Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.
Medical Marijuana in Pediatric Oncology: What Your Patients Are ThinkingDavid Brumbaugh, MD MSCS FAAPDepartment of Pediatrics, University of Colorado School of MedicineChildren’s Hospital Colorado13123 E. 16th Avenue, B290Aurora, CO 80045720-777-6426David.email@example.comWord count: 837Short Running Title: Medical Marijuana in Pediatric OncologyKeywords: marijuana, cannabis, complementary, pediatricsAbbreviations:MM Medical MarijuanaAYA Adolescent/young adultTHC TetrahydrocannabinolUse of complementary therapies occurs by up to 40-80% of pediatric oncology patients.1,2 Although cannabis is hardly new to the scene as a complementary treatment, legalization of both medical and recreational marijuana in many states has made these products ubiquitous. Use of and interest in medical marijuana (MM) by hospitalized pediatric patients appears to be concentrated in oncology units for the purpose of relieving symptoms such as nausea, pain, and anorexia.3 Yet clinical practitioners are still limited by the absence of high-quality research in MM to guide them. FDA approval of Epidiolex™ for specific pediatric epilepsy syndromes was an important research milestone, but marijuana remains classified as a Drug Enforcement Administration Schedule I drug, imposing an enormous barrier for clinical researchers.So how should pediatric oncology programs approach the topic of MM? In this issue of Pediatric Blood and Cancer , Ananth and colleagues used a qualitative research design to characterize patient and family perception of MM from a single institution in a state with permissive rules towards both medical and recreational marijuana. The authors interviewed both parents of younger children as well as adolescent/young adult (AYA) patients. In this cohort of pediatric oncology patients/families, although the proportion of subjects using MM was only 27%, a higher proportion were interested in MM, though with concerns about safety and effectiveness.In the Ananth study, patients/families were primarily using or interested in MM for treatment of nausea, anorexia, and anxiety. A concerning number of families in this study expressed a hope that MM would be effective as anti-cancer therapy. With the absence of high-quality randomized controlled trials of MM for treatment of cancer or treatment-related symptoms in children to inform practitioners on safety, dosing, and toxicity, there is no evidence base for pediatric oncologists to base a recommendation of MM. But should we be dissuading interested families from using MM products because they are harmful?Regarding safety of MM use, most parents and nearly all AYA patients minimized risks. When expressed, safety concerns of MM were perceived as less than with alcohol, illicit drugs, or other prescribed medications. This is not surprising, as perceived risk of marijuana in AYA has been steadily failing over last five years in the National Survey on Drug Use and Health.4 Understandably, in this study safety concerns focused on the potential for addiction, which would be associated with MM products enriched in Tetrahydrocannabinol (THC), the principal psychoactive cannabinoid found in cannabis. However, cannabis is a complex plant with over 70 distinct cannabinoids, and the MM industry now contains a broad range of different types of products that have varying concentrations of THC and consequent psychoactive potential. Carver and colleagues noted in their study of 19 hospitalized patients actively using MM, the majority were using products enriched in Cannabidiol with low concentration of THC. One limitation of the study by Ananth, et al. is that there was no attempt to classify the type of MM either being actively used or of interest to patients and parents, so the appropriateness of the concern for addiction cannot be assessed. Absent in patients/families’ perception of risk was any potential for interaction with chemotherapeutics or other prescribed medications. Since both THC and Cannabidiol can impact drug bioactivation and metabolism through multiple pathways, this potential safety concern should be known to the patient and treatment team.Despite the high level of interest in MM in their study population, the minority of patients/families had discussed MM with their oncologist and in those cases, the patient/family initiated the conversation. Absent advice from their treatment team, there was reliance on friends, family, and the internet for more information. A majority of parents desired the involvement of their physician team in any consideration of MM, and previous research has shown a high level of willingness amongst pediatric oncology providers to consider MM use by their patients, particularly when patients are seriously ill, so what stands in the way of talking about it? Providers are concerned about the absence of good research and are less knowledgeable in the domain of rules/laws regulating access to MM, particularly at the state level where there has been so much change over the last decade.5 These gaps may explain why we don’t bring up the topic of MM with our patients and families as often as they would like.Institutions may consider designating a multidisciplinary team of providers to develop greater experience in the legal and pharmacologic aspects of MM use. This team can support providers in the shared decision-making process around MM. In some institutions, it may make sense to house this expertise within the pediatric palliative care program supporting oncology patients.In summary, MM presently is an important part of the complementary therapeutic options available to pediatric oncology patients and their families, who desire the involvement of their provider team in decision making around MM. Despite the lack of evidence supporting use of MM, many patients are using MM products or may in the future, so we should invite this discussion as this will strengthen our therapeutic partnership.1. Fernandez CV, Stutzer CA, MacWilliam L, Fryer C. Alternative and complementary therapy use in pediatric oncology patients in British Columbia: prevalence and reasons for use and nonuse. J Clin Oncol. 1998;16(4):1279-1286.2. Kelly KM, Jacobson JS, Kennedy DD, Braudt SM, Mallick M, Weiner MA. Use of unconventional therapies by children with cancer at an urban medical center. J Pediatr Hematol Oncol. 2000;22(5):412-416.3. Carver AE, Jorgensen J, Barberio MW, Lomuscio CE, Brumbaugh D. A Pediatric Hospital Policy for Medical Marijuana Use. Pediatrics.2020;146(2).4. Administration SAaMHS. 2019 NSDUH Detailed Tables. samhsa.gov/data/report/2019-nsduh-detailed-tables. Published 2019. Accessed.5. Ananth P, Ma C, Al-Sayegh H, et al. Provider Perspectives on Use of Medical Marijuana in Children With Cancer. Pediatrics.2018;141(1).
Emicizumab is a recombinant, humanized, and bispecific monoclonal antibody that bridges activated factor (F) IX and FX in place of FVIII to restore hemostasis in persons with hemophilia A (PHA). Data on the efficacy and safety of emicizumab in young children is limited. Immunologic naivety, physiologically decreased production of vitamin K dependent proteins, specifically FIX, and enhanced clearance of emicizumab in infants may support decreased emicizumab effectiveness. We report on the facilitation of care rendered by using emicizumab in young PHA with inhibitors and extend data on the efficacy and safety in PHA < 3 years.
Cytopenias are common among neonates in neonatal intensive care units (NICU). Although, bone marrow aspirations (BMA) are often performed as part of diagnostic work up but trephine marrow biopsies (BMB) have not been reported from living neonates. BMB is indispensable to accurately assess the cellularity and architecture. There is paucity of literature regarding the technique of BMB in neonates. In this report, for the first time, we describe trephine BMB from Posterior superior iliac crest (PSIC) using 18 guage BMA needle in six living neonates admitted to NICU where bone marrow biopsy findings helped in understanding the underlying mechanism and diagnosis of cytopenias.
Comment on: The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis1Paige Vicenzi, OMS-IV, 2Zahra Jiwani, DO, 3Ricardo Guirola, MD,1,4Tyler Hamby, PhD, 5Anish Ray, MD1Texas College of Osteopathic Medicine, University of North Texas Health Science Center2Department of Pediatrics, Children’s Hospital of Michigan3Department of Pediatric Rheumatology, Cook Children’s Health Care System4Department of Research Operations, Cook Children’s Health Care System5Department of Pediatric Hematology/Oncology, Cook Children’s Health Care SystemCorresponding Author:Anish Ray, MD1500 Cooper St., 5th floor,Fort Worth, TX 76104Phone: 425-205-0926Anish.Ray@CookChildrens.orgWord Count: 497Number of Tables: 0Number of Figures: 1Running Title: Anakinra in Secondary HLHKeywords: hemophagocytic lymphohistiocytosis, anakinra, pediatricThe authors have no financial support or conflicts of interest.Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially fatal systemic disease arising from uncontrolled activation of the immune system. According to the Histiocyte Society’s 2004 guidelines, patients must meet five of eight criteria to be diagnosed with HLH . HLH may be classified into primary and secondary. Primary, or familial, HLH is attributed to underlying defects in genes that control natural killer (NK) and cytotoxic T-lymphocyte (CTL) cell degranulation. Secondary HLH, in contrast, may occur in the context of triggers, such as malignancy, rheumatologic disease, or infection. Systemic-onset juvenile idiopathic arthritis (SoJIA) is a well-recognized trigger of HLH and both share overlapping features (e.g. fever and elevated ferritin). Management of SoJIA includes the immunomodulator Anakinra, an interleukin 1 (IL-1) receptor antagonist hypothesized to dampen an overactive immune system. Three patients treated for HLH with concomitant SoJIA diagnosis at Cook Children’s Medical Center between 2014 and 2019 are described below in order to examine the role of immunomodulators in their clinical course and outcome.Three Hispanic patients (aged 8-15) presented with a constellation of systemic symptoms, including fever, generalized rash, fatigue, and weight loss. Upon fulfilment of necessary criteria and subsequent diagnosis of HLH, they were treated accordingly with HLH-2004 protocol. Case 3, whose HLH was suspected to be secondary to Epstein-Barr Virus (EBV) infection, rapidly responded to treatment and, therefore, briefly discontinued Etoposide; however, she tolerated this poorly and resumed treatment after a six-week hiatus with the addition of weekly Rituximab to mitigate rising EBV titers. All patients achieved remission.Past medical history for case 3 included autoimmune disorders such as celiac disease, type 1 diabetes and suspected idiopathic juvenile arthritis for which she did not require ongoing care prior to presenting with features of secondary HLH. Cases 1 and 2 were diagnosed with SoJIA following their HLH diagnosis. Cases 1 and 3 relapsed with HLH within months of their initial encounter. Due to their concurrent diagnosis of SoJIA, both received daily Anakinra. Case 3 experienced rapid resolution of symptoms. In contrast, Case 1 had unsatisfactory response of musculoskeletal manifestations prompting switch from Anakinra to weekly Tocilizumab—another biologic that antagonizes IL-6 receptor—with favorable response. Case 2 was started on daily Anakinra immediately following his diagnosis of SoJIA and has yet to relapse. In summary, all cases have yet to experience an additional relapse following introduction of Anakinra or Tocilizumab. Figure 1 provides the treatment timelines for Cases 1-3 who had 5.37, 2.87, and 4.62 years of follow up, respectively.Though traditional therapy for HLH includes intensive courses of etoposide and corticosteroids with substantial risk for morbidity and mortality, biologics represent a newer class of medications highly effective in treating diseases with inflammatory or immune-mediated components . In a reimaging of the HLH treatment algorithm, a recent study proposes Anakinra as initial treatment with sequential escalation of immunosuppression to mitigate adverse effects . This case series reinforces that immunomodulators, such as Anakinra, are safe and promising treatment options in pediatric patients with secondary HLH.
Childhood cancer survivors are at increased risk for treatment-related late effects; data are lacking on how COVID-19 infection impacts this cohort. We assessed COVID-19-related symptoms; SARS-CoV-2 IgG seroprevalence; and rate of COVID-19-related hospitalization among 321 asymptomatic survivors of childhood cancer or transplantation seen for routine long-term follow-up between May-September 2020 in a New York City tertiary cancer center. While 11% (n=35) reported possible COVID-19-related symptoms, 7.8% (n=20) of those tested had positive SARS-CoV-2 IgG, and only 1 patient (0.3%) required COVID-19 related hospitalization. This report suggests that childhood cancer survivors are at low risk for COVID-19 complications.
The care of patients with vascular anomalies is quickly becoming a complex field requiring high quality, coordinated multidisciplinary care. In this article, we review the history of multidisciplinary care in this field, discuss the benefits of this model of care, and outline some of the essential components and structure of a successful vascular anomalies team. We provide an overview of two example programs and a roadmap for other centers to develop their own multidisciplinary vascular anomalies teams.
Background: Sickle cell disease (SCD), the commonest monogenic disorder, affects more than 300,000 births annually, with 44,000 in India. While the clinical phenotype of SCD is considered to be milder in aboriginal populations in India, there is a paucity of data on outcomes. To determine the severity of SCD in this population, we studied mortality rates and causes of mortality in a longitudinal cohort of patients with SCD in a remote aboriginal community in India receiving community-based comprehensive care. Procedures: Causes of death in this cohort from January 2008 to December 2018 were analyzed. Details were collected from hospital records and in case of deaths at home, by utilizing the WHO verbal autopsy questionnaire. Results: The cohort consisted of 157 patients belonging to the Paniya, Betta Kurumba, Kattunyakan, and Mullu Kurumba tribes. During the study period, there were 22 deaths, all from the Paniya tribe. Twelve deaths (54.5%) occurred in the hospital and the remaining at home (45.5%) reflecting a crude mortality rate of 140 per 1000 population. 25% of deaths occurred in the 6-18 age group. There were no deaths in the 0-5 age group. The median age of death was 25 years, which was 20 years less than in the non-SCD aboriginal population. The leading causes of death were acute chest syndrome, anemia, and sepsis among the SCD patients and stroke and suicides in the non-SCD aboriginal population Conclusion: SCD is a severe disease among the Gudalur Valley’s aboriginal population with a significant risk of premature mortality.
BACKGROUND: Irinotecan is a drug active against pediatric sarcomas with a toxicity profile that theoretically allows for its association with more myelotoxic drugs. We examined the feasibility of a dose-density strategy integrating irinotecan in standard chemotherapy regimens for patients with high-risk sarcomas. METHODS: Between November 2013 and January 2020, 23 patients < 21 years old with metastatic (11 children) or recurrent (12 children) sarcomas were treated with 9 IrIVA/IrVAC cycles. All newly-diagnosed patients received IrIVA (ifosfamide 3g/m2 on days 1 and 2, vincristine 1.5 mg/m2 on day 1, actinomycin D 1.5 mg/m2 on day 1, irinotecan 20 mg/m2 for 5 consecutive days starting on day 8). Two relapsed patients received IrIVA and 10 IrVAC (cyclophosphamide 1.5 g/m2 on day 1 instead of ifosfamide). Feasibility was assessed in terms of toxicity and time to complete the treatment. RESULTS: 17 rhabdomyosarcomas, 4 Ewing sarcomas, 2 desmoplastic round cell tumors received a total of 181 cycles (range 2-10). Grade 4 neutropenia occurred in 62.4% of the cycles. 13 patients had febrile neutropenia. Diarrhea occurred in 14 cycles. The median time to complete the treatment was 195 days (range 170-231), 83.4% of cycles were administered on time or with a delay <1 week. With a median follow-up of 2.6 years (range 0.2-5.0), 12 patients are alive, 9 complete remissions, 3 with the disease. Conclusions: A dose density strategy combining irinotecan with standard chemotherapy is feasible. This approach will be investigated in the next trial coordinated by the European pediatric Soft tissue sarcoma Study Group.
Background: Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. The onset of obesity during childhood ALL has been well established and is associated with inferior survival rates and increased treatment-related toxicities. This pilot study sought to determine if a dietary intervention is feasible and minimizes weight gain during the initial phases of treatment for ALL. Methods: Participants were recruited from four institutions, fluent in English or Spanish, between 5-21 years old, and enrolled within three days of starting induction therapy. Participants were counseled for six months to follow a low glycemic diet. Dietary and anthropometric data were collected at baseline, end of induction, and end of month six (NCT03157323). Results: Twenty-three of 28 participants (82.1%) were evaluable and included in the analysis. Dietary intake of several nutrients targeted by the nutrition intervention declined (sugar, P = 0.003 and glycemic load, P = 0.053). We also observed a persistent increase in total vegetables across each timepoint (P = 0.015) and by the end of the intervention (P = 0.033). Importantly, we did not observe an increase in body mass index z-score during induction or over the six-month intervention period. Most families found the nutrition intervention easy to follow (60%) and affordable (95%) despite simultaneous initiation of treatment for ALL. Conclusions: A six-month nutrition intervention initiated during the initial phase of treatment for childhood ALL is feasible and may prevent weight gain. Our preliminary findings need to be confirmed in a larger clinical trial.
Population-based data on survival from childhood cancers in sub-Saharan Africa is sparse. We report data for nine childhood cancers in the population of Kampala Uganda. Survival for eight out of nine cancers was below the WHO’s global target of 60% (the exception was Hodgkin lymphoma (86% at 3 years)). There was significant (p<0.05) decline in survival between 1 and 3 years for Wilms tumour and Kaposi sarcoma (30% and 34% at 3-years respectively). Survival from Burkitt lymphoma, Wilms tumour and Kaposi sarcoma has not changed since 2005.
Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) is limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [3 without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in 4 eyes, and worse in 2 eyes; visual and radiologic outcome were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.
Background Disruption of critical cell cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein. Methods Palbociclib was administered orally starting at 50 mg/m2 daily for the first 21 days of a 28 day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (Stratum I) and heavily pretreated (Stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities. Pharmacogenetic analyses were based on pre-treatment samples. Results A total of 21 patients were enrolled on Stratum I and 14 patients on Stratum II. The MTD for both strata was 75 mg/m2. Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. No patients had an objective response to palbociclib therapy. Conclusions Palbociclib was safely administered to children and adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by 7 days of rest in both strata. Future studies will be required to establish its optimal utilization in pediatric patients with brain tumors.
Comment on: Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib1Paige Vicenzi, OMS-IV, 2Anish Ray, MD1Texas College of Osteopathic Medicine, University of North Texas Health Science Center2Department of Pediatric Hematology/Oncology, Cook Children’s Health Care SystemCorresponding Author:Anish Ray, MD1500 Cooper St., 5th floor,Fort Worth, TX 76104Phone: 425-205-0926Anish.Ray@CookChildrens.orgWord Count: 513Number of Tables: 0Number of Figures: 0Running Title: Langerhans cell histiocytosis treated by trametinibKeywords: Langerhans cell histiocytosis, MAP2K1, trametinib, pediatricThe authors have no financial support or conflicts of interest.Langerhans cell histiocytosis (LCH) is a rare but heterogenous myeloid malignancy. The discovery of mitogen-activated protein kinase (MAPK) pathway activating mutations as key oncogenic drivers offered only equivocal implications at best; the promise of targeted therapy was often eclipsed by a more severe clinical course, risk organ involvement, poorer response to standard therapy, and higher risk of relapse.1 There is, however, mounting evidence in support of MAPK pathway inhibition for patients with BRAF V600E mutations. A recent report outlines rapid and durable response of relapsed, multisystemic LCH with either BRAF p.N486_P490 or MAP2K1 p.K57_G61 deletion to MEK inhibitor trametinib.2 Two of the three patients achieved nonactive disease, including a 2-year-old male with MAP2K1 deletion who, despite reports attributing trametinib resistance to MAP2K1 mutations3, continues to thrive. We take this opportunity to describe an analogous experience treating a relapsed LCH patient with trametinib at Cook Children’s Medical Center from early 2020 to present.Our patient is a 4-year-old male who presented in March 2017 with new onset central diabetes insipidus (DI) and skin rash; skin biopsy provided diagnosis of LCH, but skeletal survey was negative for bone involvement. He was treated with twelve cycles of cytarabine (100 milligram (mg)/m2 intravenous daily for five days, every four weeks) and DDAVP for DI. At the completion of cytarabine, a second skin biopsy revealed recurrence of LCH, which warranted treatment with hydroxyurea (20 mg/kilogram (Kg) daily) and methotrexate (2.5 mg at 0.12 mg/Kg twice a week). This was continued for 52 weeks despite a brief interruption of methotrexate due to dermatitis. Three months following completion of this therapy, brain MRI revealed a 7 mm lesion of the skull. Curettage by neurosurgery confirmed relapse of LCH in January 2020. Genetic testing of this sample was negative forBRAF mutation, but positive for a mutation in the MAP2K1 gene, specifically a point mutation resulting in a substitution of Q56P. Shortly after his biopsy, the patient developed a soft tissue swelling on his skull. Due to these results and his multiple relapses, the patient was started on trametinib (2.5 mg daily) in February 2020 with rapid resolution of skull swelling and transient but dramatic reduction of his desmopressin dose from 3.2 mg twice a day to 0.2 mg twice a day. He has not experienced toxicity and continues to tolerate the drug well.Though trametinib presents a promising treatment for high-risk, relapsed LCH, it is not without limitations. In 2020, we also treated a 15-year-old male with relapsed LCH and BRAF V600E with trametinib monotherapy. Due to skin rash (Grade II), the patient became noncompliant. Despite stopping altogether after a month of treatment, he has yet to experience disease recurrence. But as stated in the aforementioned report, sufficient dose and treatment length to attain MAPK pathway suppression merits further investigation. In our similar experience treating a young child with multisystemic LCH and MAP2K1 mutation, we remain encouraged that MEK inhibition via trametinib monotherapy is a viable treatment option. In the context of genomic landscaping, we hope to incite further exploration of targeted therapy, and consequently, greater consensus on LCH management.
Background: Acute chest syndrome (ACS) is the leading cause of death for children with sickle cell disease (SCD). Recurrent ACS has detrimental effects on pulmonary health and healthcare costs. Neighborhood characteristics affect the outcomes of many pediatric chronic diseases, but their role in SCD is not well investigated. In this study, we investigated the effects of area-level socioeconomic deprivation and racial composition on the recurrence of ACS. Study design: We performed a retrospective cross-sectional analysis of clinical data from a large pediatric SCD center. Patients’ residential addresses were geocoded and linked to a composite Area Deprivation Index (ADI) and percent African American population at the level of Census block groups. The association of recurrent ACS with neighborhood characteristics was evaluated using logistic regression analysis. Results: The sample included 709 children with SCD. Residence in a socioeconomically deprived neighborhood was associated with 27% less risk of recurrent ACS, and residence in a predominantly African American neighborhood was associated with 41% less risk of ACS recurrence. The racial composition explained the protective effect of living in a high-deprivation area after adjusting for sociodemographic and clinical covariates. Demographic and clinical factors associated with recurrent ACS included older age, male gender, asthma, hydroxyurea use, and chronic transfusion therapy. Conclusions: This is the first study to report a protective effect of residing in a predominantly African American community for ACS recurrence. Further prospective studies are needed to confirm the association and to understand the mechanisms of such relationship.
Background: Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define the better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children’s Oncology Group (COG). Methods: We retrospectively identified patients with ARMS N1 enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in RMS2005 comprised IVADo (ifosfamide, vincristine, dactinomycin, doxorubicin), IVA and maintenance (vinorelbine, cyclophosphamide); in ARST0531 it consisted on either VAC (vincristine, dactinomycin, cyclophosphamide) or VAC alternating with VI (vincristine, irinotecan). Local treatment was similar in both protocols. Results: The analysis of the clinical characteristics of 239 patients showed some differences between study groups: in RMS2005, advanced IRS Group and large tumors predominated. There were no differences in outcomes between the two groups: 5-year event-free survival (EFS), 49% (95%CI=39-59) and 44% (95%CI=30-58), and overall survival (OS), 51% (95%CI=41-61) and 53.6% (95%CI=40-68), in RMS2005 and ARST0531, respectively. In RMS2005, EFS of patients with FOXO1-positive tumors was significantly inferior to those FOXO1-negative (49.3% vs 73%, p=0.034). In contrast, in ARST0531, EFS of patients with FOXO1-positive tumors was 45% compared with 43.8% for those FOXO1-negative. Conclusions: The outcome of patients with ARMS N1 was similar using different schemas of chemotherapy. However, patients with FOXO1 fusion-negative tumors enrolled in RMS2005 showed a significantly better outcome, suggesting that this subgroup may benefit from the EpSSG strategy which included maintenance chemotherapy.