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.

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.

Chemotherapy-induced thrombocytopenia in pediatric oncology: Scope of the problem and opportunities for intervention.

BACKGROUND: Chemotherapy-induced thrombocytopenia (CIT) is a known hematologic complication of oncology treatment. This single-institution study examines the degree with which CIT impacts specific pediatric solid tumor cohorts reflected by platelet transfusion burden and treatment modifications. PROCEDURE: Data regarding clinically relevant CIT were obtained via a retrospective chart review of pediatric solid tumor patients treated at Memorial Sloan Kettering Cancer Center from 2013 to 2020. Patients were stratified based on histologic diagnoses as well as chemotherapy regimen. CIT impact was assessed through platelet transfusion means, chemotherapy dose reductions, and treatment delays. RESULTS: A total of 150 patients were included with mean age 10.3 [0.2-21.0]. Patients receiving therapy for high-risk neuroblastoma and localized Ewing sarcoma, both of which included high-dose cyclophosphamide and doxorubicin, required the most platelet transfusions over the treatment course, with a mean of 13 and 9, respectively. Reduced relative dose intensity (RDI), due in part to CIT, was greatest for the patients receiving therapy for high-risk and intermediate-risk rhabdomyosarcoma. Fifty-six percent of high-risk patients experienced a reduced RDI during the final two cycles of treatment and 69% of intermediate-risk patients experienced one during the final four cycles of treatment. CONCLUSIONS: The impact of CIT varied by the administered chemotherapy regimens and dose intensity of chemotherapy agents. This study demonstrated that CIT causes both marked platelet transfusion burden as well as treatment reduction and delay within certain solid tumor cohorts. This can lend to future studies aimed at reducing the burden of CIT and targeting the most at-risk populations.

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.

COVID-19 has changed the way we think about training future pediatric hematologists/oncologists.

COVID-19 has upended medical practice and education, but has also catalyzed enhancements in the field. Early on, a local group of researchers united to investigate the impact of the pandemic on pediatric hematology oncology (PHO). From this group, a regional educational series was established, "virtual-Symposium of Pediatric Hematology/Oncology of New York" (v-SYMPHONY). The implementation of these endeavors while PHO fellowship applications are declining has highlighted our perceptions that education, mentoring, and career expectations are not keeping up with the needs of current trainees. We describe our regional experience joining together to further education and research, and reflect on the current landscape of PHO training and workforce.

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.

Romiplostim for Immune Thrombocytopenia in Neuroblastoma Patients Receiving Chemotherapy.

Thrombocytopenia, a serious complication of myelosuppressive chemotherapy in cancer patients, is managed with platelet transfusions until recovery of platelet counts. However, children receiving chemotherapy can rarely develop immune thrombocytopenia (ITP) that is refractory to transfused platelets. This limits the ability to achieve adequate platelet counts and administer further myelosuppressive chemotherapy safely, especially if first-line ITP therapy is ineffective. We report 2 cases of intravenous immunoglobulin refractory ITP in children receiving chemotherapy for high-risk neuroblastoma. ITP was successfully treated with the thrombopoietin-receptor-agonist romiplostim, allowing safe and timely continuation of antineuroblastoma therapies in these high-risk patients.

Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial.

Importance: Induction chemotherapy followed by high-dose therapy with autologous stem cell transplant and subsequent antidisialoganglioside antibody immunotherapy is standard of care for patients with high-risk neuroblastoma, but survival rate among these patients remains low. Objective: To determine if tandem autologous transplant improves event-free survival (EFS) compared with single transplant. Design, Setting, and Participants: Patients were enrolled in this randomized clinical trial from November 2007 to February 2012 at 142 Children's Oncology Group centers in the United States, Canada, Switzerland, Australia, and New Zealand. A total of 652 eligible patients aged 30 years or younger with protocol-defined high-risk neuroblastoma were enrolled and 355 were randomized. The final date of follow-up was June 29, 2017, and the data analyses cut-off date was June 30, 2017. Interventions: Patients were randomized to receive tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan (n = 176) or single transplant with carboplatin/etoposide/melphalan (n = 179). Main Outcomes and Measures: The primary outcome was EFS from randomization to the occurrence of the first event (relapse, progression, secondary malignancy, or death from any cause). The study was designed to test the 1-sided hypothesis of superiority of tandem transplant compared with single transplant. Results: Among the 652 eligible patients enrolled, 297 did not undergo randomization because they were nonrandomly assigned (n = 27), ineligible for randomization (n = 62), had no therapy (n = 1), or because of physician/parent preference (n = 207). Among 355 patients randomized (median diagnosis age, 36.1 months; 152 [42.8%] female), 297 patients (83.7%) completed the study and 21 (5.9%) were lost to follow-up after completing protocol therapy. Three-year EFS from the time of randomization was 61.6% (95% CI, 54.3%-68.9%) in the tandem transplant group and 48.4% (95% CI, 41.0%-55.7%) in the single transplant group (1-sided log-rank P=.006). The median (range) duration of follow-up after randomization for 181 patients without an event was 5.6 (0.6-8.9) years. The most common significant toxicities following tandem vs single transplant were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%). Conclusions and Relevance: Among patients aged 30 years or younger with high-risk neuroblastoma, tandem transplant resulted in a significantly better EFS than single transplant. However, because of the low randomization rate, the findings may not be representative of all patients with high-risk neuroblastoma. Trial Registration: ClinicalTrials.gov Identifier: NCT00567567.

Treatment and outcome of adult-onset neuroblastoma.

Adult-onset neuroblastoma is rare and little is known about its biology and clinical course. There is no established therapy for adult-onset neuroblastoma. Anti-GD2 immunotherapy is now standard therapy in children with high-risk neuroblastoma; however, its use has not been reported in adults. Forty-four adults (18-71 years old) diagnosed with neuroblastoma between 1979 and 2015 were treated at Memorial Sloan Kettering Cancer Center. Five, 1, 5 and 33 patients had INSS stage 1, 2, 3 and 4 diseases, respectively. Genetic abnormalities included somatic ATRX (58%) and ALK mutations (42%) but not MYCN-amplification. In the 11 patients with locoregional disease, 10-year progression-free (PFS) and overall survival (OS) was 35.4 ± 16.1% and 61.4 ± 15.3%, respectively. Among 33 adults with stage 4 neuroblastoma, 7 (21%) achieved complete response (CR) after induction chemotherapy and/or surgery. Seven patients with primary refractory neuroblastoma (all with osteomedullary but no soft tissue disease) received anti-GD2 antibodies, mouse or humanized 3F8. Antibody-related adverse events were similar to those in children, response rate being 71.4%. In patients with stage 4 disease at diagnosis, 5-year PFS was 9.7± 5.3% and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years, 10-year OS being only 19.0 ± 8.2%. Patients who achieved CR after induction had superior PFS and OS (p = 0.006, p = 0.031, respectively). Adult-onset neuroblastoma appeared to have different biology from pediatric or adolescent NB, and poorer outcome. Complete disease control appeared to improve long-term survival. Anti-GD2 immunotherapy was well tolerated and might be beneficial.

A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma.

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50-75 mg m-2  day-1 after a loading dose of 100-200 mg m-2 on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1-5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed µM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal 123 I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings (i) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; (ii) support perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and (iii) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable.

Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study.

BACKGROUND: The rationale for studying the combination of bevacizumab, irinotecan, and temozolomide (BIT) in neuroblastoma (NB) is based on the following: (i) vascular endothelial growth factor (VEGF) expression is associated with an aggressive phenotype, (ii) anti-VEGF antibody bevacizumab enhances irinotecan-mediated suppression of NB xenografts, (iii) bevacizumab safety has been established in pediatric phase I studies, and (iv) irinotecan + temozolomide (IT) is a standard salvage chemotherapy. PROCEDURE: We conducted a phase II study of BIT in patients with measurable/evaluable refractory or relapsed high-risk NB (www.clinicaltrials.gov, NCT01114555). Each cycle consisted of bevacizumab (15 mg/kg intravenously [IV]) on days 1 and 15 plus irinotecan (50 mg/m2 /day IV) and temozolomide (150 mg/m2 /day orally) on days 4-8. Patients could have previously received, but not relapsed on, IT. An early stopping rule mandated continuing therapy only if more than five patients of 27 evaluable patients achieved partial response (PR) or complete response (CR) after four cycles. RESULTS: Thirty-three heavily pretreated patients (nine primary refractory; 24 relapsed) received one to eight cycles of BIT. Toxicities were expected and transient. Grade 4 toxicities were neutropenia (30%) and thrombocytopenia (24%). Grade 3 toxicities included hepatic transaminitis (15%), proteinuria (9%), and diarrhea (3%). Overall responses were as follows: three CR (all in prior IT-treated patients), 18 no response, and 12 progressive disease. Only one of 23 patients assessable for the early stopping rule regarding efficacy achieved PR/CR, so patient accrual was discontinued. Median progression-free survival and overall survival was 7.7 ± 1.7 and 31.5 ± 5.6 months, respectively; all patients continued anti-NB therapy post-BIT. CONCLUSIONS: BIT was well tolerated, but the addition of bevacizumab did not improve response rates in resistant NB compared to historical data for IT.

Osteochondroma in long-term survivors of high-risk neuroblastoma.

BACKGROUND: Osteochondromas are benign bony protrusions that can be spontaneous or associated with radiotherapy (RT). Current treatment of high-risk neuroblastoma includes dose-intensive chemotherapy, local RT, an anti-GD2 monoclonal antibody (MoAb), and isotretinoin. Late effects are emerging. METHODS: The authors examined osteochondromas in 362 patients who were aged <10 years when diagnosed with neuroblastoma, had received a MoAb plus isotretinoin since 2000, and had survived >24 months from the time of the first dose of the MoAb. The incidence rate of osteochondroma was determined using the competing risks approach, in which the primary event was osteochondroma calculated from the date of neuroblastoma diagnosis and the competing event was death without osteochondroma. RESULTS: A total of 21 osteochondroma cases were found among 14 patients who were aged 5.7 to 15.3 years (median, 10.4 years) and 3.1 to 11.2 years (median, 8.2 years) from the time of neuroblastoma diagnosis. The cumulative incidence rate was 0.6% at 5 years and 4.9% at 10 years from the neuroblastoma diagnosis. Nine osteochondromas were revealed incidentally during assessments of neuroblastoma disease status or bone age. Thirteen osteochondromas were detected outside RT portals and had characteristics of spontaneous forms. Complications were limited to pain necessitating surgical resection in 3 patients, but follow-up was short at 0.3 to 7.7 years (median, 3.5 years). CONCLUSIONS: Osteochondromas in long-term survivors of neuroblastoma should be expected because these benign growths can be related to RT and these patients undergo radiologic studies over years, are monitored for late toxicities through and beyond adolescence, and receive special attention (because of concerns about disease recurrence) if they develop a bony protuberance. A pathogenic role for chemotherapy, anti-GD2 MoAbs, or isotretinoin remains speculative.

Striking dichotomy in outcome of MYCN-amplified neuroblastoma in the contemporary era.

BACKGROUND: The authors exploited a large database to investigate the outcomes of patients with high-risk neuroblastoma in the contemporary era. METHODS: All patients with high-risk neuroblastoma aged <12 years who were treated during induction at the authors' institution from 2000 through 2011 were studied, including 118 patients with MYCN-amplified [MYCN(+)] disease and 127 patients aged >18 months with MYCN-nonamplified [MYCN(-)] stage 4 disease. RESULTS: A complete response/very good partial response (CR/VGPR) to induction was correlated with significantly superior event-free survival (EFS) (P < .001) and overall survival (OS) (P < .001) compared with a partial response or less. Patients with MYCN(+) and MYCN(-) disease had similar rates of CR/VGPR to induction (P = .366), and those with MYCN(+) and MYCN(-) disease who attained a CR/VGPR had similar EFS (P = .346) and OS (P = .542). In contrast, only MYCN(+) patients had progressive disease as a response to induction (P < .001), and early death from progressive disease (<366 days after diagnosis) was significantly more common (P < .001) among those with MYCN(+) disease. Overall, among patients who had a partial response or less, MYCN(+) patients had significantly inferior EFS (P < .001) and OS (P < .001) compared with MYCN(-) patients, which accounted for the significantly worse EFS (P = .008) and OS (P = .002) for the entire MYCN(+) cohort versus the MYCN(-) cohort. CONCLUSIONS: Patients with MYCN(-), high-risk neuroblastoma display a broad, continuous spectrum with regard to response and outcome, whereas MYCN(+) patients either have an excellent response to induction associated with good long-term outcome or develop early progressive disease with a poor outcome. This extreme dichotomy in the clinical course of MYCN(+) patients points to underlying biologic differences with MYCN(+) neuroblastoma, the elucidation of which may have far-reaching implications, including improved risk classification at diagnosis and the identification of targets for treatment.

Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma.

Studies defining normal and disrupted human neural crest cell development have been challenging given its early timing and intricacy of development. Consequently, insight into the early disruptive events causing a neural crest related disease such as pediatric cancer neuroblastoma is limited. To overcome this problem, we developed an in vitro differentiation model to recapitulate the normal in vivo developmental process of the sympathoadrenal lineage which gives rise to neuroblastoma. We used human in vitro pluripotent stem cells and single-cell RNA sequencing to recapitulate the molecular events during sympathoadrenal development. We provide a detailed map of dynamically regulated transcriptomes during sympathoblast formation and illustrate the power of this model to study early events of the development of human neuroblastoma, identifying a distinct subpopulation of cell marked by SOX2 expression in developing sympathoblast obtained from patient derived iPSC cells harboring a germline activating mutation in the anaplastic lymphoma kinase (ALK) gene.

Ifosfamide, carboplatin, and etoposide for neuroblastoma: a high-dose salvage regimen and review of the literature.

BACKGROUND: The authors report a retrospective analysis of high-dose ifosfamide, carboplatin, and etoposide (HD-ICE) for patients with refractory or relapsed neuroblastoma (NB). A major reason for using this regimen was the long time since patients received previous treatment with a platinum compound. The authors also summarized the published experience on ICE in patients with NB. METHODS: Treatment comprised ifosfamide (2000 mg/m(2) daily for 5 days), carboplatin (500 mg/m(2) daily for 2 days), and etoposide (100 mg/m(2) daily for 5 days). Patients who had poor hematologic reserve (platelet count <100,000/µL) from previous therapy received peripheral blood stem cells (PBSCs) after HD-ICE. Disease status before and after HD-ICE was defined according to International Neuroblastoma Response Criteria (expanded to include (123) I-metaiodobenzylguanidine findings). Publications that were informative about ICE for NB were reviewed. RESULTS: Seventy-four patients received 92 cycles of ICE, including 37 patients who received PBSC rescue. Grade 3 toxicities were rare: 1-3 patients had encephalopathy, mucositis, or gastroenteritis. Bacteremia was documented in 24 of 92 cycles (26%). The absolute neutrophil count reached 500/µL on day 17-30 (median, day 22) in patients who had satisfactory hematologic reserve. Disease regressions (major and minor responses) were achieved by 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory NB, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy (P = .005). In the literature, patients received ICE at lower dosages and achieved major response rates >36% in phase 1 and 2 studies (in which less comprehensive staging evaluations were used) that involved resistant NB and >70% in induction for newly diagnosed NB. CONCLUSIONS: HD-ICE is appealing as salvage treatment or consolidative therapy because of its anti-NB activity and the low risk of major nonhematologic toxicity. PBSC support is unnecessary for patients who had intact hematologic reserve.

Posterior reversible encephalopathy syndrome in neuroblastoma patients receiving anti-GD2 3F8 monoclonal antibody.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) comprises clinical and radiologic findings with rapid onset and potentially dire consequences. Patients experience hypertension, seizures, headache, visual disturbance, and/or altered mentation. Magnetic resonance imaging reveals edematous changes in the brain (especially in the parietal and occipital lobes). In this report, the authors describe PRES associated with antidisialoganglioside (anti-GD2 ) monoclonal antibody (MoAb) immunotherapy, which is now standard for high-risk neuroblastoma but has not previously been implicated in PRES. METHODS: Successive clinical trials using the anti-GD2 MoAb 3F8 (a murine immunoglobulin 3 MoAb specific for GD2) for patients with neuroblastoma involved multiple cycles of standard-dose 3F8 (SD-3F8) (20 mg/m2 daily for 5 days per cycle) or 2 cycles of high-dose 3F8 (HD-3F8) (80 mg/m2 daily for 5 days per cycle) followed by cycles of SD-3F8. RESULTS: PRES was diagnosed in 5 of 215 patients (2.3%), including 3 of 160 (1.9%) who received SD-3F8 and 2 of 55 (3.6%) who received HD-3F8 (P = .6). All 5 patients had a rapid return to clinical-radiologic baseline. PRES occurred in 3 of 26 patients (11.5%) whose prior treatment included external-beam radiotherapy to the brain (2 of 6 patients status-post total body irradiation and 1 of 20 patients status-post craniospinal irradiation) compared with 2 of 189 patients (1.1%) who had not received prior brain irradiation (P = .01). Hypertension, which is strongly linked to PRES, reached grade 3 toxicity in 12 of 215 patients (5.6%), including the 5 patients with PRES and 7 patients without PRES. CONCLUSIONS: Patients who receive anti-GD2 MoAb immunotherapy should be closely monitored for, and undergo urgent treatment or evaluation of, symptoms that may herald PRES (eg, hypertension or headaches). Prior brain irradiation may be a predisposing factor for PRES with this immunotherapy.

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.

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.

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.