.

The tandem transplant does not increase toxicity or regimen-related mortality, and the benefit of tandem ASCT remains following anti-GD2-directed immunotherapy.

*Data in the presentation differ slightly from the abstract

Tandem ASCT for neuroblastoma comes with caveat