DISCUSSION
This is the first COG study to examine the impact of CS in the setting of tandem AHCT. Our study identified optimal CS cut points with prognostic significance at diagnosis (CS=12) and EOI (CS=0) in a subset of patients with INSS stage 4 disease who received tandem AHCT on COG ANBL0532. Patients with a CS< 12 at diagnosis had a statistically significantly higher 3-year EFS and OS when compared to those with a CS>12 at the same timepoint. Patients with a CS=0 at EOI also had a statistically significantly higher 3-year EFS and OS than those with CS>0 at EOI.
The role of CS as a prognostic indicator in high-risk neuroblastoma has been reported within the context of clinical trials utilizing single AHCT, both within COG and European cooperative groups.12,13,22-24 In a prior COG study, we found no correlation between CS at diagnosis and subsequent outcome following a single AHCT.12 In contrast, a prior SIOPEN study noted the prognostic impact of skeletal-only mIBG scores at initial diagnosis, using either a SIOPEN-specific or a CS system for analysis.13,14 Within both COG and SIOPEN, an optimal mIBG cut point at EOI was described for single AHCT recipients, with EOI CS≤2 associated with improved outcomes in patients treated on COG A397312 or SIOPEN-HR-NBL-1.13 Our current study confirmed this optimal CS cut point (CS=2) in single AHCT recipients, though the differences in EFS (CS< 2 vs CS>2) were not significant.
Important distinctions should be noted between the CS performed on tandem AHCT recipients on COG ANBL0532 and the scoring performed on single AHCT recipients on COG A3973. Curie scoring in ANBL0532 involved a more contemporary group of patients, with 70% of patients receiving immunotherapy with dinutuximab and cytokines following tandem AHCT. In contrast, less than 20% of patients with Curie scoring performed in COG A3973 received similar immunotherapy. Whereas CS from patients treated on COG A3973 identified an ultra-high-risk group of patients with poor outcomes (3-year EFS=15%), our current CS analysis of ANBL0532 tandem AHCT recipients did not identify an ultra-high-risk group, but instead identified a potentially more favorable risk group (CS=0 at EOI) with promising 3-year EFS (73%) and 3-year OS (83%). Conversely, tandem AHCT recipients with a CS>0 at EOI in our current analysis had similar 3-year EFS as the “favorable” risk group (CS<2) identified in our prior COG A3973 analysis, with 3-year EFS of 46.5% and 44.9% respectively.12
The current practice for disease response evaluation has changed since the COG A3973 analysis, with the revision of the INRC in 2017.18 The revised INRC include assessment of response in the primary tumor, bone marrow and metastatic disease sites, with CS now incorporated into the metastatic response assessment. In particular, INRC currently define a metastatic response as a 50% reduction in Curie scores from diagnosis to the evaluation timepoint. However, based upon our current analysis, the absolute score should be considered instead of a “relative reduction in score” for assessing response in metastatic sites. We found no difference in outcomes based upon the relative reduction of CS from diagnosis to EOI (TABLE 2) . Several previous studies also reported that relative reductions in CS did not provide additional prognostic information when compared with absolute scores alone, including results from COG A3973,12 the German Neuroblastoma Trial NB97,22 and SIOPEN HR-NBL1.13 In future studies, we will prospectively examine the CS cut points at diagnosis and EOI using both an absolute CS and a 50% relative reduction in CS, to determine if the INRC definition of metastatic response should be redefined for EOI response.
The outcome differences noted in our study were most striking in patients with MYCN -amplified disease, in which patients with a diagnostic CS>12, or CS>0 at EOI had extremely poor outcomes. Definitive conclusions regarding the impact of CS in patients with MYCN -amplified disease are difficult to make, given the small sample size of the MYCN -amplified cohort in our current study. Further analysis of the impact of CS in patients withMYCN -amplified disease will be performed in upcoming COG high-risk neuroblastoma therapy trials.
One major limitation of this study is the potential for selection bias, as a more favorable group of patients may have comprised the subset that underwent randomization and completed consolidation treatment on ANBL0532. Our study excluded patients with neuroblastoma progression during induction (or prior to consolidation therapy), patients who refused randomization, and patients who died and/or had organ toxicity that precluded continuation on protocol therapy during induction. The small sample size of the patient cohort in the current analysis was also a limitation, particularly for those with MYCN- amplified tumors.