Transformation of an abnormal karyotype to acute erythroid leukemia in a pediatric patient with Fanconi anemia: a case reportCorresponding Author: Lauren Hernandez, D.O.Pediatric Hematology/Oncology FellowUniversity of North Carolina at Chapel Hill170 Manning Drive1185A Houpt Physicians’ Office BuildingChapel Hill, NC 27599-7236Email: [email protected]: 321-501-4891 | Fax: 919-966-7629Thomas B. Alexander, M.D., M.P.H.Assistant Professor of PediatricsDivision of Pediatric Hematology and OncologyUniversity of North Carolina at Chapel HillJonathan Galeotti, M.D.Assistant Professor of HematopathologyDepartment of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillStuart Gold, M.D.Distinguished Professor of PediatricsDivision of Pediatric Hematology and OncologyUniversity of North Carolina at Chapel HillWord count: 842Figures: 1Keywords: acute erythroid leukemia, pediatric, Fanconi anemia, monosomy 7Abbreviations:

Practical Challenges Associated with Efanesoctocog Alfa (ALTUVIIIO) Prophylaxis in a 19-month-oldwith Severe Hemophilia AJessica N. Mistretta1, Maria G. Español1,2, Michael D. Tarantino1,2, Dane C. Christ1, Maureen D. Jones1,Jonathan C. Roberts1,21Bleeding & Clotting Disorders Institute, Peoria IL USA2Departments of Pediatrics and Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL USA

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.

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.

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.

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.

Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by the clonal proliferation of Langerhans-like cells. Colony-stimulating Factor 1 receptor (CSF1R) is a membrane-bound receptor that is highly expressed in LCH cells and tumor-associated macrophages. In this study, a soluble form of CSF1R protein (sCSF1R) was identified by plasma proteome profiling, and its role in evaluating LCH prognosis was explored. We prospectively measured plasma sCSF1R levels in 104 LCH patients and 10 healthy children using ELISA. Plasma sCSF1R levels were greater in LCH patients than in healthy controls ( P < 0.001) and significantly differed among the three disease extents, with the highest level in MS RO+ LCH patients ( P < 0.001). Accordingly, immunofluorescence showed the highest level of membrane-bound CSF1R in MS RO+ patients. Furthermore, the plasma sCSF1R concentration at diagnosis could efficiently predict the prognosis of LCH patients treated with standard first-line treatment (AUC =0.782, P < 0.001). Notably, dynamic monitoring of sCSF1R levels could predict relapse early in patients receiving BRAF inhibitor treatment. In vitro drug sensitivity data showed that sCSF1R increased resistance to Ara-C in THP-1 cells expressing ectopic BRAF-V600E. Overall, the plasma sCSF1R level at diagnosis and during follow-up is of great clinical importance in pediatric LCH patients.

The EPICO-SEHOP platform gathers data from children with SARS-CoV-2 in Spain, allowing comparison between children with cancer or allogeneic hematopoietic stem cell transplantation (alloHSCT) and those without. The infection is milder in the cancer/alloHSCT group than in children without comorbidities (7.1% vs. 15%), except in children with recent alloHSCT (less than 300 days), of which 35.7% experienced severe COVID-19. These data have been shared with the SEHOP members to support treatment and isolation policies akin to those for children without cancer, except for those with recent alloHSCT or additional comorbidities. This highlights the collaborative registries potential in managing pandemic emergencies.

Background: Thrombin is a critical protease modulating thrombosis as well as inflammation which are one of the main pathophysiological mechanisms in sickle vasculopathy, and its levels were reported to be high in sickle cell disease (SCD). The thrombin-thrombomodulin complex activates an inhibitor of fibrinolysis called TAFI acting by reducing plasmin affinity for its substrate hindering fibrinolysis. Objective: We aimed to determine the influence of the Thr325Ile single nucleotide polymorphism on TAFI antigen levels and potential effects on the severity of SCD in a cohort of Egyptian patients. Methods: Genotyping of Thr325lle polymorphism using Taq-Man SNP genotyping assay and TAFI level measurement using an Enzyme-Linked Immunosorbent Assay (ELISA) were performed for 80 SCD patients and 80 health control subjects. Results: Plasma TAFI levels were higher in SCD patients with Thr325Ile polymorphism, yet the difference was not statistically significant (p=0.204). SCD patients with polymorphic genotypes had a greater number of hospital admissions (p=0.03), Ten patients with acute chest syndrome had the homozygous polymorphic genotype (GG), and all patients with pulmonary hypertension had the polymorphic genotype (6 were homozygous [GG] and 5 were heterozygous [GA]). SCD patients complicated with pulmonary hypertension showed significantly higher plasma TAFI levels (p= 0.044). Conclusion: The analysis of Thr325Ile polymorphism combined with plasma TAFI level possibly suggests that the analyzed SNP could influence plasma levels and subsequently disease severity and hospitalization rate, which might be regarded as predictors for complex disease.

We conducted a feasibility study to evaluate micronutrients and body mass index. Fat soluble vitamins A, D, E and trace elements copper (Cu), selenium (Se) and zinc (Zn) levels were evaluated. Weight, height, body mass index (BMI) and Z-scores were recorded. Side effects or specific adverse events were documented. No patients had a Z score for height, weight, or BMI of <2SD or >2SD. Ninety percent of patients had one or more micronutrient levels below normal. These results suggest that micro-nutrient abnormalities are common despite no obvious evidence of malnutrition. Side effects of chemotherapy may be exacerbated by micronutrient depletion.

Objective: Childhood spinal tumors often present with musculoskeletal symptoms, potentially causing a misdiagnosis and delays in diagnosis and treatment. This study aims to identify, characterize, and compare children with spinal tumors who had prior musculoskeletal misdiagnoses to those without, analyzing clinical presentation, diagnostic interval, and outcome. Study design: This retrospective cohort study evaluated all children aged 0-14 years diagnosed with a spinal tumor in Denmark from 1996 to 2018. The cohort was identified through the Danish Childhood Cancer Registry, and the registry data were supplemented with data from medical records. The survival was compared using the Kaplan-Meier method. Results: Among 58 patients, 57% (33/58) recieved musculoskeletal misdiagnoses before the spinal tumor diagnosis. Misdiagnoses were mostly non-specific (64%, 21/33), involving pain and accidental lesions, while 36% (12/33) were rheumatic diagnoses. The patients with prior misdiagnosis had less aggressive tumors, fewer neurological/general symptoms, and 5.5 months median diagnostic interval versus 3 months for those without a misdiagnosis. Those with prior misdiagnoses tended to have a higher 5-year survival of 83% (95% CI 63-92%) compared to 66% (95% CI 44-82%) for those without (p=0.15) Conclusion: Less aggressive spinal tumors may manifest as gradual skeletal abnormalities and musculoskeletal symptoms without neurological/general symptoms, leading to misdiagnoses and delays.

OBJECTIVES In the etiology of childhood cancers, many genetic and environmental factors play a role. One of these factors is cigarette smoking and the main source of tobacco smoke exposure of children is parental smoking. However, establishing a causal relationship between parental smoking and childhood cancers has proven challenging due to difficulties in accurately detecting tobacco smoke exposure METHODS To address this issue, we used hair cotinine analysis and a questionnaire to get information about tobacco smoke exposures of pediatric cancer patients and healthy children. 104 pediatric cancer patients and 99 healthy children participated in our study. Parental smoking behaviours (pre-conceptional, during pregnancy and current smoking) and environmental tobacco smoke (ETS) exposures of children are compared. RESULTS We have found no differences between two groups by means of maternal smoking behaviours. However, the rates of paternal pre-conceptional smoking and smoking during pregnancy were significantly low in cancer patients (p<0,05). These data suggests that social desirability bias among fathers of cancer patients may have contributed to this discrepancy. According to questionnaire cancer patients had significantly lower ETS exposures than healthy children (p<0,05). However, ETS exposure assessment through cotinine analysis demonstrated that cancer patients had higher exposure to ETS compared to healthy children (p<0.001). CONCLUSION Our findings provide evidence supporting the potential role of smoking as a risk factor for childhood cancers. This study also revealed that questionnaires could cause biases. We suggest that cotinine analysis along with validated questionnaires can be used to prevent biases in studies of tobacco smoke in the etiology of childhood cancers.

In utero tumor development and identification ofCTNNB1 mutation in a newborn case of ossifying renal tumor of infancy Shin Kasai1, Minori Tamai1, Eiji Sugihara2, Naoki Oishi3, Kyoko Hinata1, Koshi Akahane1, Kumiko Goi1, Yuko Hata2, Tetsuo Kondo3, Takahiko Mitsui4, Mio Tanaka5, and Takeshi Inukai1*1) Departments of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan2) Division of Gene Regulation, Cancer Center and Open Facility Center, Research Promotion Headquarters, Fujita Health University School of Medicine, Toyoake, Aichi, Japan3) Department of Pathology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan4) Department of Urology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan5) Department of Pathology, Kanagawa Children’s Medical Center, Yokohama, Japan.*Corresponding authorTakeshi Inukai, Department of Pediatrics, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409–3898, Japan. Email: [email protected] count: 849/850 wordsFigures: 2Supplemental Tables: 2Supplemental Figures: 5Running title: CTNNB1 mutation in ossifying renal tumor of infancy (44/50 characters)Key words: CTNNB1, Ossifying renal tumor of infancy, β-catenin, hematuria, calcification, renal tumorAn abbreviations keyORTI: Ossifying renal tumor of infancyWES: Whole exome sequencingEMA: Epithelial membrane antigenPBMC: Peripheral blood mononuclear cellsCNV: Copy number variationILNR: Intralobar nephrogenic restCNSET: Calcifying nested stromal-epithelial tumor

Air-leak syndrome (ALS) is an independent poor prognosis factor among adult patients who have received hematopoietic stem cell transplantation (HSCT), which 5-year overall survival (OS) is less than 30%. However, the clinical features of ALS among post-transplant pediatric patients have rarely been explored.We retrospectively reviewed 2,206 pediatric patients who received an allo-HSCT between January 2013 and December 2019 at the Hebei Yanda Lu Daopei Hospital and analyzed the role of ALS in their prognosis following HSCT.We divided ALS into two categories: 15 cases of bronchiolitis obliterans syndrome (BOS) and 13 cases of idiopathic pneumonia syndrome (IPS).Following treatment of the ALS, 18 patients survived (18/28, 64.3%) and 10 patients died of respiratory failure or infection (10/28, 35.7%). The OS of ALS in our hospital is significantly higher than that cited in previous reports which may be related to early diagnosis and timely FAM treatment.