Study Highlights Risks of Tandem ASCT in High-Risk Neuroblastoma

Zahra Hudda, MD

High-dose chemotherapy with tandem autologous stem cell transplants (ASCT) is standard for pediatric high-risk neuroblastoma, but severe complications impact outcomes. A multicenter study found a 94% 6-month survival rate post-ASCT, though conditions like veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) significantly lowered survival.¹

The retrospective multicenter study included 255 pediatric patients with HR-NB undergoing tandem ASCT between January 2014 and June 2021. Data collected included disease characteristics, transplant-related toxicities, and survival outcomes.

“Endothelial disorders were diagnosed in 5% of patients following Auto 1, preventing progression to Auto 2, and in 23% of patients following Auto 2, underscoring the need for routine screening and early intervention. Our 6-month overall survival of 94% highlights that organ toxicities, often linked to endothelial disorders, remain a significant cause of morbidity and mortality,” said Zahra Hudda, MD, pediatric bone marrow transplant physician at the Department of Pediatrics, University of Cincinnati College of Medicine, during a presentation of the data at the 2025 Tandem Meetings.

Among the 255 patients, 60% were male, and the median age at the time of diagnosis was 38.0 months (IQR, 24.6-62.5). Overall, 90.6% of patients had neuroblastoma, while 8.6% and 0.8% had ganglioneuroblastoma nodular and ganglioneuroma maturing/unspecified, respectively. The primary site of disease was seen in the abdomen/pelvis for 80.8% of patients, chest for 11%, neck for 2%, and was unspecified in 6.3%. Further, 85.9% of patients had unfavorable histology, 94.2% had metastatic disease, 74.1% had bone marrow involvement, MYC-N status was non-amplified or unspecified in 59.6% of patients, amplified in 32.3% of patients, and gain (3-4 copies) in 3.1% of patients.

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In the cohort, 242 (95%) completed both ASCT cycles, while 14 (5%) did not proceed to the second transplant due to persistent disease, VOD, TMA, immune dysregulation, or respiratory failure.

The primary end point of the study was to define the day-180 acute regimen-related toxicities in pediatric patients with HR-NV after tandem transplant, and the secondary end point was the cumulative incidence and day 180 overall survival (OS) of patients with endothelial disorders, including VOD, diffuse alveolar hemorrhage (DAH), and transplant-associated TMA (TA-TMA).

A total of 255 patients received their first transplant at a median of 45 months (range, 33.0-73.2 months) and a median cell dose of approximately 6 × 10⁶/kg. Patients were hospitalized for a median of 26 days (range, 22.0-33.0).

When assessing endothelial outcomes, 1 patient developed TMA, 9 patients developed VOD, 1 had diffuse alveolar hemorrhage, and 2 had both TMA and VOD. In total, 5% of patients were diagnosed with an endothelial disorder following the first autologous transplant.

Looking at the second autologous transplant, 6% of patients were unable to proceed. Among these 14 patients, 9 died following auto 1—7 of whom had refractory disease at the time of death. One patient experienced engraftment failure, and 1 had respiratory failure. Five patients survived, but 1 had severe multifocal pneumonia, 1 developed immune dysregulation, and 3 had the combination of TMA and VOD, preventing progression to tandem transplant.

A total of 241 patients proceeded to tandem transplant. These patients had a median age of 48 months (range 32.4-65.9), the median number of days was 56 (range, 50.0-62.0) between auto 1 and auto 2, and the median stem cell dose was 6.2 × 10⁶/kg. Patients were hospitalized for a median of 28 days (range, 23.0-37.0).

Among the 242 patients completing tandem ASCT, 17.1% developed bloodstream infections, 19.9% required ICU admission, and 12% experienced respiratory failure requiring intubation. Pulmonary hypertension was reported in 2.9% of cases. Acute kidney injury occurred in 17.8% of patients, with 4.6% requiring dialysis. Hypertension requiring 2 or more antihypertensives was observed in 14.9%.

Following tandem-transplant, 40 patients (16%) had TMA, 22 (9%) had VOD, and 9 (4%) had DAH. Regarding overlap of diagnoses, 27 patients had isolated TMA, 14 had isolated VOD, and one had isolated DAH. Six patients had both TMA and VOD, 6 had TMA and DAH, and 1 patient had all 3 conditions.

Risk Factors and Outcomes

Looking at TA-TMA, 40 patients met the diagnostic criteria and were treated. Among the 241 patients included in the study, 105 (43.6%) were prospectively screened for TMA, while 136 (56.4%) were not. The cumulative incidence of screened TMA was 25.7%, with most diagnoses occurring within 60 days post-transplant. A total of 9.5% of unscreened patients (n = 13) were diagnosed with TMA, with some diagnoses occurring up to 100 days post-transplant. Ninety-five percent of patients received 1 or more therapeutic agents, with 36 receiving a complement blocker, 4 undergoing plasmapheresis, and 4 receiving another agent.

Significant risk factors for TA-TMA included DAH, increased fever days, development of AKI, ICU admission, and respiratory failure requiring intubation. Death by day 180 was also significantly associated with TA-TMA. Attempts to analyze OS using Kaplan-Meier curves were inconclusive due to low event rates.

For VOD, the cumulative incidence was 9% (n = 22), and all patients were treated with defibrotide, with 3 receiving high-dose steroids. Five patients required peritoneal drain placement. Six-month OS was lower in patients with VOD, though statistical significance was limited due to sample size. Significant risk factors for VOD included increased fever days, bloodstream infections, AKI, ICU admission, and respiratory failure requiring intubation. Death by day 180 was also significantly associated with VOD.

Further, patients with DAH had significantly worse OS, though this result may be confounded by the fact that 7 of 9 patients with DAH also had TA-TMA, which was strongly associated on univariate analysis. However, the data highlight that patients with DAH tend to have poor outcomes overall.

At six months post-transplant, OS was 94%, with 14 patients dying at a median of 41 days (IQR, 8.5-82). The primary causes of death included respiratory failure (n = 4), multi-organ failure (n = 4), and primary VOD (n = 1). All deaths were likely driven by underlying endothelial activation. Other causes of death included infection, cardiac arrest, and relapsed disease.

“Future studies will focus on long-term outcomes, relapse rates, and the correlation of outcomes with prognostic factors and induction responses. As novel targeted agents and cellular therapies emerge, reducing endothelial dysfunction should remain a key focus,” Hudda concluded.

REFERENCE:

1. Hudda Z, Long Schoettler M, Rotz SJ, et al. Acute toxicities and early outcomes of tandem autologous stem cell transplantation in pediatric high-risk neuroblastoma: A multicenter study. Presented at the 2025 Tandem Meeting; February 12-15, 2025; Honolulu, HI. Presentation ID 441.