Intraoperative Radiation Therapy for Relapsed or Refractory High-Risk Neuroblastoma: A 27-Year Experience.

PURPOSE: To evaluate outcomes after intraoperative radiation therapy (IORT) in high-risk neuroblastoma (NB), including local control, overall survival, and toxicity. METHODS AND MATERIALS: This was a single institution retrospective study of 92 pediatric patients with NB treated with IORT from 1995 to 2022. Each IORT application was considered a separate event for a total of 110 sites treated. Local failure was calculated using the cumulative incidence function and survival by Kaplan-Meier method from the day of surgery. RESULTS: All patients had high-risk relapsed or treatment refractory disease. Median age was 6 years (range, 2-34 years). Median follow-up for all patients and surviving patients was 16 months and 4 years, respectively. All patients previously received chemotherapy, 93% had prior external beam radiation therapy to the site of IORT (median dose, 21.6 Gy; range, 10-36 Gy), and 94% had a prior surgery for tumor resection. The median IORT dose was 12 Gy (range, 8-18 Gy) and median area treated was 18 cm2 (range, 2.5-60 cm2). The cumulative incidence of local failure was 23% at 2 years and 29% at 5 years. The overall survival (OS) was 44% at 2 years and 29% at 5 years. Local failure after IORT was associated with worse OS (hazard ratio, 1.74; 95% CI, 1.07-2.84; P = .0267). Toxicity from IORT was rare, with postoperative complications likely related to IORT seen in 7 (8%) patients. CONCLUSIONS: Our study represents the largest, most recent analysis of the efficacy and safety of IORT in patients with relapsed or refractory NB. Less than one-third of patients failed locally at 5 years, and achieving local control affected overall survival. Minimal toxicities directly related to IORT were observed. Overall, IORT is an effective and safe technique to achieve local control in high-risk relapsed or refractory neuroblastoma.

Anaplastic Lymphoma Kinase Inhibitors for Therapy of Neuroblastoma in Adults.

PURPOSE: Adult-onset neuroblastoma (AON) differs significantly in biology and clinical behavior from childhood-onset disease. AON poses therapeutic challenges since tolerance of intensive multimodality therapies that are standard of care for pediatric neuroblastoma (NB) is poor. AON is enriched for somatic mutations including anaplastic lymphoma kinase (ALK), deemed to be an oncogenic driver in NB. ALK inhibitors (ALKis), therefore, have the potential to be of therapeutic benefit. The purpose of this study is to report on their use in AON. METHODS: A single-center retrospective review of adults with NB receiving ALKi (2012-2022) was performed. Response was evaluated using International Neuroblastoma Response Criteria. RESULTS: Fifteen patients with ALK-mutated AON were treated with US Food and Drug Administration-approved ALKi starting at a median age of 34 (16-71) years. Initial ALKi was lorlatinib, crizotinib, and alectinib in seven, five, and three patients respectively; seven received multiple ALKis due to progressive disease/intolerability of one agent. All patients experienced ≥grade 2 adverse events (AEs): crizotinib and alectinib were associated primarily with gastrointestinal AEs, lorlatinib with neurologic AEs, weight gain, and hyperlipidemia resulting in dose reduction or discontinuation of ALKi in several patients. No responses were observed with crizotinib (n = 5 patients), ceritinib, alectinib, or brigatinib (n = 1 each). Of the 13 patients receiving lorlatinib, four, five, and four patients had a complete or partial response (major response rate 69%), and stable disease, respectively. Responses were noted in all disease compartments; complete metabolic response was seen in two L2 patients. Ten of 13 patients remain progression-free at a median of 19 (6-50) months on lorlatinib. Three (two receiving dose-reduced therapy) had progressive disease. Median survival from start of first ALKi was 43 ± 26 months. CONCLUSION: ALKis, particularly lorlatinib, are effective treatment options for AON. However, AEs necessitating dose reduction are common.

Stage 4N neuroblastoma before and during the era of anti-GD2 immunotherapy.

Patients with stage 4N neuroblastoma (distant metastases limited to lymph nodes) stand out as virtually the only survivors of high-risk neuroblastoma (HR-NB) before myeloablative therapy (MAT) and immunotherapy with anti-GD2 monoclonal antibodies (mAbs) became standard. Because no report presents more recent results with 4N, we analyzed our large 4N experience. All 51 pediatric 4N patients (<18 years old) diagnosed 1985 to 2021 were reviewed. HR-NB included MYCN-nonamplified 4N diagnosed at age ≥18 months and MYCN-amplified 4N. Among 34 MYCN-nonamplified high-risk patients, 20 are relapse-free 1.5+ to 37.5+ (median 12.5+) years post-diagnosis, including 13 without prior MAT and 5 treated with little (1 cycle; n = 2) or no mAb (n = 3), while 14 patients (7 post-MAT, 8 post-mAbs) relapsed (all soft tissue). Of 15 MYCN-amplified 4N patients, 7 are relapse-free 2.1+ to 26.4+ (median 11.6+) years from the start of chemotherapy (all received mAbs; 3 underwent MAT) and 4 are in second remission 4.2+ to 21.8+ years postrelapse (all soft tissue). Statistical analyses showed no significant association of survival with either MAT or mAbs for MYCN-nonamplified HR-NB; small numbers prevented these analyses for MYCN-amplified patients. The two patients with intermediate-risk 4N (14-months-old) are relapse-free 7+ years postresection of primary tumors; distant disease spontaneously regressed. The natural history of 4N is marked by NB confined to soft tissue without early relapse in bones or bone marrow, where mAbs have proven efficacy. These findings plus curability without MAT, as seen elsewhere and at our center, support consideration of treatment reduction for MYCN-nonamplified 4N.

Clonal evolution during metastatic spread in high-risk neuroblastoma.

Patients with high-risk neuroblastoma generally present with widely metastatic disease and often relapse despite intensive therapy. As most studies to date focused on diagnosis-relapse pairs, our understanding of the genetic and clonal dynamics of metastatic spread and disease progression remain limited. Here, using genomic profiling of 470 sequential and spatially separated samples from 283 patients, we characterize subtype-specific genetic evolutionary trajectories from diagnosis through progression and end-stage metastatic disease. Clonal tracing timed disease initiation to embryogenesis. Continuous acquisition of structural variants at disease-defining loci (MYCN, TERT, MDM2-CDK4) followed by convergent evolution of mutations targeting shared pathways emerged as the predominant feature of progression. At diagnosis metastatic clones were already established at distant sites where they could stay dormant, only to cause relapses years later and spread via metastasis-to-metastasis and polyclonal seeding after therapy.

Outpatient administration of naxitamab in combination with granulocyte-macrophage colony-stimulating factor in patients with refractory and/or relapsed high-risk neuroblastoma: Management of adverse events.

BACKGROUND: Naxitamab is a humanized GD2-binding monoclonal antibody that received accelerated approval from the U.S. Food and Drug Administration for refractory or relapsed high-risk neuroblastoma limited to bone or bone marrow. Trial 201 (NCT03363373) is an ongoing global clinical trial to evaluate the efficacy and safety of naxitamab in combination with granulocyte-macrophage colony-stimulating factor in this population. AIMS: Here, we review the safety profile and adverse event (AE) management associated with naxitamab administration in a pediatric population, based on Trial 201 protocol guidelines and clinical trial experience. METHODS AND RESULTS: At least 50% of patients experienced pain, hypotension, bronchospasm, cough, vomiting, diarrhea, nausea, and tachycardia, with the following reported at grade ≥3 AEs for at least 10% of patients: pain, hypotension, urticaria, and bronchospasm. These AEs were generally manageable in the outpatient setting using premedications, supportive therapies, and appropriate monitoring post-infusion. Algorithms were established for infusion-related AEs, including hypotension and bronchospasm, to provide guidance to investigators for early recognition and timely intervention, including medication and infusion rate modification or interruption, or treatment discontinuation, based on AE severity. Educating patients and caregivers on what to expect regarding premedication at home, experience during the infusion cycle, and post-infusion monitoring helps optimize naxitamab treatment and supportive therapies and may reduce treatment burden. CONCLUSION: This article highlights the protocol-based recommendations for the management of acute AEs associated with outpatient naxitamab treatment in Trial 201. The authors recommend close monitoring and timely implementation of measures to ensure that patients can remain on treatment and obtain maximum clinical benefit from naxitamab therapy.

Immunotherapy with anti-GD2 monoclonal antibody in infants with high-risk neuroblastoma.

Anti-GD2 monoclonal antibodies (mAb) improve the prognosis of high-risk neuroblastoma (HR-NB). Worldwide experience almost exclusively involves toddlers and older patients treated after multimodality or second-line therapies, that is, many months postdiagnosis. In contrast, at our center, infants received anti-GD2 mAbs because this immunotherapy started during or immediately after induction chemotherapy. We now report on the feasibility, safety, and long-term survival in this vulnerable age group. Thirty-three HR-NB patients were <19 months old when started on 3F8 (murine mAb; n = 21) or naxitamab (humanized-3F8; n = 12), with 30″ to 90″ intravenous infusions. Patients received analgesics and antihistamines. Common toxicities (pain, urticaria, cough) were manageable, allowing outpatient treatment. Capillary leak, posterior reversible encephalopathy syndrome, and mAb-related long-term toxicities did not occur. Two 3F8 cycles were aborted due to bradycardia (a preexisting condition) and asthmatic symptoms, respectively. One patient received ½ dose of Day 1 naxitamab because of hypotension; full doses were subsequently administered. Post-mAb treatments included chemotherapy, radiotherapy, and anti-NB vaccine. Among 3F8 patients, 17/21 are in complete remission off all treatment at 5.6+ to 24.1+ (median 13.4+) years from diagnosis. Among naxitamab patients, 10/12 remain relapse-free post-mAb at 1.7+ to 4.3+ (median 3.1+) years from diagnosis. Toxicity was similar with short outpatient infusions and matched that observed with these and other anti-GD2 mAbs in older patients. These findings were reassuring given that naxitamab is dosed >2.5× higher (~270 mg/m2 /cycle) than 3F8, dinutuximab, and dinutuximab beta (70-100 mg/m2 /cycle). HR-NB in infants proved to be highly curable.

Effect of Oral ß-Glucan on Antibody Response to Ganglioside Vaccine in Patients With High-Risk Neuroblastoma: A Phase 2 Randomized Clinical Trial.

Importance: Among patients with high-risk relapsed metastatic neuroblastoma, oral ß-glucan adjuvant during GD2/GD3 ganglioside vaccine boost has stimulated IgG antibody response, which was associated with improved survival; however, the effectiveness of oral ß-glucan during the vaccine priming phase remains unproven. Objective: To isolate the adjuvant effect of oral ß-glucan on antibody response to GD2/GD3 ganglioside vaccine in patients with high-risk neuroblastoma. Design, Setting, and Participants: In this phase 2 randomized clinical trial, enrolled patients with high-risk neuroblastoma were randomized to 2 groups to receive the GD2/GD3 vaccine at a large cancer center in a major metropolitan area from October 2018 to September 2020. Data were analyzed from October 7, 2021, to February 28, 2022. Interventions: Eligible patients receiving GD2/GD3 vaccine were randomly assigned to group 1 (n = 54) to receive no ß-glucan or group 2 (n = 53) to receive an oral ß-glucan regimen during the first 5 weeks of vaccine priming. From week 6 onwards, all 107 patients received oral ß-glucan during vaccine boost for 1 year or until disease progression. Main Outcomes and Measures: Primary end point was comparison of anti-GD2 IgG1 response before vaccine injection 6 (week 32) in group 1 vs group 2. Seroconversion rate and the association of antibody titer with ß-glucan receptor dectin-1 single nucleotide polymorphism (SNP) rs3901533 were also assessed. Results: In all, 107 patients with high-risk neuroblastoma were randomized to the 2 groups: 54 patients (median [range] age, 5.2 [1.0-17.3] years; 28 [52%] male and 26 [48%] female) in group 1; and 53 patients (median [range] age, 6.2 [1.9-18.4] years; 25 [47%] male and 28 [53%] female) in group 2; both groups were also comparable in their first remission status at study entry (70% vs 70%). Adding oral ß-glucan during the first 5 weeks of vaccine priming elicited a higher anti-GD2 IgG1 antibody response in group 2 (1.80; 90% CI, 0.12-3.39; P = .08; planned type I error, 0.10). Anti-GD2 IgG1 titer of 230 ng/mL or greater by week 8 was associated with statistically favorable PFS. Antibody titer correlated significantly with dectin-1 SNP. The genotype frequency, seroconversion rates, and vaccine-related toxic effects were similar in the 2 groups. Conclusions and Relevance: This phase 2 randomized clinical trial found that adding oral ß-glucan during vaccine priming increased anti-GD2 IgG1 titer among genetic responders without added toxic effects. Because responder dectin-1 SNP was identical in the 2 randomized groups, no difference was detected in seroconversion rates. Alternative or additional adjuvants may be needed to enhance seroconversion. Trial Registration: ClinicalTrials.gov Identifier: NCT00911560.

Clinical outcomes of pediatric patients receiving multimodality treatment of second central nervous system relapse of neuroblastoma.

BACKGROUND: In high-risk neuroblastoma, multimodality therapy including craniospinal irradiation (CSI) is effective for central nervous system (CNS) relapse. Management of post-CSI CNS relapse is not clearly defined. PROCEDURE: Pediatric patients with neuroblastoma treated with CSI between 2000 and 2019 were identified. Treatment of initial CNS disease (e.g., CSI, intraventricular compartmental radioimmunotherapy [cRIT] with 131 I-monoclonal antibodies targeting GD2 or B7H3) and management of post-CSI CNS relapse ("second CNS relapse") were characterized. Cox proportional hazards models to evaluate factors associated with third CNS relapse and overall survival (OS) were used. RESULTS: Of 128 patients (65% male, median age 4 years), 19 (15%) received CSI with protons and 115 (90%) had a boost. Most (103, 81%) received cRIT, associated with improved OS (hazard ratio [HR] 0.3, 95% confidence interval [CI]: 0.1-0.5, p < .001). Forty (31%) developed a second CNS relapse, associated with worse OS (1-year OS 32.5%, 95% CI: 19-47; HR 3.8; 95% CI: 2.4-6.0, p < .001), and more likely if the leptomeninges were initially involved (HR 2.5, 95% CI: 1.3-4.9, p = .006). Median time to second CNS relapse was 6.8 months and 51% occurred outside the CSI boost field. Twenty-five (63%) patients underwent reirradiation, most peri-operatively (18, 45%) with focal hypofractionation. Eight (20%) patients with second CNS relapse received cRIT, associated with improved OS (HR 0.1; 95% CI: 0.1-0.4, p < .001). CONCLUSIONS: CNS relapse after CSI for neuroblastoma portends a poor prognosis. Surgery with hypofractionated radiotherapy was the most common treatment. Acknowledging the potential for selection bias, receipt of cRIT both at first and second CNS relapse was associated with improved survival. This finding necessitates further investigation.

Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies.

BACKGROUND: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. PATIENTS AND METHODS: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. RESULTS: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. CONCLUSIONS: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. TRIAL REGISTRATION: clinicaltrials.gov NCT00089245, August 5, 2004.

Early-phase clinical trial eligibility and response evaluation criteria for refractory, relapsed, or progressive neuroblastoma: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting.

BACKGROUND: International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking. METHODS: A National Cancer Institute-sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma. RESULTS: Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established. CONCLUSIONS: The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma.

Bone Marrow Surveillance of Pediatric Cancer Survivors Identifies Clones that Predict Therapy-Related Leukemia.

PURPOSE: Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of nonrelapse mortality among pediatric cancer survivors. Although the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children. EXPERIMENTAL DESIGN: We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric patients with solid tumor. RESULTS: We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10 and DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13 of 17 patients at a median of 15 months before t-MDS/AL diagnosis (range, 1.3-32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14 and 1/21, respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared with transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Last, only 1% of pediatric patients with solid tumor evaluated had CH involving myeloid genes. CONCLUSIONS: These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients.

Skeletal muscle metastases in neuroblastoma share common progenitors with primary tumor and biologically resemble stage MS disease.

Introduction: While subcutaneous metastases are often observed with stage MS neuroblastoma, an entity that usually resolves spontaneously, skeletal muscle metastases (SMM) have been rarely described. The purpose of this retrospective study was to investigate the significance of SMM in neuroblastoma. Patients and methods: Seventeen patients with neuroblastoma SMM were diagnosed at a median age of 4.3 (0.1-15.6) months. All had SMM at diagnosis and metastases at other sites. Fifteen (88%) had ≥ 2 SMM in disparate muscle groups. One, 14, and 2 patients had low, intermediate, and high-risk disease respectively. Fifteen tumors had favorable histology without MYCN amplification, and 2 were MYCN-amplified. Most SMM (80%; n=12/15 evaluated) were MIBG-avid. Results: Only 1 patient (with MYCN-non-amplified neuroblastoma) had disease progression. All survive at median follow-up of 47.9 (16.9-318.9) months post-diagnosis. Biological markers (histology, chromosomal and genetic aberrations) were not prognostic. Whole genome sequencing of 3 matched primary and SMM lesions suggested that both primary and metastatic tumors arose from the same progenitor. SMM completely resolved in 10 patients by 12 months post-diagnosis. Of 4 patients managed with watchful observation alone without any cytotoxic therapy, 3 maintain complete remission with SMM resolving by 5, 13, and 21 months post-diagnosis respectively. Conclusions: Children with neuroblastoma SMM have an excellent prognosis, with a clinical course suggestive of stage MS disease. Based on these results, the initial management of infants with non-MYCN-amplified NB with SMM could be watchful observation, which could eliminate or reduce exposure to genotoxic therapy.

Phase I Trial of Oral Yeast-Derived ß-Glucan to Enhance Anti-GD2 Immunotherapy of Resistant High-Risk Neuroblastoma.

Beta glucans, complex polysaccharides, prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of complement-activating monoclonal antibodies. We conducted a phase I study (clinicaltrials.gov NCT00492167) to determine the safety of the combination of yeast-derived beta glucan (BG) and anti-GD2 murine monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. Patients received intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10-200 mg/kg/day × 17 days in cohorts of 3-6 patients each). Forty-four patients completed 141 cycles. One patient developed DLT: transient self-limiting hepatic transaminase elevation 5 days after starting BG (120 mg/kg/day). Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. Progression-free and overall survival at 2 years were 28% and 61%, respectively. BG lacked major toxicity. Treatment with 3F8 plus BG was associated with anti-neuroblastoma responses in patients with resistant disease. Although the maximal tolerated dose for yeast BG was not reached, considering the large volume of oral BG, we recommended 40 mg/kg/day as the phase II dose.

Differential Impact of ALK Mutations in Neuroblastoma.

PURPOSE: The tyrosine kinase receptor anaplastic lymphoma kinase (ALK) can be abnormally activated in neuroblastoma, and somatic ALK mutations occur in 6%-10% of patients. The differential clinical impact of these mutations has not been clearly elucidated. METHODS: Data on patients with neuroblastoma harboring ALK mutations were retrospectively analyzed. ALK sequencing was performed by whole-genome sequencing, hybrid-based capture of targeted exomes, or hotspot ALK mutation profiling. The differential impact of ALK mutation site on clinical characteristics, response to treatment, and survival was analyzed. In a subgroup of patients with locoregional neuroblastoma diagnosed after 2014, the impact of all ALK mutations was compared with wild-type ALK. RESULTS: Of 641 patients with neuroblastoma with ALK status analyzed on at least one tumor sample, 103 (16%) had tumors harboring ALK mutations. Mutations existed across all ages (birth to 67.8 years), stages (30% locoregional and 70% metastatic), and risk groups (20%, 11%, and 69% with low-, intermediate-, and high-risk disease, respectively). Mutation sites included F1174 (51%), R1275 (29%), R1245 (10%), and others (10%). Mutation site was not prognostic for progression-free survival or overall survival in the entire cohort, high-risk subgroup, or locoregional subgroup. Locoregional tumors with any ALK mutation were generally invasive: L2 by International Neuroblastoma Research Group staging in 30/31 patients with a 2-year progression-free survival (59%, 95% CI, 37.4 to 80.5) that was inferior to historical controls. This observation was corroborated in the post-2014 subgroup in which gross total resection was less likely for ALK-mutated tumors. CONCLUSION: Somatic ALK mutations are present across all stages and risk groups of neuroblastoma. No specific mutation carries differential prognostic significance. Locoregional neuroblastoma has an invasive phenotype when harboring somatic ALK mutations in this population.

Association of BRAF V600E mutations with vasoactive intestinal peptide syndrome in MYCN-amplified neuroblastoma.

Very rarely, vasoactive intestinal peptide-related diarrhea (VIP-D) is observed in patients with high-risk neuroblastoma (HR-NB) where the associated fluid and electrolyte abnormalities can pose a major clinical challenge for administering the required aggressive multimodality treatment. Two patients with HR-NB developed VIP-D during induction and were found to have a somatic BRAF V600E mutation. Serum VIP levels and diarrhea promptly resolved in both patients after initiating treatment with BRAF and MEK inhibitors. This illustrates an association of VIP-D with BRAF V600E mutations and demonstrates a therapeutic strategy in the specific context of VIP-D and BRAF V600E mutations in HR-NB patients. The addition of BRAF and MEK inhibitors allows continued conventional tumor-directed treatment by decreasing the severity of symptoms caused by this life-threatening complication.

Mandibular metastases in neuroblastoma: Outcomes and dental sequelae.

BACKGROUND: Although metastatic involvement of bony sites including cranial bones is common in neuroblastoma (NB), mandibular metastases (MM) are uncommon, and specific outcomes have not been reported upon in the modern therapeutic era. METHODS: In this retrospective study, medical records on patients with MM from NB were reviewed. Statistical analysis was performed using the Kaplan-Meier method. RESULTS: Of 29 patients, nine (31%) had MM at diagnosis, whereas in 20 (69%) MM were first detected at NB relapse at a median time of 26 (6-89) months from diagnosis. Median maximal diameter of lesions was 3 (range 0.8-4.9) cm. MM were unilateral in 83% of patients, with ascending ramus (55%) and mandibular body (38%) being the two most common sites. All patients received systemic chemotherapy, and 26 (93%) patients received radiotherapy to MM. At a median follow-up of 37.3 (24.2-219.5) months, eight of nine patients with MM at diagnosis did not experience mandibular progressive disease. Eighteen of 20 patients with MM at relapse received therapeutic radiotherapy; objective responses were noted in 78%. Seventy-two percent (5/18) had not experienced relapse within the radiation field at a median of 12 (2-276) months postradiotherapy. Dental findings at follow-up after completion of NB therapy included hypodontia, hypocalcification of enamel, and trismus. Median 3-year overall survival in patients with relapsed MM was 51 ± 12% months from relapse. CONCLUSION: MM when detected at diagnosis is associated with a prognosis similar to that for other skeletal metastases of NB. Radiotherapy is effective for control of MM detected both at diagnosis and relapse. Significant dental abnormalities posttherapy warrant regular dental evaluations and appropriate intervention.

Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression.

PURPOSE: Anti-GD2 monoclonal antibody (mAb) has proven efficacy in high-risk neuroblastoma (HR-NB). A small phase I GD2/GD3 vaccine trial (n = 15) described long-term survival and a favorable safety profile among patients with a history of disease progression (PD). The kinetics of mounting antibody response to vaccine and its prognostic impact on survival are now investigated in a phase II study (ClinicalTrials.gov identifier: NCT00911560). PATIENTS AND METHODS: One hundred two patients with HR-NB who achieved remission after salvage therapies were enrolled in this trial. They received seven subcutaneous injections of GD2/GD3 vaccine spanning 1 year plus oral ß-glucan starting at week 6 after the third dose of vaccine. Serum anti-vaccine antibody titers were quantified by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms (SNPs) were determined by quantitative polymerase chain reaction. Kaplan-Meier and landmark Cox Regression models were used for survival estimates. RESULTS: Patients had a history of one (63%), two (21%), or three to six (16%) episodes of PD. 82% of them progressed following anti-GD2 mAb (m3F8/dinutuximab/naxitamab) therapy. Vaccine-related toxicities were self-limited injection-associated local reactions and fever without any > grade 3 toxicities. The progression-free survival (PFS) was 32% ± 6%, and the overall survival (OS) was 71% ± 7% at 5 years. Serum anti-GD2 (immunoglobulin G1 [IgG1] and IgM) and anti-GD3 (IgG1) titers showed notable increases following the initiation of ß-glucan at week 6. There was an association between IgG1 titer and SNP rs3901533 of dectin-1, the ß-glucan receptor. Multivariable analyses showed that anti-GD2-IgG1 titer ≥ 150 ng/mL by week 8 was associated with favorable PFS and OS, while having prior episodes of PD and the time from last PD to vaccine were associated with PFS. CONCLUSION: GD2/GD3 vaccine plus ß-glucan elicited robust antibody responses in patients with HR-NB with prior PD. Higher anti-GD2-IgG1 titer was associated with improved survival.

Reduced-dose craniospinal irradiation for central nervous system relapsed neuroblastoma.

PURPOSE: In patients with high-risk neuroblastoma, there is an increased recognition of relapse in the central nervous system (CNS). Craniospinal irradiation (CSI) has been an effective treatment but carries significant long-term complications. It is unclear whether reducing the CSI dose from 21 to 18 Gy can achieve similar CNS tumor control. PATIENTS AND METHODS: A retrospective review of pediatric patients with CNS-relapsed neuroblastoma treated with CSI and boost to parenchymal lesions between 2003 and 2019 was performed. The goal was to assess CNS control comparing 18 Gy and 21 Gy regimens. RESULTS: Ninety-four patients with CNS-relapsed neuroblastoma were treated with CSI followed by intraventricular compartmental radioimmunotherapy. Median age at the time of CNS disease was 4 years (range 1-13 years). Forty-one patients (44%) received 21 Gy CSI prior to an institutional decision to lower the dose; 53 patients (56%) received 18 Gy CSI. Seventy-nine patients (84%) received additional boosts. With a median follow up of 4.1 years for surviving patients, 2-year CNS relapse-free survival was 74% for 18 Gy group versus 77% for 21 Gy group, and 5-year CNS relapse-free survival was 66% for 18 Gy versus 72% for 21 Gy group, respectively (P = .40). Five-year overall survival rate was 43% in 18 Gy group versus 47% in 21 Gy group (P = .72). CONCLUSION: For patients with CNS-relapsed neuroblastoma, CNS disease control is comparable between 18 Gy and 21 Gy CSI dose regimens, in conjunction with radioimmunotherapy and CNS penetrating chemotherapy. More than 65% of the patients remain CNS disease free after 5 years. The findings support 18 Gy as the new standard CSI dose for CNS-relapsed neuroblastoma.

Treatment and revaccination of children with paraneoplastic opsoclonus-myoclonus-ataxia syndrome and neuroblastoma: The Memorial Sloan Kettering experience.

OBJECTIVE: To review the treatment and revaccination of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome (OMAS) patients at Memorial Sloan Kettering Cancer Center (MSK). PROCEDURE: Institutional Review Board approval was obtained for this retrospective study of patients with neuroblastoma-associated OMAS followed at MSK from 2000 to 2016. RESULTS: Fourteen patients (nine female) were 9-21 (median 17) months old at diagnosis of neuroblastoma and OMAS syndrome. They had stage 1 (n = 12), stage 2B, or intermediate-risk stage 4. Tumor histology was favorable in 11 patients, unfavorable in two, and unknown in one patient. No patient had amplified MYCN. All patients underwent tumor resection at diagnosis. Anti-neuroblastoma treatment was limited to chemotherapy in one patient. Overall survival is 100% at 3-16 (median 10) years. For OMAS, 13 patients received intravenous immune globulin (IVIg), adrenocorticotropic hormone (ACTH), and rituximab, and one received ACTH and IVIg. Seven patients experienced OMAS relapse. For these relapses, five patients received low-dose cyclophosphamide and two received rituximab. The mean total OMAS treatment was 20-96 (median 48) months. Seven patients started rituximab ≤3 months from diagnosis and did not relapse. The other six experienced OMAS relapse. To date, six patients have been revaccinated at a minimum of 2 years after completion of OMAS therapy without OMAS recurrence. CONCLUSIONS: Patients with neuroblastoma-associated OMAS had excellent overall survival. Early initiation of rituximab, IVIg, and ACTH may reduce risks of OMAS relapse. Revaccination can be resumed without exacerbation of OMAS. Further investigation with a larger cohort of patients is needed.