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Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.

Congenital afibrinogenemia is a rare disorder characterized by a lack of detectable fibrinogen. The mainstay of treatment for acute bleeding episodes or perioperative management is replacement with fibrinogen concentrate or fibrinogen-containing blood products. The development of neutralizing antibodies and severe allergic reactions to fibrinogen replacement is rarely reported in afibrinogenemia patients. Here the treatment regimen is described for a 6-year-old girl with a severe allergic reaction to multiple fibrinogen-containing products who became refractory to treatment because of a presumed inhibitor to fibrinogen.

Acute myeloid leukemia (AML) is a clinically, morphologically, and genetically heterogeneous disorder. Like many malignancies, the genomic landscape of pediatric AML has been mapped recently through sequencing of large cohorts of patients. Much has been learned about the biology of AML through studies of specific recurrent genetic lesions. Further, genetic lesions have been linked to specific clinical features, response to therapy, and outcome, leading to improvements in risk stratification. Lastly, targeted therapeutic approaches have been developed for the treatment of specific genetic lesions, some of which are already having a positive impact on outcomes. While the advances made based on the discoveries of sequencing studies are significant, much work is left. The biologic, clinical, and prognostic impact of a number of genetic lesions, including several seemingly unique to pediatric patients, remains undefined. While targeted approaches are being explored, for most, the efficacy and tolerability when incorporated into standard therapy is yet to be determined. Furthermore, the challenge of how to study small subpopulations with rare genetic lesions in an already rare disease will have to be considered. In all, while questions and challenges remain, precisely defining the genomic landscape of AML, holds great promise for ultimately leading to improved outcomes for affected patients.

Black and Hispanic children with acute myeloid leukemia (AML) have worse outcomes compared with White children. AML is a heterogeneous disease with numerous genetic subtypes in which these disparities have not been specifically investigated. In this study, we used the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database to examine the association of race-ethnicity with leukemia cytogenetics, clinical features, and survival outcomes within major cytogenetic subgroups of pediatric AML. Compared with White non-Hispanic patients, t(8;21) AML was more prevalent among Black (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.28-3.74) and Hispanic patients (OR, 1.74; 95% CI, 1.05-2.83). The poor prognosis KMT2A rearrangement t(6;11)(q27;q23) was more prevalent among Black patients (OR, 6.12; 95% CI, 1.81-21.59). Among those with KMT2Ar AML, Black race was associated with inferior event-free survival (EFS) (hazard ratio [HR], 2.31; 95% CI, 1.41-3.79) and overall survival (OS) (HR, 2.54; 1.43-4.51). Hispanic patients with KMT2Ar AML also had inferior EFS (HR, 2.20; 95% CI, 1.27-3.80) and OS (HR, 2.07; 95% CI, 1.09-3.93). Similarly, among patients with t(8;21) or inv(16) AML (ie, core-binding factor [CBF] AML), Black patients had inferior outcomes (EFS HR, 1.93; 95% CI, 1.14-3.28 and OS HR, 3.24; 95% CI, 1.60-6.57). This disparity was not detected among patients receiving gemtuzumab ozogamicin (GO). In conclusion, racial-ethnic disparities in survival outcomes among young people with AML are prominent and vary across cytogenetic subclasses. Future studies should explore the socioeconomic and biologic determinants of these disparities.

Purpose of Review Acute myeloid leukemia (AML) in children remains a challenging disease to cure with suboptimal outcomes particularly when compared to the more common lymphoid leukemias. Recent advances in the genetic characterization of AML have enhanced understanding of individualized patient risk, which has also led to the development of new therapeutic strategies. Here, we review key cytogenetic and molecular features of pediatric AML and how new therapies are being used to improve outcomes. Recent Findings Recent studies have revealed an increasing number of mutations, including WT1, CBFA2T3-GLIS2, and KAT6A fusions, DEK-NUP214 and NUP98 fusions, and specific KMT2A rearrangements, which are associated with poor outcomes. However, outcomes are starting to improve with the addition of therapies such as gemtuzumab ozogamicin and FLT3 inhibitors, initially developed in adult AML. Summary The combination of advanced risk stratification and ongoing improvements and innovations in treatment strategy will undoubtedly lead to better outcomes for children with AML.

IKAROS family zinc finger 1 (IKZF1) alterations represent a diverse group of genetic lesions that are associated with an increased risk of relapse in B-lymphoblastic leukemia (B-ALL). Due to the heterogeneity of concomitant lesions it remains unclear how IKZF1 abnormalities directly affect cell function and therapy resistance and whether their consideration as a prognostic indicator is valuable in improving outcome. We used CRISPR/Cas9 to engineer multiple panels of isogeneic lymphoid leukemia cell lines with a spectrum of IKZF1 lesions in order to measure changes in chemosensitivity, gene expression, cell cycle, and in vivo engraftment dynamics that can be directly linked to loss of IKAROS protein. IKZF1 knockout and heterozygous null cells displayed relative resistance to a number of commonly employed therapies for B-ALL including dexamethasone, vincristine, asparaginase, and daunorubicin. Transcription profiling revealed a stem/myeloid cell-like phenotype and JAK/STAT upregulation after IKAROS loss. We also used a CRISPR homology-directed repair (HDR) strategy to knock-in the dominant-negative IK6 isoform tagged with GFP into the endogenous locus and observed a similar drug resistance profile with the exception of retained sensitivity to dexamethasone. Interestingly, IKZF1 knockout and IK6 knock-in cells both have significantly increased sensitivity to cytarabine, suggesting intensification of nucleoside analog therapy may be specifically effective for IKZF1-deleted B-ALL. Both types of IKZF1 lesions decreased survival time of xenograft mice, with higher numbers of circulating blasts and increased organ infiltration. Given these findings, exact specification of IKZF1 status in patients may be a beneficial addition to risk stratification and could inform therapy.Key pointsEngineered IKZF1 perturbations result in a stem-cell like expression signature, enhanced engraftment in vivo, and multi-drug resistanceLoss of IKAROS may result in new vulnerabilities due to increased sensitivity to cytarabine and upregulation of JAK/STAT and mAb targets

Acute promyelocytic leukemia (APL) is a rare disease accounting for only 5%−10% of pediatric acute myeloid leukemia (AML) and fewer than 1000 cases occur annually in the United States across all age groups. Characterized by t (15; 17), with a resultant PML-RARA gene fusion driving leukemia development, advances in therapy have improved outcomes for APL significantly in the past several decades, now making APL the most curable form of AML in both children and adults. Cure rates in APL are now comparable to pediatric B-lymphoid leukemias. The success of APL treatment is due, in part, to the breadth of understanding of the driver PML-RARA mutation as well as collaborative efforts to quickly introduce and maximize the benefit of new therapies. Here, we review the presentation, clinical features, pathogenesis, and treatment advances in pediatric APL.

Splenic dysfunction, particularly acute splenic sequestration crisis (ASSC), is a leading cause of death in the first decade of life of patients with sickle cell disease (SCD). Despite the severity of splenic disease in SCD, few large-scale studies have been performed to assess the natural progression of splenic complications, particularly in the less common sickle cell genotypes and with the onset of early use of hydroxyurea. We performed a retrospective chart review of patients with SCD born between January 2011 and December 2018 and treated at the Texas Children's Hospital Sickle Cell Center. We extracted data from our electronic medical record system to identify patients with documented splenic complications based on ICD9 and ICD10 codes. We then reviewed charts for these patients to confirm diagnoses and obtain additional information about these complications. We identified 688 patients treated for SCD at our center during the study period. Of these, 113 (16.4%) were diagnosed with one or more splenic complications. The overall prevalence of splenic complications was highest in patients with hemoglobin Sβ 0 thalassemia (Sβ 0) at 50.0%, compared to 20.7% in hemoglobin SS (SS) patients, 6.9% in hemoglobin SC (SC) patients, and 0% in hemoglobin Sβ + (Sβ +) patients and patients with other genotypes (Table 1). ASSC and splenectomy were likewise most prevalent in Sβ 0, less so in SS, and rare in SC, Sβ +, and other genotypes. To further delineate the incidence of ASSC, we performed an in-depth analysis of patients from our cohort for whom detailed information was available. Compared to patients with the SS genotype, the incidence rate ratio (IRR) for ASSC was significantly higher for Sβ 0 patients and significantly lower for SC patients (Table 2). The mean age of onset of ASSC was similar between SS, Sβ 0, and SC patients, but survival curves for time to the first event differed significantly between genotypes. We examined the association between early hydroxyurea therapy and ASSC in SS and Sβ 0 patients by comparing patients who initiated hydroxyurea therapy by the age of two years to those who initiated therapy after this age. ASSC were more frequent among patients initiated on hydroxyurea by the age of two years (Table 3, upper panel). We also compared patients on hydroxyurea to those not on this therapy and found a similar effect, with ASSC occurring more frequently among patients on hydroxyurea (Table 3, lower panel). Survival curves for time to first ASSC also diverged significantly between these groups of patients. Our data indicate that the prevalence and severity of splenic problems vary widely between different sickle cell genotypes in the first decade of life, with SC patients having relatively mild complications while Sβ 0 patients have the most severe and frequent complications. The association between hydroxyurea use and incidence of ASSC also suggests that hydroxyurea therapy may increase the risk of this complication of SCD, particularly when initiated before two years of age. Figure 1 Figure 1. Disclosures George: Global Blood Therapeutics: Consultancy, Speakers Bureau; Wolters Kluwer: Patents & Royalties.

Introduction: Racial disparities in pediatric acute myeloid leukemia (AML) outcomes have consistently demonstrated inferior event-free survival (EFS) and overall survival (OS) in minority populations with the worst outcomes in Black children. However, AML is a heterogenous disease classified by recurrent genetic aberrations, and these disparities have not been thoroughly investigated within specific cytogenetic groups. In addition, race-based response to individual chemotherapy agents in AML has not been explored. Here, we use data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database to describe the effects of race on outcomes and response to gemtuzumab ozogamicin (GO) therapy in core binding factor (CBF) AML, a favorable risk AML subtype. Methods: CBF AML patient data was extracted from the online TARGET database. Race and ethnicity were self-reported. Estimates of 2-year OS and EFS were calculated using the Kaplan-Meier method and analyzed via log-rank statistic. Pearson's Chi-squared test and Fisher's exact test were used to analyze patient variables. Results: The OS in CBF AML differed significantly based on race/ethnicity at 87% (95% CI, 82-93%) for White non-Hispanic (WNH), 77% (95% CI, 67-89%) for Hispanic, and 71% (95% CI, 58-88%) for Black children (p=0.005). EFS was also significantly lower in Black (46%; 95% CI, 32-66%) compared to non-Black children (66%; 95% CI, 60-73%)(p=0.023). When assessed by CBF AML subtype, EFS and OS in t(8;21) AML varied significantly based on ethnicity at 50% (95% CI, 34-75%) and 67% (95% CI, 50-88%) in Black patients, 63% (95% CI, 49-82%) and 69% (95% CI, 55-87%) in Hispanic patients, and 82% (95% CI, 72-92%)(p=0.01) and 90% (95% CI, 93-98%)(p=0.006) in WNH patients. In inv(16) AML, Hispanic patients experienced the highest EFS (71%; 95% CI, 55-92%) followed by WNH (54%; 95% CI, 43-66%) and Black (36%; 95% CI, 17-79%) patients though this did not reach statistical significance (p=0.12). There was no impact of race/ethnicity on OS in inv(16) AML. The use of GO did not alter OS in any subset of CBF AML. EFS appeared to be slightly improved but was not statistically significant. However, Black children with any type of CBF AML had preferential improvement with GO with significantly higher EFS (69% v. 26%, p=0.03) and a trend toward improved OS (81% v. 63%, p=0.19) with GO therapy. These improvements were primarily driven by a significant increase in EFS in inv(16) AML when treated with GO (80% v. 50%, p=0.01) and a similar but non-significant improvement in OS in this group. In Hispanic children there was a trend toward inferior EFS with the use of GO (63% v. 73%, p=0.37) in CBF AML, particularly in t(8;21) patients with a 1-year EFS of 56% (95% CI, 37-87%) compared to 81% (95% CI, 64-100%)(p=0.23). WNH children were more likely to achieve Complete Remission (CR) after course 1 (OR 2.36, 95% CI 1.09-5.10, p=0.03), and Black children were more likely to have persistent Minimal Residual Disease (MRD) after course 2 (OR 9.64, 95% CI 2.48-37.43, p Conclusion: Children with CBF AML represent a favorable cytogenetic risk group with an EFS of 70% and OS of 85%. However, the impact of race/ethnicity on outcome is significant with Black children experiencing the lowest EFS and OS at 46% and 71%, respectively, with this trend persisting across cytogenetic subtypes. Black children were also more likely to remain MRD positive after Induction II and less likely than WNH patients to achieve CR. However, while the addition of GO to standard therapy did not improve outcomes in CBF AML overall, Black children selectively benefited from GO therapy. Black children trended toward improved EFS and OS with GO with the most pronounced effect on EFS in inv(16) which was improved from 50% to 80% at 1 year. These results demonstrate that Black children with CBF AML are disproportionately at risk for poor outcomes compared to other ethnicities, but these risks may be mitigated by the use of GO which increase EFS and OS primarily in this group. Conversely, Hispanic patients trended toward worse EFS with GO, particularly in t(8;21) AML, possibly due to treatment-related toxicity. As CD33 expression and certain ABCB1 SNPs are known to predict response to GO therapy, our ongoing work investigates racial differences in these variables as a potential explanation for the differing responses to GO. Disclosures Rau: Jazz Pharmaceuticals, Inc.: Consultancy, Other: Travel Fees.

BACKGROUND AND OBJECTIVE: Short courses of antibiotics are often indicated for uncomplicated skin and soft tissue infections (uSSTIs). Our objective was to decrease duration of antibiotics prescribed in children hospitalized for uSSTIs by using quality improvement (QI) methods. METHODS: QI methods were used to decrease duration of antibiotics prescribed upon hospital discharge for uSSTIs. We sought to accomplish this goal by increasing outpatient prescriptions for short courses of therapy (≤7 days). Key drivers included awareness of evidence among physicians, changing the culture of prescribing, buy-in from prescribers, and monitoring of prescribing. Physician education, modification of antibiotic order sets for discharge prescriptions, and continual identification and mitigation of therapy plans, were key interventions implemented by using plan-do-study-act cycles. A run chart assessed the impact of the interventions over time. RESULTS: We identified 641 index admissions for uSSTIs over a 23-month period for patients aged >90 days to 18 years. The proportion of children discharged with short courses of antibiotics increased from a baseline median of 23% to 74%, which was sustained for 6 months. Differences in the proportion of children admitted for treatment failure or recurrence before and after project initiation were not significant. CONCLUSIONS: Using QI methodology, we decreased duration of antibiotics prescribed in children hospitalized for uSSTIs by increasing prescriptions for short courses of antibiotics. Modification of electronic order sets for discharge prescriptions allowed for sustained improvement in prescribing practices. Our findings support the use of shorter outpatient antibiotic courses in most children with uSSTIs, and suggest criteria for complicated SSTIs.