MRD at the end of induction and EFS in T-cell lymphoblastic lymphoma: Children's Oncology Group trial AALL1231.

ABSTRACT: Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children's Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). Optional bone marrow samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 patients with T-LL accrued to this trial submitted samples for MRD assessment. Patients with MRD <0.1% (n = 75) at EOI had a superior 4-year EFS vs those with MRD ≥0.1% (n = 11) (89.0% ± 4.4% vs 63.6% ± 17.2%; P = .025). Overall survival did not significantly differ between the 2 groups. Cox regression for EFS using arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (hazard ratio, 3.73; 95% confidence interval, 1.12-12.40; P = .032), which was independent of treatment arm assignment. Consideration to incorporate MRD at EOI into future trials will help establish its value in defining risk groups. CT# NCT02112916.

Phase II study of vemurafenib in children and young adults with tumors harboring BRAF V600 mutations: NCI-COG pediatric MATCH trial (APEC1621) Arm G.

BACKGROUND: This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. METHODS: Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. RESULTS: Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (n = 7) and prior BRAF inhibitor therapy (n = 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. CONCLUSION: There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).

Pediatric nasal chondromesenchymal hamartomas: a case series.

PURPOSE: Nasal chondromesenchymal hamartomas (NCMH) are rare, predominantly benign tumors of the sinonasal tract. The distinction from higher grade malignancy may be challenging based on imaging features alone. To increase the awareness of this entity among radiologists, we present a multi-institutional case series of pediatric NCMH patients showing the varied imaging presentation. METHODS: Descriptive assessment of imaging appearances of the lesions on computed tomography (CT) and magnetic resonance imaging (MRI) was performed. In addition, we reviewed demographic information, clinical data, results of genetic testing, management, and follow-up data. RESULTS: Our case series consisted of 10 patients, with a median age of 0.5 months. Intraorbital and intracranial extensions were both observed in two cases. Common CT findings included bony remodeling, calcifications, and bony erosions. MRI showed heterogeneous expansile lesion with predominantly hyperintense T2 signal and heterogenous post-contrast enhancement in the majority of cases. Most lesions exhibited increased diffusivity on diffusion weighted imaging and showed signal drop-out on susceptibility weighted images in the areas of calcifications. Genetic testing was conducted in 4 patients, revealing the presence of DICER1 pathogenic variant in three cases. Surgery was performed in all cases, with one recurrence in two cases and two recurrences in one case on follow-up. CONCLUSION: NCMHs are predominantly benign tumors of the sinonasal tract, typically associated with DICER1 pathogenic variants and most commonly affecting pediatric population. They may mimic aggressive behavior on imaging; therefore, awareness of this pathology is important. MRI and CT have complementary roles in the diagnosis of this entity.

Imaging of pediatric brain tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee/ASPNR White Paper.

Tumors of the central nervous system are the most common solid malignancies in children and the most common cause of pediatric cancer-related mortality. Imaging plays a central role in diagnosis, staging, treatment planning, and response assessment of pediatric brain tumors. However, the substantial variability in brain tumor imaging protocols across institutions leads to variability in patient risk stratification and treatment decisions, and complicates comparisons of clinical trial results. This White Paper provides consensus-based imaging recommendations for evaluating pediatric patients with primary brain tumors. The proposed brain magnetic resonance imaging protocol recommendations balance advancements in imaging techniques with the practicality of deployment across most imaging centers.

Revolutionizing pediatric neuroimaging: the era of CT, MRI, and beyond.

PURPOSE: To review the evolution of cross-sectional imaging in pediatric neuroradiology from early developments to current advancements and future directions. METHODS: Information was obtained through a PubMed literature search as well as referenced online resources and personal experience from radiologists currently practicing pediatric neuroimaging and those who experienced the era of nascent cross-sectional imaging. RESULTS: The advent of computed tomography (CT) and magnetic resonance imaging (MRI) in the 1970s and 1980s brought about a revolutionary shift in the field of medical imaging, neurosurgical and neurological diagnosis. These cross-sectional imaging techniques ushered in a new era by enabling the visualization of soft tissue structures within the brain and spine. Advancements in these imaging modalities have continued at a remarkable pace, now providing not only high high-resolution and 3-dimensional anatomical imaging, but also functional assessment. With each stride forward, CT and MRI have provided clinicians with invaluable insights, improving the accuracy and precision of diagnoses, facilitating the identification of optimal surgical targets, and guiding the selection of appropriate treatment strategies. CONCLUSION: This article traces the origins and early developments of CT and MRI, chronicling their journey from pioneering technologies to their current indispensable status in clinical applications and exciting possibilities that lie ahead in the realm of medical imaging and neurologic diagnosis.

MRI Radiogenomics of Pediatric Medulloblastoma: A Multicenter Study.

Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (WNT) and non-sonic hedgehog (SHH) MB and then differentiates therapeutically relevant WNT from SHH. Further, a classifier that distinguishes high-risk group 3 from group 4 MB was developed. An independent, binary subgroup analysis was conducted to uncover radiomics features unique to infantile versus childhood SHH subgroups. The best-performing models from six candidate classifiers were selected, and performance was measured on holdout test sets. CIs were obtained by bootstrapping the test sets for 2000 random samples. Model accuracy score was compared with the no-information rate using the Wald test. Results The study cohort comprised 263 patients (mean age ± SD at diagnosis, 87 months ± 60; 166 boys). A two-stage classifier outperformed a single-stage multiclass classifier. The combined, sequential classifier achieved a microaveraged F1 score of 88% and a binary F1 score of 95% specifically for WNT. A group 3 versus group 4 classifier achieved an area under the receiver operating characteristic curve of 98%. Of the Image Biomarker Standardization Initiative features, texture and first-order intensity features were most contributory across the molecular subgroups. Conclusion An MRI-based machine learning decision path allowed identification of the four clinically relevant molecular pediatric medulloblastoma subgroups. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chaudhary and Bapuraj in this issue.

Feasibility of rapid spine magnetic resonance evaluation for spinal cord syrinx in the pediatric population.

PURPOSE: This study investigates the feasibility of ultrafast fluid sensitive techniques for evaluation of pediatric spinal cord syrinx. Rapid imaging could obviate the need for sedation, which is often required for children undergoing lengthier standard spine imaging. METHODS: Children undergoing standard spine imaging for Chiari malformation, suspected Chiari malformation, or syrinx were included. Patients who provided informed consent were imaged with rapid acquisition sagittal and axial T2 HASTE spine sequences in addition to standard spine imaging. Standard and rapid spine imaging were then reviewed separately by a pediatric neuroradiologist. The presence or absence of syrinx, syrinx diameter, and length were assessed. The degree of cerebellar tonsillar ectopia, conus position, and evaluation of the filum were also recorded. RESULTS: Seventy-six patients aged 1 month to 18 years (mean 7 years) met the inclusion criteria. The sensitivity and specificity of rapid spine imaging for syrinx was 87.8% and 94.7% respectively. All syrinxes > 2.3 mm in diameter were identified with the rapid spine sequences. There was no statistically significant difference between rapid and standard spine imaging in assessment of syrinx diameter or length. Compared with standard spine imaging, rapid spine sequences demonstrated a 100% sensitivity for low-lying conus and a 98.2% sensitivity for cerebellar tonsillar ectopia. The filum was identified on only 31.6% of the rapid spine studies. CONCLUSION: Rapid T2 imaging demonstrated a high sensitivity for the presence and extent of spinal cord syrinx and may provide an alternative to traditional, lengthier standard spine imaging in selected patients.

Trauma-associated Pott's puffy tumor: an ophthalmologic perspective.

Pott's puffy tumor is a significant complication of frontal sinusitis that leads to frontal bone osteomyelitis and can be associated with frontal swelling, subperiosteal abscess, and intracranial abscess. It may be associated with antecedent trauma and typically presents in adolescents. Orbital involvement is rarely reported. We describe the case of a 15-year-old male who presented after blunt facial trauma with orbital hematoma and developed Pott's puffy tumor with orbital cellulitis and subperiosteal abscess. Management required a collaborative, multidisciplinary effort that yielded a good outcome.

Rapid MRI evaluation of acute intracranial hemorrhage in pediatric head trauma.

INTRODUCTION: Rapid MRI with ultrafast T2 sequences can be performed without sedation and is often used in place of computed tomography (CT) to evaluate pediatric patients for indications such as hydrocephalus. This study investigated the sensitivity of rapid magnetic resonance imaging (MRI) for detection and follow-up of acute intracranial hemorrhage in comparison to CT, which is commonly the first-line imaging. METHODS: Patients presenting to a pediatric hospital with acute intracranial hemorrhage on CT and follow-up rapid MRI within 48 h were included. Rapid MRI studies consisted of three plane ultrafast T2 sequences either with or without axial gradient echo (GRE) sequences. Identification of hemorrhage on rapid MRI was assessed by readers both blinded and unblinded to prior CT results. RESULTS: One hundred two acute hemorrhages in 61 patients were identified by CT. Rapid MRI detection of subdural and epidural hemorrhages was modest in the absence of prior CT for comparison (sensitivity 61-74 %), but increased with review of the prior CT (sensitivity 80-86 %). Hemorrhage size was a significant predictor of detection (p < 0.0001). Three plane fast T2 images alone without GRE sequences were poor at detecting subarachnoid hemorrhage (sensitivity 10-25 %); rapid MRI with GRE sequences identified the majority of subarachnoid hemorrhage (sensitivity 71-93 %). GRE modestly increased detection of other extra-axial hemorrhages. CONCLUSIONS: Rapid MRI with GRE sequences is sensitive for most acute intracranial hemorrhages only when a prior CT is available for review. Rapid MRI is not adequate to replace CT in initial evaluation of intracranial hemorrhages but may be helpful in follow-up of known hemorrhages.

ALARA: Impact of Practice Quality Improvement Initiative on Dose Reduction in Pediatric Voiding Cystourethrogram.

OBJECTIVE: This practice quality improvement study of pediatric voiding cystourethrogram (VCUG) investigated the adequacy of substituting last-image capture for digital-spot images and dose reduction when this substitution was implemented and determined correlations between dose-area products (DAPs), patient ages, and fluoroscopy times. MATERIALS AND METHODS: The study consisted of three phases: phase 1 documented baseline data and evaluated diagnostic accuracy between last-image capture and digital-spot images. Phase 2 documented the change in dose after substituting last-image capture for digital-spot images. Phase 3 measured doses 3 years later. Each phase-1 VCUG study was segregated into two image sets: last-image capture and digital-spot images. Three radiologists graded vesicoureteral reflux on each side using the international grading scale. Weighted kappa statistics assessed grading differences between image sets. Patient age, fluoroscopy time, and DAP were assessed with parametric and nonparametric statistics. RESULTS: Seventy-seven, 65, and 71 VCUGs were assessed for phases 1, 2, and 3, respectively. Weighted κ = 0.94-0.99 indicated nearly perfect agreement between last-image-capture and digital-spot-image interpretations. For phase 2, last-image capture was substituted for digital-spot images for early-filling and voiding images. DAP decreased for all three radiologists (p ≤ 0.01). Five of six (83%) correlations between DAP and age were higher than the correlations between DAP and fluoroscopy time. The dose remained significantly lower in phase 3. CONCLUSION: This project changed practice by substituting last-image capture for digital-spot images without affecting vesicoureteral reflux grading while reducing radiation exposure. Monitoring DAP is a better assessment of radiation exposure than is fluoroscopy time.

Reworking Classification of First Branchial Cleft Anomalies.

OBJECTIVES: To evaluate the clinical features of first branchial cleft anomalies (BCAs) and their relationship to pre-operative imaging, pathologic data, and post-operative surveillance outcomes. Additional aims were to assess the validity of the Work classification and describe features of recurrent cysts. METHODS: Records for 56 children (34 females, 22 males; age at surgery of 5.6 ± 4.4 years) collected over a 12-year period (2009-2021) were reviewed. Imaging and pathologic slides were re-reviewed in a blinded fashion by experts in those respective areas. Parents were contacted via telephone to obtain extended follow-up. An alternate classification method based on the presence (type II) or absence (type I) of parotid involvement is provided. RESULTS: Only 55% of first BCAs could be successfully classified using Work's method. First BCAs within the parotid were more likely to present with recurrent infections, involve scarred tissue planes and lymphadenopathy, and demonstrate enlarged lymphoid follicles on pathology. The overall recurrence rate was 16%, and recurrence was 5.3 times more likely when external auditory canal cartilage was not resected. Preoperative imaging was useful for predicting the extent of surgery required and the presence of scarred tissue planes. CONCLUSION: First BCAs within the parotid gland involve more difficult and extensive surgical resection and the potential for morbidity related to facial nerve dissection. Appropriately aggressive surgical resection, which may include the resection of involved ear cartilage, is necessary to prevent morbidity related to recurrence. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:459-465, 2024.

Imaging Assessment of Radiation Therapy-Related Normal Tissue Injury in Children: A PENTEC Visionary Statement.

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium has made significant contributions to understanding and mitigating the adverse effects of childhood cancer therapy. This review addresses the role of diagnostic imaging in detecting, screening, and comprehending radiation therapy-related late effects in children, drawing insights from individual organ-specific PENTEC reports. We further explore how the development of imaging biomarkers for key organ systems, alongside technical advancements and translational imaging approaches, may enhance the systematic application of imaging evaluations in childhood cancer survivors. Moreover, the review critically examines knowledge gaps and identifies technical and practical limitations of existing imaging modalities in the pediatric population. Addressing these challenges may expand access to, minimize the risk of, and optimize the real-world application of, new imaging techniques. The PENTEC team envisions this document as a roadmap for the future development of imaging strategies in childhood cancer survivors, with the overarching goal of improving long-term health outcomes and quality of life for this vulnerable population.

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.

PURPOSE: The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor. METHODS: As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS). RESULTS: Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months. CONCLUSION: Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

An international study presenting a federated learning AI platform for pediatric brain tumors.

While multiple factors impact disease, artificial intelligence (AI) studies in medicine often use small, non-diverse patient cohorts due to data sharing and privacy issues. Federated learning (FL) has emerged as a solution, enabling training across hospitals without direct data sharing. Here, we present FL-PedBrain, an FL platform for pediatric posterior fossa brain tumors, and evaluate its performance on a diverse, realistic, multi-center cohort. Pediatric brain tumors were targeted due to the scarcity of such datasets, even in tertiary care hospitals. Our platform orchestrates federated training for joint tumor classification and segmentation across 19 international sites. FL-PedBrain exhibits less than a 1.5% decrease in classification and a 3% reduction in segmentation performance compared to centralized data training. FL boosts segmentation performance by 20 to 30% on three external, out-of-network sites. Finally, we explore the sources of data heterogeneity and examine FL robustness in real-world scenarios with data imbalances.

Superficial Parotidectomy for Juvenile Recurrent Parotitis.

OBJECTIVES: To investigate long-term outcomes, imaging, and pathologic findings in pediatric patients who underwent superficial parotidectomy for recalcitrant juvenile recurrent parotitis (JRP). METHODS: Records for 20 children (23 parotidectomies; 9 females, 11 males; age at surgery of 8.6 ± 3.7 years) collected over a 10-year period (2012-2021) were reviewed. Parents were contacted via telephone to obtain extended follow-up. A simplified scoring system was used to assess imaging findings and an additional pathologic review was conducted to further clarify the underlying disease process. RESULTS: All but one patient experienced resolution of their recurrent symptoms after superficial parotidectomy. Three of the patients studied required surgery on the contralateral side, and this could be predicted based on their imaging at the time of the initial surgery. Pathologic findings included ductal fibrosis, metaplasia, and dilatation as well as parenchymal atrophy and fatty deposition. There were no major surgical complications, however, the incidence of Frey's syndrome in this sample was 43.5% of surgical sites. CONCLUSION: For patients with frequent recalcitrant symptoms or significant quality of life impairment related to JRP, superficial parotidectomy represents a potential treatment option with the noted reduction in symptom burden following surgery. Further longitudinal studies are needed. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1495-1500, 2023.

Tazemetostat for tumors harboring SMARCB1/SMARCA4 or EZH2 alterations: results from NCI-COG pediatric MATCH APEC1621C.

BACKGROUND: National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat. METHODS: Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat. RESULTS: Twenty patients (median age = 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n = 8) and malignant rhabdoid tumor (n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), atypical teratoid rhabdoid tumor (n = 1), and renal medullary carcinoma (n = 1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports. CONCLUSIONS: Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6 months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.

Magnetic resonance angiography-defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose-6-phosphate dehydrogenase mutation in children with sickle cell anaemia.

Silent cerebral infarct (SCI) is the most commonly recognized cause of neurological injury in sickle cell anaemia (SCA). We tested the hypothesis that magnetic resonance angiography (MRA)-defined vasculopathy is associated with SCI. Furthermore, we examined genetic variations in glucose-6-phosphate dehydrogenase (G6PD) and HBA (α-globin) genes to determine their association with intracranial vasculopathy in children with SCA. Magnetic resonance imaging (MRI) of the brain and MRA of the cerebral vasculature were available in 516 paediatric patients with SCA, enrolled in the Silent Infarct Transfusion (SIT) Trial. All patients were screened for G6PD mutations and HBA deletions. SCI were present in 41·5% (214 of 516) of SIT Trial children. The frequency of intracranial vasculopathy with and without SCI was 15·9% and 6·3%, respectively (P < 0·001). Using a multivariable logistic regression model, only the presence of a SCI was associated with increased odds of vasculopathy (P = 0·0007, odds ratio (OR) 2·84; 95% Confidence Interval (CI) = 1·55-5·21). Among male children with SCA, G6PD status was associated with vasculopathy (P = 0·04, OR 2·78; 95% CI = 1·04-7·42), while no significant association was noted for HBA deletions. Intracranial vasculopathy was observed in a minority of children with SCA, and when present, was associated with G6PD status in males and SCI.

MR Imaging of Pediatric Brain Tumors.

Primary brain tumors are the most common solid neoplasms in children and a leading cause of mortality in this population. MRI plays a central role in the diagnosis, characterization, treatment planning, and disease surveillance of intracranial tumors. The purpose of this review is to provide an overview of imaging methodology, including conventional and advanced MRI techniques, and illustrate the MRI appearances of common pediatric brain tumors.

Phase II Study of Selumetinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic Alterations: Arm E of the NCI-COG Pediatric MATCH Trial.

PURPOSE: The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II studies of molecularly targeted therapies on the basis of detection of predefined genetic alterations. Patients with tumors harboring mutations or fusions driving activation of the mitogen-activated protein kinase (MAPK) pathway were treated with the MEK inhibitor selumetinib. METHODS: Patients received selumetinib twice daily for 28-day cycles until disease progression or intolerable toxicity. The primary end point was objective response rate; secondary end points included progression-free survival and tolerability of selumetinib. RESULTS: Twenty patients (median age: 14 years) were treated. All were evaluable for response and toxicities. The most frequent diagnoses were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7). Twenty-one actionable mutations were detected: hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1 (n = 7), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease including two patients with HGG (NF1 mutation, six cycles; KRAS mutation, 12 cycles). Six-month progression-free survival was 15% (95% CI, 4 to 34). Five patients (25%) experienced a grade 3 or higher adverse event that was possibly or probably attributable to study drug. CONCLUSION: A national histology-agnostic molecular screening strategy was effective at identifying children and young adults eligible for treatment with selumetinib in the first Pediatric MATCH treatment arm to be completed. MEK inhibitors have demonstrated promising responses in some pediatric tumors (eg, low-grade glioma and plexiform neurofibroma). However, selumetinib in this cohort with treatment-refractory tumors harboring MAPK alterations demonstrated limited efficacy, indicating that pathway mutation status alone is insufficient to predict response to selumetinib monotherapy for pediatric cancers.