Search

IMPORTANCE: Mindfulness curricula can improve physician burnout, but implementation during residency presents challenges. OBJECTIVE: To examine whether a novel mindfulness curriculum implemented in the first 6 months of internship reduces burnout. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, multicenter, stratified cluster randomized clinical trial of a mindfulness curriculum randomized 340 pediatric interns to the intervention or control arm within program pairs generated based on program size and region. Fifteen US pediatric training programs participated from June 14, 2017, to February 28, 2019. INTERVENTIONS: The intervention included 7 hour-long sessions of a monthly mindfulness curriculum (Mindfulness Intervention for New Interns) and a monthly mindfulness refresher implemented during internship. The active control arm included monthly 1-hour social lunches. MAIN OUTCOMES AND MEASURES: The primary outcome was emotional exhaustion (EE) as measured by the Maslach Burnout Inventory 9-question EE subscale (range, 7-63; higher scores correspond to greater perceived burnout). Secondary outcomes were depersonalization, personal accomplishment, and burnout. The study assessed mindfulness with the Five Facet Mindfulness Questionnaire and empathy with the Interpersonal Reactivity Index subscales of perspective taking and empathetic concern. Surveys were implemented at baseline, month 6, and month 15. RESULTS: Of the 365 interns invited to participate, 340 (93.2%; 255 [75.0%] female; 51 [15.0%] 30 years or older) completed surveys at baseline; 273 (74.8%) also participated at month 6 and 195 (53.4%) at month 15. Participants included 194 (57.1%) in the Mindfulness Intervention for New Interns and 146 (42.9%) in the control arm. Analyses were adjusted for baseline outcome measures. Both arms’ EE scores were higher at 6 and 15 months than at baseline, but EE did not significantly differ by arm in multivariable analyses (6 months: 35.4 vs 32.4; adjusted difference, 3.03; 95% CI, −0.14 to 6.21; 15 months: 33.8 vs 32.9; adjusted difference, 1.42; 95% CI, −2.42 to 5.27). None of the 6 secondary outcomes significantly differed by arm at month 6 or month 15. CONCLUSIONS AND RELEVANCE: A novel mindfulness curriculum did not significantly affect EE, burnout, empathy, or mindfulness immediately or 9 months after curriculum implementation. These findings diverge from prior nonrandomized studies of mindfulness interventions, emphasizing the importance of rigorous study design and suggesting that additional study is needed to develop evidence-based methods to reduce trainee burnout. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03148626

A recent shift in public attention to racism, racial disparities, and health equity have resulted in an abundance of calls for relevant papers and publications in academic journals. Peer-review for such articles may be susceptible to bias, as subject matter expertise in the evaluation of social constructs, like race, is variable. From the perspective of researchers focused on neonatal health equity, we share our positive and negative experiences in peer-review, provide relevant publicly available data regarding addressing bias in peer-review from 12 neonatology-focused journals, and give recommendations to address bias and knowledge gaps in the peer review process of health equity research.

PDF file - 263K

Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy.Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas.Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10−2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10−3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10−3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts.Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect. Clin Cancer Res; 17(16); 5490–500. ©2011 AACR.

PDF file - 115K

PDF - 76K

PurposeAdvances in genomic research have led to the diagnosis of rare, early-onset diseases for thousands of individuals. Unfortunately, the benefits of advanced genetic diagnostic technology are not distributed equitably among the population, as has been seen in many other healthcare contexts. Even quantifying and describing inequities in genetic diagnostic yield is challenging due to variation in referrals to clinical genetics practices and other barriers to clinical genetic testing.MethodsThe Rare Genomes Project (RGP) at the Broad Institute of MIT and Harvard offers research genome sequencing to individuals with rare disease who remain genetically undiagnosed through direct interaction with the individual or family. This presents an opportunity for diagnosis beyond the clinical context, thus eliminating many barriers to access.FindingsAn initial goal of RGP was to equalize access to genomic sequencing by decoupling testing access from proximity to a major medical center and physician referral. However, our study participants are overwhelmingly non-disadvantaged, as evidenced by their access to specialist care and genetic testing prior to RGP enrollment, and are also predominantly white.ImplicationsWe therefore describe our novel initiative to diversify RGP enrollment in order to advance equity in rare disease genetic diagnosis and research. In addition to the moral imperative of medical equity, this is also critical in order to fully understand the genomic underpinnings of rare disease. We utilize a mixed methods approach to understand the priorities and values of underrepresented communities, existing disparities, and the obstacles to addressing them: all of which is necessary to promote equity in future genomic medicine initiatives.

BACKGROUND AND OBJECTIVES High-risk infant follow-up programs (HRIFs) are a recommended standard of care for all extremely low birth weight (ELBW) infants to help mitigate known risks to long-term health and development. However, participation is variable, with known racial and ethnic inequities, though hospital-level drivers of inequity remain unknown. We conducted a study using a large, multicenter cohort of ELBW infants to explore within- and between-hospital inequities in HRIF participation. METHODS Vermont Oxford Network collected data on 19 503 ELBW infants born between 2006 and 2017 at 58 US hospitals participating in the ELBW Follow-up Project. Primary outcome was evaluation in HRIF at 18 to 24 months’ corrected age. The primary predictor was infant race and ethnicity, defined as maternal race (non-Hispanic white, non-Hispanic Black, Hispanic, Asian American, Native American, other). We used generalized linear mixed models to test within- and between-hospital variation and inequities in HRIF participation. RESULTS Among the 19 503 infants, 44.7% (interquartile range 31.1–63.3) were seen in HRIF. Twenty six percent of the total variation in HRIF participation rates was due to between-hospital variation. In adjusted models, Black infants had significantly lower odds of HRIF participation compared with white infants (adjusted odds ratio, 0.73; 95% confidence interval, 0.64–0.83). The within-hospital effect of race varied significantly between hospitals. CONCLUSIONS There are significant racial inequities in HRIF participation, with notable variation within and between hospitals. Further study is needed to identify potential hospital-level targets for interventions to reduce this inequity.

Context Infant race and ethnicity are used ubiquitously in research and reporting, though inconsistent approaches to data collection and definitions yield variable results. The consistency of these data has an impact on reported findings and outcomes. Objective To systematically review and examine concordance among differing race and ethnicity data collection techniques presented in perinatal health care literature. Data Sources PubMed, CINAHL, and Ovid were searched on June 17, 2021. Study Selection English language articles published between 1980 and 2021 were included if they reported on the United States’ infant population and compared 2 or more methods of capturing race and/or ethnicity. Data Extraction Two authors independently evaluated articles for inclusion and quality, with disagreements resolved by a third reviewer. Results Our initial search identified 4329 unique citations. Forty articles passed title/abstract review and were reviewed in full text. Nineteen were considered relevant and assessed for quality and bias, from which 12 studies were ultimately included. Discordance in infant race and ethnicity data were common among multiple data collection methods, including those frequently used in perinatal health outcomes research. Infants of color and those born to racially and/or ethnically discordant parents were the most likely to be misclassified across data sources. Limitations Studies were heterogeneous in methodology and populations of study and data could not be compiled for analysis. Conclusions Racial and ethnic misclassification of infants leads to inaccurate measurement and reporting of infant morbidity and mortality, often underestimating burden in minoritized populations while overestimating it in the non-Hispanic/Latinx white population.

Infant Follow Up Programs (IFUPs) provide developmental surveillance for preterm infants after hospital discharge but participation is variable. We hypothesized that infants born to Black mothers, non-English speaking mothers, and mothers who live in “Very Low” Child Opportunity Index (COI) neighborhoods would have decreased odds of IFUP participation. There were 477 infants eligible for IFUP between 1/1/2015 and 6/6/2017 from a single large academic Level III NICU. Primary outcome was at least one visit to IFUP. We used multivariable logistic regression to identify factors associated with IFUP participation. Two hundred infants (41.9%) participated in IFUP. Odds of participation was lower for Black compared to white race (aOR 0.43, p = 0.03), “Very Low” COI compared to “Very High” (aOR 0.39, p = 0.02) and primary non-English speaking (aOR 0.29, p = 0.01). We identified disparities in IFUP participation. Further study is needed to understand underlying mechanisms to develop targeted interventions for reducing inequities.

Infants born preterm and with low birth weight have increased risk for neurodevelopmental challenges later in life compared to term-born peers. These include functional motor impairment, cognitive and speech delays, neurobehavioral disorders, and atypical social development. There are well-documented inequities in the population distributions of preterm birth and associated short-term morbidities by race, ethnicity, language, and nativity. Far less is known about how these inequities affect long-term outcomes, though the impact of unequal access to post-discharge support services for preterm infants raises concerns about widening gaps in health, development, and functioning. In this review, we describe what is currently known about the impact of race, ethnicity, nativity, and language on long-term outcomes. We provide a framework for understanding inequities in social, political, and historical context. And we offer guidance for next steps to delineate mechanistic pathways and to identify interventions to eliminate inequities in long-term neurodevelopmental outcomes through research, intervention, and advocacy.

I arrived to my shift early, nervous about caring for critically ill patients as a first-year fellow. I sat in the workroom alone, paralyzed, not sure how to preround despite being months into fellowship. The senior fellow appeared minutes before sign-out; fresh, knowledgeable, and calm, despite her busy night and lack of sleep. She asked me how I was doing. With tears in my eyes, my emotions poured out. I explained that I felt lost, unsure of myself, my place, and my knowledge. For the first time, I confessed out loud, “I don’t think I’m supposed to be here. I have no idea what I’m doing.” I could trust her in a way I couldn’t trust others. She was like me: othered by her identity, minoritized by society. Though different from my own, her identity allowed her to understand my own experiences. We were different from one another and we were also the same. Unlike the senior faculty, it was safe to talk to her. And, unlike my other cofellows, there was a kinship between us in our otherness. She looked at me, closed the door, and shared words of strength that I needed to hear. I belonged. I was more than enough. She shared that the pressure I was experiencing was common among systematically minoritized individuals; she too had felt it before. Sitting with her, I was finally seen, supported, and comforted. As a peer mentor from a minoritized background, she provided a sense of security and belonging that had not been provided in my training and was distinct from the support of senior faculty.

The coronavirus disease 2019 (COVID-19) pandemic, resulting from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused severe and widespread illness in adults, including pregnant women, while rarely infecting neonates. An incomplete understanding of disease pathogenesis and viral spread has resulted in evolving guidelines to reduce transmission from infected mothers to neonates. Fortunately, the risk of neonatal infection via perinatal/postnatal transmission is low when recommended precautions are followed. However, the psychosocial implications of these practices and racial/ethnic disparities highlighted by this pandemic must also be addressed when caring for mothers and their newborns. This review provides a comprehensive overview of neonatal-perinatal perspectives of COVID-19, ranging from the basic science of infection and recommendations for care of pregnant women and neonates to important psychosocial, ethical, and racial/ethnic topics emerging as a result of both the pandemic and the response of the healthcare community to the care of infected individuals.

Although Mendelian genetic disorders are individually rare, they are collectively more common and contribute disproportionately to pediatric morbidity and mortality. Remarkable advances in the past decade have led to identification of the precise genetic variants responsible for many of these conditions. Confirming the molecular diagnosis through genetic testing allows for individualized treatment plans in addition to ending the diagnostic odyssey, which not only halts further unnecessary testing but may also result in immense psychological benefit, leading to improved quality of life. However, ensuring equitable application of these advances in genomic technology has been challenging. Though prior studies have revealed disparities in testing for genetic predisposition to cancer in adults, little is known about the prevalence and nature of disparities in diagnostic testing in the pediatric rare disease population. While it seems logical that those with impaired access to healthcare would be less likely to receive the genetic testing needed to end their odyssey, few studies have addressed this question directly and the potential impact on health outcomes. This review synthesizes the available evidence regarding disparities in pediatric genetic diagnosis, defining the need for further, prospective studies with the ultimate goal of delivering precision medicine to all who stand to benefit. IMPACT: Social determinants of health are known to contribute to inequality in outcomes, though the impact on pediatric rare disease patients is not fully understood. Diagnostic genetic testing is a powerful tool, though it may not be available to all in need. This article represents the first effort, to our knowledge, to evaluate the existing literature regarding disparities in genetic testing for pediatric rare disease diagnosis and identify gaps in care.

Neonatal patients and families from historically marginalized and discriminated communities have long been documented to have differential access to health care, disparate health care, and as a result, inequitable health outcomes. Fundamental to these processes is an understanding of what race and ethnicity represent for patients and how different levels of racism act as social determinants of health. The NICU presents a unique opportunity to intervene with regard to the detrimental ways in which structural, institutional, interpersonal, and internalized racism affect the health of newborn infants. The aim of this article is to provide neonatal clinicians with a foundational understanding of race, racism, and antiracism within medicine, as well as concrete ways in which health care professionals in the field of neonatology can contribute to antiracism and health equity in their professional careers.

Background Physician burnout affects many physicians and is associated with decreased patient safety and physician health. Mindfulness curricula can reduce burnout but are often impractical to implement during residency. Objectives: To determine how a novel 6-month mindfulness curriculum designed for pediatric trainees impacts physician burnout, mindfulness, and empathy. Methods 15 pediatric residency programs’ interns participated in a stratified, cluster randomized controlled trial of the “Mindfulness Intervention for New Interns” (MINdI) curriculum. Participants completed the Maslach Burnout Inventory, Five Facet Mindfulness Questionnaire, and 2 Interpersonal Reactivity Index empathy scales and measures of mindfulness-related knowledge, attitudes and behaviors. Burnout was defined as an emotional exhaustion (EE) score >= 27 or a depersonalization (DP) score >= 10. The primary outcome was EE score. Missing data was addressed by conducting 20 data imputations. To determine impact of study arm on outcomes, we conducted logistic and GEE regressions clustered on site while controlling for factors that differed by arm. Results 340/365 invited interns completed the baseline survey (93.1%), and 254 completed follow-up (69.6%). At baseline, the mean EE score of the MINdI and control arms did not significantly differ (coef. -0.25; 95% CI: -4.54, 4.04), but the odds of burnout was significantly higher in the MINdI arm than controls (OR 2.73; 95% CI: 1.005, 7.43). Compared to controls, there were significantly higher mindfulness-related knowledge, attitudes, and behavior and higher EE scores in the MINdI arm at follow-up (coef. 2.45; 95% CI: 0.90, 6.66). At follow-up, burnout, mindfulness, or empathy scores did not significantly differ by arm. Conclusion Interns randomized to experience MINdI had higher EE despite increased knowledge, attitudes, and behaviors about mindfulness. The MINdI curriculum did not affect burnout, mindfulness nor empathy. As the curricula improved some measures of learning but increased EE future rigorous study of curricula to reduce physician burnout is needed.

Yarden S Fraiman,1,2 Nathan Cuka,3 Denise Batista,3 Milena Vuica-Ross,3 Alison R Moliterno4 1Department of Pediatrics, Harvard Medical School, 2Department of Pediatrics, Boston University School of Medicine, Boston, MA, 3Department of Pathology, 4Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Abstract: Paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by intravascular hemolysis, thrombosis, and bone marrow failure, is associated with mutations in the PIG-A gene, resulting in a deficiency of glycosylphosphatidylinositol-anchored proteins. Many hypotheses have been posed as to whether PNH and PIG-A mutations result in an intrinsic survival benefit of CD55-/CD59- cells or an extrinsic permissive environment that allows for their clonal expansion within the bone marrow compartment. Recent data have identified the concurrence of PIG-A mutations with additional genetic mutations associated with myeloproliferative disorders, suggesting that some presentations of PNH are the result of a stepwise progression of genetic mutations similar to other myelodysplastic or myeloproliferative syndromes. We report for the first time in the literature the development of clinically significant PNH in a patient with JAK2V617F-negative, CALR-positive essential thrombocythemia, providing further support to the hypothesis that the development of PNH is associated with the accumulation of multiple genetic mutations that create an intrinsic survival benefit for clonal expansion. This case study additionally highlights the utility of genomic testing in diagnosis and the understanding of disease progression in the clinical setting. Keywords: calreticulin, myelofibrosis, SNP array, PIGA deletion

Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10−2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10−3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10−3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts. Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect. Clin Cancer Res; 17(16); 5490–500. ©2011 AACR.

[Figure][1] A 73-year-old man without prior personal or family history of anemia developed a chronic hemolytic anemia characterized by an absolute reticulocyte count of 347 000/mm3 (13%) and spherocytic red-cell morphology (see panel A). Antiglobulin testing was negative but osmotic

Background FLT3 is expressed in most human acute leukemias. When activated by FL, wild type (wt) FLT3 dimerizes and initiates downstream signals that result in proliferation and inhibition of apoptosis and differentiation. Activating FLT3 mutations (internal tandem duplications (ITDs) or point mutations) are common in AML and rare in ALL. ITD mutations confer a poor outcome in AML. In vitro, mutant FLT3 signaling can be further enhanced by binding of FL. Peripheral blood (PB) plasma FL levels rise in adults with AML, peaking about two weeks after initiation of chemotherapy. We sought to determine plasma levels of FL in pediatric patients after chemotherapy, and the functional effect of various levels of FL on both wt and mutant FLT3 leukemia cells. Methods FL levels were measured using FL ELISA on plasma samples (n=352) isolated from PB of children (n=75) enrolled on 4 multi-center acute leukemia clinical trials. Functional studies were performed on AML and ALL cell lines with wt FLT3 (HL60, RS4;11, SEMK2, and KOPN-8) and mutant FLT3 (MOLM14, MV4-11, and HB-1119). 72 hr etoposide IC50 was determined by WST-1 for each line. Cells were plated (250,000 cell/mL) for 72hr at etoposide IC50 in RPMI 1640 along with increasing concentrations of recombinant human FL (62.5 to 4,000 pg/ml). Cell cycle and apoptosis were analyzed using propidium iodide staining and annexin V/7-AAD binding, respectively. To explore the mechanism of FL effects, Ba/F3-ITD cells were incubated for 72hr in serum-free conditions with either 4,000 pg/mL (“high”), 62.5 pg/mL (“low”), or no FL. After washing, total and phosphorylated FLT3 protein levels were determined by Western blot. Results Pediatric patients receiving chemotherapy for the treatment of acute leukemia demonstrate a pattern of plasma FL rise with low levels at baseline (mean 41 pg/ml) and peak levels at day 11-14 following initiation of therapy (mean: 1,190 pg/mL; max: 5,783 pg/mL)(Fig 1A). Cell lines with FLT3 activating mutations selectively demonstrate resistance to etoposide-induced apoptosis (Fig 1B) and G2/M cell cycle arrest (Fig 1C) at low concentrations of FL (62.5 pg/mL). Dose-dependent reduction of etoposide resistance is seen with increasing concentrations of FL up to 4,000 pg/mL, suggesting that optimal etoposide-induced killing of FLT3-mutant leukemias may occur when FL plasma levels are at their peak. Ba/F3-ITD cells pre-incubated with peak concentrations of FL showed diminished baseline FLT3 phosphorylation, suggesting that the interaction of FL and FLT3/ITD exhibits substrate inhibition kinetics and results in a loss of FLT3/ITD-induced activation with high level FL exposure, thus providing a mechanistic basis for the observed loss of etoposide resistance. Conclusions Plasma FL rises to peak levels 11-14 days after initiation of chemotherapy. Through substrate inhibition of mutant FLT3 enzymatic activity, peak FL levels may reduce the etoposide resistance that characterizes FLT3-mutant leukemia cells exposed to pre-chemotherapy levels of FL. Thus, introduction of etoposide in a “time sequential” manner during periods of peak plasma FL levels may enhance killing of residual chemoresistant FLT3-mutant leukemia cells. Disclosures: No relevant conflicts of interest to declare.

Abstract 568 Background: Infant acute lymphoblastic leukemia (ALL) is clinically and biologically distinct from ALL in older children. About 80% of infant ALL cases harbor MLL rearrangements (MLLr). MLLr infant ALL is an aggressive disease with poor prognosis, particularly in cases diagnosed at Methods: We prospectively characterized 54 consecutive diagnostic leukemia specimens from infants with ALL enrolled on AALL0631 with respect to: 1) Quantitative surface FLT3 protein expression (s-FLT3) using FACS CD135 mean fluorescence index (MFI); 2) FLT3 inhibitor (lestaurtinib: 0 to 100 nM) in vitro sensitivity using 48 hour WST-1 cytotoxicity assays; samples defined as “sensitive” if 100 nM produced ≥40% inhibition of cell viability compared to vehicle controls; 3) Identification and quantification of putative leukemia stem cell (LSC) subpopulation by flow cytometric immunophenotyping (% CD34+, CD38− viable cells). Studies were performed blinded to clinical information and MLL status; data were later correlated with age at diagnosis ( Results: Of 54 cases, 42 (78%) are MLLr and 12 (22%) are MLLwt. For MLLr cases, fusion partners are AF4 (n=13), ENL (n=17), AF9 (n=3), AF1p (n=2), and other (n=7). Of MLLr cases, 10 (24%) were 90days (mean MFI 62.6 vs. 22.0, p We analyzed FLT3 inhibitor sensitivity according to MLL genotype and s-FLT3. All 42 of the MLLr samples were evaluable, with 35 (83%) sensitive and 7 (17%) resistant; 11 of 12 MLLwt samples were evaluable (1 had excessively poor viability), with 6 (55%) sensitive and 5 (45%) resistant. We thus found a significant association between MLLr and FLT3 inhibitor sensitivity (Chi square 4.125, p=0.042). In the s-FLT3 analysis, the sensitive samples trended towards higher s-FLT3 than the resistant samples (mean MFI 31.3 vs. 16.7, p=0.17). Finally, we compared s-FLT3 in the putative LSC-like subpopulation fraction (if present) with the “bulk” leukemia population. Of the 54 samples analyzed, 35 (65%) had a clearly identifiable LSC-like population (i.e., comprising >0.5% of the total viable leukemia population). Within these 35 samples, s-FLT3 was significantly higher in the LSC-like fraction than in the bulk leukemia population (mean MFI 40.4 vs. 31.2, p=0.05). Conclusions: We have for the first time prospectively compared FLT3 expression and FLT3 inhibitor sensitivity in unselected representative cohorts of MLLr and MLLwt infants, confirming that MLLr cases express significantly higher levels of surface FLT3 protein and are more sensitive to the cytotoxic effects of FLT3 inhibition. Novel findings include higher surface FLT3 protein expression in MLL-AF9 cases relative to MLL-AF4 cases, and the strikingly higher surface FLT3 protein expression in MLLr cases in the youngest infants. An intriguing finding is the presence of phenotypically-defined subpopulations of “LSC-like” cells in the majority of cases, and that this LSC-like population expresses significantly higher levels of FLT3 protein than the “bulk” population. These findings provide further evidence that FLT3 overexpression plays a role in MLLr leukemogenesis. If these findings correlate with clinical responses in COG AALL0631, they may prove to be useful predictive biomarkers in selecting patients for whom FLT3-targeted therapy is most appropriate. Disclosures: No relevant conflicts of interest to declare.