Systemic Inflammatory Response Post Alemtuzumab and Low-Dose Total Body Irradiation in Pediatric Patients with Sickle Cell Disease: A Case SeriesRozalyn Chok1, Katherine Girgulis2, Robert S Nickel3,4, Gregory MT Guilcher2*.Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Lucile Packard Children’s Hospital, Stanford University, Stanford, California, United States.Section of Oncology/BMT, Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, Canada.Division of Hematology and Division of Blood and Marrow Transplantation, Children’s National Hospital, Washington, District of Columbia, United States.Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States.*Correspondence to:Gregory Guilcher, MD, Section of Oncology/BMT, University of Calgary, Alberta Children’s Hospital, 28 Oki Drive Trail NW, Calgary, AB, T3B 6A8. Email: [email protected] word count: 786 wordsRunning title: SIRS Post TBI in SCD PatientsKeywords: Sickle Cell Disease, Total Body Irradiation, Alemtuzumab, Hematopoietic Stem Cell TransplantFigures: 0Tables: 2

Clinical Relapse versus Treatment failureThe case for surveillance for reappearance of minimal measurable disease in pediatric patients with higher risk B-ALL.Paul S. Gaynon1 and Linwei Li21. University of Southern California, Keck School of Medicine, Los Angeles CA 900892. University of Texas, Rio Grande Valley School of Medicine, Edinburg, TX 78541Despite impressive progress in childhood acute lymphoblastic leukemia, an urgent clinical need remains. Patients still relapse and outcomes after relapse have changed little between 1996- 2006 and 2004 – 2014.1 Despite progress with late marrow relapse (1st remission (CR1) > 36 months), treatment of early relapse (CR1 < 36 months) remains unsatisfactory,2 especially in patients deemed higher risk at diagnosis, such as adolescents and young adults (AYA’s).3Progress to date derives from improved primary therapy. Further improvements in primary therapy have an ever-increasing price. Going from 50% to 70%, a 40% reduction in relapses, 5 patients need to be treated to prevent one relapse. Similarly, going from 75% to 85%, again a 40% reduction relapses, 10 patients need to be treated to prevent one relapse. With improving outcomes with primary therapy, we are facing an increasing number needed to treat for further improvement.4 All patients need to bear the burden of a novel intervention to benefit an ever smaller percentage. Not all interventions are successful.Recent experience suggests that we are reaching the limits of “intensification” of therapy, despite improvements in supportive care.5 For some patients such AYA’s, we may have surpassed tolerable limits. Querying the Pediatric Health Information system database, Gupta et al found a higher incidence of intensive care unit stays and increased toxicities in almost every organ system for AYA’s.6 Serious complications may prevent delivery of best care, resulting in relapse.Personalized molecularly targeted medicine is complicated by the vast interpatient diversity of ALL7 and intra-patient oligoclonality.8 Inhibition of a single driver pathway is unlikely sufficient for cure.9We have, however, newer modalities, such as inotuzumab,10,11 blinatumomab,12,13and chimeric antigen re-arranged (CAR) T-cells14,15that target large subsets of B-ALL. Blinatumomab has demonstrated value in relapsed B-ALL.12,13 Emerging experience has shown that blinatumomab and CAR T-cells work better at lower disease burdens.14-17 In 2017, blinatumomab was licensed for children and adults with B-ALL in 1st or second remission with measurable residual disease > 0.1%.18The presence of 25% marrow lymphoblasts blasts has long been the threshold for clinical marrow relapse. 19 Earlier reports showed that early detection of overt clinical relapse provides no clinical benefit.20,21 However, treatment fails, i.e., blast proliferation exceeds blast kill, prior to clinical relapse. We now have reliable technologies to identify low levels of re-appearing leukemia.22 Serial assessment of MRD and prompt intervention has yet to be tested systematically.In B-ALL, flow cytometry has largely overcome our inability to distinguish lymphoblasts from hematogones and recovery myeloblasts. Current flow cytometric or polymerase chain reaction technologies allows reliable detection of re-appearing lymphoblasts at levels 2 log10 below 1%.22 Next generation sequencing (NGS) allows detection 4 log10 below 1% and restaging of some patients called mistakenly classified MRD positive because of low numbers of low specificity targets.23 A new international consensus proposes that the confirmed presence of 1% lymphoblasts after the third month of therapy constitutes relapse or induction failure, if not preceded by a remission.24Flow cytometry, PCR, NGS, FISH, cytogenetics, and /or RT-PCR when relevant may be employed.Reappearance of MRD greater than some number predicts relapse in adult25 and pediatric trials.26Cheng et al report that reappearance of MRD reliably predicted relapse in their 30 patient cohort.27Early intervention may have clinical value. Wang et al reported on 1030 children who achieved MRD negative remission. One hundred fifty had MRD reappearance at a median time of 11 months. At 5 years, the EFS was 88.5% for continuously negative MRD and 38.4% for reemergent MRD. Eighty-five MRD reemergent patients subsequently relapsed at a median of 4.1 months. Reappearance of MRD was the most powerful adverse prognostic factor in multivariate analyses. An MRD cutoff of 0.15% gave the best discrimination. After reemergent MRD, 113 continued chemotherapy at their families’ choice and 37 underwent HSCT in CR1. The 2-year overall survival was 89% for HSCT and 46% for continued chemotherapy (p< 0.001); the cumulative incidence of relapse was 23% and 64% (p< 0.001).28MRD surveillance is not yet standard in pediatric ALL. However, MRD surveillance is already included in adult ALL guidelines.29,30 “Bone marrow aspirate can be considered as clinically indicated at a frequency of up to 3 to 6 months for at least 5 years.” 30In the past marrow sampling has been required as marrow and peripheral blood are unpredictably discordant in B-ALL. 31 Marrow aspiration is painful, and children often receive anesthesia. Marrow aspirates include a variable proportion of peripheral blood affecting the precision of MRD estimates. NGS may allow peripheral blood sampling.NGS has further lowered the limits of quantification to 10-6 and raised the possibility of peripheral blood monitoring in B-ALL.31 Rau et al found that end induction peripheral blood (PB) NGS was positive in nearly all cases marrow MRD by flow was positive at 0.01%. Muffly et al found that clinical relapse followed reappearance of peripheral blood NGS with a median of 90 days after HSCT and 60 days following CAR T therapy. Peripheral blood NGS surveillance of higher risk B-ALL patients seems worthy of investigation.Clinical features, molecular features, and response to therapy allow us to identify patients at greater or lesser risk of relapse.32 The adolescent and young adult population seems apt for a trial of such a strategy. Favorable cytogenetics are uncommon, and the marrow relapse rate is substantial.33 The burden of current therapy is already extreme and the efficacy of conventional salvage therapy poor.12Estimating a 20% relapse rate between 10 months and 36 months and q3month sampling, 8/10 patients would have 72 negative assays, and two relapsing patients might have 9 assays, for a total of 81 assays with about 1/40 being positive.Serial PB sampling adds little to the burden of treatment. Detection of confirmed treatment failure at an MRD level, allows immediate use of blinatumomab or CAR T-cells with a high probability to proceed to transplant MRD negative. Another round of toxic cytotoxic chemotherapy, much like the therapy that already failed, might be avoided. “If not now, when.”References1. Rheingold SR, Bhojwani D, Ji L, et al. Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children’s Oncology Group study. Leukemia. 2024.2. Rheingold SR, Ji L, Xu X, et al. Prognostic factors for survival after relapsed acute lymphoblastic leukemia (ALL): A Children’s Oncology Group (COG) study. In: American Society of Clinical Oncology; 2019.3. Freyer DR, Devidas M, La M, et al. Postrelapse survival in childhood acute lymphoblastic leukemia is independent of initial treatment intensity: a report from the Children’s Oncology Group. Blood. 2011;117(11):3010-3015.4. Hasan H, Goddard K, Howard AF. Utility of the number needed to treat in paediatric haematological cancer randomised controlled treatment trials: a systematic review. BMJ open. 2019;9(2):e022839.5. van Binsbergen AL, de Haas V, van der Velden VHJ, de Groot-Kruseman HA, Fiocco MF, Pieters R. Efficacy and toxicity of high-risk therapy of the Dutch Childhood Oncology Group in childhood acute lymphoblastic leukemia. Pediatric blood & cancer. 2022;69(2):e29387.6. Gupta A, Damania RC, Talati R, O’Riordan MA, Matloub YH, Ahuja SP. Increased Toxicity Among Adolescents and Young Adults Compared with Children Hospitalized with Acute Lymphoblastic Leukemia at Children’s Hospitals in the United States. Journal of adolescent and young adult oncology. 2021;10(6):645-653.7. Chang TC, Chen W, Qu C, et al. Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024:Jco2302238.8. Pieters R, Mullighan CG, Hunger SP. Advancing Diagnostics and Therapy to Reach Universal Cure in Childhood ALL. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;41(36):5579-5591.9. Kleppe M, Levine RL. Tumor heterogeneity confounds and illuminates: assessing the implications. Nature medicine. 2014;20(4):342-344.10. Dhillon S. Inotuzumab Ozogamicin: First Pediatric Approval.Paediatric drugs. 2024;26(4):459-467.11. O’Brien MM, Ji L, Shah NN, et al. Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children’s Oncology Group Protocol AALL1621. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;40(9):956-967.12. Brown PA, Ji L, Xu X, et al. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. Jama. 2021;325(9):833-842.13. Hogan LE, Brown PA, Ji L, et al. Children’s Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;41(25):4118-4129.14. Lamble AJ, Myers RM, Taraseviciute A, et al. Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells.Blood advances. 2023;7(4):575-585.15. Park JH, Rivière I, Gonen M, et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. The New England journal of medicine. 2018;378(5):449-459.16. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531.17. Queudeville M, Stein AS, Locatelli F, et al. Low leukemia burden improves blinatumomab efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Cancer. 2023;129(9):1384-1393.18. Jen EY, Xu Q, Schetter A, et al. FDA Approval: Blinatumomab for Patients with B-cell Precursor Acute Lymphoblastic Leukemia in Morphologic Remission with Minimal Residual Disease. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019;25(2):473-477.19. Mastrangelo R, Poplack D, Bleyer A, Riccardi R, Sather H, D’Angio G. Report and recommendations of the Rome workshop concerning poor-prognosis acute lymphoblastic leukemia in children: biologic bases for staging, stratification, and treatment. Medical and pediatric oncology. 1986;14(3):191-194.20. Rogers PC, Bleyer WA, Coccia P, et al. Yield of unpredicted bone-marrow relapse diagnosed by routine marrow aspiration in children with acute lymphoblastic leukaemia. A report from the Children’s Cancer Study Group. Lancet (London, England). 1984;1(8390):1320-1322.21. Rubnitz JE, Hijiya N, Zhou Y, Hancock ML, Rivera GK, Pui CH. Lack of benefit of early detection of relapse after completion of therapy for acute lymphoblastic leukemia. Pediatric blood & cancer. 2005;44(2):138-141.22. Contreras Yametti GP, Ostrow TH, Jasinski S, Raetz EA, Carroll WL, Evensen NA. Minimal Residual Disease in Acute Lymphoblastic Leukemia: Current Practice and Future Directions. Cancers. 2021;13(8).23. Svaton M, Skotnicova A, Reznickova L, et al. NGS better discriminates true MRD positivity for the risk stratification of childhood ALL treated on an MRD-based protocol. Blood. 2023;141(5):529-533.24. Buchmann S, Schrappe M, Baruchel A, et al. Remission, treatment failure, and relapse in pediatric ALL: an international consensus of the Ponte-di-Legno Consortium. Blood. 2022;139(12):1785-1793.25. Raff T, Gökbuget N, Lüschen S, et al. Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials. Blood. 2007;109(3):910-915.26. Paganin M, Fabbri G, Conter V, et al. Postinduction minimal residual disease monitoring by polymerase chain reaction in children with acute lymphoblastic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(31):3553-3558.27. Cheng S, Inghirami G, Cheng S, Tam W. Simple deep sequencing-based post-remission MRD surveillance predicts clinical relapse in B-ALL.Journal of hematology & oncology. 2018;11(1):105.28. Wang Y, Xue YJ, Jia YP, Zuo YX, Lu AD, Zhang LP. Re-Emergence of Minimal Residual Disease Detected by Flow Cytometry Predicts an Adverse Outcome in Pediatric Acute Lymphoblastic Leukemia. Frontiers in oncology. 2020;10:596677.29. Gökbuget N, Boissel N, Chiaretti S, et al. Management of ALL in adults: 2024 ELN recommendations from a European expert panel.Blood. 2024;143(19):1903-1930.30. Network NCC. Acute Lymphoblastic Leukemia (Version 2.2024) 2024.31. Pierce E, Mautner B, Mort J, et al. MRD in ALL: Optimization and Innovations. Current hematologic malignancy reports. 2022;17(4):69-81.32. Hunger SP, Loh ML, Whitlock JA, et al. Children’s Oncology Group’s 2013 blueprint for research: acute lymphoblastic leukemia.Pediatric blood & cancer. 2013;60(6):957-963.33. Burke MJ, Devidas M, Chen Z, et al. Outcomes in adolescent and young adult patients (16 to 30 years) compared to younger patients treated for high-risk B-lymphoblastic leukemia: report from Children’s Oncology Group Study AALL0232. Leukemia. 2022;36(3):648-655.

Background: Sinusoidal obstruction syndrome (SOS), a serious complication after hematopoietic cell transplant (HCT), is associated with multi-organ dysfunction (MOD) and a high mortality rate. In severe cases, continuous kidney replacement therapy (CKRT) is initiated to manage fluid overload (FO) and acute kidney injury. Studies that evaluate the use of CKRT in this population are lacking. The aim of our study was to assess the outcome of critically ill children with severe SOS post HCT who received CKRT. We also sought to assess factors associated with survival and liberation post CKRT. Procedure: Retrospective review of all children admitted to the intensive care unit (ICU) with SOS post HCT who received CKRT from January 2010 to August 2022. Results: Among the 53 children who received CKRT post HCT, 13 had severe SOS. The median age was 6 years; 62% were males, and most (77%) received allogeneic HCT. In this cohort, 92% required respiratory support and 85% required vasopressor support. The ICU survival rate was 62%. Survivors experienced lower cumulative FO on the 2 days following CKRT initiation (-4.2% in survivors versus -0.5% in non-survivors, p=0.07). Higher urine output on D1 and D2 after discontinuation of CKRT was associated with successful liberation. Conclusions: In this study of post-HCT children with SOS and MOD who received CKRT, 62% survived until ICU discharge. This survival rate is encouraging as it approximates the survival rates of general pediatric cohorts treated with CKRT. Reducing FO after initiation of CKRT can improve survival in these children.

Impact of Duffy-Associated Neutrophil Count on Maintenance Chemotherapy Management in a Child with Acute Lymphoblastic LeukemiaDerek K. Zachman1,2, Jonathan G. Bardahl1, Laurie A. Graves1, and Lars M. Wagner11Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham NC2Corresponding author:2301 Erwin Road, Durham NC 27710Phone: 919-684-3401, Fax: [email protected] Counts: 828Number of Figures/Tables/Supporting Documents: 1 FigureRunning Title: Duffy Associated Neutrophil Count in Pediatric LeukemiaKeywords: pediatric oncology, acute lymphoblastic leukemia, Duffy-associated neutrophil countAbbreviations:

IntroductionTAM is characterized by a transient proliferation of abnormal myeloid cells in the bone marrow, leading to an excess of immature cells circulating in the peripheral blood [2]. TAM diagnosis is associated with the presence of GATA1 mutations, but other features such as blasts on peripheral blood smear, flow cytometry immunophenotype or cytogenetics can be indicative of TAM. This patient’s case is unusual due to the GATA1 mutation-negative status. The GATA1 gene encodes a transcription factor crucial for normal hematopoiesis and mutations in this gene are associated with myeloid disorders including TAM [3]. TAM leads to a wide range of hematologic abnormalities and clinical complications including hyperviscosity syndrome with potential for thrombosis, hydrops fetalis, pericardial effusion, respiratory distress, hypereosinophilia, pseudohyperkalemia, hyperbilirubinemia with liver failure, multi-organ failure and potential for death [1,2,5,14]. Patients with TAM require timely diagnosis as well as close follow up, as 20-30% of these patients subsequently develop myeloid leukemia associated with Down Syndrome (ML-DS) before the age of four [4]. GATA1 mutations have, to date, been discovered in nearly all patients with TAM and ML–DS [7]. The absence of aGATA1 mutation in this case raises the question of an alternative molecular mechanism contributing to the development of TAM and extreme thrombocytosis in this patient.

Acute lymphoblastic leukemia (ALL) is a rare cause of hypereosinophilia (HE). We present a case of B-ALL and HE-associated lung inflammation to shed light on the diagnostic challenges in this rare entity. Bone marrow examination in the context of persistent HE is crucial, even in the absence of other cellular morphological abnormalities in the peripheral blood. This form of ALL is associated with severe complications and inferior outcome due to HE-induced organ damage, therefore a quick initiation of therapy is essential. Furthermore, reports of higher incidence of thromboembolic complications merit careful monitoring during therapy and evaluation of prophylactic measures.

Two Common Diagnostic Challenges of Juvenile Myelomonocytic LeukemiaJinjun Cheng MD PhD1,3,4*, Sarah Harney MD1, 2, David Jacobsohn MD1, 2, Reuven Schore MD1,2*Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DCDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USADivision of Pathology and Laboratory Medicine, Children’s National Hospital, Washington, DCDepartments of Pathology and Pediatrics, The George WashingtonUniversity School of Medicine and Health Sciences, Washington, District of Columbia, USA

Upfront immunotherapy for synchronous high-grade glioma and B-lymphoma in a pediatric patient with CMMRD syndrome.De Vanssay T1, El Riachy N2, Donze C1,3, Appay R2,4, Scavarda D5,6, Testud B7, Andre N1,3, Revon-Rivière G1,31. Department of Pediatric Hematology, Immunology and Oncology, APHM, La Timone Children's Hospital, Marseille, France. 2. Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, GlioME Team, Marseille, France3. REMAP4KIDS, CNRS, INSERM, CRCM, Aix Marseille University, Marseille, France.4. APHM, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France5. Department of Pediatric Neurosurgery. APHM Timone Children’s hospital. Marseille France6. Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, Marseille, France7. Department of Neuroradiology, APHM, La Timone, Marseille INTRODUCTIONConstitutional Mismatch Repair Deficiency (CMMRD)1, is a rare pediatric cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors.2 It results from bi-allelic inactivation of mismatch repair (MMR) genes, predominantly PMS2 followed by MSH6, MLH1 and MSH2.3 CMMRD predisposes individuals to various malignancies including CNS glioma, gastrointestinal cancer, and hematologic malignancy.4 With an incidence of 1 per million5,6, diagnosing CMMRD is challenging, but early detection is crucial as surveillance significantly impact overall survival (OS). Durno et al. reported a five-year overall survival rate of 90% with systematic surveillance versus 50% without it for asymptomatic cancer.7 Diagnosing CMMRD leads to the use of immunotherapy to treat ultra-hypermutated CMMRD-derived tumors with a Tumor Mutation Burden (TMB) ≥100 mutations/megabase.8 Immune checkpoints inhibitors (ICIs) have shown durable responses in paediatric high-grade glioma arising in CMMRD patients,9, 9 contrasting with their limited efficacy in most other types of pediatric cancers.10 A 2024 international cohort highlighted better outcomes for patients treated with immunotherapy,  regardless of cancer type.3 Consequently, ICIs were approved for advanced paediatric solid tumors in the context of CMMRD, irrespective of histology.9 We report a case of a twelve-year-old CMMRD patient with synchronous high-grade glioma (HGG) and B-cell lymphoma, treated with upfront ICIs alongside with conventional treatment.

Background/Objective: Osteosarcoma treatment incorporates chemotherapy and surgery. Resection of the primary tumor usually occurs after induction chemotherapy. Occasionally, scheduling challenges and medical complications result in delay. The goal of this study is to determine if an increased interval between completion of neoadjuvant therapy and surgical resection correlates with decreased tumor necrosis and inferior outcomes in children and young adults with osteosarcoma. Design/Method: We conducted a retrospective chart review of 121 patients age less than 40 years diagnosed with osteosarcoma treated at a single tertiary medical center between 2000-2022. Inclusion criteria included receipt of two cycles of neoadjuvant methotrexate, cisplatin, and doxorubicin. Association of the interval from completion of induction chemotherapy to resection with tumor necrosis (Spearman’s correlation) and outcomes (multivariable Cox hazard regression) were analyzed. Results: There was no significant correlation between interval length and tumor necrosis. However, patients with an interval greater than 16 days had lower 5-year event free survival (p=0.019). Multivariable adjusted analysis of patients with initially localized disease revealed that each day increase in interval length corresponds with a 1.1 times greater hazard of having an event (95% CI: 1.02 to 1.19; p=0.016). Conclusion: Delays in local control were not associated with tumor necrosis. This is consistent with the hypothesis that tumor necrosis is a biologic marker of a tumor’s sensitivity to chemotherapy and may not be affected by minor regimen aberrations. However, surgical delay from completion of induction chemotherapy may confer worse outcomes. Longer intervals generally confer worse outcomes in patients with initially localized disease.

Background : The gift of post-mortem tissue donation is critical to pediatric CNS research. As a “Center of Excellence” for the Gift from a Child Program, our institution has a well-established post-mortem tissue donation program. Our objective was to determine if differences exist between patients that participated in and those that declined research-based autopsy. Procedure: We performed a single-institution retrospective chart review of pediatric patients with CNS malignancies who died from their disease between 1/1/2021 and 12/31/2022. Individual clinical, demographic, and socioeconomic data were assessed. Population-level data were estimated using Zip Code Tabulation Areas. Descriptive statistics were used to compare categorical data. Results : Among the 23 patient families approached during the study time frame, 8/23 (35%) consented to participation. In the consented (C) vs. declined (D) group, there was a higher percentage of White, Non-Hispanic/Latino patients by self-reported race (C: 88% vs. D: 55%) and no patients who identified as Asian or Hispanic/Latino (C: 0% & 0% vs. D: 13% & 27%). Of all patients approached, 2 required interpreters (9%) and both families declined participation. The rate of private insurance was higher in the consented group (C: 75% vs D: 47%) compared to Medicaid as primary insurance in the declined group (C: 13% vs D: 53%). Conclusions : Future research should aim to understand and improve identified disparities to ensure research advancements benefit all children with CNS malignancies. One area we plan to address is improved communication with non-English speaking families by partnering with our interpreter services.

A document by Panagiotis Tsarouhas. Click on the document to view its contents.

Incorporating Innovative B-Cell Targeting Therapeutics into a Combined-Modality Bridging Approach Followed by Timely Consolidative Haploidentical Transplantation to Salvage a Pediatric Patient with Relapsed/Refractory Diffuse Large B-Cell LymphomaYu-Ju Chao1, Pei-Ing Lee2, Tzu-Hsien Yang3, Li-Hua Fang4, Yu-Chun Tsai5, Ming-Yuan Lee6, Yun-Hsin Wang7, Liuh-Yow Chen3, and Rong-Long Chen1*1Department of Pediatric Hematology and Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan2Department of Nuclear Medicine, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan3 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan4Department of Pharmacy, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan5Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan6Department of Pathology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan7Department of Molecular Medicine, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan*Corresponding author: RL ChenName : Rong-Long Chen, M.D.Tel. no. : 886-2-2897-0011; Fax no. : 886-2-2896-2591E-mail : [email protected] : No. 125, Lih-Der Road, Pei-Tou District, Taipei, Taiwan, 11259Word count : Main text (excludes Title page, Abstract, Conflicts of Interest Statement, Acknowledgments, References, Tables, Figures, and Legends) 850.Number of Tables, Figures, and Supporting Information files: 2Running title : Novel Salvage of Resistant Large Cell lymphomaKeywords : Antibody-drug conjugates; chimeric antigen receptor T-cells; diffuse large B-cell lymphoma; HLA haplo-identical transplantation; childhood; peripheral blood stem cell transplantation.

Chronic myeloid leukemia (CML) is rare in children, accounting for 2-3% of pediatric leukemias. We present a case of a 10-year-old with acute appendicitis leading to the incidental discovery of CML. Due to concerns about leukostasis and tumor lysis syndrome, immediate surgical intervention was deferred in favor of medical management with antibiotics and hydroxyurea, followed by appendectomy once the leukocytosis improved. This case highlights the successful use of medical management as a bridge to surgery, providing novel insights into management of co-occurring appendicitis and CML in pediatric patients.

Treatment of Acute Lymphoblastic Leukemia is associated with neurocognitive deficits in young children. While computerized measures have been utilized in pediatric oncology research, they exclude patients below the age of 4 years old. Patients enrolled on “Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia in Children and Adolescents” were offered participation in an optional cognitive study. Three-year old patients did not differ from four-year old patients on their ability to complete tests or perform tests. Including patients diagnosed at age 3 will serve to improve our understanding of at-risk patients and the cognitive trajectory of this age group both during treatment.

Title: A Diagnostic Challenge: Leukemia Cutis Masquerading as Infantile Hemangioma

Background Neuroendocrine tumors (NETs), although rare, are considered one of the most common gastrointestinal and bronchopulmonary pediatric neoplasms. We aimed to determine the incidence, tumor characteristics, management, and outcome of NETs and explore the role of genetic predisposition in a Danish pediatric population. Methods Using the Danish National Pathology Registry, we conducted a nationwide retrospective study including all Danish children aged ≤18 years diagnosed with a pathology-proven NET between 1995 and 2020. Results We identified 220 patients, with a 1.89:1 girl to boy ratio. The yearly incidence for Danish pediatric NETs was 6.84 per 1 million children, with no significant change in incidence throughout the observation period. NETs were located in the appendix (93.2%), the pulmonary system (4.5%) and pancreas (2.3%). One recurrence was noted in the pancreas in a genetically predisposed patient with multiple neuroendocrine neoplasia type 1 (MEN1), resulting in an overall recurrence rate of 0.5% (0% in appendiceal NETs; 0% in bronchopulmonary NETs; 20.0% in pancreatic NETs). No NET-related mortality was registered. Four patients had a known predisposing genetic condition, one appendiceal NET and neurofibromatosis type 1, and three pancreatic NETs associated with MEN1. Postsurgical surveillance regimes, choice of tumor markers, and imaging modality varied throughout the study period. Conclusions We confirmed a stable incidence of pediatric NETs during the study period. The overall recurrence rate was 0.5% and no NET-related mortality was observed. Known genetic predisposition was present in 1.8% of patients. Future guidelines should consider the apparent indolent nature and excellent prognosis of these tumors.

Genetically-targeted medications are emerging as important therapies for lymphatic malformations (LMs) unresponsive to sirolimus. We describe two patients with EML4::ALK positive LMs, one with Gorham Stout Disease and one with a large genitourinary (GU) LM, who were successfully treated with ALK inhibitors. This report adds ALK inhibitors to the growing toolbox of molecularly-targeted therapies for LMs.

Article type: Letter – To the editorTitle: Comment on: Implementation of a formalized evaluation and planning tool to improve pediatric oncology outcomes in KenyaSubtitle: Bridging Gaps: AI-Driven Healthcare Equity for Low and Middle-Income CountriesAnoud Khana, Aryan Tareena