10029 Background: Several aggressive pediatric and young adult cancers are characterized by loss of INI1 expression, including malignant rhabdoid tumor, ATRT, epithelioid sarcoma and poorly differentiated chordoma. These cancers have a poor prognosis and limited effective treatments for relapsed or refractory disease. Prior data nominated immune checkpoint inhibition as a potential strategy for INI1-deficient tumors. Methods: In this phase II multicenter trial of nivolumab and ipilimumab, patients 6 months to 40 years with relapsed or refractory INI1-deficient cancers were enrolled in two strata: extracranial solid tumors (Stratum 1) and CNS tumors (Stratum 2). The primary endpoint was objective response ≥partial response (PR) by RECIST v1.1 (Stratum 1) or RANO (Stratum 2). Secondary endpoints included progression-free survival, overall survival and 12-month disease control rate. Patients received nivolumab 3mg/kg and ipilimumab 1mg/kg every 3 weeks for 4 cycles followed by nivolumab 3mg/kg every 2 weeks for up to 1 year. A Simon’s two-stage design targeted a response rate >25%, with each stratum assessed separately. Interim analysis at Stage 1 required ≥1 of 10 patients to have response ≥PR to proceed to Stage 2; at Stage 2, ≥3 of 20 patients with response ≥PR for evidence of efficacy. Evaluable patients received study treatment and were assessed for response or had progressive disease. Results: Thirty patients from six centers enrolled across both Strata from 8/2020 to 5/2025 and 27 were evaluable for the primary endpoint. Three inevaluable Stratum 1 patients were replaced per protocol. In Stratum 1, 1 patient (with poorly-differentiated chordoma) of 20 evaluable patients had ≥PR (ORR: 5%; 95% CI: 0.1-25%). In Stratum 1 (n=20), the 3-month EFS±SE and OS±SE were 20%±9% and 60%±11%, respectively, and the proportion of patients who were progression-free at 12-months was 5% (95%CI=0.1%-25%). Stratum 2 closed early with 7 patients enrolled, too few for Stage 1 interim analysis. No Stratum 2 patients had ≥PR [ORR: 0% (n=7)]. Patients received a median of 2 cycles of study treatment. The most common ≥ grade 3 treatment-related adverse events were decreased lymphocyte count (n=3), increased AST (n=3) anemia (n=2), and pneumonitis (n=2). Conclusions: The study did not meet the predetermined threshold for efficacy for Stratum 1. Immune checkpoint inhibitor therapy could warrant further exploration in poorly differentiated chordoma. Clinical trial information: NCT04416568 . Patient characteristics (n=27 evaluable patients). Median (Range) Age at enrollment (years) 7.1 (0.6-37.6) Lines of prior therapy 2 (1-7) n (%) Age group <18 yrs 24 (89%) ≥18 yrs 3 (11%) Sex Male 15 (56%) Female 12 (44%) Cancer diagnosis Stratum 1 20 (74%) Malignant Rhabdoid Tumor 12 (60%) Poorly Differentiated Chordoma 3 (15%) Epithelioid Sarcoma 2 (10%) Other 3 (15%) Stratum 2 7 (26%) Atypical Teratoid Rhabdoid Tumor 7 (100%)

10028 Background: Neuroblastoma is a malignant childhood tumor with a low somatic mutation rate, making targeted therapy challenging. Using a targeted NGS panel in a large real-world cohort, we identified recurrent variants and assessed the clinical impact of NGS for this disease. Methods: A real-world cohort of 185 peripheral neuroblastic tumor samples from 181 patients were sequenced with a targeted NGS assay (OncoPanel). Samples were either obtained at baseline (“diagnostic”) or at relapse/progression (“relapse”). Variants include SNVs, CNAs, and SVs and were manually curated for pathogenicity. Recurrently altered genes were those curated as Pathogenic/Likely Pathogenic and occurring in more than 4% of samples. Clinically impactful findings were those with therapeutic implications (e.g., targetable ALK aberration) and those with prognostic implications at diagnosis (e.g. MYCN amplifications or segmental chromosomal aberrations (SCAs) included in the Children’s Oncology Group (COG) risk stratification system). SCAs were defined as regions of loss or gain of at least 3Mb. Mutual exclusivity analyses utilized false-discovery rate corrected Fisher exact tests. Results: All COG risk groups were represented. At time of last follow-up (median 65.9 months), 103 (59%) were alive with no disease, 31 (18%) were alive with disease or unknown disease status, and 41 (23%) were deceased. Of the diagnostic cohort (n=144), 78 (54%) had at least one clinically impactful alteration (n=42 prognostic only, n=13 therapeutic only, n=23 both). Of the relapse cohort (n=41), 14 (34%) had a therapeutically impactful variant. Recurrently altered genes in the diagnostic samples included MYCN , ALK, ATRX and MYCN , ALK, ATRX, BRAF, CREBBP, MLH3, PHOX2B and TERT in the relapse samples . The most commonly observed SCA was 17q gain. Among the 144 diagnostic samples, no patients were observed to have both MYCN amplification and an ATRX variant nor MYCN amplification and 11q loss; this mutual exclusivity was statistically significant for MYCN amplification and 11q loss (adjusted p <0.001). Conclusions: Targeted NGS panels provided clinically impactful results in a majority of cases in a real-world cohort of children with neuroblastoma. Future analyses will include survival analysis by genomic features and comparison of NGS to standard clinical testing. Key genomic findings across clinical cohorts. Diagnosis (n=144) Relapse (n=41) High-risk (HR)(n=53) Non-HR(n=62) ALK variant 29 (20.1%) 8 (19.5%) 14 (26.4%) 9 (14.5%) ATRX variant 7 (4.9%) 3 (7.3%) 5 (9.4%) 1 (1.6%) BRAF variant 1 (0.7%) 3 (7.3%) 0 (0%) 1 (1.6%) PHOX2B variant 5 (3.5%) 2 (4.9%) 4 (7.5%) 1 (1.6%) MYCN amplification 27 (18.8%) 10 (24.4%) 16 (30.2%) 3 (4.8%) 17q gain 87 (60.4%) 27 (65.9%) 33 (62.3%) 39 (62.9%) 1p loss 17 (11.8%) 11 (26.8%) 12 (22.6%) 3 (4.8%) 11q loss 35 (24.3%) 12 (29.3%) 14 (26.4%) 17 (27.4%)

ABSTRACT:Langerhans cell histiocytosis (LCH) and non-Langerhans cell (non-LC) histiocytosis are rare neoplastic diseases with variable behavior. Although chemotherapy is often effective, some patients respond poorly to treatment, experience disease recurrence and/or develop long-term complications. Clofarabine (Clolar), a deoxyadenosine analog, has shown encouraging activity in histiocytic disorders. Here, we report a prospective, multicenter, phase 2 study evaluating the efficacy and toxicity of clofarabine in recurrent/refractory (R/R) LCH (stratum 1) and non-LC histiocytosis (stratum 2). All participants received clofarabine on days 1 through 5 of each 28-day cycle. Response was assessed after 2 cycles; participants without evidence of disease progression received 4 additional cycles. A total of 25 participants enrolled: 20 in stratum 1 and 5 in stratum 2. In stratum 1, 17 of 20 participants (85%; 95% confidence interval [CI], 62%-97%) were responders, and 3 had stable disease after cycle 2. Overall, 19 stratum-1 participants completed 6 cycles; 1 withdrew after cycle 3. No stratum-1 participants progressed during treatment and 3 had disease recurrence after cycle 6, resulting in 2-year progression-free survival ± standard error and overall survival of 89% ± 7% and 100%, respectively (n = 20; median follow-up, 40.9 months [range, 2.7-49.4]). In stratum 2, 3 of 4 evaluable participants (75%; 95% CI, 19%-99%) had partial response. Overall, 20 of 25 (80%) of participants had ≥1 grade ≥3 toxicity attributed to protocol therapy. In conclusion, clofarabine is active and tolerable in children with R/R LCH and warrants further study in patients with non-LC histiocytosis. Further study of clofarabine in these populations is warranted. This trial was registered at www.clinicaltrials.gov (#NCT02425904).

Abstract Sickle cell disease (SCD) is characterized by chronic hemolysis, and painful vaso-occlusive episodes (VOE). High levels of fetal hemoglobin (HbF) attenuate the disease phenotype. We used a lentivirus vector (LVV) expressing a short hairpin RNA embedded in a microRNA (shmiR) that targets BCL11A in erythrocytes to induce HbF in a first-in-human study in SCD. The purpose of the study was to assess hematopoietic stem/progenitor cells collection, transduction parameters, safety, HbF induction, and durability. Eleven eligible patients with SCD underwent hematopoietic stem cell (HSC) collection. Plerixafor-mobilized peripheral blood HSCs required for manufacturing were obtained in 1 mobilization cycle for 10 of 11 participants, and 11 of 11 patient products were successfully manufactured with a median time to release of product of 39 days. Ten patients were infused with HSCs transduced with the shmiR vector. Engraftment occurred in all 10 patients. At a median follow-up of 58 months (range, 35-82) after infusion, there were no adverse events attributed to the vector. The transduction efficiency was 93.1%. One patient demonstrated low engraftment of the transduced cells and had suboptimal HbF induction. In the remaining 9 patients, at 2 years after treatment, the peripheral blood demonstrated 71% F cells with 11.9 pg HbF per F cells, and both parameters remained stable in 9 patients with ≥48 months follow-up. All patients who had VOEs before gene therapy demonstrated sustained mitigation of pain events. These data demonstrate excellent manufacturing efficiency, efficacy and safety of targeting BCL11A using a shmiR LVV, and long-term durability of the shmiR vector, leading to a pivotal, multisite, phase 2 trial that is currently underway (NCT05353647). This trial was registered at www.clinicaltrials.gov as NCT03282656.

PURPOSE More than a decade ago, researchers identified tovorafenib as a potential therapeutic option for the most common pediatric benign brain tumor, the KIAA1549:BRAF -fused low-grade glioma. Our study aimed to establish the safety, tolerability, dosing, and preliminary efficacy of this drug. PATIENTS AND METHODS We conducted a phase I investigator-initiated trial of tovorafenib. Eligible patients were age 1 to 25 years with radiographically recurrent/progressive mitogen-activated protein kinase pathway–altered tumors. The first phase (IA) followed a 3 + 3 design. Based on initial observed responses and pharmacokinetic data, the trial was modified to include phase IB using a subgroup-specific time to event (Sub-TITE) design to better determine dosing within two subgroups defined by body surface area (BSA ≤1.5 m 2 and >1.5 m 2 ). Toxicities were graded according to Common Terminology Criteria for Adverse Events version 5. Response was classified as complete response (CR), partial response (PR), or stable disease (SD). RESULTS We treated 44 eligible patients (phase IA: 9; phase IB: 35) with high-(n = 6) or low-grade (n = 38) tumors. Pilocytic astrocytoma (n = 19) was the most common diagnosis; KIAA1549:BRAF fusion was the most common molecular alteration (n = 27). No dose-limiting toxicities (DLTs) occurred in phase IA. Phase IB included 6 DLTs: three in each BSA subgroup, all at 530 mg/m 2 /dose, all grade 3. The most common adverse reactions were skin-related. The most common grade 3 adverse event was growth suppression while on treatment. Preliminary response data for 36 evaluable patients in the combined cohorts included 32 patients with CR/PR/SD. Four patients had progressive disease. CONCLUSION This study established the initial tolerability and preliminary efficacy of oral tovorafenib once every week. The recommended phase II dose was 420 mg/m 2 administered orally, once every week. Growth suppression while on drug was an unexpected side effect.

BACKGROUND:We describe clinical and biologic characteristics of neuroblastoma in older children, adolescents, and young adults (OCAYA); describe survival outcomes in the post-immunotherapy era; and identify if there is an age cut-off that best discriminates outcomes. METHODS:Patients diagnosed with neuroblastoma at ≥547 days between 2003 and 2022 from the International Neuroblastoma Risk Group Data Commons were compared by age subgroups. Recursive partitioning, dividing younger versus older at all monthly cut-points between 18 months and 15 years, was undertaken using Cox regression models of event-free survival (EFS), overall survival (OS), and OS post-relapse (OSPR). Kaplan-Meier curves of clinical/biologic subgroups were compared with log-rank tests. RESULTS:7,835 patients met inclusion criteria: 18 months to <5 years (n = 5841), 5 to <10 years (n = 1488), 10 to <15 years (n = 357), and ≥15 years (n = 149) at diagnosis. Younger patients were more likely to have MYCN amplification (18 months to 5 years: 31%; 5-10 years: 15%) than older (10-15 years: 8%; ≥15 years: 7%) (p < 0.0001), metastatic disease (p < 0.0001), and high mitosis-karyorrhexis index (MKI) (p < 0.0001) and less likely to have diploid tumors (p < 0.001). Repeatedly dichotomizing the cohort, younger patients had superior EFS and OS (p < 0.05) for all cut-offs ≤40 months (hazard ratios: 1.1-1.3). Among high-risk OCAYA (International Neuroblastoma Staging System [INSS] Stage 4; n = 5005 [64% of cohort]), those diagnosed 2010-2022 had superior EFS/OS versus 2003-2009 in each age group (p < 0.0001). OSPR remained poor for all OCAYA (5-year OSPR 14% ± 0.7%). CONCLUSIONS:For patients ≥547 days old, any age cut-off ≤40 months discriminated younger (superior EFS/OS) versus older patients; no cut-off was optimal. OCAYA diagnosed 2010-2022 (post-immunotherapy era) had superior outcomes versus 2003-2009. Stratification by comprehensive molecular biomarkers will likely best inform novel therapeutic strategies for OCAYA.

Abstract Purpose: ALRN-6924 is a stapled peptide that disrupts MDM2/MDMX-mediated inhibition of p53. We evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ALRN-6924 in children with advanced malignancies. Patients and Methods: Patients with TP53 wild-type malignancies were enrolled in a monotherapy arm (solid/central nervous system tumors) or a combination arm with cytarabine (acute leukemia). Monotherapy dosing used the Targeted-Agent Continual Reassessment Method design for dose escalation. Pharmacodynamic assessment included serum macrophage inhibitory cytokine-1 (MIC-1) as a biomarker of p53 activation. Circulating tumor DNA (ctDNA) was analyzed for emergent TP53 mutations. Results: Twenty-two patients enrolled; 20 received treatment (17 monotherapy and 3 combination). The most common diagnosis was Ewing sarcoma (n = 5). One dose-limiting toxicity (DLT) occurred at monotherapy dose level 2 (2.7 mg/kg). Six patients were treated at dose level 3 (3.5 mg/kg) without DLT, and 1 patient was treated at dose level 4 (4.3 mg/kg) without DLT before study closure. No DLT occurred on the combination arm. Common treatment-related adverse events included anemia (90%) and nausea (70%). MIC-1 levels increased 30- to 50-fold by 24 hours after dose at dose levels 2 to 4, confirming on-target p53 activation. Among 19 response-evaluable patients, 1 partial remission occurred in a patient with relapsed acute lymphoblastic leukemia on the combination arm. Drug exposure was lower than in adults at equivalent doses. One patient with Ewing sarcoma had an emergent TP53 mutation detected in their baseline on-therapy ctDNA sample. Conclusions: ALRN-6924 was well tolerated in children, with on-target activity. Future efforts to evaluate this agent should focus on biomarker-selected populations, combination strategies, and the evaluation of higher dose levels.

We conducted a first-in-human phase 1 dose-finding pilot and feasibility study testing the safety of gene therapy using a lentivirus vector (LVV) expressing a microRNA embedded shRNA (shmiR) targeting BCL11A in sickle cell disease (SCD) (NCT03282656). Eleven eligible subjects with SCD (HbSS or HbS/Hbβ0) had stem cell collection; one patient withdrew prior to infusion and 10 were infused with autologous hematopoietic stem and progenitor cells transduced with the shmiR vector. Engraftment occurred in all 10 patients. With a median follow-up of 58 months (range: 35-82) after infusion, no adverse events attributed to the gene vector have occurred. Plerixafor mobilized peripheral blood hematopoietic stem cells (HSC) required for manufacturing were obtained in 1 mobilization cycle (2 consecutive days of collection) for 10/11 subjects, with one patient requiring 2 cycles (mean of 2.3 apheresis days per patient for product manufacturing). Median time from first day of apheresis to final release of product was 39 days (range: 22–151; n=11), with only one product released after >50 days. The manufacturing efficiency, defined as the number of CD34+ cells in the final product divided by the number of CD34+ cells collected was 63% (mean, range 41-82%). Transduction efficiency was 93.1% (median, range: 62%-100%, n=11) with a vector copy number of 3.7+/-1.4 (mean+/-SD, n=11) and final product cell count was 5.1 (median, range: 3.1-8.7, n=11) CD34+ x 106cells/kg. BCL11A was effectively targeted with a median of 88% (range: 67-100%) of individual erythroid colonies derived from the manufactured product containing ≥30% fetal hemoglobin (HbF) by HPLC analysis. After busulfan conditioning and infusion, all subjects engrafted promptly (neutrophils 18-30d, platelets 26-62d) and at 6 months, the median vector copy number in whole blood (WB) was 0.7 copies/diploid genome (range: 0.2-1.5) which remained stable over the entire follow-up time. The subject with the lowest in vivo VCN (BCL-010) had the lowest HbF post-infusion of 14.1% at 6 months that remained low but stable over the entire follow-up time, defining the lower dosage of effective gene modfication. Of the remaining nine infused subjects there was a robust HbF induction with WB HbF 27.8% (range: 20.8%-38.2%), F cells 71% (range: 55.3%-80.3%) and F/Fcells 11.9 pg (range: 9.4-13.6 pg) at 2 years that remained stable at 48 months (N=8), with mRNA knock-down of BCL11A stable from 42-74% and no significant change in BCL11A expression in CD19+ B cells. These data defined the manufacturing parameters required for improved overall HbF induction and further increase in F cell numbers post-infusion that were implemented in the subsequent phase 2 GRASP trial (NCT05353647). Due to the cases of leukemia and myelodysplastic syndrome in two Group A subjects with SCD in the Lentiglobin HGB-206 gene addition trial, clonal hematopoiesis was monitored in all subjects by sequencing of defined clonal hematopoiesis-associated genes, in addition to tracking insertion site analysis (ISA). No subject had ISA-defined clones larger than 3% at any time during follow-up. One subject had a clonal pathogenic DNMT3A mutation noted after infusion that was retrospectively determined to be present prior to cell manufacturing below validated detection limits. The variant allele fraction of this mutation increased after infusion to a maximum of 9.3%, and has remained stable for over 4 years of follow-up with no evidence of dysplasia on the 2-year post-GT bone marrow. All patients demonstrated sustained mitigation of SCD phenotypes. These data demonstrate first-in-human efficiency, durability, safety and efficacy of targeting BCL11A using a shmiR LVV leading to a pivotal multi-site phase 2 trial currently underway (NCT05353647). Funding Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656

Next generation sequencing (NGS) assays are standard clinical care for most adult and some pediatric solid cancers. The significance of molecular tumor profiling for the care of children, adolescents and young adults with sarcomas is not well understood. We aimed to determine the clinical impact of identifying genomic alterations by NGS for relapsed, refractory, high-risk sarcoma patients (pts) enrolled on the GAIN/iCat2 study. Eligible participants had an extracranial solid tumor diagnosed at age <30 years and recurrent/refractory (R/R), or newly diagnosed high-risk disease (NDHR). Each pt had targeted DNA NGS performed on tumor samples. Selected pt tumors had targeted and bulk RNA sequencing (RNAseq). Test results were returned to the oncologist and follow-up treatment and response data were collected. Identified genomic alterations were classified according to evidence of impact on diagnosis, prognosis or response to matched targeted therapy (MTT) using established guidelines. Therapeutic relevance was defined as a variant with preclinical, clinical evidence, or FDA approval suggesting potential benefit of MTT. Response to MTT was defined as a radiographic response according to RECIST or duration of therapy >4 months in pts with evaluable or measurable disease at treatment start. Pts receiving chemotherapy combined with MTT were ineligible for response. Between 11/1/2015 and 1/31/2025, 825 pts were accrued; 512 (62%) had a sarcoma diagnosis and an NGS result. 486/512 (95%) sarcoma pts were eligible for assessment of MTT. The median age at enrollment for sarcoma pts was 14.9 years (0-32). 57% were male, 70% were white, and 88% were non-Hispanic. The most common diagnoses were osteosarcoma (OS, n=151, 30%), Ewing (n=101, 20%), and rhabdomyosarcoma (RMS, n=77, 15%), though 35% had less common sarcoma diagnoses. 332 (65%) pts were R/R and 180 (35%) pts were NDHR at enrollment. 694 somatic DNA NGS tests were performed for 512 pts, 86 targeted fusion RNAseq tests were done for 72 pts (14%), and 35 bulk RNAseq tests were done for 32 pts (6%). Diagnostically significant variants were present in 428/512 (84%) pts. For 26 (5%) pts, the diagnostic variant clarified the diagnosis beyond routine site clinical testing. Variants with prognostic significance were identified in 192/329 (58%) of pts with OS, Ewing and RMS. Common prognostically significant variants for these diagnoses were the PAX/FOXO fusion, TP53 and STAG2 mutations, and MYC amplification. 369/512 (72%) pts had at least one variant identified with therapeutic relevance. 30/486 (6%) pts received matched MTT. Three pts responded to MTT for a response rate of 10%. In a study enrolling R/R and NDHR pts <30 years of age at diagnosis from 12 pediatric oncology practices, 62% of enrolling pts had a sarcoma diagnosis associated with poor outcome. NGS frequently identifies diagnostic and prognostic variants in sarcoma pts. The low proportion of pts receiving MTT and even lower proportion with responses to MTT speaks to lagging drug development for advanced sarcomas impacting young people. Hannah Y Comeau, Lorena Lazo de la Vega, Pei-Chi Kao, Catherine M Albert, Navin Pinto, Luke D. Maese, Rochelle Bagatell, AeRang Kim, Laura J Klesse, Theodore W Laetsch, Margaret E Macy, Mark A Applebaum, Susan I Colace, Amit J Sabnis, Daniel A Weiser, Filemon Dela Cruz, Darrell J Yamashiro, Steven G DuBois, Natalie B Collins, Wendy B London, Alanna J Church, Katherine A Janeway. The clinical impact of targeted next-generation sequencing for advanced pediatric and AYA sarcoma patients in the iCat2/GAIN Consortium Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A003.

ABSTRACT Background Fimepinostat, an oral dual inhibitor of histone deacetylase (HDAC) and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K), has shown activity in preclinical models of Myc‐driven pediatric malignancies. This Phase 1 trial aimed to determine the recommended pediatric Phase 2 dose (RPP2D), describe the toxicity profile, and evaluate the pharmacokinetics of fimepinostat in children with relapsed and refractory solid and central nervous system (CNS) tumors. Methods This multicenter, Phase 1 study enrolled patients ages 1–21 years with relapsed or refractory solid tumors, CNS tumors, or lymphoma. The dose‐escalation phase followed a 3 + 3 design, starting at 27.5 mg/m2 and escalating to 45 mg/m2. Following dose escalation, three expansion cohorts were opened including cohorts for patients with Myc(n)‐driven neuroblastoma, Myc‐driven extracranial solid tumors, and diffuse large B‐cell lymphoma or Burkitt lymphoma. The pharmacokinetics of fimepinostat and its metabolites were studied after the first dose. Results Twenty‐six patients were enrolled, with 25 receiving treatment. The median age was 13.6 years (range: 4.1–20.9). In the dose‐escalation phase, 12 patients were evaluable for DLT assessment. The RPP2D was initially determined to be 45 mg/m2 but was revised to 35 mg/m2 after observing DLTs in the dose‐expansion phase. Treatment‐related adverse events were primarily hematologic and gastrointestinal. No objective responses were observed in 23 evaluable patients. Three patients had stable disease for over four cycles, including a patient with MYCN amplified neuroblastoma with stable disease for 24 cycles. Pharmacokinetic analysis showed significant interpatient variability and rapid conversion of fimepinostat to its metabolites. Conclusion Fimepinostat was tolerable at a dose of 35 mg/m2 in children with relapsed and refractory solid and CNS tumors, but lacked significant clinical activity. Discovery of drugs to target Myc continues to be a high priority for childhood cancers. Trial Registration ClinicalTrials.gov identifier: NCT02909777

INTRODUCTION:Tumor histology at diagnosis is used in conjunction with other prognostic features to risk stratify patients with neuroblastoma and to assign therapy regimens. In patients with high-risk disease, adjustment of therapy is tailored to treatment response, largely based on disease imaging following induction chemotherapy and resection of the primary tumor. The goals of this study were to (i) quantify changes in histologic features in the primary tumor between diagnosis and resection, and (ii) assess the prognostic capability of such alterations. METHODS:Tumor histology from paired samples at diagnosis and resection was evaluated from 94 patients with high-risk neuroblastoma enrolled in Children's Oncology Group (COG) trials from 2001 to 2013. Presence of Schwannian stroma, neuropil, degree of differentiation, mitosis karyorrhexis index (MKI), necrosis, and percentage of neuroblastic cells were annotated. Changes in tumor histology between diagnosis and resection were analyzed for association with overall survival (OS) and progression-free survival (PFS). RESULTS:Significant changes between diagnosis and resection were observed in all histologic parameters (p < 0.01), suggesting a more phenotypically differentiated tumor following induction therapy. A higher percentage of intermediate-high MKI in tumor cells at diagnosis was associated with a lower PFS and OS (p < 0.05). No other histologic factor was associated with survival at diagnosis or resection. The tumor percentage of intermediate-high MKI decreased by a mean of 75% from diagnosis to resection (p < 0.0001). The shift from intermediate/high MKI at diagnosis to low MKI at resection had a PFS hazard ratio (HR) of 2.1 (95% CI: 0.9, 4.9; p = 0.0908) and OS HR = 2.3 (95% CI: 0.9, 5.9; p = 0.0773). CONCLUSION:Our findings suggest that primary neuroblastoma tumors undergo a significant morphologic shift following induction chemotherapy to a differentiated, less mitotically active phenotype. However, the alterations are not prognostic of patient outcome either at resection alone, or when the change from diagnosis to resection is considered.

Importance:Eltrombopag, a thrombopoietin receptor agonist, is approved by the US Food and Drug Administration for children with chronic immune thrombocytopenia. Efficacy of eltrombopag during the newly diagnosed phase of pediatric immune thrombocytopenia is unknown. Objective:To determine if the proportion of patients with a platelet response is significantly greater in patients with newly diagnosed immune thrombocytopenia treated with eltrombopag than in those treated with standard therapy (first-line treatments). Design, Setting, and Participants:This phase 3, randomized clinical trial enrolled patients (aged 1-<18 years) with newly diagnosed primary immune thrombocytopenia (platelet count <30 × 109/L who required pharmacological treatment but did not have severe bleeding or need a rapid increase in platelet count) from May 7, 2019, to January 25, 2024, at 23 centers participating in the Pediatric ITP Consortium of North America. Final follow-up occurred on February 26, 2025. Interventions:Eltrombopag was administered orally based on a standard dosing schedule (n = 78) vs standard therapy (investigator choice of glucocorticoids, intravenous immunoglobulin, or anti-D immunoglobulin) (n = 40). Main Outcomes and Measures:The primary outcome was a sustained platelet response defined as 3 or more of 4 platelet counts greater than 50 × 109/L during weeks 6 to 12 without rescue treatment. The secondary outcomes included bleeding scores, change in health-related quality of life, and serious adverse events. Results:Of 118 pediatric patients (median age, 8 years [IQR, 4-12 years]; 49% were male), 63% experienced an initial treatment failure after observation or medical therapy. Enrollment ended after a planned interim analysis met a prespecified threshold for efficacy. Of 71 patients in the eltrombopag group, 46 (65% [95% CI, 54%-76%]) had a sustained platelet response compared with 13 of 37 patients (35% [95% CI, 20%-51%]) in the standard therapy group (between-group difference, 30% [95% CI, 11%-49%]; P = .002), which crossed the monitoring boundary for efficacy. Overall, there was no between-group difference in the number and type of adverse events. Conclusions and Relevance:In pediatric patients with newly diagnosed immune thrombocytopenia requiring pharmacological treatment, eltrombopag resulted in a higher rate of sustained platelet response compared with standard therapy. Eltrombopag may be an effective option for pediatric patients with newly diagnosed immune thrombocytopenia with nonsevere bleeding who warrant medical intervention. Trial Registration:ClinicalTrials.gov Identifier: NCT03939637.

10034 Background: Meta-iodobenzylguanidine radiolabeled with iodine-131 ( 131 I-MIBG) is used to treat high-risk neuroblastoma (HRNB) as monotherapy as well as in combination with other therapies, however associated late toxicities have not been well studied. The aim of this study was to describe the characteristics of HRNB survivors who received 131 I-MIBG and determine if 131 I-MIBG is associated with subsequent malignancy, growth impairment, thyroid toxicities, and other major organ (musculoskeletal, gonadal, gastrointestinal, cardiac, or pulmonary) toxicities. Methods: The Children’s Oncology Group LEAHRN study, ALTE15N2, evaluated HRNB survivors diagnosed after 2000 and at least five years from diagnosis. Clinical history was abstracted via study questionnaires. Clinical characteristics, treatment history, and the prevalence of late effects were descriptively summarized for subjects treated with 131 I-MIBG (cases). Subjects who did not receive 131 I-MIBG therapy were randomly selected and matched by age at diagnosis and relapse history (controls) in a 1:2 case-control study design. Chi-squared analysis was used to evaluate the association between 131 I-MIBG and late toxicities. P-values were adjusted using the Holm-Bonferroni approach. Results: Of 375 subjects enrolled in LEARHN, 32 (8.5%) received 131 I-MIBG. Of these, 17 (53%) reported relapsed or refractory disease. Mean age at 131 I-MIBG treatment was 5.1 years. 56% were male. Disease extent included an adrenal primary in 62%, multiple bone metastases in 72%, and bone marrow involvement in 63%. Thyroid toxicity (hypothyroidism, hyperthyroidism, or thyroid nodules) was similar in both groups, reported in 10/32 cases compared with 11/63 controls. One case (1/32) and four controls (4/64) reported a subsequent malignancy. Growth failure was reported in 35% of cases (11/31) and 23% of controls (16/63). Other major organ toxicities were also similar with no significant differences between cases and controls. Conclusions: In survivors of HRNB, the burden of late toxicities appeared similar in those treated with 131 I-MIBG compared to those who were not. This provides critical information for long-term follow-up care and clinical trial design.

Background: The Pediatric ITP Newly diagnosed patients Eltrombopag vs Standard therapy (PINES) trial, NCT03939637, was an investigator-initiated, prospective, open label, randomized, multi-center trial sponsored by the ITP Consortium of North America (ICON) and funded by Novartis. Patients (pts) ages 1-<18 with primary ITP, ≤3 months from diagnosis, with platelet count <30 x109/L who required pharmacologic treatment per the treating clinician were randomized 2:1 to receive the experimental treatment, eltrombopag (epag), or investigator's choice of one of 3 standard first-line therapies (SOC): prednisone, IVIg, or anti-D globulin at specified doses. The primary platelet response endpoint within 12 weeks was achieved by 67% pts in the epag arm, compared with 35% pts in the SOC arm; the trial closed early for efficacy per DSMB recommendation (Shimano et al, ASH 2024). We now report secondary objectives from study completion. Methods: Pts were followed on study for 1 year. From weeks 13-52, pts randomized to epag could continue the study drug, with dosage weans per protocol. Pts in the SOC arm who had persistent ITP and those in the epag arm who had not responded could receive second-line therapies after week 12. Platelet counts were measured at 6 months and 1 year, as well as at monthly intervals for those remaining on epag. Complete response (CR) at 1 year was defined as platelet count ≥150 x109/L. Disease resolution at 1 year was defined as CR ≥3 months after discontinuing most recent platelet active medication, without having received rituximab or splenectomy. Pts were evaluable for secondary objectives if they received at least one dose of protocol therapy. Analyses were performed a) within the subgroup with known data at 1 year, and b) with last-observation-carried-forward (LOCF) to address missing data. Results: 78 pts were randomized to epag and 40 to SOC therapy. 12 pts came off study early due to withdrawal of consent (4), lost to follow-up (6), or other (2). Median duration of therapy in the epag arm was 111 days (range 7-390). 27 (35%) pts in the epag arm vs 22 (56%) in the SOC arm did not require any treatment after week 12, p=0.02, and 43 (55%) vs 25 (64%) did not require any treatment after 6 months, p=0.35. The most commonly used subsequent agents were romiplostim, rituximab, and mycophenolate mofetil in pts randomized to epag, and epag and romiplostim for pts randomized to SOC. 106 pts completed the full 1-year study (73 [94%] for epag; 33 [83%] for SOC).18 pts (25%) in the epag arm remained on study drug at 1 year. 24/73 (33%) pts in the epag arm vs 11/33 (33%) pts in the SOC arm remained on platelet active medication at 1 year. Disease resolution by 1 year occurred in 50 (47%) pts overall, and in 33 (45%) epag pts vs 17 (52%) SOC pts, p=0.55, with similar results for CR and for LOCF analyses. Disease resolution at 1 year was no different among age groups [15/28 (54%) epag arm vs 7/11 (64%) SOC ages 1-<6; 11/26 (42%) vs 5/12 (42%) ages 6-<12; and 7/19 (37%) vs 5/10 (50%) ages 12-<18]. Disease resolution at 1 year occurred in 16/26 (62%) epag vs 10/13 (77%) SOC treatment-naïve pts who enrolled on the trial as upfront therapy. 33 (45%) pts in epag arm vs 15 (45%) in SOC arm had “primary remission,” defined as CR at 1 year with no second-line agents and ≥3 months after discontinuing most recent platelet active medication. 8 (11%) in epag arm vs 3 (9%) in SOC arm had “disease stability,” defined as platelets between 50-150 x109/L and were ≥3 months after discontinuing most recent platelet active medication. Sustained response off treatment (SROT, inclusive of those with disease resolution or disease stability) occurred in 41 (56%) in epag arm vs 20 (61%) in SOC. There were 14 adverse events (AEs) (including 4 serious AEs) during weeks 13-52 in 9 pts (6 epag, 3 SOC). Conclusions: In this population of pediatric pts with newly diagnosed ITP, 47% overall had disease resolution by 1 year, with no difference between treatment arms in 1-year response rates. SROT at 12 months was 56% in epag and 61% in SOC. Many pts on the epag arm were able to discontinue medication quickly, within a median of 4 months. Given these findings and the improved sustained platelet response to epag compared to SOC during weeks 6-12, epag should be considered for upfront and early use in pediatric pts with newly diagnosed ITP who require pharmacologic treatment in order to obtain a more stable platelet count.

10052 Background: Outcomes for high-risk neuroblastoma (HR-NBL) following relapse are poor, although there is a paucity of data on overall survival post-relapse (OSPR) in the contemporary era. Prognostic factors associated with OSPR across all neuroblastoma risk groups (INSS stage, MYCN status and time to first relapse) have previously been described. Here we present an analysis focussed specifically on HR-NBL. Methods: We conducted a retrospective analysis using INRG Data Commons including HR-NBL patients diagnosed ≥1985 with relapse/progression ≤2022. HR-NBL was defined as age ≥547days at diagnosis with INRGSS M; or INRGSS L2 MYCN-amplified disease. The final cohort excluded patients without relapse/progression and with death as first event. Primary endpoint was OSPR, with Kaplan-Meier estimates of survival and sub-group comparisons using log-rank tests. Results: Of the 25,245 NBL patients in the INRG Data Commons, 4045 were included in the final analysis. The majority had INRGSS M disease (96%) and were < 5 years at diagnosis (74%), with MYCN amplification in 36% of those with available data. OSPR was 22±0.7% at 2 years and 8±0.4% at 5 years, with median OSPR 0.76 years (95% CI: 0.73-0.82). OSPR improved over time; for example, 2-year OSPR was 16+/-2.8% for patients diagnosed 1985-1989 vs 32%±2.8% for 2015-2019 (p < 0.0001). Across the whole cohort, patients with a diagnosis of NBL (vs nodular ganglioneuroblastoma), greater number of involved metastatic compartments (MSI) or elevated LDH at diagnosis, tumors with MYCN amplification, higher MKI, 1p LOH and presence of ALK mutation had statistically significantly worse OSPR than respective counterparts. OSPR for INRGG M was significantly better than for INRGSS L2. Serum ferritin, tumor grade and ploidy were not associated with OSPR, while 11q LOH and age showed non-proportional hazards, with patients aged ≥5 years at diagnosis having a better early OSPR but poorer long-term outcome than those < 5 years. Conclusions: In this, the largest analysis of patients with relapsed HR-NBL, multiple factors at diagnosis were associated with OSPR, emphasising the importance of tumor biology and disease burden. The finding of improved OSPR for INRG M vs L2 is unexpected but may relate to MYCN amplification. Further analyses will focus on changes in prognostic factors over time, non-proportional hazards and the impact of upfront and relapse treatment paradigms on OSPR and prognostic factors.

Eltrombopag, a thrombopoietin receptor agonist, is approved by the US Food and Drug Administration for children with chronic immune thrombocytopenia. Efficacy of eltrombopag during the newly diagnosed phase of pediatric immune thrombocytopenia is unknown. To determine if the proportion of patients with a platelet response is significantly greater in patients with newly diagnosed immune thrombocytopenia treated with eltrombopag than in those treated with standard therapy (first-line treatments). This phase 3, randomized clinical trial enrolled patients (aged 1-<18 years) with newly diagnosed primary immune thrombocytopenia (platelet count <30 × 10 9 /L who required pharmacological treatment but did not have severe bleeding or need a rapid increase in platelet count) from May 7, 2019, to January 25, 2024, at 23 centers participating in the Pediatric ITP Consortium of North America. Final follow-up occurred on February 26, 2025. Eltrombopag was administered orally based on a standard dosing schedule (n = 78) vs standard therapy (investigator choice of glucocorticoids, intravenous immunoglobulin, or anti-D immunoglobulin) (n = 40). The primary outcome was a sustained platelet response defined as 3 or more of 4 platelet counts greater than 50 × 10 9 /L during weeks 6 to 12 without rescue treatment. The secondary outcomes included bleeding scores, change in health-related quality of life, and serious adverse events. Of 118 pediatric patients (median age, 8 years [IQR, 4-12 years]; 49% were male), 63% experienced an initial treatment failure after observation or medical therapy. Enrollment ended after a planned interim analysis met a prespecified threshold for efficacy. Of 71 patients in the eltrombopag group, 46 (65% [95% CI, 54%-76%]) had a sustained platelet response compared with 13 of 37 patients (35% [95% CI, 20%-51%]) in the standard therapy group (between-group difference, 30% [95% CI, 11%-49%]; P = .002), which crossed the monitoring boundary for efficacy. Overall, there was no between-group difference in the number and type of adverse events. In pediatric patients with newly diagnosed immune thrombocytopenia requiring pharmacological treatment, eltrombopag resulted in a higher rate of sustained platelet response compared with standard therapy. Eltrombopag may be an effective option for pediatric patients with newly diagnosed immune thrombocytopenia with nonsevere bleeding who warrant medical intervention. ClinicalTrials.gov Identifier: NCT03939637

BACKGROUND:Toddlers (age 365-<547 days) with MYCN non-amplified (MYCN-NA) metastatic neuroblastoma (NBL) that have at least one unfavorable biologic feature ("mixed biology toddlers") are a rare NBL subgroup in need of further study. METHODS:Using the International Neuroblastoma Risk Group (INRG) Data Commons, we identified all toddlers with newly diagnosed metastatic, MYCN-NA NBL. Unfavorable biologic features included (1) unfavorable histology, (2) DNA index ≤1, (3) 1p loss of heterozygosity (LOH), and (4) 11q LOH. Kaplan-Meier curves of event-free survival (EFS) and overall survival (OS) were generated and compared using a log rank test; Cox proportional hazard regression models were used for multivariable analysis. RESULTS:Of the 450 patients identified, 157 had ≥1 unfavorable biologic feature and 26 had all favorable features. After adjusting for unfavorable biologic features, only high ferritin and high lactate dehydrogenase (LDH) remained significantly associated with worse EFS and OS. A total of 5-year EFS for mixed biology toddlers was 74.3% versus 88.5% for those with all favorable biologic features; 5-year OS was 79.3% versus 100%, respectively. CONCLUSION:Mixed biology toddlers have lower EFS and OS compared to those whose tumors have favorable biologic features. Inclusion in high-risk NBL trials should be considered for this rare subgroup.