Enrollment on upfront high-risk neuroblastoma trials by race, ethnicity, and poverty status: A report from the Children's Oncology Group.

It is not clear whether trial access disparities exist in the Children's Oncology Group (COG). Here, we leverage a cohort of children with high-risk neuroblastoma (HR-NBL) enrolled on the COG ANBL00B1 neuroblastoma biology study to examine subsequent enrollment to upfront COG therapeutic trials by race, ethnicity, and proxied poverty status. Among 1917 children with HR-NBL enrolled on ANBL00B1, 696 (36.3%) subsequently enrolled on an upfront therapeutic trial with no difference by race, ethnicity, or proxied poverty status. In neuroblastoma, trial access disparities are not comparable to adult oncology, and efforts to advance equity should prioritize other mechanisms of survival disparities.

Yoga as a non-pharmacologic therapy to reduce dinutuximab-induced pain in patients with neuroblastoma.

BACKGROUND: Anti-GD2 antibodies are key components of treatment for high-risk neuroblastoma; however, they cause neuropathic pain. Yoga therapy may help reduce pain and distress associated with anti-GD2 therapy. PROCEDURE: Children 3 years of age or older with neuroblastoma participated in individualized yoga therapy while receiving the anti-GD2 antibody dinutuximab (DIN). Yoga therapy was deemed feasible if patients participated during 60% or more of DIN admissions. Patients and caregivers assessed pain/distress before and after yoga therapy with a distress thermometer (DT) and Wong-Baker FACES pain rating scale and completed questionnaires regarding satisfaction with yoga therapy. Therapy was deemed efficacious if there was a ≥1 point pain score change and reduction in distress after yoga. RESULTS: Eighteen patients were enrolled; 52 encounters (admissions for DIN) were evaluable. Ten of 18 were female, three of 18 were Hispanic, and 10/18 were White. Median age at enrollment was 5.5 years (range: 3-11). Yoga therapy was feasible in 39/52 (75%) encounters. Significant reductions in caregiver-reported pain and distress and reductions in patient-reported pain and distress after yoga therapy were reported. Twelve of 18 caregivers completed questionnaires: seven agreed/strongly agreed that yoga was valuable, and nine agreed/strongly agreed to continued participation in yoga. Thirty-four of 36 clinicians reported that they would recommend yoga therapy for other patients receiving DIN. CONCLUSIONS: Yoga therapy was feasible during DIN therapy and may be effective in reducing DIN-associated pain and distress. Future studies are needed to evaluate changes in opioid usage with the addition of yoga therapy during anti-GD2 antibody therapy.

Percutaneous biopsy for the diagnosis, risk stratification, and molecular profiling of neuroblastoma: A single-center retrospective study.

PURPOSE: To determine whether percutaneous core needle biopsy (PCNB) is adequate for the diagnosis and full molecular characterization of newly diagnosed neuroblastoma. MATERIALS AND METHODS: Patients with newly diagnosed neuroblastoma who underwent PCNB in interventional radiology at a single center over a 5-year period were included. Pre-procedure imaging and procedure details were reviewed. Rates of diagnostic success and sufficiency for International Neuroblastoma Pathology Classification (INPC), risk stratification, and evaluation of genomic markers utilized in the Children's Oncology Group risk stratification, and status of the anaplastic lymphoma kinase (ALK) gene were assessed. RESULTS: Thirty-five patients (13 females, median age 2.4 years [interquartile range, IQR: 0.9-4.4] and median weight 12.4 kg [IQR: 9.6-18]) were included. Most had International Neuroblastoma Risk Group Stage M disease (n = 22, 63%). Median longest axis of tumor target was 8.8 cm [IQR: 6.1-12]. A 16-gauge biopsy instrument was most often used (n = 20, 57%), with a median of 20 cores [IQR: 13-23] obtained. Twenty-five specimens were assessed for adequacy, and 14 procedures utilized contrast-enhanced ultrasound guidance. There were two post-procedure bleeds (5.7%). Thirty-four of 35 procedures (97%) were sufficient for histopathologic diagnosis and risk stratification, 94% (n = 32) were sufficient for INPC, and 85% (n = 29) were sufficient for complete molecular characterization, including ALK testing. Biologic information was otherwise obtained from bone marrow (4/34, 12%) or surgery (1/34, 2.9%). The number of cores did not differ between patients with sufficient versus insufficient biopsies. CONCLUSION: In this study, obtaining multiple cores with PCNB resulted in a high rate of diagnosis and successful molecular profiling for neuroblastoma.

Factors influencing parents' choice of palliative treatment goals for children with relapsed or refractory neuroblastoma: A multi-site longitudinal survey study.

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

Children's Oncology Group's 2023 blueprint for research: Neuroblastoma.

Neuroblastoma is the most common extra-cranial solid tumor in children and is known for its clinical heterogeneity. A greater understanding of the biology of this disease has led to both improved risk stratification and new approaches to therapy. Outcomes for children with low and intermediate risk disease are excellent overall, and efforts to decrease therapy for such patients have been largely successful. Although survival has improved over time for patients with high-risk disease and treatments evaluated in the relapse setting are now being moved into earlier phases of treatment, much work remains to improve survival and decrease therapy-related toxicities. Studies of highly annotated biobanked samples continue to lead to important insights regarding neuroblastoma biology. Such studies, along with correlative biology studies incorporated into therapeutic trials, are expected to continue to provide insights that lead to new and more effective therapies. A focus on translational science is accompanied by an emphasis on new agent development, optimized risk stratification, and international collaboration to address questions relevant to molecularly defined subsets of patients. In addition, the COG Neuroblastoma Committee is committed to addressing the patient/family experience, mitigating late effects of therapy, and studying social determinants of health in patients with neuroblastoma.

Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children's Oncology Group.

BACKGROUND: Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end-of-induction (EOI) Curie scores (CS) was previously described in patients undergoing a single course of high-dose chemotherapy (HDC) and autologous hematopoietic cell transplant (AHCT) as consolidation therapy. OBJECTIVE: We now examine the prognostic significance of CS in patients randomized to tandem HDC and AHCT on the Children's Oncology Group (COG) trial ANBL0532. STUDY DESIGN: A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either single or tandem HDC (n = 80). Optimal CS cut points maximized the outcome difference (≤CS vs. >CS cut-off) according to the Youden index. RESULTS: For recipients of tandem HDC, the optimal cut point at diagnosis was CS = 12, with superior event-free survival (EFS) from study enrollment for patients with CS ≤ 12 (3-year EFS 74.2% ± 7.9%) versus CS > 12 (59.2% ± 7.1%) (p = .002). At EOI, the optimal cut point was CS = 0, with superior EOI EFS for patients with CS = 0 (72.9% ± 6.4%) versus CS > 0 (46.5% ± 9.1%) (p = .002). CONCLUSION: In the setting of tandem transplantation for children with high-risk neuroblastoma, CS at diagnosis and EOI may identify a more favorable patient group. Patients treated with tandem HDC who exhibited a CS ≤ 12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points.

Neuroblastic Tumor Recurrence Associated With Opsoclonus Myoclonus Ataxia Syndrome Relapse a Decade After Initial Resection and Treatments.

Opsoclonus myoclonus ataxia syndrome (OMAS) is a rare disorder that causes significant neurodevelopmental sequelae in children. Approximately half of pediatric OMAS cases are paraneoplastic, typically associated with localized neuroblastic tumors. Since early persistence or relapse of OMAS symptoms is common even after tumor resection, OMAS relapses may not routinely prompt reevaluation for recurrent tumors. We report a 12-year-old girl with neuroblastic tumor recurrence associated with OMAS relapse a decade after initial treatment. Providers should be aware of tumor recurrence as a trigger for distant OMAS relapse, raising intriguing questions about the role of immune surveillance and control of neuroblastic tumors.

Impact of Genomic and Clinical Factors on Outcome of Children ≥18 Months of Age with Stage 3 Neuroblastoma with Unfavorable Histology and without MYCN Amplification: A Children's Oncology Group (COG) Report.

PURPOSE: Patients ≥18 months of age with International Neuroblastoma Staging System (INSS) stage 3 unfavorable histology (UH), MYCN-nonamplified (MYCN-NA) tumors have favorable survival rates compared with other high-risk neuroblastoma populations. The impact of select clinical and biological factors on overall survival (OS) and event-free survival (EFS) were evaluated. EXPERIMENTAL DESIGN: Patients enrolled on Children's Oncology Group (COG) A3973 (n = 34), ANBL0532 (n = 27), and/or biology protocol ANBL00B1 (n = 72) were analyzed. Tumors with available DNA (n = 65) and RNA (n = 42) were subjected to whole-exome sequencing (WES) and RNA sequencing. WES analyses and gene expression profiling were evaluated for their impact on survival. Multivariate analyses of EFS/OS using significant factors from univariate analyses were performed. RESULTS: 5-year EFS/OS for patients treated with high-risk therapy on A3973 and ANBL0532 were 73.0% ± 8.1%/87.9% ± 5.9% and 61.4% ± 10.2%/73.0% ± 9.2%, respectively (P = 0.1286 and P = 0.2180). In the A3973/ANBL0532 cohort, patients with less than partial response (PR; n = 5) at end-induction had poor outcomes (5-year EFS/OS: 0%/20.0% ± 17.9%. Univariate analyses of WES data revealed that subjects whose tumors had chromosome 1p or 11q loss/LOH and chromosome 5 or 9 segmental chromosomal aberrations had inferior EFS compared with those with tumors without these aberrations. Multivariate analysis revealed that 11q loss/LOH was an independent predictor of inferior OS [HR, 3.116 (95% confidence interval, 1.034-9.389), P = 0.0435]. CONCLUSIONS: Patients ≥18 months of age at diagnosis who had tumors with UH and MYCN-NA INSS stage 3 neuroblastoma assigned to high-risk therapy had an 81.6% ± 5.3% 5-year OS. Less than PR to induction therapy and chromosome 11q loss/LOH are independent predictors of inferior outcome and identify patients who should be eligible for future high-risk clinical trials.

KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group.

BACKGROUND: In the Children's Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and temozolomide (I/T) combined with either temsirolimus (TEMS) or immunotherapy (the anti-GD2 antibody dinutuximab (DIN) and granulocyte macrophage colony stimulating factory (GM-CSF)) was administered. The response rate among patients treated with I/T/DIN/GM-CSF in the initial cohort (n=17) was 53%; additional patients were enrolled to permit further evaluation of this chemoimmunotherapy regimen. Potential associations between immune-related biomarkers and clinical outcomes including response and survival were evaluated. METHODS: Patients were evaluated for specific immunogenotypes that influence natural killer (NK) cell activity, including killer immunoglobulin-like receptors (KIRs) and their ligands, Fc gamma receptors, and NCR3. Total white cells and leucocyte subsets were assessed via complete blood counts, and flow cytometry of peripheral blood mononuclear cells was performed to assess the potential association between immune cell subpopulations and surface marker expression and clinical outcomes. Appropriate statistical tests of association were performed. The Bonferroni correction for multiple comparisons was performed where indicated. RESULTS: Of the immunogenotypes assessed, the presence or absence of certain KIR and their ligands was associated with clinical outcomes in patients treated with chemoimmunotherapy rather than I/T/TEMS. While median values of CD161, CD56, and KIR differed in responders and non-responders, statistical significance was not maintained in logistic regression models. White cell and neutrophil counts were associated with differences in survival outcomes, however, increases in risk of event in patients assigned to chemoimmunotherapy were not clinically significant. CONCLUSIONS: These findings are consistent with those of prior studies showing that KIR/KIR-ligand genotypes are associated with clinical outcomes following anti-GD2 immunotherapy in children with neuroblastoma. The current study confirms the importance of KIR/KIR-ligand genotype in the context of I/T/DIN/GM-CSF chemoimmunotherapy administered to patients with relapsed or refractory disease in a clinical trial. These results are important because this regimen is now widely used for treatment of patients at time of first relapse/first declaration of refractory disease. Efforts to assess the role of NK cells and genes that influence their function in response to immunotherapy are ongoing. TRIAL REGISTRATION NUMBER: NCT01767194.

Systematic review of clinical drug development activities for neuroblastoma from 2011 to 2020.

BACKGROUND: Understanding the landscape of clinical trials for patients with neuroblastoma may inform efforts to improve drug development. PROCEDURE: We evaluated therapeutic trials for patients with neuroblastoma from 2011 to 2020 in our search using clinical trial information from ClinicalTrials.gov, Clinicaltrialregister.eu, PubMed, and American Society of Clinical Oncology (ASCO) annual meeting collection. Trends in trials and treatments over time were evaluated qualitatively. RESULTS: A total of 192 trials met inclusion criteria. A median of 20.5 trials were started per year, which was stable over time. There were 87 (45%) phase 1, 100 (51%) phase 2, and only five (2.6%) phase 3 trials. The median time to completion was 4.9 years for phase 1 and 2 trials (no phase 3 trials reported as completed during the study period). In all, 34% of trials were international, while 20% of trials were intercontinental. Eighty-nine percent of nonmyeloablative trials included at least one novel agent. 48% of these trials studied combination therapies, and 86% of these combinations included conventional chemotherapy. Among 157 trials that included a targeted agent, 78 targets were identified, with GD2 being the primary target under investigation in 16.7% of these trials. Only eight trials were included in regulatory decisions, which led to European Medicines Agency (EMA) or Food and Drug Administration (FDA) approval for neuroblastoma. CONCLUSIONS: The large number of trials initiated per year, the range of targets, and the rate of intercontinental collaboration are encouraging. The paucity of late-stage trials, the prolonged trial duration, and relative lack of combination studies are major causes of concern. This work will inform future drug development for neuroblastoma.

Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor.

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

Outcomes Following GD2-Directed Postconsolidation Therapy for Neuroblastoma After Cessation of Random Assignment on ANBL0032: A Report From the Children's Oncology Group.

PURPOSE: Postconsolidation immunotherapy including dinutuximab, granulocyte-macrophage colony-stimulating factor, and interleukin-2 improved outcomes for patients with high-risk neuroblastoma enrolled on the randomized portion of Children's Oncology Group study ANBL0032. After random assignment ended, all patients were assigned to immunotherapy. Survival and toxicities were assessed. PATIENTS AND METHODS: Patients with a pre-autologous stem cell transplant (ASCT) response (excluding bone marrow) of partial response or better were eligible. Demographics, stage, tumor biology, pre-ASCT response, and adverse events were summarized using descriptive statistics. Event-free survival (EFS) and overall survival (OS) from time of enrollment (up to day +200 from last ASCT) were evaluated. RESULTS: From 2009 to 2015, 1,183 patients were treated. Five-year EFS and OS for the entire cohort were 61.1 ± 1.9% and 71.9 ± 1.7%, respectively. For patients ≥ 18 months old at diagnosis with International Neuroblastoma Staging System stage 4 disease (n = 662) 5-year EFS and OS were 57.0 ± 2.4% and 70.9 ± 2.2%, respectively. EFS was superior for patients with complete response/very good partial response pre-ASCT compared with those with PR (5-year EFS: 64.2 ± 2.2% v 55.4 ± 3.2%, P = .0133); however, OS was not significantly different. Allergic reactions, capillary leak, fever, and hypotension were more frequent during interleukin-2-containing cycles than granulocyte-macrophage colony-stimulating factor-containing cycles (P < .0001). EFS was superior in patients with higher peak dinutuximab levels during cycle 1 (P = .034) and those with a high affinity FCGR3A genotype (P = .0418). Human antichimeric antibody status did not correlate with survival. CONCLUSION: Analysis of a cohort assigned to immunotherapy after cessation of random assignment on ANBL0032 confirmed previously described survival and toxicity outcomes. EFS was highest among patients with end-induction complete response/very good partial response. Among patients with available data, higher dinutuximab levels and FCGR3A genotype were associated with superior EFS. These may be predictive biomarkers for dinutuximab therapy.

Novel ATXN1/ATXN1L::NUTM2A fusions identified in aggressive infant sarcomas with gene expression and methylation patterns similar to CIC-rearranged sarcoma.

CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report two high-grade CNS sarcomas of unclear histological diagnosis and one disseminated tumor of unknown origin with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement. All three patients were infants with aggressive diseases, and two experienced rapid disease deterioration and death. Whole-transcriptome sequencing identified an ATXN1-NUTM2A fusion in the two CNS tumors and an ATXN1L-NUTM2A fusion in case 3. ETV1/4/5 and WT1 overexpression were observed in all three cases. Methylation analyses predicted CIC-rearranged sarcoma for all cases. Retrospective IHC staining on case 2 demonstrated ETV4 and WT1 overexpression. ATXN1 and ATXN1L interact with CIC forming a transcription repressor complex. We propose that ATXN1/ATXN1L-associated fusions disrupt their interaction with CIC and decrease the transcription repressor complex, leading to downstream PEA3 family gene overexpression. These three cases with novel ATXN1/ATXN1L-associated fusions and features of CIC-rearranged sarcomas may further expand the scope of "CIC-rearranged" sarcomas to include non-CIC rearrangements. Additional cases are needed to demonstrate if ATXN1/ATXN1L-NUTM2A fusions are associated with younger age and more aggressive diseases.

Efficacy of post-induction therapy for high-risk neuroblastoma patients with end-induction residual disease.

BACKGROUND: High-risk neuroblastoma patients with end-induction residual disease commonly receive post-induction therapy in an effort to increase survival by improving the response before autologous stem cell transplantation (ASCT). The authors conducted a multicenter, retrospective study to investigate the efficacy of this approach. METHODS: Patients diagnosed between 2008 and 2018 without progressive disease with a partial response or worse at end-induction were stratified according to the post-induction treatment: 1) no additional therapy before ASCT (cohort 1), 2) post-induction "bridge" therapy before ASCT (cohort 2), and 3) post-induction therapy without ASCT (cohort 3). χ2 tests were used to compare patient characteristics. Three-year event-free survival (EFS) and overall survival (OS) were estimated by the Kaplan-Meier method and survival curves were compared by log-rank test. RESULTS: The study cohort consisted of 201 patients: cohort 1 (n = 123), cohort 2 (n = 51), and cohort 3 (n = 27). Although the end-induction response was better for cohort 1 than cohorts 2 and 3, the outcomes for cohorts 1 and 2 were not significantly different (P = .77 for EFS and P = .85 for OS). Inferior outcomes were observed for cohort 3 (P < .001 for EFS and P = .06 for OS). Among patients with end-induction stable metastatic disease, 3-year EFS was significantly improved for cohort 2 versus cohort 1 (P = .04). Cohort 3 patients with a complete response at metastatic sites after post-induction therapy had significantly better 3-year EFS than those with residual metastatic disease (P = .01). CONCLUSIONS: Prospective studies to confirm the benefits of bridge treatment and the prognostic significance of metastatic response observed in this study are warranted.

Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer.

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors.

Guideline for Children With Cancer Receiving General Anesthesia for Procedures and Imaging.

Children with cancer and those undergoing hematopoietic stem cell transplantation frequently require anesthesia for imaging as well as diagnostic and therapeutic procedures from diagnosis through follow-up. Due to their underlying disease and side effects of chemotherapy and radiation, they are at risk for complications during this time, yet no published guideline exists for preanesthesia preparation. A comprehensive literature review served as the basis for discussions among our multidisciplinary panel of oncologists, anesthesiologists, nurse practitioners, clinical pharmacists, pediatric psychologists, surgeons and child life specialists at the Children's Hospital of Philadelphia. Due to limited literature available, this panel created an expert consensus guideline addressing anesthesia preparation for this population.

Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor.

PURPOSE: Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND METHODS: Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation. RESULTS: One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events. CONCLUSION: A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.

Phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors.

BACKGROUND: Sorafenib,an orally bioavailable, multitarget tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated activity in pediatric and adult malignancies. We evaluated the toxicity, pharmacokinetic (PK), and pharmacogenomic (PGX) profile of sorafenib with irinotecan in children with relapsed or refractory solid tumors and assessed the feasibility of incorporating patient-reported outcome (PRO) measures as an adjunct to traditional endpoints. METHODS: Sorafenib, continuous oral twice daily dosing, was administered with irinotecan, orally, once daily days 1-5, repeated every 21 days (NCT01518413). Based on tolerability, escalation of sorafenib followed by escalation of irinotecan was planned. Three patients were initially enrolled at each dose level. Sorafenib and irinotecan PK analyses were performed during cycle 1. PRO measurements were collected during cycles 1 and 2. RESULTS: Fifteen patients were evaluable. Two of three patients at dose level 2 experienced dose-limiting toxicity (DLT), grade 3 diarrhea, and grade 3 hyponatremia. Therefore, dose level 1 was expanded to 12 patients and two patients had DLT, grade 4 thrombocytopenia, grade 3 elevated lipase. Nine of 15 (60%) patients had a best response of stable disease with four patients receiving ≥6 cycles. CONCLUSIONS: The recommended dose for pediatric patients was sorafenib 150 mg/m2 /dose twice daily with irinotecan 70 mg/m2 /dose daily × 5 days every 21 days. This oral outpatient regimen was well tolerated and resulted in prolonged disease stabilization. There were no significant alterations in the PK profile of either agent when administered in combination. Patients were willing and able to report their subjective experiences with this regimen.

Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group.

PURPOSE: Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker. METHODS: Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor MYCN status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2). RESULTS: Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with MYCN amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2 MYCN nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months (MYCN) or 12-18 months (MYCN, histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively. CONCLUSION: A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.