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After receiving dose-intensive chemotherapy and gross total resection (GTR), patients with high-risk neuroblastoma (HR-NB) are treated with adjuvant radiation therapy (RT) to the primary site, typically to a dose of approximately 21 Gy. This regimen is associated with excellent local control. However, in these young children, late toxicities to bone, pancreas, and other organs as well as second cancer risk are a major concern. After favorable results in a pilot trial using 18 Gy in 25 patients, we sought to prospectively evaluate local control with a further dose reduction to 15 Gy. Eligible patients included those with HR-NB (as defined by the Children's Oncology Group risk stratification schema) who have achieved a GTR of the primary site of disease after induction systemic therapy. Any patients with macroscopic residual disease at the primary site after surgery were excluded. Following surgery, patients were treated with 15 Gy to the primary site in 1.5 Gy fractions twice daily. The primary outcome of the trial was to assess the local failure (LF) rate, as determined by radiographic imaging. Gray's test was used to compare the incidence of LF across MYCN status. Secondary outcomes included an assessment of event-free survival (EFS), overall survival (OS), and both acute (< 6 months) and late (≥ 6 months) toxicity, as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A total of 53 patients were enrolled between 2018-2023 at a single institution. Median follow up from time of RT was 22 months (range = 4-65 months). Median age at the time of RT was 3.5 years (range = 0.8-10.9 years). Primary site was abdominal in 50 patients (94%) and mediastinal in 3 (6%). Forty-four patients (83%) received proton RT. Four patients experienced LF at the primary site of disease (crude risk 7.5%). These failures occurred 1, 3, 8, and 16 months after RT (median 5.5 months). The estimated risk of LF 2 years after RT was 8.4% (95% confidence interval = 2.6%-19%). The risk of LF was not significantly different between patients with MYCN -amplified disease (n = 28) versus those who had non- MYCN -amplified disease (n = 25) (P > 0.9). Six of the 53 patients died (11%); the median OS was not reached. There were 19 instances of any neuroblastoma progression (36%); median EFS was not reached. Of the 53 patients, 16 patients experienced acute toxicity, which included grade 1-2 fatigue, nausea, decreased appetite, diarrhea, and dermatitis. There were no toxicities above grade 2. There were no late toxicities of any grade observed in the cohort of patients, with current dates of follow up. For patients with HR-NB who have a GTR of the primary site, reduced-dose RT of 15 Gy is associated with a 2-year LF rate of 8.4%, in line with published data after 21 Gy. The treatment was well-tolerated, with only grade 1-2 acute toxicities and no late toxicities. These data support continued use of 15 Gy for HR-NB. More follow-up is needed to verify a reduction in late effects. [ABSTRACT FROM AUTHOR]

ALL cures require many MRD therapies. This strategy should drive experiments and trials in metastatic bone sarcomas.

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.

Anti-G D2 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-G D2 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-G D2 mAbs in older patients. These findings were reassuring given that naxitamab is dosed >2.5× higher (~270 mg/m 2 /cycle) than 3F8, dinutuximab, and dinutuximab beta (70-100 mg/m 2 /cycle). HR-NB in infants proved to be highly curable., (© 2022 UICC.)

X-linked lymphoproliferative disease type 1 (XLP1) is a primary immunodeficiency disorder caused by pathogenic variants in the SH2D1A gene (SH2 domain containing protein 1A). Patients with XLP1 may present acutely with fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, and/or B-cell non-Hodgkin lymphoma (B-NHL). We report a boy who developed 2 clonally distinct B-NHL 4 years apart and was found to have previously unrecognized XLP1. The report highlights the importance of clonal analysis and XLP1 testing in males with presumed late recurrences of B-NHL, and the role of allogeneic stem cell transplant (allo-SCT) in XLP1 patients and their affected male relatives., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)