Congenital dyserythropoietic anemia type IV (CDAIV) is a rare inherited hematological disorder presenting severe anemia due to altered erythropoiesis and hemolysis, with variable needs for recurrent transfusions. We present a case of a transfusion-dependant male newborn who required an intrauterine transfusion and presented at birth with severe hemolytic anemia. Genetic testing rapidly identified a KLF1 gene mutation, a CDAIV variant. This case highlights the advantages of next-generation sequencing testing for congenital hemolytic anemia: diagnostic speed, guidance on natural history, and optimized clinical management and anticipatory guidance for parents and clinicians. We reviewed the literature for all CDAIV cases.

Background To assess the outcomes of pediatric patients with Undifferentiated Embryonal Sarcoma of the Liver (UESL) and treatment including at least surgery and systemic chemotherapy. Methods This study included patients aged up to 21 years with a pathological diagnosis of UESL prospectively enrolled from 1995 to 2016 in three european trials focusing on the effects of surgical margins, preoperative chemotherapy, use of radiotherapy (RT) and chemotherapy. Results Out of 65 patients with a median age at diagnosis of 8.7 years (0.6-20.8), 15 had T2 tumors, and 1 had lymph node spread, 14 were Intergroup Rhabdomyosarcoma Study (IRS) I, 9 IRSII, 38 IRSIII, and 4 IRSIV. Twenty-eight upfront surgeries resulted in 5 operative spillages and 11 infiltrated surgical margins, whereas 37 delayed surgeries resulted in no spillages (P= 0.0119) and 3 infiltrated margins (P=0.0238). All patients received chemotherapy, including anthracyclines in 47. Radiotherapy was administered in 15 patients. With a median follow-up of 78.6 months, 5 year overall and event free survivals (EFS) were 90.1% (95%CI 79.2-95.5) and 89.1% (95%CI 78.4-94.6), respectively. Two out 4 local relapses had previous infiltrated margins and 2 out of 3 patients with metastatic relapses received reduced doses of alkylating agents. Infiltrated margins (P=0.1607), T2 stage (P=0.3870), use of RT (P= 0.8731), and anthracycline-based chemotherapy (P= 0.1181) were not correlated with EFS. Conclusions Neoadjuvant chemotherapy for pediatric patients with UESL increases the probability of complete surgical resection. The role of anthracyclines and radiotherapy for localized disease remains unclear. The use of alkylating agents is recommended.

In this retrospective study, we examined the prevalence and spectrum of germline variants in cancer predisposition genes in 38 children and young adults with melanocytic lesions who underwent germline genetic testing at St. Jude Children’s Research Hospital. Diagnoses included malignant melanoma (n=19; 50%), spitzoid melanoma (n=14; 37%), and uveal melanoma (n=5; 13%). Five patients (13%) harbored pathogenic variants: one with bi-allelic PMS2, and one each with heterozygous 17q21.31 deletion, TP53, BRIP1, and ATM pathogenic variants. In this convenience cohort, 13% of children and young adults with melanoma who underwent germline testing harbored an underlying cancer predisposition syndrome.

Delayed but Successful T Cell Immune Reconstitution Following Umbilical Cord Blood Transplantation Conditioned with Thymoglobulin alone in IL-7Rα-mutated SCID Eman T. Al-Antary, MD1,5, Mary Caverly, CPNP2, Steve Buck3, Sharat Chandra, MD4, Süreyya Savaşan, MD1-3, 5

A document by Oscar González-Llano. Click on the document to view its contents.

Prolonged Remission in Multiple Relapsed MLL-rearranged Infant B-ALL with Inotuzumab OzogamicinAkhila Lattupally MD1, Adonis Lorenzana MD1, Gregory Anthony Yanik MD2, Danielle Bell MD1,31. Ascension St. John Children’s Hospital, Detroit, Michigan, United States.2. C.S. Mott Children’s Hospital – University of Michigan, Ann Arbor, Michigan, United States.3. Children’s Hospital of Michigan, Detroit, Michigan, United States.Corresponding Author: Akhila Lattupally MDAddress: 22101 Moross Rd, PB2, Suite 70, Detroit, Michigan 48236Phone: 469-468-7978Fax: 313-343-4756Email:[email protected] Count: Main text: 841 wordsNumber of Tables: 0 Number of Figures: 0 Number of Supporting Information Files: 0Running Title: Remission in Infant ALL with Inotuzumab Ozogamicin.Keywords: Infant Leukemia, ALL Relapse, Immunotherapy

Pediatric immune thrombocytopenia (ITP) is an acquired disorder associated with autoimmune destruction and impairment of platelet production in children. Some children exhibit poor or transient response to ITP-directed treatments and are referred to as having refractory ITP (rITP). There is currently no consensus on the definition of rITP, nor evidence-based treatment guidelines for patients with rITP. After a survey of pediatric ITP experts demonstrated lack of consensus on pediatric rITP, we pursued a systematic review to examine the reported clinical phenotypes and treatment outcomes in pediatric rITP. The search identified 253 relevant manuscripts; following review, 11 studies proposed a definition for pediatric rITP with no consensus amongst them. Most definitions included sub-optimal response to medical management, while some outlined specific platelet thresholds to define this sub-optimal response. Common attributes identified in this study should be used to propose a comprehensive definition, which will facilitate outcome comparisons of future rITP studies.

Concurrence of a Kinase-dead BRAF and an OncogenicKRAS Gain-of-function Mutation in Juvenile Xanthogranuloma

Hematological toxicity (hematotoxicity) is the most common long-term adverse effect following the use of CD19-chimeric antigen receptor (CD19-CAR) T-cell therapies. However, its management remains unclear. We present the case of a 21-year-old who received CD19-CAR T-cell therapy for relapse following a haploidentical transplant. He developed hematotoxicity and consequently multiple life-threatening infections. We administered a CD34+ hematopoietic stem cell boost (HSCB) from his transplant donor that led to hematopoietic recovery and resolution of his infections without any effect on the activity of CD19-CAR T cells. CD34+ HSCB can be a safe and effective option to treat hematotoxicity following CD19-CAR T-cell therapy.

Background: Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies. Procedure: We present our ten-year experience (October 2012-October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose-busulfan (BU), fludarabine (FLU) and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4yr) with acute myeloid leukemia (AML, n=17), myelodysplastic syndrome (MDS, n=4), or chronic myeloid leukemia (CML, n=2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was MSD PBSC (n=7), MUD PBSC (n=2), UCB (n=3) or haploidentical-BMT (n=11). Risk stratification was low (n=2), intermediate (n=15), high (=3) and very high risk (n=1). The two patients with CML had failed tyrosine kinase inhibitor therapies. Results: With a median follow-up of 39.6 months the relapse rate is only 4.5% with an OS 100%, PFS 95.5% and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the GvHD prophylaxis regimen significantly impacted grades II-IV aGvHD 66.7% versus 19.2% ( P=0.039) and cGvHD 66.7% versus 0% ( P=0.002) in the patients receiving matched sibling (MSD) or matched unrelated donor (MUD) PBSC compared to haplo-BMT respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor PBSCT ( P=0.025). Conclusions: Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT but in the setting of PBSC grafts with CSA-MTX GvHD prophylaxis it results in an unacceptably high incidence of GvHD.

Childhood and adolescent/young adult (AYA) cancer survivors experience poor health outcomes in adulthood. Adverse Childhood Experiences (ACEs) also portend poor health outcomes for the general population. Resilience can mitigate effects of ACEs. We examined the feasibility of assessing ACEs and resilience in childhood/AYA cancer patients. We also described occurrences of ACEs, resilience, and poor health outcomes. Of 52 participants, most rated their study experience favorably, with privacy in answering sensitive questions. Half reported ACEs, and those with ACEs had lower resilience, X2(3,N=52)=9.39, p=0.02. Further investigations of ACEs and resilience in larger cohorts are warranted to delineate associations with long-term health outcomes.

Background: Pediatric CNS tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision making. Methods: We conducted a retrospective analysis of pediatric patients (age <21) diagnosed with a primary CNS tumor at four upstate New York hospitals from 2008 to 2021. Clinical and histopathologic data were identified from each patient, including genomic analysis of somatic mutations and tumor mutation burden (TMB) where available. These variables were each compared with overall survival using cox-regression analyses. Multivariable analysis was conducted to identify patient characteristics that may independently predict survival. Results: We identified 119 patients. Common tumor types included low-grade glioma (N=51), high-grade glioma (N=29), and medulloblastoma (N=11). Common driver-mutations included TP53 inactivation (N=16), BRAF-KIAA1549 fusion (N=16), FGFR1 amplification (N=12), BRAF V600E mutation (N=12), NF1 loss (N=12), and H3F3A K28M mutation (N=6). Median TMB was 1 mutation/megabase (mut/Mb, range=0-132). Overall survival was 79.9%. Variables associated with poorer survival on univariable analysis were higher TMB (p=0.002, HR 4.97), high grade tumors (p=0.009, HR 84.3), and high-grade glioma histology (p=0.021, HR 3.14). Multivariable analyses further identified TMB (p=0.011, HR 4.46) and high-grade histology (p=0.015, HR 5.28) as independently predictive of worse survival. Tumor progression was more common in high TMB (N=15, 44%) than in low TMB tumors (N=19, 35%). Conclusions: High TMB is correlated with higher rates of progression and death as compared to low TMB tumors. These findings may help identify patients who may benefit from alternative treatments, such as immunotherapies.

Introduction: Brain tumors in children are the main cause of cancer related death in the pediatric population. Brainstem tumors incidence comprises 10.9% of all brain tumors having the Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) a fatal prognosis. Some countries have developed a national and international register database, to characterize their population. This study provides a retrospective population-based data to describe the epidemiology of children with DIPG in México from 2001-2021, and assesses the proposed prognostic factors previously described for survival outcome. Methods: Health Institutions from México were invited to fill in a retrospective registry of DIPG patients. Epidemiological, clinical, diagnostic, histopathologic and treatment variables were described. Fisher exact test was used to compare long, and short-term survivors and overall survival was estimated using the Kaplan-Meier Method. Differences between survival curves were evaluated using the Log-rank test and Cox proportional hazards regression analysis. Results: One-hundred and ten patients were included in the analysis. Median age at diagnosis was 7 years. Sixty patients (54.5%) presented with symptoms in less than 6 months being the most frequent ataxia (56.4%). Treatment was offered to 90 patients (81.8%), overall survival at 160 weeks (4 years) was 11.4%, and 16 patients (14.5%) arrived at clinical centers to die. We found no significant survival differences in any of the prognostic factors. Conclusion: This study highlights the need to develop improvement strategies to streamline healthcare processes and enhance quality of care to strengthen our situational diagnosis in Mexico.

Acute Myeloid Leukemia (AML) patients have a wide array of cytogenetic and molecular aberrations which can influence response to therapy. Monosomy7 (Mono7) is a rare subset within pediatric AML (prevalence of 4-5%), that is highly associated with poor outcomes. Fusions involving the ALK gene (14.3%) were exclusively identified within this high-risk cohort while absent across all other AML. Given the dismal outcomes of Mono7, we evaluated the use of crizotinib, an FDA-approved tyrosine kinase inhibitor, used to treat patients with ALK fusions. Our findings suggest that crizotinib may serve as a novel therapy for these patients.

The PHO workforce landscape has been evolving over the past decades, with concern for waning interest in the subspecialty. In this study, we aimed to evaluate perceptions of the PHO workforce (both fellows and faculty), the experience of seeking an initial faculty position, and its impact on fellow stress and anxiety. An anonymous survey consisting of demographics, job search experiences including barriers and helpful tools, and emotional health impacts such as stress and anxiety was developed and distributed to all PHO fellowship programs. Seventy-nine fellows and 83 faculty responded. Faculty were less likely than fellows to perceive that fellows are struggling to find jobs ( P=0.0198). However, faculty were more likely than fellows to perceive that fellows are either “extremely stressed” or “stressed” due to job search ( P=0.0003). By June 2021, 30 of 44 (68%) candidates had been offered a position, and 80% of those had accepted. There were no significant associations between fellow stress level and job offering, proximity to their ideal goals, or change in career type. Common barriers to the job search included geographic constraints and partner employment. Respondents identified centralized job listings, formal training on career development strategies, introduction to various career paths, and more transparency about the job search as needed interventions. The perception of difficulty and stress regarding the job search is endorsed by most, identifying a need for more interventions to improve the job search experience. These data also highlight unmet mentorship and educational needs among PHO fellows in preparing for the job search.

Sickle cell disease is the most prevalent inherited blood disorder in the world, with significant morbidity and mortality. Patients often have recurrent painful vaso-occlusive episodes, and the American Society of Hematology gives a conditional recommendation for the use of regional anesthesia for acute sickle cell pain management. This scoping review summarizes the current evidence and identifies gaps for future research. Our screening process is outlined, and articles that mentioned the use of regional anesthesia for acute sickle cell crises were included. We present and interpret our results and highlight opportunities for future investigation.

Acute Lymphoblastic Leukemia of the Central Nervous System Presenting with Rapid Weight GainConnor P. Hall1 and Alan D. Friedman11Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USACorrespondence: Alan D. Friedman, MDJohns Hopkins UniversityCRB I, Rm. 253 1650 Orleans St. Baltimore, Maryland 21231 Phone: 410-955-2095; Fax: 410-955-8897 Email: [email protected] Count: 863Number of Figures: 1Running Title: Rapid Weight Gain in ALLKey Words: acute lymphoblastic leukemia/ relapse/ weight gain/ central nervous systemAbbreviations:

We conducted a cross-sectional study using a questionnaire to explore the late effects in survivors of juvenile myelomonocytic leukemia (JMML). The attending pediatric hematologist oncologists completed the questionnaires. All survivors (N=30) had undergone allogeneic hematopoietic stem cell transplantation. Approximately 83% survivors showed more than one late effect. The identified late effects included endocrine, dental, skin, ophthalmologic, musculoskeletal, pulmonary, neurocognitive, and cardiovascular dysfunction. The prevalence of short stature and cardiovascular and kidney dysfunction was significantly elevated among survivors aged ≥18 years. Therefore, a multidisciplinary follow-up system for survivors of JMML is crucial.