Development and pilot validation of a novel disfigurement severity scale for plexiform neurofibromas in children with neurofibromatosis type 1.

BACKGROUND/AIMS: We developed an observer disfigurement severity scale for neurofibroma-related plexiform neurofibromas to assess change in plexiform neurofibroma-related disfigurement and evaluated its feasibility, reliability, and validity. METHODS: Twenty-eight raters, divided into four cohorts based on neurofibromatosis type 1 familiarity and clinical experience, were shown photographs of children in a clinical trial (NCT01362803) at baseline and 1 year on selumetinib treatment for plexiform neurofibromas (n = 20) and of untreated participants with plexiform neurofibromas (n = 4). Raters, blinded to treatment and timepoint, completed the 0-10 disfigurement severity score for plexiform neurofibroma on each image (0 = not at all disfigured, 10 = very disfigured). Raters evaluated the ease of completing the scale, and a subset repeated the procedure to assess intra-rater reliability. RESULTS: Mean baseline disfigurement severity score for plexiform neurofibroma ratings were similar for the selumetinib group (6.23) and controls (6.38). Mean paired differences between pre- and on-treatment ratings was -1.01 (less disfigurement) in the selumetinib group and 0.09 in the control (p = 0.005). For the disfigurement severity score for plexiform neurofibroma ratings, there was moderate-to-substantial agreement within rater cohorts (weighted kappa range = 0.46-0.66) and agreement between scores of the same raters at repeat sessions (p > 0.05). In the selumetinib group, change in disfigurement severity score for plexiform neurofibroma ratings was moderately correlated with change in plexiform neurofibroma volume with treatment (r = 0.60). CONCLUSION: This study demonstrates that our observer-rated disfigurement severity score for plexiform neurofibroma was feasible, reliable, and documented improvement in disfigurement in participants with plexiform neurofibroma shrinkage. Prospective studies in larger samples are needed to validate this scale further.

Tolerance of dinutuximab therapy for treatment of high-risk neuroblastoma in two patients with end-stage renal disease on dialysis.

Autologous hematopoietic cell transplant (aHCT) has a significant survival advantage in patients with high-risk (HR) neuroblastoma. Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication and may result in chronic renal disease leading to delay in subsequent posttransplant therapy and limitations of treatment options. Dinutuximab represents an important therapeutic advance in the treatment of pediatric HR neuroblastoma, but historically has not been administered in patients with GFR < 60 mL/m2 /min. Here, we present the safe outcome of dinutuximab administration while on renal replacement therapy in two cases of HR neuroblastoma with end-stage renal disease secondary to TA-TMA.

A safety and feasibility trial of 131 I-MIBG in newly diagnosed high-risk neuroblastoma: A Children's Oncology Group study.

INTRODUCTION: 131 I-meta-iodobenzylguanidine (131 I-MIBG) is effective in relapsed neuroblastoma. The Children's Oncology Group (COG) conducted a pilot study (NCT01175356) to assess tolerability and feasibility of induction chemotherapy followed by 131 I- MIBG therapy and myeloablative busulfan/melphalan (Bu/Mel) in patients with newly diagnosed high-risk neuroblastoma. METHODS: Patients with MIBG-avid high-risk neuroblastoma were eligible. After the first two patients to receive protocol therapy developed severe sinusoidal obstruction syndrome (SOS), the trial was re-designed to include an 131 I-MIBG dose escalation (12, 15, and 18 mCi/kg), with a required 10-week gap before Bu/Mel administration. Patients who completed induction chemotherapy were evaluable for assessment of 131 I-MIBG feasibility; those who completed 131 I-MIBG therapy were evaluable for assessment of 131 I-MIBG + Bu/Mel feasibility. RESULTS: Fifty-nine of 68 patients (86.8%) who completed induction chemotherapy received 131 I-MIBG. Thirty-seven of 45 patients (82.2%) evaluable for 131 I-MIBG + Bu/Mel received this combination. Among those who received 131 I-MIBG after revision of the study design, one patient per dose level developed severe SOS. Rates of moderate to severe SOS at 12, 15, and 18 mCi/kg were 33.3%, 23.5%, and 25.0%, respectively. There was one toxic death. The 131 I-MIBG and 131 I-MIBG+Bu/Mel feasibility rates at the 15 mCi/kg dose level designated for further study were 96.7% (95% CI: 83.3%-99.4%) and 81.0% (95% CI: 60.0%-92.3%). CONCLUSION: This pilot trial demonstrated feasibility and tolerability of administering 131 I-MIBG followed by myeloablative therapy with Bu/Mel to newly diagnosed children with high-risk neuroblastoma in a cooperative group setting, laying the groundwork for a cooperative randomized trial (NCT03126916) testing the addition of 131 I-MIBG during induction therapy.

Prognostic significance of pretreatment 18F-FDG positron emission tomography/computed tomography in pediatric neuroblastoma.

BACKGROUND: 18F-2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) shows tumor activity in most neuroblastomas, but the role of 18F-FDG PET/CT in neuroblastoma remains to be defined. OBJECTIVE: This study explored the prognostic significance of 18F-FDG PET in newly diagnosed neuroblastic tumors. MATERIALS AND METHODS: This retrospective study reviewed all 18F-FDG PET/CT examinations performed for a new diagnosis of suspected neuroblastoma. MYCN amplification status, tumor recurrence and survival were abstracted from the medical record. Primary tumors were manually segmented to measure maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), tumor volume and total lesion glycolysis. Univariate and multivariable analyses using Cox proportional hazards regression testing assessed the predictive performance of PET indices for event-free survival and overall survival with thresholds determined using receiver operating characteristic curve analysis. RESULTS: Fifty-five children were included, with a median age of 2.9 years (interquartile range [IQR] 1.8-3.0 years). SUVmax, tumor volume and total lesion glycolysis were higher in MYCN-amplified tumors (P=0.012, P<0.0001, P<0.0001, respectively) and in higher International Neuroblastoma Risk Group (INRG) stages (P=0.0008, P=0.0017, P=0.0017, respectively). After adjusting for age, tumor SUVmax (P=0.028) and SUVmean (P=0.045) were associated with overall survival. An SUVmax threshold of 4.77 (P=0.028) best predicted overall survival, with median overall survival of 2,604 days (SUVmax>4.77) vs. >2,957 days (SUVmax≤4.77). No PET parameters were independently significantly associated with overall survival or event-free survival after controlling for MYCN status, stage or treatment risk stratification. CONCLUSION: Tumor metabolic activity is higher in higher-stage MYCN-amplified neuroblastic tumors. Higher SUVmax and SUVmean were associated with worse overall survival but were not independent of other prognostic markers.

Sentinel lymph node biopsy in head and neck rhabdomyosarcoma.

Head and neck rhabdomyosarcoma lymph node staging is challenging due to varied patterns of lymphatic drainage and the suboptimal predictive value of available imaging modalities. Furthermore, regional relapse rates are unacceptably high, and the toxicity of empiric radiation is undesirable in the pediatric and young adult population. In an attempt to improve locoregional control without excess morbidity, we have adopted routine sentinel lymph node biopsy in head and neck rhabdomyosarcoma, which is safe and feasible in pediatric patients. Of six procedures reported here, pathologic findings led to intensification of regional and/or systemic therapy in two patients.

Change in liver, spleen and bone marrow magnetic resonance imaging signal intensity over time in children with solid abdominal tumors.

BACKGROUND: Reticuloendothelial system MRI signal hypointensity is common in pediatric oncology patients with solid abdominal tumors. OBJECTIVE: To assess changes in liver, spleen and bone marrow T2-weighted MRI signal intensity over time and their relationship to blood transfusion history in children with solid abdominal tumors. MATERIALS AND METHODS: In this retrospective study we measured liver, spleen and bone marrow signal intensity on axial T2-weighted MR images obtained December 2009 through February 2016 in children with hepatoblastoma, neuroblastoma, ganglioneuroblastoma and Wilms tumor. All signal intensity measurements were normalized to paraspinal muscle signal intensity. We used linear mixed models (including a day*day quadratic term) to determine whether organ signal intensity changed over time and whether change was associated with blood transfusion volume or tumor type. RESULTS: We included 133 children (mean age at diagnosis =2.9 years); 56 had neuroblastoma, 42 hepatoblastoma, 28 Wilms tumor and 7 ganglioneuroblastoma. Seventy-nine (59.4%) children received transfusions (median: 8 transfusions, range: 1-30; mean volume: 1,148.5 mL). Hepatic, splenic and bone marrow signal intensity ratios changed quadratically over time for the study population, initially decreasing and then increasing (P<0.0001). Children receiving less than the mean blood transfusion volume showed no significant change in tissue signal intensity, while those receiving more than the mean volume showed significant changes in signal intensity over time (P<0.0001). Compared to children with Wilms tumor, those with neuroblastoma exhibited significantly lower hepatic (P=0.03) signal intensity ratios. CONCLUSION: Liver, spleen and bone marrow T2-weighted MRI signal intensity ratios change over time in some pediatric patients with solid abdominal tumors, likely from tissue iron deposition related to blood transfusions and perhaps because of tumor type.

Single and multidimensional measurements underestimate neuroblastoma response to therapy.

BACKGROUND: Changes in three-dimensional (3D) measurements of neuroblastoma are used to assess response. Linear measurements may not accurately characterize tumor size due to the infiltrative character of these tumors. The purpose of this study was to assess the accuracy of one-dimensional (1D), two-dimensional (2D), and 3D measurements in characterizing neuroblastoma response compared to a reference standard of tumor volume. PROCEDURE: We retrospectively reviewed imaging for 34 patients with stage 3 or 4 neuroblastoma. Blinded readers contoured or made linear measurements of tumors. Correlation coefficients were used to compare linear measurements to volumetric and 3D measurements. Bland-Altman analyses were used to assess bias between measurements. Sensitivity and specificity for patient events and survival were calculated for each measurement technique. RESULTS: Mean patient age was 2.9 ± 3.0 years (range 0-15 years). There was strong correlation between volumetric and 1D (r = 0.78, P < 0.0001), 2D (r = 0.86, P < 0.0001), and 3D (r = 0.88, P < 0.0001) measurements. Mean bias between volumetric measurements and 1D, 2D, and 3D measurements was 37.1% (95% limits: 6.2-67.9%), 16.1% (95% limits: -11.7-43.8%), and 7.7% (95% limits: -19.7-35.1%), respectively. 1D and 2D measurements undercategorized response versus volumetric change in 88.2% (30/34) and 29.4% (10/34) of cases. 3D measurements incorrectly characterized response in 16.7% (4/24) of cases versus volumetric change. 3D measurements were highly sensitive for patient events and survival, but all measurement techniques had poor specificity. CONCLUSIONS: 3D measurements most accurately quantify neuroblastoma size response versus volumetric change in patients with stage 3 and 4 neuroblastoma. 1D and 2D measurements underrepresent tumor response.

MIBG in Neuroblastoma Diagnostic Imaging and Therapy.

Neuroblastoma is a common malignancy observed in infants and young children. It has a varied prognosis, ranging from spontaneous regression to aggressive metastatic tumors with fatal outcomes despite multimodality therapy. Patients are divided into risk groups on the basis of age, stage, and biologic tumor factors. Multiple clinical and imaging tests are needed for accurate patient assessment. Iodine 123 ((123)I) metaiodobenzylguanidine (MIBG) is the first-line functional imaging agent used in neuroblastoma imaging. MIBG uptake is seen in 90% of neuroblastomas, identifying both the primary tumor and sites of metastatic disease. The addition of single photon emission computed tomography (SPECT) and SPECT/computed tomography to (123)I-MIBG planar images can improve identification and characterization of sites of uptake. During scan interpretation, use of MIBG semiquantitative scoring systems improves description of disease extent and distribution and may be helpful in defining prognosis. Therapeutic use of MIBG labeled with iodine 131 ((131)I) is being investigated as part of research trials, both as a single agent and in conjunction with other therapies. (131)I-MIBG therapy has been studied in patients with newly diagnosed neuroblastoma and those with relapsed disease. Development and implementation of an institutional (131)I-MIBG therapy research program requires extensive preparation with a focus on radiation protection.

Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas.

BACKGROUND: Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies. METHODS: This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index). RESULTS: For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment. CONCLUSIONS: With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.

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.

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results.

Vα24-invariant natural killer T cells (NKTs) have anti-tumor properties that can be enhanced by chimeric antigen receptors (CARs). Here we report updated interim results from the first-in-human phase 1 evaluation of autologous NKTs co-expressing a GD2-specific CAR with interleukin 15 (IL15) (GD2-CAR.15) in 12 children with neuroblastoma (NB). The primary objectives were safety and determination of maximum tolerated dose (MTD). The anti-tumor activity of GD2-CAR.15 NKTs was assessed as a secondary objective. Immune response evaluation was an additional objective. No dose-limiting toxicities occurred; one patient experienced grade 2 cytokine release syndrome that was resolved by tocilizumab. The MTD was not reached. The objective response rate was 25% (3/12), including two partial responses and one complete response. The frequency of CD62L+NKTs in products correlated with CAR-NKT expansion in patients and was higher in responders (n = 5; objective response or stable disease with reduction in tumor burden) than non-responders (n = 7). BTG1 (BTG anti-proliferation factor 1) expression was upregulated in peripheral GD2-CAR.15 NKTs and is a key driver of hyporesponsiveness in exhausted NKT and T cells. GD2-CAR.15 NKTs with BTG1 knockdown eliminated metastatic NB in a mouse model. We conclude that GD2-CAR.15 NKTs are safe and can mediate objective responses in patients with NB. Additionally, their anti-tumor activity may be enhanced by targeting BTG1. ClinicalTrials.gov registration: NCT03294954 .

Molecular therapies for tuberous sclerosis and neurofibromatosis.

Neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) are autosomal-dominant genetic disorders that result from dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. NF1 is caused by mutations in the NF1 gene on chromosome 17q11.2. Its protein product, neurofibromin, functions as a tumor suppressor and ultimately produces constitutive upregulation of mTOR. TSC is caused by mutations in either the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p.13.3) genes. Their protein products, hamartin and tuberin, respectively, form a dimer that acts via the GAP protein Rheb (Ras homolog enhanced in brain) to directly inhibit mTOR, again resulting in upregulation. Specific inhibitors of mTOR are in clinical use, including sirolimus, everolimus, temsirolimus, and deforolimus. Everolimus has been shown to reduce the volume and appearance of subependymal giant cell astrocytomas (SEGA), facial angiofibromas, and renal angiomyolipomas associated with TSC, with a recent FDA approval for SEGA not suitable for surgical resection. This article reviews the use of mTOR inhibitors in these diseases, which have the potential to be a disease-modifying therapy in these and other conditions.

Examining Violence Against Women at a Regional Level 1 Trauma Center During the COVID-19 Pandemic.

INTRODUCTION: There is a growing concern that certain public health restrictions imposed to prevent the spread of coronavirus disease 2019 (COVID-19) could result in more violence against women (VAW). We sought to determine if the rates and types of VAW changed during the COVID-19 pandemic at our level 1 trauma center (L1TC). METHODS: We performed a retrospective review of female patients who presented to our L1TC because of violence from 2019 through 2020. Patients were grouped into a pre-COVID or COVID period. The primary aim of this study was to compare rates of VAW between groups. Secondary aims sought to evaluate for any difference in traumatic mechanism between periods and to determine if a temporal relationship existed between COVID-19 and VAW rates. RESULTS: There was no difference in rates of VAW between the pre-COVID and COVID period (3.1% vs 3.6%, P = .6); however, rates of penetrating trauma were greater during the COVID period (38.2% vs 10.3%, P = .01). After controlling for patient age and race, the odds of penetrating trauma increased during the pandemic (OR 5.8, 95% CI 1.6-28.5, P < .01). From February 2020 through October 2020, there was a direct relationship between rates of COVID-19 and VAW (r2 .78, P < .01). CONCLUSION: Rates of VAW were unchanged between the pre-COVID and COVID periods, yet the odds of penetrating VAW were 5 times greater during the pandemic. Moving forward, trauma surgeons must remain vigilant for signs of violence and ensure that support services are available during future crises.

Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity.

BACKGROUND: Selumetinib was recently approved for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF1). This parallel phase II study determined the response rate to selumetinib in children with NF1 PN without clinically significant morbidity. METHODS: Children with NF1 and inoperable PNs, which were not yet causing clinically significant morbidity but had the potential to cause symptoms, received selumetinib at 25 mg/m2 orally twice daily (1 cycle = 28 days). Volumetric magnetic resonance imaging analysis and outcome assessments, including patient-reported (PRO), observer-reported, and functional outcome measures were performed every 4 cycles for 2 years, with changes assessed over time. A confirmed partial response (cPR) was defined as PN volume decrease of ≥20% on at least 2 consecutive scans ≥3 months apart. RESULTS: 72% of subjects experienced a cPR on selumetinib. Participants received selumetinib for a median of 41 cycles (min 2, max 67) at data cutoff. Approximately half of the children rated having some target tumor pain at baseline, which significantly decreased by pre-cycle 13. Most objectively measured baseline functions, including visual, motor, bowel/bladder, or airway function were within normal limits and did not clinically or statistically worsen during treatment. CONCLUSIONS: Selumetinib resulted in PN shrinkage in most subjects with NF1 PN without clinically significant morbidity. No new PN-related symptoms developed while on selumetinib, and PRO measures indicated declines in tumor-related pain intensity. This supports that selumetinib treatment may prevent the development of PN-related morbidities, though future prospective studies are needed to confirm these results. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01362803.

MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus.

The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

Management of neurofibromatosis type 1-associated plexiform neurofibromas.

Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG).

BACKGROUND: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. METHODS: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D. RESULTS: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). CONCLUSIONS: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.

Use of sentinel node biopsy for staging parameningeal rhabdomyosarcoma.

Identification of nodal involvement is important for treatment planning in patients with rhabdomyosarcoma, and is facilitated by sentinel node biopsy. Although it is employed primarily for extremity tumors, we report using sentinel node biopsy in a patient with parameningeal rhabdomyosarcoma arising in the ethmoid sinus. Lymphoscintigraphy with single photon emission computed tomography following injection of tracer at the tumor site helped identify contralateral cervical node involvement not previously recognized by physical exam, cross sectional imaging, or other functional imaging. This case demonstrates how information from sentinel node identification and biopsy can change therapy recommendations in patients with parameningeal rhabdomyosarcoma.

NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas.

PURPOSE: Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis. METHODS: Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m2/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses. RESULTS: Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings. CONCLUSION: To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m2/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.

Myeloablative Busulfan/Melphalan Consolidation following Induction Chemotherapy for Patients with Newly Diagnosed High-Risk Neuroblastoma: Children's Oncology Group Trial ANBL12P1.

Consolidation using high-dose chemotherapy with autologous stem cell transplantation (ASCT) is an important component of frontline therapy for children with high-risk neuroblastoma. The optimal preparative regimen is uncertain, although recent data support a role for busulfan/melphalan (BuMel). The Children's Oncology Group (COG) conducted a trial (ANBL12P1) to assess the tolerability and feasibility of BuMel ASCT following a COG induction. Patients with newly diagnosed high-risk neuroblastoma who did not progress during induction therapy and met organ function requirements received i.v. busulfan (every 24 hours for 4 doses based on age and weight) and melphalan (140 mg/m2 for 1 dose), followed by ASCT. Busulfan doses were adjusted to achieve to an average daily area under the curve (AUC) <5500 µM × minute. The primary endpoint was the occurrence of severe sinusoidal obstruction syndrome (SOS) or grade ≥4 pulmonary complications within the first 28 days after completion of consolidation therapy. A total of 146 eligible patients were enrolled, of whom 101 underwent BuMel ASCT. The overall incidence of protocol-defined unacceptable toxicity during consolidation was 6.9% (7 of 101). Six patients (5.9%) developed SOS, with 4 (4%) meeting the criteria for severe SOS. An additional 3 patients (3%) experienced grade ≥4 pulmonary complications during consolidation. The median busulfan AUC was 4558 µM × min (range, 3462 to 5189 µM × minute) for patients with SOS and 3512 µM × min (2360 to 5455 µM × minute) (P = .0142). No patients died during consolidation. From the time of study enrollment, the mean 3-year event-free survival for all 146 eligible patients was 55.6 ± 4.2%, and the mean 3-year overall survival was 74.5 ± 3.7%. The BuMel myeloablative regimen following COG induction was well tolerated, with acceptable pulmonary and hepatic toxicity.