PURPOSE:Chemoimmunotherapy with irinotecan, temozolomide, and dinutuximab (I/T/DIN) has emerged as first-line therapy for relapsed/refractory (r/r) high-risk neuroblastoma (HRNB) in North America. Topotecan and cyclophosphamide (T/C) are often used in combination with dinutuximab in the setting of lack of response, progression, or incomplete response following I/T/DIN, but efficacy and tolerability are unknown. METHODS:Eligible patients received one or more cycles of T/C/DIN for r/r HRNB. Response was assessed using the 2017 International Neuroblastoma Response Criteria. RESULTS:Fifty-four patients with r/r HRNB were included. Patients received a median of four cycles of T/C/DIN (range = 1-16); 48 (89%) had previously received I/T/DIN. Twenty-three patients (42.6%) had an objective response (complete/partial/minor; OR) to T/C/DIN, 21 (38.9%) had stable disease, and 10 (18.5%) had progressive disease as best response. Among patients who previously received I/T/DIN, objective response rate (ORR) to T/C/DIN was 54% in those with prior OR to I/T/DIN and 23% in those without prior OR (adjusted odds ratio 4.40, 95% confidence interval [CI]: 1.09-17.75). Patients who had experienced on-therapy progression with I/T/DIN had a similar ORR to T/C/DIN compared to those who never progressed (38% vs. 41%, p = 1.0). Twenty-one patients (39%) required T/C/DIN dose modification-11 (52%) due to hematologic toxicity. Seven patients (13%) discontinued T/C/DIN due to toxicity. CONCLUSION:T/C/DIN is an effective regimen for patients with r/r HRNB, producing ORRs similar to prior reports in chemoimmunotherapy-naïve patients treated with I/T/DIN. Prior chemoimmunotherapy response may predict response to T/C/DIN, but even patients who progress while receiving I/T/DIN may benefit from the T/C/DIN combination.

Importance Whether population-based racial and ethnic survival disparities for children with high-risk neuroblastoma persist in the clinical trial setting is unknown. Objective To investigate racial and ethnic survival disparities among children with high-risk neuroblastoma treated on frontline clinical trials. Design, Setting, and Participants This retrospective cohort study used data from Children’s Oncology Group (COG) high-risk neuroblastoma trials from January 1, 2007, to December 31, 2016, with a data freeze on June 30, 2021. Children with high-risk neuroblastoma were analyzed in 2 cohorts: induction/consolidation trial participants and post-consolidation trial participants. Statistical analyses were performed from September 2, 2021, to December 30, 2024. Exposures Race and ethnicity were the primary exposures, categorized as Hispanic, non-Hispanic Black, non-Hispanic other (American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander), or non-Hispanic White. Main Outcomes and Measures Primary outcomes included overall survival (OS) and event-free survival (EFS) from time of trial enrollment, estimated by Kaplan-Meier methods. Associations with race and ethnicity were evaluated by log-rank tests and Cox proportional hazards regression models. Secondary outcomes included induction delays, early trial withdrawal, relapse as first event, death as first event, postrelapse OS, and early phase trial enrollment. Results The induction/consolidation cohort (median follow-up, 8.3 years [IQR, 6.1-9.8 years]) included 696 patients (404 males [58.1%]; 79 Hispanic patients [11.4%], 109 non-Hispanic Black patients [15.7%], 27 patients of non-Hispanic other race [3.9%], and 481 non-Hispanic White patients [69.1%]). The post-consolidation cohort (median follow-up, 7.5 years [IQR, 5.8-9.4 years]) included 935 patients (567 males [60.6%]; 87 Hispanic patients [9.3%], 145 non-Hispanic Black patients [15.5%], 41 patients of non-Hispanic other race [4.4%], and 662 non-Hispanic White patients [70.8%]). In multivariable Cox proportional hazards regression models, Hispanic children experienced significantly inferior OS (hazard ratio [HR], 1.78; 95% CI, 1.25-2.53; P = .01) on induction/consolidation studies compared with non-Hispanic White children; EFS did not differ. Non-Hispanic Black (HR, 1.54; 95% CI, 1.13-2.11) and Hispanic children (HR, 1.63; 95% CI, 1.09-2.43) experienced inferior OS on post-consolidation studies compared with non-Hispanic White children ( P = .009); Hispanic children in post-consolidation studies experienced inferior EFS (HR, 1.68; 95% CI, 1.14-2.47; P = .02). Death as first event and postrelapse OS also differed by race and ethnicity. Conclusions and Relevance This study suggests that Black and Hispanic children with high-risk neuroblastoma experienced inferior OS despite uniform planned treatment on frontline COG clinical trials. Investigated mechanisms did not completely explain survival disparities. Future evaluation of disparate treatment-related toxicities and postrelapse care as explanatory mechanisms are key next steps to promote equity.

Importance Whether population-based racial and ethnic survival disparities for children with high-risk neuroblastoma persist in the clinical trial setting is unknown. Objective To investigate racial and ethnic survival disparities among children with high-risk neuroblastoma treated on frontline clinical trials. Design, Setting, and Participants This retrospective cohort study used data from Children's Oncology Group (COG) high-risk neuroblastoma trials from January 1, 2007, to December 31, 2016, with a data freeze on June 30, 2021. Children with high-risk neuroblastoma were analyzed in 2 cohorts: induction/consolidation trial participants and post-consolidation trial participants. Statistical analyses were performed from September 2, 2021, to December 30, 2024. Exposures Race and ethnicity were the primary exposures, categorized as Hispanic, non-Hispanic Black, non-Hispanic other (American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander), or non-Hispanic White. Main Outcomes and Measures Primary outcomes included overall survival (OS) and event-free survival (EFS) from time of trial enrollment, estimated by Kaplan-Meier methods. Associations with race and ethnicity were evaluated by log-rank tests and Cox proportional hazards regression models. Secondary outcomes included induction delays, early trial withdrawal, relapse as first event, death as first event, postrelapse OS, and early phase trial enrollment. Results The induction/consolidation cohort (median follow-up, 8.3 years [IQR, 6.1-9.8 years]) included 696 patients (404 males [58.1%]; 79 Hispanic patients [11.4%], 109 non-Hispanic Black patients [15.7%], 27 patients of non-Hispanic other race [3.9%], and 481 non-Hispanic White patients [69.1%]). The post-consolidation cohort (median follow-up, 7.5 years [IQR, 5.8-9.4 years]) included 935 patients (567 males [60.6%]; 87 Hispanic patients [9.3%], 145 non-Hispanic Black patients [15.5%], 41 patients of non-Hispanic other race [4.4%], and 662 non-Hispanic White patients [70.8%]). In multivariable Cox proportional hazards regression models, Hispanic children experienced significantly inferior OS (hazard ratio [HR], 1.78; 95% CI, 1.25-2.53; P = .01) on induction/consolidation studies compared with non-Hispanic White children; EFS did not differ. Non-Hispanic Black (HR, 1.54; 95% CI, 1.13-2.11) and Hispanic children (HR, 1.63; 95% CI, 1.09-2.43) experienced inferior OS on post-consolidation studies compared with non-Hispanic White children (P = .009); Hispanic children in post-consolidation studies experienced inferior EFS (HR, 1.68; 95% CI, 1.14-2.47; P = .02). Death as first event and postrelapse OS also differed by race and ethnicity. Conclusions and Relevance This study suggests that Black and Hispanic children with high-risk neuroblastoma experienced inferior OS despite uniform planned treatment on frontline COG clinical trials. Investigated mechanisms did not completely explain survival disparities. Future evaluation of disparate treatment-related toxicities and postrelapse care as explanatory mechanisms are key next steps to promote equity.

PURPOSE:We conducted a phase I trial to determine the safety, tolerability, and preliminary antitumor activity of 131I-metaiodobenzylguanidine (MIBG) combined with the anti-GD2 antibody dinutuximab with or without the histone deacetylase inhibitor vorinostat in patients with relapsed/refractory neuroblastoma (rNBL). METHODS:In part A, patients with MIBG-avid rNBL received MIBG intravenously (IV) on day 1 at 12, 15, or 18 mCi/kg per the rolling six design and dinutuximab (17.5 mg/m2 once daily) IV on days 8-11 and 29-32 and granulocyte-macrophage colony-stimulating factor (250 mcg/m2 once daily) subcutaneously on days 8-17 and 29-38. Autologous stem cells were infused on day 15. In part B, vorinostat at 180 mg/m2 once daily was given orally on days 0-13 in combination with the part A recommended phase II dose (RP2D). Patients could receive two courses. RESULTS:Forty-five eligible patients enrolled, of whom 31 were evaluable. The median age was 7.5 (range, 2.9-24.1) years. For part A (n = 19), no dose-limiting toxicities (DLTs) occurred across all dose levels and courses, establishing the RP2D of MIBG to be 18 mCi/kg. In part B (n = 12), 1 DLT (grade 3 hypokalemia) occurred during course 1, and 3 of 11 patients who received a second course experienced DLT: grade 3 ALT increase, grade 4 hypoxia and grade 5 pneumonitis, and grade 3 fatigue. The best overall response rate (BORR; complete response [CR] + partial response [PR]) on part A was 42% with a CR/PR/minor response (MR) rate of 46%, and 19% progressive disease (PD) rate. For part B, the BORR was 42% with a CR/PR/MR rate of 75% and 0% PD rate. CONCLUSION:MIBG combined with dinutuximab was well tolerated with encouraging antitumor activity. Vorinostat added to this combination may augment responses in this heavily pretreated patient population.

Background: Response to induction chemotherapy has been shown to predict outcome in patients with high-risk neuroblastoma (HR-NB), with those achieving a complete response (CR) having superior outcomes. Methods: We evaluated whether conventional prognostic factors remain prognostic in subsets of patients defined by response to induction. 1244 Patients from four COG high-risk trials were included. End-induction response was coded as CR, partial response (PR) or better, less than PR without progressive disease (PD), and PD. Cox regression models were performed to calculate event-free and overall survival (EFS, OS) hazard ratios, including interaction terms between induction response and prognostic factors including sex, age, stage, primary tumor location, LDH, ferritin, ploidy, MYCN status, ALK status, histology, MKI, grade, and study era. Results: Among patients who achieved a CR after induction, INSS stage 4 disease and trial era were the only factors that remained significantly associated with inferior OS. For those who achieved less than a PR, adrenal primary site, MYCN amplification, and 1p LOH were associated with inferior outcomes. Multivariable models showed that end-induction response remained prognostic of EFS and OS even after controlling for other factors. Multiple significant statistical interactions were observed between end-induction response and other prognostic factors. Conclusion: The impact of conventional prognostic factors is not static in patients with HR-NB. Instead, response to induction chemotherapy modifies the effect of conventional prognostic factors. These data can help to further refine prognosis for patients with variable responses to induction and help to identify candidates who might benefit from treatment other than standard post-induction therapy.

10004 Background: Post-consolidation anti-GD2 antibody-based immunotherapy has improved survival for newly diagnosed patients (pts) with high-risk neuroblastoma (HRNBL). However, nearly half of newly diagnosed pts relapse. Based upon the efficacy of anti-GD2 antibody dinutuximab given with chemotherapy (chemoimmunotherapy) in the relapse setting, we hypothesized that post-consolidation chemoimmunotherapy may further improve frontline outcomes. ANBL19P1 first assessed the feasibility of delivering chemoimmunotherapy after tandem high-dose chemotherapy with autologous stem cell transplant (ASCT). Methods: Pts <31 years old with HRNBL who received 4-6 cycles of Induction chemotherapy +/- up to 4 cycles of post-Induction chemotherapy or chemoimmunotherapy, underwent tandem ASCT, had no evidence of progressive disease (PD), and met organ function criteria were eligible. Therapy, administered every 28 days, consisted of temozolomide and irinotecan on Days 1-5, dinutuximab on Days 2-5, and sargramostim on Days 6-12 during Cycles 1-5; isotretinoin on Days 8-21 during Cycles 1-6. Therapy was deemed feasible if the 95% confidence interval (CI) placed on the percentage of pts that completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks contained 75%, and if the interim monitoring rules for feasibility and excessive toxicity were not triggered. Event-free (EFS) and overall survival (OS) were determined from time of enrollment. Results: From 11/30/20-6/30/23, 40 eligible pts enrolled and started protocol therapy. 87.5% (n=35) were ≥18 months old and 97.5% (n=39) had INRG Stage M disease, at diagnosis. 87.5% (95% CI 73.9%, 94.5%) completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks, exceeding the feasibility benchmark of 75%. Feasibility and monitoring rules were not triggered. Five pts were removed from protocol therapy prior to Cycle 4 [physician determination (n=2), pt/parent refusal of further therapy (n=2), and PD (n=1)]. No unacceptable toxicities or deaths on protocol therapy were reported. Toxicities of interest are summarized (Table). One-year EFS and OS were 90.0±5.0% and 97.5±2.7%, respectively (median follow-up time for pts without event=1.2 years). Conclusions: Administration of post-consolidation chemoimmunotherapy in pts who underwent tandem ASCT is tolerable and met pre-defined feasibility criteria. The impact of this approach on survival outcomes will be studied in a future COG trial. Clinical trial information: NCT04385277 . [Table: see text]

Change in BM and Blood NB5 ÃŽâ€Ct for patients with progressive disease vs. non-progressive disease. Change in NB5 ÃŽâ€Ct was assessed between pairs of time points where both NB5 ÃŽâ€Ct and clinical disease assessments were performed. Observations are classified by whether there was clinical disease progression or not between the time points.

Supplementary Figure Legends for A1-A3

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123 I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45–115 mg/m 2 /dose in children and 100–150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m 2 . The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib’s rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988 .

BACKGROUND:Many parents of children with advanced cancer report curative goals and continue intensive therapies that can compound symptoms and suffering. Factors that influence parents to choose palliation as the primary treatment goal are not well understood. The objective of this study was to examine experiences impacting parents' report of palliative goals adjusted for time. The authors hypothesized that awareness of poor prognosis, recall of oncologists' prognostic disclosure, intensive treatments, and burdensome symptoms and suffering would influence palliative goal-setting. METHODS:The authors collected prospective, longitudinal surveys from parents of children with relapsed/refractory neuroblastoma at nine pediatric cancer centers across the United States, beginning at relapse and continuing every 3 months for 18 months or until death. Hypothesized covariates were examined for possible associations with parental report of palliative goals. Generalized linear mixed models were used to evaluate factors associated with parents' report of palliative goals at different time points. RESULTS:A total of 96 parents completed surveys. Parents were more likely to report a primary goal of palliation when they recalled communication about prognosis by their child's oncologist (odds ratio [OR], 52.48; p = .010). Treatment intensity and previous ineffective therapeutic regimens were not associated with parents' report of palliative goals adjusted for time. A parent who reported new suffering for their child was less likely to report palliative goals (OR, 0.13; p = .008). CONCLUSIONS:Parents of children with poor prognosis cancer may not report palliative goals spontaneously in the setting of treatment-related suffering. Prognostic communication, however, does influence palliative goal-setting. Evidence-based interventions are needed to encourage timely, person-centered prognostic disclosure in the setting of advanced pediatric cancer. PLAIN LANGUAGE SUMMARY:Many parents of children with poor-prognosis cancer continue to pursue curative treatments that may worsen symptoms and suffering. Little is known about which factors influence parents to choose palliative care as their child's main treatment goal. To explore this question, we asked parents of children with advanced neuroblastoma across the United States to complete multiple surveys over time. We found that the intensity of treatment, number of treatments, and suffering from treatment did not influence parents to choose palliative goals. However, when parents remembered their child's oncologist talking about prognosis, they were more likely to choose palliative goals of care.

PURPOSE Although chemoimmunotherapy is widely used for treatment of children with relapsed high-risk neuroblastoma (HRNB), little is known about timing, duration, and evolution of response after irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) therapy. PATIENTS AND METHODS Patients eligible for this retrospective study were age < 30 years at diagnosis of HRNB and received ≥ 1 cycle of I/T/DIN/GM-CSF for relapsed or progressive disease. Patients with primary refractory disease who progressed through induction were excluded. Responses were evaluated using the International Neuroblastoma Response Criteria. RESULTS One hundred forty-six patients were included. Tumors were MYCN-amplified in 50 of 134 (37%). Seventy-one patients (49%) had an objective response to I/T/DIN/GM-CSF (objective response; 29% complete response, 14% partial response [PR], 5% minor response [MR], 21% stable disease [SD], and 30% progressive disease). Of patients with SD or better at first post-I/T/DIN/GM-CSF disease evaluation, 22% had an improved response per International Neuroblastoma Response Criteria on subsequent evaluation (13% of patients with initial SD, 33% with MR, and 41% with PR). Patients received a median of 4.5 (range, 1-31) cycles. The median progression-free survival (PFS) was 13.1 months, and the 1-year PFS and 2-year PFS were 50% and 28%, respectively. The median duration of response was 15.9 months; the median PFS off all anticancer therapy was 10.4 months after discontinuation of I/T/DIN/GM-CSF. CONCLUSION Approximately half of patients receiving I/T/DIN/GM-CSF for relapsed HRNB had objective responses. Patients with initial SD were unlikely to have an objective response, but > 1 of 3 patients with MR/PR on first evaluation ultimately had complete response. I/T/DIN/GM-CSF was associated with extended PFS in responders both during and after discontinuation of treatment. This study establishes a new comparator for response and survival in patients with relapsed HRNB.

Table A1. Therapies received for samples submitted on this study; Table A2. Genes and Primer and Probe Sets for NB5 assay; Table A3. Clinical Evaluations and NB5 TLDA Assays Performed; Table A4. Contribution of Individual Gene to NB5 Signature and AUC.

BACKGROUND:Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma. METHODS:Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein. RESULTS:Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for <PR; p = .0014). VMAT2 H-score was not significantly associated with PR or higher versus less than PR, though patients with PR or higher had lower VMAT2 staining intensity (p = .005). VMAT2 H-score was significantly lower in patients with complete response (median 40 vs. 210 for patients with <complete response; p = .0049). VMAT2 H-scores were significantly higher in ganglioneuroblastoma (vs. neuroblastoma; p = .037), differentiated/poorly differentiated tumors (vs. undifferentiated; p = .0047), and tumors lacking MYCN amplification (vs. MYCN amplified; p = .0011). CONCLUSIONS:Markers of lower NET and VMAT2 protein expression are associated with higher likelihood of response to 131 I-MIBG therapy in patients with relapsed/refractory neuroblastoma. Increased VMAT2 protein expression is associated with a more differentiated disease phenotype.

Correlation of morphologically-defined NB cells in BM and MIBG Curie score. Analysis of BM biopsies and MIBG scans were performed concurrently on 173 patients.

Supplemental Figure 1. PCR cycle count for NET mRNA expression in peripheral blood mononuclear cells from 7 patients obtained on Day 1 and/or 3 of protocol therapy.

131I-metaiodobenzylguanidine (131I-mIBG) is a targeted radiation therapy developed for the treatment of advanced neuroblastoma. We have previously shown that this patient cohort can be used to predict absorbed dose associated with early 131I exposure, 72 h after treatment. We now expand these studies to identify gene expression differences associated with 131I-mIBG exposure 15 days after treatment. Total RNA from peripheral blood lymphocytes was isolated from 288 whole blood samples representing 59 relapsed or refractory neuroblastoma patients before and after 131I-mIBG treatment. We found that several transcripts predictive of early exposure returned to baseline levels by day 15, however, selected transcripts did not return to baseline. At 72 h, all 17 selected pathway-specific transcripts were differentially expressed. Transcripts CDKN1A (P < 0.000001), FDXR (P < 0.000001), DDB2 (P < 0.000001), and BBC3 (P < 0.000001) showed the highest up-regulation at 72 h after 131I-mIBG exposure, with mean log2 fold changes of 2.55, 2.93, 1.86 and 1.85, respectively. At day 15 after 131I-mIBG, 11 of the 17 selected transcripts were differentially expressed, with XPC, STAT5B, PRKDC, MDM2, POLH, IGF1R, and SGK1 displaying significant up-regulation at 72 h and significant down-regulation at day 15. Interestingly, transcripts FDXR (P = 0.01), DDB2 (P = 0.03), BCL2 (P = 0.003), and SESN1 (P < 0.0003) maintained differential expression 15 days after 131I-mIBG treatment. These results suggest that transcript levels for DNA repair, apoptosis, and ionizing radiation-induced cellular stress are still changing by 15 days after 131I-mIBG treatment. Our studies showcase the use of biodosimetry gene expression panels as predictive biomarkers following early (72 h) and late (15 days) internal 131I exposure. Our findings also demonstrate the utility of our transcript panel to differentiate exposed from non-exposed individuals up to 15 days after exposure from internal 131I.

10026 Background: 131I-metaiodobenzylguanidine (131I-MIBG) has demonstrated efficacy as a single agent for patients with neuroblastoma. Recent trials have focused on 131I-MIBG combination strategies, though little is known about the impact of combination agents on markers of radiation exposure. Methods: NANT11-01 (NCT02035137) was a multicenter, open label, randomized phase II clinical trial that evaluated 131I-MIBG therapy alone (Arm A) or in combination with vincristine/irinotecan (Arm B) or vorinostat (Arm C) for patients with resistant/relapsed neuroblastoma. We collected blood samples at baseline, 72 hours, 96 hours, and 15 days after 131I-MIBG infusion and determined levels of plasma FLT3 ligand, serum amylase, and gene expression for selected RNA transcripts (apoptosis, DNA damage response and cell cycle related). We evaluated marker association with treatment arm, clinical response using NANT response criteria, toxicity, and whole-body radiation dose. Results: The cohort included 99 patients who had at least one biomarker available for analysis (32 Arm A; 35 Arm B; 32 Arm C). We observed both positive and negative significant modulation in most biomarkers between baseline, 72 hours, and 96 hours following 131I-MIBG. Patients in Arm C had the lowest degree of modulation in FLT3 ligand. Elevated baseline levels of FLT3 ligand were significantly associated with improved Curie response but not overall response. Lower baseline BCL2 levels were associated with higher overall and Curie response. Patients with increased FLT3 ligand at 96 hours after 131I-MIBG therapy were significantly more likely to have grade 4 thrombocytopenia.Peripheral blood gene expression of the BCL2 family of apoptotic markers (BCL2/L1 and BAX) was significantly associated with grade 4 hematological toxicity. Whole-body radiation dose and PRKDC fold change at 72 hours were significantly correlated. No other individual biomarkers were correlated with whole body radiation dose at 72 or 96 hours post 131I-MIBG. Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation over time after 131I-MIBG treatment. Biomarkers related to hematopoietic damage and apoptosis were associated with hematological toxicity. Patients treated with vorinostat and 31I-MIBG had differential modulation of FLT3-ligand Further use of these biomarkers may improve our ability to care for patients treated with 131I-MIBG.

e22003 Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. The clinical and biologic predictors of response to MIBG therapy have not been systematically characterized in a recent era trial. Methods: Patients 1-30 years were enrolled on the randomized phase 2 trial of MIBG vs. MIBG/vincristine/irinotecan vs. MIBG/vorinostat for relapsed/refractory neuroblastoma (NANT2011-01, NCT02035137) between 2014-2019. Data were compared between those who had an objective response (partial response or better using NANT response criteria) to MIBG after the first cycle and those who did not according to clinical features (age at study enrollment; sex; response to prior therapy; prior receipt of MIBG therapy; bone marrow involvement at study enrollment; and measurable disease status at study enrollment) and MYCN status. Univariate analyses were performed using odds ratio and Fisher exact tests. Multivariate logistic regression analysis was used to identify predictors of response to MIBG therapy while controlling for key confounders. Results: 105 response-evaluable patients were included in the analytic cohort. Across the 3 study arms, 20% (21/105) had an objective response to the treatment. Only measurable disease status was statistically significantly associated with response to therapy, with higher rates of response among patients without measurable disease at study enrollment (30% vs. 13%, p = 0.049). Response to prior therapy, sex, MYCN status, and measurable disease status showed univariate odds ratios of 2 or greater (Table). Only measurable disease status remained statistically significant in the multivariate analysis (p = 0.043, Table). Conclusions: Patients without measurable disease have a higher rate of objective responses to MIBG therapy. Understanding these differences based upon predictors of response may help to inform stratification methods for future MIBG clinical trials.[Table: see text]