Glanzmann Thrombasthenia (GT) is an inherited bleeding disorder of poor platelet function secondary to a defect in platelet membrane glycoprotein IIb/IIIa (GPIIb/IIIa). Patients with GT may develop anti-platelet antibodies including anti-GPIIb/IIIa which can lead to severe refractory thrombocytopenia and life-threatening bleeding, management of which is challenging. We report successful use of imlifidase, a novel IgG protease enzyme, as part of a multimodal approach for management of severe platelet refractoriness and alloimmunization in a child with GT and primary graft failure following hematopoietic stem cell transplant (HSCT). The patient had no detectable anti-platelet alloantibodies following imlifidase, and underwent a second HSCT.

Background: Proton therapy (PT) has potential advantages in pediatric Hodgkin lymphoma (pHL). However, there is limited data on PT, specifically to infradiaphragmatic targets. We report on PT planning details, doses achieved to organs at risk (OARs), and clinical and toxicity outcomes for patients with pHL who received PT to infradiaphragmatic regions. Methods: This is a retrospective study including patients treated between 2011-2022. Demographic and clinical factors were collected, and toxicity was reported using CTCAE version 5.0. Dosimetric and clinical factors associated with key outcomes were assessed via Cox regression. Photon plans were generated for all patients, and the paired t-test or Wilcoxon signed rank sum test were used for dosimetric comparisons. Results: Twenty-one patients comprising 22 PT courses were included. Median follow-up was 5.0 years and mean age was 14.2 years. Median dose was 21 Gray equivalent (GyE) over 14 fractions. Top acute grade 1 (G1) toxicities included fatigue (59%) and anorexia (36%). Rates of acute G2 and G3+ toxicity were 18% and 0%, respectively. After PT, no local or marginal failures occurred. 5% experienced disease progression which were all successfully salvaged, and all patients were alive and disease-free at last follow-up. No secondary malignancies developed. Compared to photon radiation, PT achieved significantly lower doses to the bowels, stomach, spleen, pancreatic tail, liver, and kidneys. Conclusions: PT is well-tolerated and leads to excellent oncologic and toxicity outcomes with long-term follow-up. PT confers dosimetric advantages when compared to photons.

Background The last major North American cooperative group clinical trial for relapsed favorable histology Wilms tumor (FHWT) was completed in 2002. The outcomes of patients with relapsed Wilms tumor subsequently treated outside of clinical trials is unknown. The aim of this study was to assess the efficacy and toxicity of salvage therapies used for patients with FHWT suffering first relapse. Methods We conducted a retrospective chart review of patients treated for first relapse of FHWT at six large North American institutions from January 2002 through August 2018. Results Ninety-four patients were identified. Thirty-six patients were classified as standard-risk relapse (SRR), 49 patients as high-risk relapse (HRR) and seven patients as very high-risk relapse (VHRR). Twenty-one patients with SRR were treated with Regimen I. The 4-year EFS and OS for SRR was 82.4% and 93.3%, respectively, with median follow up of 72 months. Twenty-eight HRR/VHRR patients were treated with ICE therapy while 13 received NWTS5 Stratum C. No patient completed protocol therapy per stratum C; median maintenance cycles administered was 2. The 4-year EFS and OS for HRR/VHRR was 32.6% and 58.3%, respectively, with median follow up of 33 months. Conclusions Outcomes for all strata of relapsed WT patients treated in a non-clinical setting appear to have similar outcomes as historical cohorts treated on NWTS5. Improved strategies are urgently needed for HRR and VHRR relapses.

Atypical hemolytic uremic syndrome (aHUS) is an infrequently encountered complement-mediated thrombotic microangiopathy (TMA) usually associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI) with severe hypertension arise due to aberrant complement protein activation in the circulation and significant endothelial damage. Transplant-associated thrombotic microangiopathy has been increasingly recognized after high dose carboplatin, etoposide, and melphalan-chemotherapy followed by autologous hematopoietic stem cell rescue for treatment of children with neuroblastoma (NB). We report the case of a 13-month-old boy with metastatic neuroblastoma who developed aHUS during the first cycle of induction chemotherapy. Germline testing revealed a Complement factor H (CFH) gene mutation, Cys357Arg, which is currently classified as a variant of uncertain significance (VUS), although likely pathogenic based on molecular modeling as well as this patient’s clinical presentation. The patient has been successfully managed with complement blockade therapy with no recurrence of disease. We review presentations of neuroblastoma with hypertension, along with AKI and thrombocytopenia, to raise awareness about the potential for aHUS in patients with newly diagnosed NB.

Background and aims Patients affected by metastatic germ cell tumors may occasionally experience enlargement of metastatic lesions with concurrent normalization of tumor markers after chemotherapy. This phenomenon is described as Growing Teratoma Syndrome (GTS). The aim of the present study is to assess the prevalence of GTS in the pediatric population and its implications in terms of surgical outcome. Methods The clinical notes of patients diagnosed with stage III and IV malignant germ cell tumors from January 2010 until December 2020 at our Institution were retrospectively reviewed. Patients with residual disease after chemotherapy were studied; the occurrence of GTS, treatment strategies, survival and outcome were analyzed. Results Thirty-three patients with high stage malignant germ cell tumors were diagnosed in our Institution in the analyzed period. Eleven patients (34%) had radiologic evidence of enlargement of metastases after chemotherapy; nine of them (28%) had normal markers after chemotherapy and were classified as GTS patients. All nine patients underwent resection of metastatic lymph nodes and six had surgery on visceral metastases. In six patients, radical excision of all metastatic sites was achieved; five patients are alive and in complete remission while one died for peri-operative complications. Out of the three patients who could not achieve radical excision of the metastases, two died for progressive disease and one is alive with progressive disease. Conclusions Patients affected by GTS have a risk of progression of chemotherapy-resistant disease and death. Radical surgical excision is essential to achieve disease control and long-term survival.

Background: Hydroxyurea remains underutilized in the pediatric sickle cell population despite its well-known efficacy in decreasing sickle cell complications and hospitalizations. Access to refills and liquid formulation remains a critical barrier to adherence to hydroxyurea regimens. This study was undertaken to determine the clinical impact of home-delivering compounded liquid hydroxyurea (LHU) to pediatric patients with sickle cell disease. Procedure/Methods: A retrospective cohort study was conducted using electronic health records and pharmacy databases. Pediatric patients younger than 21 years of hydroxyurea initiation from March 2016 to July 2020 who received compounded LHU from Boston Medical Center Pharmacy were included. The primary outcomes of the study were drug adherence (assessed by evaluating the proportion of days covered), rates of acute care utilization, laboratory values, and growth metrics before and after enrolling in the LHU delivery program. Results: The final cohort included 41 patients. Significant increases in hemoglobin 0.34 g/dl (95% CI: 0.04-0.63, p=0.02) and mean corpuscular volume 3.2 FI (95% CI: 0.92-5.4, p=0.007) occurred. Hospitalizations decreased by 51.3% (p=0.01), and acute chest syndrome episodes decreased by 86.4% (p=0.02) post-initiation of the LHU delivery program. Drug adherence had a median value of 0.95 one-year post-initiation of LHU. Conclusions: Home delivery of compounded LHU improved drug adherence, decreased hospitalizations, and improved laboratory outcomes in pediatric patients with sickle cell disease by overcoming barriers to access. Nationwide implementation of similar home delivery programs can significantly improve outcomes among pediatric patients with sickle cell disease.

Pediatric secondary Chronic myelogenous leukemia in a patient with Hemophagocytic lymphohistiocytosis carrying UNC13D,LYST and ITK variantChengshuang Huang1, 2, 3 Pei Huang1, 3 Xi Luo1, 3 Zhixu He1, 3 Yan Chen1, 31Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, 563000, China2Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, PR China3Department of Pediatrics, Guizhou Children’s Hospital, Zunyi, 563000, ChinaAddress correspondence to: Yan Chen, MD, The Second Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou, 563000, China, [email protected], +86-0851-28608293Short title: Pediatric secondary CML in a patient with HLHKeywords: Hemophagocytic lymphohistiocytosis; Secondary CML; Chemotherapy; Genetic screeningText: 839 wordsNumber of Tables: 1

Abstract: Introduction: Germ cell tumors (GCT) encompass a wide variety of neoplasms with varying clinical behavior dependent on histology, staging, and site. GCT remain relatively uncommon in the pediatric population and most patients have a favorable prognosis. However, the well-established co-occurrence of primary mediastinal GCT (PMGCT) and acute myeloid leukemia (AML) has a dismal prognosis with few reported patients achieving sustained remission. Case presentation: An 18 y.o. male was concurrently diagnosed with PMGCT and AML, type M7. Cytogenetic analysis revealed a complex set of chromosomal alterations along with homozygous deletion of TP53. His concurrent oncologic processes were managed with a variety of chemotherapy regimens, complete surgical resection of the mediastinal mass, and hematopoietic stem cell transplant (HSCT). He is one of few patients with concurrent PMGCT and AML able to achieve remission with no evidence of disease nearly 5 years after completion of treatment. Conclusion: The rare, but well-identified, association between PMGCT and concurrent or subsequent AML has a dismal prognosis. Modern genetics sequencing has identified common aberrations, including i(12p), trisomy/tetrasomy 8, TP53, and PTEN mutations. With this knowledge, it may allow for future tailoring of therapy to improve the predicted outcome of patients with PMGCT and AML.

Background Ganglioneuroblastoma intermixed (GNBi) and ganglioneuroma (GN) are benign subtypes of neuroblastic tumors. Primary observation has become accepted management for some patients with surgical operative strategies evolving to be less aggressive. Objectives Our study examines evolving management in a UK cohort investigating natural history, biology and clinical features of GN and ganglioneuroblastoma-intermixed (GNBi) in those having observation or surgery. Methods Retrospective review of histologically confirmed GN and GNBi managed over a 30 year period. Clinical, pathological features, tumor dimensions, management and outcomes are all recorded. Results A total of 259 patients were identified (GN= 163, GNBi = 93, median age = 62 months). 201(78%) had upfront surgery and 58 (22%) were actively observed. Of the 58 observed - 21 (36%) later required surgery due to progressive tumour growth (52%). Gross total resection was achieved in 79% of patients with a 19% complication rate. Presence of image defined risk factors and large tumour size correlated with incomplete resection (p < 0.05 in both). Forty-five index cases (39%) had change in pathology between biopsy and surgery with 14 patients (12%) altered from ‘favourable‘ to ‘unfavourable’. Conclusion Our findings show surveillance alone may be considered a safe approach. However, a significant number of index patients may eventually require operative surgery with development of symptoms. Extent of surgical resection did not impact overall survival (OS); however it improved symptom(s) resolution.

Background: Chimeric Antigen Receptor (CAR) T cell therapy provides promising outcomes in relapsed/refractory B Acute Lymphoblastic Leukemia (ALL) yet still carries high toxicities rates and relatively poor long-term survival. Efficacy has yet to be demonstrated in other diagnoses while toxicity and risk profiles remain formidable. To date, treatment-related symptom burden is gleaned from clinical trial toxicity reports; the patient perspective remains understudied. Methods: English or Spanish-speaking patients (ages 8-25 years) undergoing CAR T cell therapy for any malignancy and their primary caregiver were recruited from Seattle Children’s Hospital (SCH), St. Jude Children’s Research Hospital (SJCRH), and the Pediatric Oncology Branch of the National Cancer Institute (NCI). Both patient and caregiver completed semi-structured dyadic interviews 3-months post-treatment. We used directed content analysis for codebook development and thematic network analysis for inductive qualitative analysis. Results: Twenty families completed interviews (13 patients, 15 parents). Patients were a median age 16.5 years, predominantly female (65%), white (75%), and diagnosed with ALL (75%). Global themes included “A clear decision,” “Coping with symptoms,” and “Unforeseen psychosocial challenges.” When families were asked to describe the “most challenging part of treatment,” most described “the unknown.” Most reported “the symptoms really weren’t that bad,” even among patients hospitalized for severe toxicity events. Fatigue, pain, and nausea were the most prevalent symptoms. Importantly, only one family would have chosen a different therapy, if given another opportunity. Conclusions: Although physical symptoms were largely tolerable, recognizing supportive care opportunities remains imperative, particularly psychosocial concerns.

Title: Mixed Coagulopathy in Patient with Peroxisomal Disorder, Zellweger SyndromeAuthors: Nicholas Farris, MD1; Angela Sandell, MD2AffiliationsAssistant Professor, University of Rochester Medical Center, Division of Pediatric Hematology and Oncology, Rochester, NYAssistant Professor, University of Rochester Medical Center, Division of Gastroenterology, Rochester, NYCorresponding Author:Nicholas FarrisEmail: [email protected]: 601 Elmwood Ave, Box 777, Rochester NY, 14642Phone: 585-273-4189Fax: 575-273-1039Word Count: 462Tables, Figures, Supporting files: 0Running Title: Mixed Coagulopathy in Patient with ZellwegersKeywords: Coagulopathy, Peroxisome, Zellwegers, Intracranial Hemorrhage

Background: Survival data for recurrent or treatment refractory pediatric atypical teratoid rhabdoid tumor (AT/RT), and its association to molecular groups is extremely limited. Methods: Single-institution retrospective study of sixty-four children <21 years old with AT/RT that was recurrent or refractory to frontline therapies (PD) treated at St. Jude Children’s Research Hospital from January 2000 to December 2020. Demographic, clinicopathologic, treatment, molecular grouping (SHH, TYR and MYC) and germline SMARCB1/SMARCA4 mutational data were collected. Progression-free survival (PFS2: time from initial PD to subsequent first progression) and overall survival (OSpostPD: time from PD to death/last follow up) were estimated by Kaplan–Meier analysis. Results: Median age at and time from initial diagnosis to PD were 2.1 years (range: 0.5-17.9 years) and 5.4 months (range: 0.5-125.6 months), respectively. Only 5/64 children (7.8%) are alive at median follow-up of 10.9 (range: 4.2-18.1) years from PD. The 2/5-year PFS2 and OSpostPD were 3.1% (±1.8%)/1.6% (±1.1%) and 20.3% (±4.8%)/7.3% (±3.5%), respectively. Children with TYR group (n=10) had a better OSpostPD compared to those with MYC (n=11) (2-year survival estimates: 60.0% ±14.3% vs. 18.2% ±9.5%; p=0.019), or those with SHH (n=21; 4.8% ±3.3%; p=0.014). In univariate analyses, OSpostPD was better with older age at diagnosis (p=0.037), female gender (p=0.008), and metastatic site of PD compared to local or combined sites of PD (p<0.001). Conclusions: Children with recurrent/refractory AT/RT have dismal outcomes. Older age at diagnosis, female gender, TYR group, and metastatic site of PD were associated with relatively longer survival in our study.

Retinoblastoma, the most common intraocular tumor in childhood, still faces challenges in diagnosis and treatment, particularly in low- and middle-income countries. Identifying strategies to improve the time to diagnosis and access to treatment is crucial to enhance survival rates and preserve ocular health. We conducted a systematic review to identify interventions that have demonstrated potential in addressing these challenges. We performed a comprehensive search across databases until March 2023. Out of the studies reviewed, twenty-one met the inclusion criteria and were categorized into five main areas: surveillance strategies, genetic counseling, education, public assistance and international partnership. Despite the obstacles faced, the initiatives identified in this review present acts towards improving the time to diagnosis and access to treatment for retinoblastoma. Based on the extracted data, we propose a comprehensive chain of initiatives. We firmly believe that implementing this chain of initiatives can lead to improved clinical outcomes for retinoblastoma patients.

Secondary histiocytoses are exceedingly rare and knowledge about pathophysiology and treatment is limited. We report the first known case of Philadelphia chromosome -like - B-lymphoblastic leukemia complicated by disseminated juvenile xanthogranuloma in an adolescent salvaged successfully with targeted MEK inhibition.

Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.

Title : Evans syndrome in the background of 22q11.2 deletion syndrome

Background: The outcome of extramedullary infiltration (EMI) in pediatric acute myeloid leukemia (AML) is controversial, and little is known about the implications of stem cell transplantation (SCT) and gemtuzumab ozogamicin (GO) treatment on AML patients with EMI. Methods: We retrieved the clinical data of 713 pediatric AML patients from the TARGET dataset and analyzed the clinical and prognostic characteristics of patients with EMI at initial diagnosis and relapse. Results: A total of 123 patients were identified to have EMI at initial diagnosis and 64 presented with EMI at relapse. We discovered that the presence of EMI was associated with age ≤2 years, M5 morphology, abnormal karyotype, and KMT2A rearrangements. Hyperleukocytosis and complex karyotype were more prevalent in EMI relapse patients. Additionally, patients with EMI at diagnosis showed a reduced incidence of FLT3 ITD-/NPM1+, whereas EMI relapse patients displayed a lower frequency of FLT3 ITD+. Patients with EMI at diagnosis exhibited a lower rate of CR1 and higher incidence of relapse. Importantly, EMI at diagnosis independently predicted both shorter EFS and OS. Regarding relapse patients, the occurrence of EMI at relapse showed no impact on OS. However, relapse patients with myeloid sarcoma exhibited a poorer OS compared to those with exclusive CNS involvement. Furthermore, in reference to patients with EMI at initial diagnosis, SCT failed to improve the survival, whereas GO treatment may potentially enhance OS. Conclusion: EMI at initial diagnosis is an independent prognostic risk factor, GO treatment has the potential to improve survival for patients with EMI at diagnosis.

The low incidence of vincristine-induced peripheral neuropathy (VIPN) in Kenyan children may result from low vincristine exposure. We performed a pharmacokinetically (PK) guided dose-escalation feasibility study of vincristine in Kenyan children (NCT05844670). Vincristine PK exposure was assessed with a previously developed nomogram. A 20% dose increase was recommended for participants with low exposure and no VIPN, hyperbilirubinemia or malnutrition. None of the fifteen participants developed VIPN. Low vincristine exposure was seen in only one participant: a dose increase was implemented without side-effects. Average vincristine exposure was high. In conclusion, the participants did not develop VIPN despite having high vincristine exposure.