Jude Children's Research Research Articles

Vancomycin Heteroresistance and Clinical Outcomes in Bloodstream Infections Caused by Coagulase-Negative Staphylococci.

Coagulase-negative staphylococci (CoNS) are a common etiology of serious and recurrent infections in immunocompromised patients. Although most isolates appear susceptible to vancomycin, a single strain might have a subpopulation of resistant bacteria. This phenomenon is termed heteroresistance and may adversely affect the response to treatment. A retrospective cohort study was performed of pediatric patients with leukemia treated at St. Jude Children's Research Hospital who developed CoNS central line-associated bloodstream infection (CLABSI). Available isolates were sequenced and tested for vancomycin heteroresistance by population analysis profiling. Risk factors for heteroresistance and the association of heteroresistance with treatment failure (death or relapse of infection) or poor clinical response to vancomycin therapy (treatment failure or persistent bacteremia after vancomycin initiation) were evaluated. For 65 participants with CoNS CLABSI, 62 initial isolates were evaluable, of which 24 (39%) were vancomycin heteroresistant. All heteroresistant isolates were of Staphylococcus epidermidis and comprised multiple sequence types. Participants with heteroresistant bacteria had more exposure to vancomycin prophylaxis (P = 0.026) during the 60 days prior to infection. Of the 40 participants evaluable for clinical outcomes, heteroresistance increased the risk of treatment failure (P = 0.012) and poor clinical response (P = 0.001). This effect persisted after controlling for identified confounders. These data indicate that vancomycin heteroresistance is common in CoNS isolates from CLABSIs in pediatric patients with leukemia and is associated with poor clinical outcomes. Validation of these findings in an independent cohort and evaluation of alternative antibiotic therapy in patients with heteroresistant infections have the potential to improve care for serious CoNS infections.

Evaluation of Chest Radiographs of Children with Newly Diagnosed Acute Lymphoblastic Leukemia

To evaluate the diagnostic yield of baseline chest radiographs (CXRs) of children with acute lymphoblastic leukemia (ALL). We reviewed the CXR findings at diagnosis for 990 patients aged 1-18years with ALL treated during the Total XV and XVI studies at St. Jude Children's Research Hospital and evaluated the associations of these findings with clinical characteristics and initial management. Common findings were peribronchial/perihilar thickening (n=187 [19.0%]), pulmonary opacity/infiltrate (n=159 [16.1%]), pleural effusion/thickening (n=109 [11.1%]), mediastinal mass (n=107 [10.9%]), and cardiomegaly (n=68 [6.9%]). Portable CXRs provided results comparable with those obtained with 2-view films. Forty of 107 patients with a mediastinal mass (37.4%) had tracheal deviation/compression. Mediastinal mass, pleural effusion/thickening, and tracheal deviation/compression were more often associated with T-cell ALL than with B-cell ALL (P<.001 for all). Pulmonary opacity/infiltrate was associated with younger age (P=.003) and was more common in T-cell ALL than in B-cell ALL (P=.001). Peribronchial/perihilar thickening was associated with younger age (P<.001) and with positive central nervous system disease (P=.012). Patients with cardiomegaly were younger (P=.031), more often black than white (P=.007), and more often categorized as low risk than standard/high risk (P=.017). Patients with a mediastinal mass, pleural effusion/thickening, tracheal deviation/compression, or pulmonary opacity/infiltrate were more likely to receive less invasive sedation and more intensive care unit admissions and respiratory support (P≤.001 for all). Cardiomegaly was associated with intensive care unit admission (P=.008). No patients died of cardiorespiratory events during the initial 7days of management. The CXR can detect various intrathoracic lesions and is helpful in planning initial management.

How Telemedicine and Centralized Care Changed the Natural History of Retinoblastoma in a Developing Country: Analysis of 478 Patients

To evaluate the efficacy of integrating a telemedicine-based twinning partnership and centralized care for retinoblastoma on survival and eye salvage. Four hundred seventy-eight retinoblastoma patients treated at a tertiary referral cancer center (King Hussein Cancer Centre [KHCC]) from 2003 through2019. Four hundred seventy-eight retinoblastoma patients treated at KHCC after implementing a telemedicine-based program with St. Jude Children's Research Hospital. We reviewed the outcomes of retinoblastoma patients who were treated at KHCC after implementing a telemedicine-based eye salvage program with St. Jude Children's Research Hospital, and we compared that with outcomes for retinoblastoma patients who were treated before implementing a telemedicine-based retinoblastoma service at KHCC. We analyzed patient demographics, clinical characteristics, treatments received, consultation type and duration, and long-term patient outcomes before and after implementing the twinning program. Over 17 years, 813 eyes from 478 children with retinoblastoma were treated at KHCC. Three hundred thirty-five patients (70%) had bilateral disease. Six patients (4%) with unilateral disease and 66 patients (20%) with bilateral disease had a family history of retinoblastoma. After the twinning program was established in 2003, the mortality rate decreased from 38% to 5% (P < 0.0001), and the overall eye salvage rate increased from 4% to 61% (98% for group A, 93% for group B, 81% for group C, and 48% for group D; P < 0.0001). Initially, all cases were discussed via telemedicine, but as knowledge transfer increased, the proportion of cases that required discussion decreased to less than 3% 10 years later. Similarly, treatment changes based on consultations decreased from 70% to 7% after 10 years. Both survival and eye-salvage rates were comparable at the early and later stages of implementing the twinning program. At a median follow-up of 120 months, 5% of patients had died of metastases or secondary neoplasms, 81% were alive, and 14% were lost to follow-up. Centralization of care at a single center in developing countries can achieve patient outcomes comparable with those of developed countries via twinning and telemedicine. This benefit can extend to a large region because two thirds of patients treated at KHCC were non-Jordanians.

COVID-19: Herd immunity and convalescent plasma transfer therapy.

Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has spread worldwide triggering a pandemic. Its first case was reported in Wuhan, the capital of China's Hubei province, and since then it has spread across world becoming one of the worst pandemics in the history of mankind1 . Its basic reproductive number (R0 ) has been determined to be 2-32 . This article is protected by copyright. All rights reserved.

Using Pharmacology to Squeeze the Life Out of Childhood Leukemia, and Potential Strategies to Achieve Breakthroughs in Medulloblastoma Treatment.

Eliminating cancer was once thought of as a war. This analogy is still apt today; however, we now realize that cancer is a much more formidable enemy than scientists originally perceived, and in some cases, it harbors a profound ability to thwart our best efforts to defeat it. However, before we were aware of the complexity of cancer, chemotherapy against childhood acute lymphoblastic leukemia (ALL) was successful because it applied the principles of pharmacology. Herein, we provide a historic perspective of the experience at St. Jude Children's Research Hospital. In 1962, when the hospital opened, fewer than 3% of patients experienced durable cure. Through judicious application of pharmacologic principles (e.g., combination therapy with agents using different mechanisms of action) plus appropriate drug scheduling, dosing, and pharmacodynamics, the survival of patients with ALL now exceeds 90%. We contrast this approach to treating ALL with the contemporary approach to treating medulloblastoma, in which genetics and molecular signatures are being used to guide the development of more-efficacious treatment strategies with minimal toxicity. Finally, we highlight the emerging technologies that can sustain and propel the collaborative efforts to squeeze the life out of these cancers. SIGNIFICANCE STATEMENT: Up until the early 1960s, chemotherapy for childhood acute lymphoblastic leukemia was mostly ineffective. This changed with the knowledge and implementation of rational approaches to combination therapy. Although the therapeutics of brain cancers such as medulloblastoma are not as refined (in part because of the blood-brain barrier obstacle), recent extraordinary advances in knowledge of medulloblastoma pathobiology has led to innovations in disease classification accompanied with strategies to improve therapeutic outcomes. Undoubtedly, additional novel approaches, such as immunological therapeutics, will open new avenues to further the goal of taming cancer.

Anesthesia Exposure during Therapy Predicts Neurocognitive Outcomes in Survivors of Childhood Medulloblastoma

To examine the contribution of anesthesia exposure during treatment for childhood medulloblastoma to neurocognitive outcomes 3years after tumor diagnosis. In this retrospective study, anesthesia data were abstracted from medical records for 111 patients treated with risk-adapted protocol therapy at St Jude Children's Research Hospital. Neurocognitive testing data were obtained for 90.9% of patients. For the 101 patients (62.4% male) who completed testing, mean age at diagnosis was 10.1years, and 74.3% were staged to have average-risk disease. Anesthesia exposure during treatment ranged from 1 to 52 events (mean=19.9); mean cumulative duration per patient was 21.1hours (range 0.7-59.7). Compared with normative expectations (16%), the group had a significantly greater frequency of at-risk scores (<1 SD) on measures of intelligence (28.7%), attention (35.2%), working memory (26.6%), processing speed (46.7%), and reading (25.8%). Including anesthesia exposure duration to linear regression models accounting for age at diagnosis, treatment intensity, and baseline IQ significantly increased the predicted variance for intelligence (r2=0.59), attention (r2=0.29), working memory (r2=0.31), processing speed (r2=0.44), and reading (r2=0.25; all P values <.001). In survivors of childhood medulloblastoma, a neurodevelopmentally vulnerable population, greater exposure to anesthesia significantly and independently predicts deficits in neurocognitive and academic functioning. When feasible, anesthesia exposure during treatment should be reduced.

Evolution of vancomycin-resistant Enterococcus faecium during colonization and infection in immunocompromised pediatric patients

Patients with hematological malignancies or undergoing hematopoietic stem cell transplantation are vulnerable to colonization and infection with multidrug-resistant organisms, including vancomycin-resistant Enterococcus faecium (VREfm). Over a 10-y period, we collected and sequenced the genomes of 110 VREfm isolates from gastrointestinal and blood cultures of 24 pediatric patients undergoing chemotherapy or hematopoietic stem cell transplantation for hematological malignancy at St. Jude Children's Research Hospital. We used patient-specific reference genomes to identify variants that arose over time in subsequent gastrointestinal and blood isolates from each patient and analyzed these variants for insight into how VREfm adapted during colonization and bloodstream infection within each patient. Variants were enriched in genes involved in carbohydrate metabolism, and phenotypic analysis identified associated differences in carbohydrate utilization among isolates. In particular, a Y585C mutation in the sorbitol operon transcriptional regulator gutR was associated with increased bacterial growth in the presence of sorbitol. We also found differences in biofilm-formation capability between isolates and observed that increased biofilm formation correlated with mutations in the putative E. faecium capsular polysaccharide (cps) biosynthetic locus, with different mutations arising independently in distinct genetic backgrounds. Isolates with cps mutations showed improved survival following exposure to lysozyme, suggesting a possible reason for the selection of capsule-lacking bacteria. Finally, we observed mutations conferring increased tolerance of linezolid and daptomycin in patients who were treated with these antibiotics. Overall, this study documents known and previously undescribed ways that VREfm evolve during intestinal colonization and subsequent bloodstream infection in immunocompromised pediatric patients.

Cardiac autonomic dysfunction in survivors of childhood acute lymphoblastic leukemia: The St. Jude Lifetime Cohort Study.

Cardiac autonomic dysfunction (CAD) is possible following treatment for childhood cancer. The aims of our analyses were to compare the prevalence of CAD between adult survivors of childhood acute lymphoblastic leukemia and controls, compare exercise response among survivors with and without CAD, and identify treatment-related risk factors for CAD. Participants were treated for childhood acute lymphoblastic leukemia at St. Jude Children's Research Hospital between 1980 and 2003 (N=338). A comparison group matched for race/ethnicity, age, and sex was also recruited (N=325). Resting heart rate (HR) was assessed via electrocardiogram, and heart rate recovery (HRR) and exercise capacity were evaluated with submaximal cardiopulmonary exercise testing. CAD was present in 33.7% of survivors and 27.6% of controls (P=0.09). Although mean resting HR did not differ between survivors and controls (74 ± 12 vs 72 ± 12 beats per minute (bpm), P=0.07), survivors had lower mean HRR than controls (22 ± 9 vs 25 ± 10bpm; P<0.001). Survivors with CAD had lower peak exercise tolerance (25.7 ± 6.5 vs 21.2 ± 4.9mL/kg/min, P<0.001) than those without. Survivors treated with cyclophosphamide in combination with vincristine ≥38mg/m2 and/or glucocorticoids ≥10000mg/m2 were 1.56 (95% CI 1.09-2.24) times more likely to have CAD than those without this treatment. Obese survivors were 1.78 (95% CI: 1.31-2.40) times more likely to have CAD than nonobese survivors (P<0.001). CAD was present in over one third of survivors and was associated with lower exercise capacity. Obese survivors and those exposed to cyclophosphamide with high doses of vincristine and/or corticosteroids were at greatest risk.

Treatment-related calvarial lesions in pediatric brain tumor survivors.

Despite improved survival, many pediatric brain tumor survivors receiving radiation therapy (RT) experience late effects. To study calvarial lesions in this population, we retrospectively reviewed records of patients undergoing neurosurgical evaluation for calvarial bone lesions detected in posttreatment follow-up imaging at St. Jude Children's Research Hospital. Primary tumor diagnosis, treatment, imaging, surgical intervention, and histopathology from patients with radiographic evidence of lesions followed for ≥2 years post-RT were studied. For 17 patients with 18 index lesions, median time to lesion manifestation was 2.34 years. Medulloblastoma patients developed lesions at a shorter interval from RT than ependymoma patients (P=.05). Twelve of 14 lesions requiring surgery were benign fibro-osseous or sclerotic. Two malignant lesions distinct from the primary tumor had genetic predisposition to malignancy. Most calvarial lesions arising post-RT are benign and fibro-osseous. Serial imaging is recommended, and high index of suspicion for malignant lesions is warranted for patients genetically predisposed to cancer.

First person profile: Leslie L. Robison, PhD: A world-renowned epidemiologist, Dr. Robison played key roles in developing both the national Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort Study.

First person profile: Leslie L. Robison, PhD: A world-renowned epidemiologist, Dr. Robison played key roles in developing both the national Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort Study.

Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial

(+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans. The phase 1a was a single-centre, dose-escalation, first-in-human study of SJ733 allowing modifications to dose increments and dose-cohort size on the basis of safety and pharmacokinetic results. The phase 1a took place at St Jude Children's Research Hospital and at the University of Tennessee Clinical Research Center (Memphis, TN, USA). Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses. Participants were fasted in seven dose cohorts and fed in one 600 mg dose cohort. Single ascending doses of SJ733 (75, 150, 300, 600, 900, or 1200 mg) were administered to participants, who were followed up for 14 days after SJ733 dosing. Phase 1a primary endpoints were safety, tolerability, and pharmacokinetics of SJ733, and identification of an SJ733 dose to test in the induced blood-stage malaria model. The phase 1b was a single-centre, open-label, volunteer infection study using the induced blood-stage malaria model in which fasted participants were intravenously infected with blood-stage P falciparum and subsequently treated with a single dose of SJ733. Phase 1b took place at Q-Pharm (Herston, QLD, Australia) and was initiated only after phase 1a showed that exposure exceeding the threshold minimum exposure could be safely achieved in humans. Participants were inoculated on day 0 with P falciparum-infected human erythrocytes (around 2800 parasites in the 150 mg dose cohort and around 2300 parasites in the 600 mg dose cohort), and parasitaemia was monitored before malaria inoculation, after inoculation, immediately before SJ733 dosing, and then post-dose. Participants were treated with SJ733 within 24 h of reaching 5000 parasites per mL or at a clinical score higher than 6. Phase 1b primary endpoints were calculation of a parasite reduction ratio (PRR48) and parasite clearance half-life, and safety and tolerability of SJ733 (incidence, severity, and drug-relatedness of adverse events). In both phases of the trial, SJ733 hydrochloride salt was formulated as a powder blend in capsules containing 75 mg or 300 mg for oral administration. Healthy men and women (of non-childbearing potential) aged 18-55 years were eligible for both studies. Both studies are registered with ClinicalTrials.gov (NCT02661373 for the phase 1a and NCT02867059 for the phase 1b). In the phase 1a, 23 healthy participants were enrolled and received one to three non-consecutive doses of SJ733 between March 14 and Dec 7, 2016. SJ733 was safe and well tolerated at all doses and in fasted and fed conditions. 119 adverse events were recorded: 54 (45%) were unrelated, 63 (53%) unlikely to be related, and two (2%) possibly related to SJ733. In the phase 1b, 17 malaria-naive, healthy participants were enrolled. Seven participants in the 150 mg dose cohort were inoculated and dosed with SJ733. Eight participants in the 600 mg dose cohort were inoculated, but two participants could not be dosed with SJ733. Two additional participants were subsequently inoculated and dosed with SJ733. SJ733 exposure increased proportional to the dose through to the 600 mg dose, then was saturable at higher doses. Fasted participants receiving 600 mg exceeded the target area under the concentration curve extrapolated to infinity (AUC0-∞) of 13 000 μg × h/L (median AUC0-∞ 24 283 [IQR 16 135-31 311] μg × h/L, median terminal half-life 17·4 h [IQR 16·1-24·0], and median timepoint at which peak plasma concentration is reached 1·0 h [0·6-1·3]), and this dose was tested in the phase 1b. All 15 participants dosed with SJ733 had at least one adverse event. Of the 172 adverse events recorded, 128 (74%) were mild. The only adverse event attributed to SJ733 was mild bilateral foot paraesthesia that lasted 3·75 h and resolved spontaneously. The most common adverse events were related to malaria. Based on parasite clearance half-life, the derived log10PRR48 and corresponding parasite clearance half-lives were 2·2 (95% CI 2·0-2·5) and 6·47 h (95% CI 5·88-7·18) for 150 mg, and 4·1 (3·7-4·4) and 3·56 h (3·29-3·88) for 600 mg. The favourable pharmacokinetic, tolerability, and safety profile of SJ733, and rapid antiparasitic effect support its development as a fast-acting component of combination antimalarial therapy. Global Health Innovative Technology Fund, Medicines for Malaria Venture, and the American Lebanese Syrian Associated Charities.

Differential adsorption of analyte and deuterated analogue onto the rotor seal of the injector in high-performance liquid chromatography/electrospray ionisation mass spectrometry.

Samples were injected onto the HPLC system via either a Valco C14W.1 internal sample injector or a Rheodyne 7125 injector, both with dissimilar Vespel rotor seals, and linked to a quadrupole time-of-flight (QTOF) mass spectrometer. Alternatively, samples were infused directly into the mass spectrometer via a syringe-driver. Electrospray ionisation in positive mode was used in both cases. Experiments demonstrated significant differential adsorption of the analyte (RAC inhibitor, NSC23766) and its tri-deuterated internal standard onto the Vespel rotor seal, with the latter seeming to be preferentially adsorbed. The deuterated analogue also showed lower electrospray sensitivity, as demonstrated by syringe infusion of a mixture of the compounds, compared with their separate infusion at the same concentration. This study has demonstrated the problem of differential adsorption onto HPLC Vespel rotor seals, and that the use of a stable-isotope-labelled analogue as internal standard does not guarantee the constancy of the analyte/internal response ratio in quantitative methods. The partial solution was to work at much higher concentration where adsorption, whilst still apparent, was relatively insignificant.

Clinical impact of post-induction resolution of pulmonary lesions in metastatic Ewing sarcoma.

Patients with metastatic Ewing sarcoma experience poor outcomes despite intensive systemic and local therapy. Early chemotherapy response of pulmonary metastases has been associated with prognosis in other pediatric malignancies. We reviewed the outcomes of patients with Ewing sarcoma and pulmonary metastases treated at our institution based on therapy received and early pulmonary response. We retrospectively reviewed patients with newly diagnosed Ewing sarcoma and pulmonary metastases at St. Jude Children's Research Hospital between 1979 and 2015. Data obtained included demographic and treatment characteristics including chemotherapy, local control measures, whole lung irradiation (WLI) administration, autologous stem cell transplantation, and outcomes. Patients were evaluated for radiographic post-induction pulmonary complete response (CR). We estimated event-free survival (EFS) and overall survival (OS) and used Cox proportional hazards regression to examine the effects of clinical and treatment factors on outcomes. Fifty-four patients (median age, 12.9 years) were evaluated. Post-induction pulmonary CR was observed in 33 (61%) patients. WLI was delivered to 16 patients (4/33 with pulmonary CR and 12/21 with non-CR). At median 3.6 years follow-up, five-year EFS and OS were 30.8% ± 6.4% and 49.6% ± 7.1%, respectively. Post-induction pulmonary CR was associated with prolonged EFS (P<0.001) but not improved OS (P=0.065). Post-induction pulmonary CR was associated with a lower incidence of lung failure (P=0.031). Post-induction pulmonary CR is associated with improved EFS in patients with Ewing sarcoma who present with pulmonary metastases.

Handoff Communication between Remote Healthcare Facilities.

Introduction:Handoffs and transitions of care are common weak points in healthcare provider communication as patients move between sites. With no consistent pattern of communication between St. Jude Children’s Research Hospital (St. Jude) and its affiliated clinics, the Affiliate Program Office at St. Jude developed and implemented a standardized communication tool to facilitate patient transitions between different healthcare sites.Methods:Each team of providers created flow diagrams to define the current state of communication when patients were transitioning between remote sites. Fishbone diagrams identified the common barriers to effective communication as a lack of consistent communication and ownership. We developed a communication tool to address these barriers, which was disseminated by secure email. We measured the percent usage of the completed hand-off tool before a patient transitioned, staff experience, and the number of errors.Results:The time to send or receive the communication bundle was <10 minutes. Within 3 months of implementing the SMART bundle at 3 pilot sites, the bundle was used completely in 6 of 8 patient transitions and was associated with somewhat improved staff satisfaction. We identified no adverse events related to the communication bundle.Conclusions:In this small pilot study, we accomplished closed-loop communication between geographically remote healthcare sites by using an electronically transmitted standardized communication bundle.

Childhood leukemia could be a target for immunotherapy

Pediatric patients with acute lymphoblastic leukemia (ALL) were shown in a recent study to have a strong immune response to their cancer, which suggests that immunotherapy may be helpful in treating the disease. The study, led by St. Jude Children's Research Hospital and published in Science Translational Medicine, indicated that although the cancer has few mutations, antitumor T cells (CD8+ T cells) recognized 86% of pediatric ALL mutations and specifically targeted 68% of the leukemic cells.1 The percentage is much greater than the 2% of solid tumor mutations that antitumor T cells are predicted to target, according to the authors. Because investigators could identify tumor-reactive T cells that were functional, cellular-based immunotherapy approaches that enable T-cell modification would likely be a better option than traditional immune checkpoint inhibitors, according to first author Anthony Zamora, PhD, a postdoctoral fellow in the St. Jude Department of Immunology. The study's findings are key because although 90% of US children with ALL become long-term survivors, those who relapse have much worse prognoses. The robust immune system response in pediatric ALL could potentially be explained by a process called immunodominance, which occurs when the immune system responds to viruses. The process leads to the production of T cells directed against a limited number of viral targets. The same scenario may occur in pediatric ALL and enable the immune system to target driver mutations that are causing the cancer, according to corresponding author Paul Thomas, PhD, a member of the St. Jude Department of Immunology.

The association of mediastinal mass in the formation of thrombi in pediatric patients with non-lymphoblastic lymphomas.

Children diagnosed with cancer are at a significantly higher risk of developing a thrombotic event (TE) compared with the general population. The rarity of these events makes it difficult to discern the specific risk factors; however, age, sex, presence of central venous lines, inherited thrombophilia, and mediastinal mass may play a role. The primary aim of this study is to identify prognostic characteristics of children diagnosed with non-lymphoblastic lymphomas associated with a greater risk of developing a TE early on in their disease, with an increased focus on mediastinal mass characteristics. Retrospective chart review of pediatric patients diagnosed with non-lymphoblastic lymphoma between 2004 and 2014 at St. Jude Children's Research Hospital. TE occurred in 8.5% (n=28/330) of individuals at a median of 21 days from the diagnosis of a non-lymphoblastic lymphoma, with 60% of TEs occurring within 30 days of diagnosis. Of the variables evaluated, only presence of a peripherally inserted central catheter (odds ratio [OR]: 3.14 [95% CI: 1.24-7.98; P=0.02]) and degree of superior vena cava (SVC) compression of>25% increased the odds of developing a TE (OR: 2.2 [95% CI: 1.01-4.93; P=0.048]). Pediatric patients with non-lymphoblastic lymphoma are at increased risk of developing TEs. In contrast to previous studies, the presence of a mediastinal mass alone was not associated with a higher risk of TE, but individuals with a mediastinal mass with 25% or greater degree of SVC compression were more likely to develop a TE. This finding highlights a high-risk group of children who may benefit from prophylactic anticoagulation.

Lentiviral Gene Therapy with Low Dose Busulfan for Infants with X-SCID Results in the Development of a Functional Normal Immune System: Interim Results of an Ongoing Phase I/II Clinical Study

Lentiviral Gene Therapy with Low Dose Busulfan for Infants with X-SCID Results in the Development of a Functional Normal Immune System: Interim Results of an Ongoing Phase I/II Clinical Study

Enhanced Transduction Lentivector Gene Therapy for Treatment of Older Patients with X-Linked Severe Combined Immunodeficiency

Enhanced Transduction Lentivector Gene Therapy for Treatment of Older Patients with X-Linked Severe Combined Immunodeficiency

Engineering Naturally Occurring CD7 Negative Cells for the Immunotherapy of CD7 Positive Leukemia

Background: CD7 has emerged as a promising target for the adoptive immunotherapy with T-cells expressing chimeric antigen receptors (CAR T-cells) of CD7+ T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). However, expressing CD7 CARs in T-cells results in fratricide due to high expression of CD7 in most T-cells. While investigators have developed strategies to overcome this limitation by additional genetic modifications of CD7 CAR T-cells, the goal of this project was to explore the feasibility of selecting and genetically modifying naturally occurring CD7 negative (CD7-) T cells for the adoptive immunotherapy of CD7+ leukemia. Methods: CD7- T-cells were isolated from PBMCs using a 2-step magnetic bead depletion/selection procedure (CD7 depletion followed by selection of CD3+ T cells from the CD7- fraction). Non-selected T-cells (bulk T-cells), CD7+ and CD7- T cells were activated and transduced with a retroviral vector encoding a second-generation CD7 CAR with a CD28 costimulatory endodomain, and expanded with IL7 and IL15. The effector function of CD7- T-cells expressing CD7 CARs (CD7 CARCD7- T cells) was assessed in vitro as well as in xenograft models. Results: To assess the feasibility of our approach, we first determined the frequency of CD7- T-cells in PBMCs. On average, 4.7 % of T cells were CD7- (range: 2% - 12.3%; N=22), and we successfully selected these cells from bulk PBMCs with a combined CD7 depletion/CD3 selection procedure. We genetically modified CD7-, CD7+ and bulk T cellsto express CD7 CARs (CD7 CARCD7-, CD7 CARCD7+, CD7 CARBulk). Transduction efficiencies ranged from 31% to 75% (± 5%) for each T-cell population. Post transduction, CD7 CARCD7- T-cells did not undergo fratricide and had similar expansion kinetics (N=6, p=ns) in comparison to non-transduced (NT) T-cell cultures (NT CD7-, NT CD7+, NT bulk). In contrast, CD7 CARCD7+or CD7 CARBulk T-cells underwent fratricide and did not expand (N=6, p&amp;lt;0.0001). CD7- T-cells (NT and CD7 CARCD7-) had a predominantly CD4+ effector memory phenotype at day 7 and 14 of culture. To assess the effector function of CD7 CARCD7- T-cells, we co-cultured them with CD7+ T-ALL cell lines (CCRF, MOLT3). CD7 CARCD7- T-cells recognized CD7+ targets in contrast to CD7- targets (BV173, Daudi) as evidenced by significant (N=6, p&amp;lt;0.0001) IFN-γ and IL-2 production. Control CAR T-cells (CD19 CARCD7-) did not recognize CD7+ target cells, confirming specificity. CD7 CARCD7- T-cells also had potent cytolytic activity against CD7+ targets in cytotoxicity assays. To assess in vivo the anti-tumor activity of CD7 CARCD7- T-cells, we used a NSG mouse xenograft model with CCRF cells, genetically modified to express firefly luciferase (CCRF.ffluc) to allow for serial bioluminescence imaging. A single infusion of CD7 CARCD7- T-cells had potent anti-leukemia activity as judged by serial imaging resulting in a significant survival (p&amp;lt;0.003) advantage in comparison to control mice. Conclusion: We have successfully generated CD7 CARCD7- T-cells from peripheral blood CD7- T-cells. CD7 CARCD7- T-cells had a predominantly CD4+ effector memory phenotype, and potent anti-leukemia activity in vitro and in vivo. Thus, naturally occurring CD7- T cells may present a promising T-cell source for the cellular immunotherapy of CD7+ leukemia. Disclosures Langfitt: MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Youngblood:MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Gottschalk:NHLBI: Research Funding; America Lebanese Syrian Associated Charities: Research Funding; ASSISI fundation of Memphis: Research Funding; California Institute for Regenerative Medicine: Research Funding; ViraCyte: Consultancy; MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy; Patents and patent applications in the fields of T-cell &amp; Gene therapy for cancer: Patents &amp; Royalties; TESSA Therapeutics: Other: Research Collaboration; Tidal: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; EMD Serono: Honoraria; Merck: Consultancy; Inmatics: Membership on an entity's Board of Directors or advisory committees. Velasquez:St. Jude: Patents &amp; Royalties: Patent Applications in the Fields of Cell and Gene Therapy ; Rally! Foundation: Membership on an entity's Board of Directors or advisory committees.

Evaluation of Factors Influencing Health Literacy in Adolescents and Adults with Sickle Cell Disease

Introduction In the United States 36% of adults have limited health literacy, which is associated with poor health outcomes (Kutner et al. National Assessment of Adult Literacy.2006). Health literacy is defined as "the capacity to obtain, process and understand basic health information and services needed to make appropriate health decisions" (Nielsen-Bohlman et al. National Academies Press.2004). Health literacy is understudied in sickle cell disease (SCD), a genetic disease affecting a minority population in the United States. SCD Preventive treatment requires patient engagement, therefore health literacy is an important determinant of health outcomes in SCD. Previous studies reported Health literacy in adolescents with SCD is suboptimal (Perry et al. J Pediatr Nur.2017), but few studies have investigated factors influencing health literacy in this population. Health literacy can be impacted by many factors such as cognition, socioeconomic status, education level and gender. This study evaluated health literacy level and factors that influenced Health literacy in adolescents and adults with SCD. In addition, we assessed the relationship of health literacy level and Hydroxyurea therapy use, one of only two FDA-approved disease-modifying therapies for SCD. Methods This was a cross- sectional study of adolescents and adults with SCD performed at St. Jude Children's Research hospital and St. Louis Children's hospital. Adolescents and adults ages 15 to 45 years completed a health literacy assessment using the newest vital sign (NVS). NVS is a validated tool with 6 questions that tests reading, mathematics and comprehension based on a nutrition label (Weiss et al. Ann Fam Med.2005). Score of 0-1 suggests high likelihood of limited health literacy, 2-3 indicates possibility of limited health literacy and 4-6 almost always suggests adequate health literacy. Self-reported demographic information was collected such as educational level, household income, age, sex, race. Additionally, SCD genotypes and hydroxyurea utilization were confirmed through chart review. Results A random sample of 125 adolescents and adults with SCD was evaluated (Table 1): 34 (28.1%) had Hb SC or Hb Sβ+-thalassemia, 87(71.9%) had Hgb SS or Hgb Sβ0-thalassemia, and 4 participants had unknown or other genotypes. Limited health literacy was prevalent, only 40 (32%) of subjects had adequate literacy, median NVS score was 2 for all participants. Participants with Hgb SS/Hgb Sβ0-thalassemia were more likely to be on hydroxyurea (p&lt;0.001, Chi-square test). NVS scores in subjects with less severe genotype were not significantly different compared to more severe genotypes (p=0.2, Man-Whitney-Wilcoxon test/MWW). There was no difference in health literacy scores between those on hydroxyurea and not on hydroxyurea (p=0.24, MWW test), however despite low health literacy being prevalent, 85 (68%) subjects with Hb SS or HbSβ0-thalassemia were on hydroxyurea. Income level was significantly different between patient on hydroxyurea not on hydroxyurea (p= 0.034, Fisher's exact test). In addition, patient whose income was $35000 or more were found to have a higher NVS score (p=0.012, Kruskal-Wallis test) (figure 1). Subjects with high NVS scores were significantly older (p=0.026, Analysis of variance test), over all education was significantly associated with health literacy (p=0.003, Fisher's exact). Conclusion This study shows a low prevalence of adequate health literacy amongst adolescents and adults with SCD. Our data corroborate previous literature which has reported limited health literacy in this population as well adds granularity to the factors that may influence this suboptimal outcome. There was a statistically significant association between health literacy, income level and education level in adolescents and young adults with SCD. Further, health literacy was not significantly associated with sickle cell genotype or hydroxyurea use. This study highlights the social determinants of health and specific need to address health literacy in SCD patients. To optimize the care of adolescents and young adults with SCD, targeted multimodal interventions that are tailored to low health literacy levels should be employed to reduce morbidity and mortality in this vulnerable population. Disclosures Kang: MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapeutics (formerly Vasculox, Inc.):: Consultancy; WUGEN: Equity Ownership. Zhao:MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Hankins:NHLBI: Research Funding; National Committee for Quality Assurance: Consultancy; Global Blood Therapeutics: Research Funding; NHLBI: Honoraria; ASPHO: Honoraria; LYNKS Foundation: Research Funding; Novartis: Research Funding; Bluebird Bio: Consultancy.