Clinical Advisory Board Research Articles

Patient experience with immuno-oncology-induced cytokine release syndrome: Developing a conceptual model of symptoms and their impacts on patients' lives.

2654 Background: Immuno-oncology (IO) therapy can cause cytokine release syndrome (CRS) events, which are a constellation of co-occurring signs and symptoms that usually present within 24–48 hours after treatment. There is no clinical consensus on the specific sign and symptom profile for IO-induced CRS. The objectives of this study were to better understand the experiences of patients with IO-induced CRS and to use data analysis, clinician insights, and patient interviews to develop a conceptual model to capture CRS symptoms and impacts on patients’ lives. Methods: A targeted literature review was conducted to identify CRS signs and symptoms across IO therapies. Clinician interviews (n=4) further defined clinical signs and symptoms and explored the impacts of CRS events on patients’ lives. An advisory boardof five academic oncologists then commented on this list of clinical signs, symptoms, and impacts. Finally, qualitative concept-elicitation interviews were conducted with US patients (ongoing at abstract submission; expected N=20 by March 2024)to confirm and describe symptom severity and impacts. The final intended patient interview sample will specifically examine symptoms and impacts across subgroups with different CRS severity levels. Results: A total of 35 signs and symptoms were initially identified from the literature review. These were assessed, confirmed, and sorted via clinician interviews, resulting in a refined list of 16 clinical signs and 28 symptoms relevant to IO-induced CRS. Based on inputs from the subsequent clinical advisory board, clinical signs indicative of CRS (such as, hypotension, fever and hypoxia) were confirmed, and a list of symptoms (such as chills, fatigue, nausea and diarrhea) recommended for inclusion in a new instrument suited to capture patient-reported experiences was generated. CRS impacts were also broadly described, emphasizing activities and behaviors affected by reduced energy and motivation levels, symptom-related distress, and the emotional burden of the experience. Ongoing patient interviews will confirm the importance of these identified CRS symptoms and provide more specific descriptions of the impacts of IO-induced CRS events on peoples’ lives. Conclusions: Key symptoms affecting patients’ daily activities included, but were not limited to, chills, fatigue, nausea, and diarrhea. These were used to develop a CRS-specific, patient-centered conceptual model that will be refined upon completion of ongoing patient interviews (full results to be presented at ASCO 2024). This research will serve as a framework to build a patient-reported outcome instrument that accurately captures patients’ experiences with CRS and is sensitive to various CRS severity levels. The proposed instrument may aid in evaluating outcomes in clinical trials and support benefit-risk and tolerability assessments.

Monitoring Respiratory Effort and Lung-distending Pressure Noninvasively during Mechanical Ventilation: Ready for Prime Time.

Monitoring Respiratory Effort and Lung-distending Pressure Noninvasively during Mechanical Ventilation: Ready for Prime Time.

2223. A comparative analysis of the detection of UTI pathogens via culture method and the Open Array-nanofluidic real time PCR method

Abstract Background Urinary tract infections (UTI) are the second most prevalent microbial infection, impacting 150 million people globally every year. Traditionally, urine culture is considered the gold standard for UTI pathogen detection. However, molecular techniques, such as real time multiplex PCR tests targeting multiple pathogens, are becoming the alternative diagnostic tools for rapid detection of pathogens with the potential to provide quick diagnosis and enable targeted treatment. Due to the serious economic and healthcare utilization burden UTIs pose, early pathogen detection with a rapid turn-around-time to results has the potential to be instrumental for improving patient care and outcomes. Methods A total of 300 deidentified patient samples that were previously tested via urine culture (ARUP laboratories, Utah) were subjected to real time PCR molecular testing employing the nanofluidic Open Array ® platform (HealthTrackRX, Texas). Statistical analyses were performed using R version 3.6.0. Results Among 300 urine specimens studied, culture detected pathogens in 183 patient samples (61%), and 117 samples were deemed negative. Culture and PCR results demonstrated an overall agreement of 75.3% (n=226) with 59% positive (n=177) and 16.3% negative (n=49). Results for 24.7% samples (n=74) were discordant. A total of 2% (n=6) were culture positive and PCR negative, and 22.7% (n=68) were culture negative and PCR positive. Agreement between PCR and culture positive results was 0.97, 95%CI (0.94, 0.99) (177/183). Among the PCR positive samples (n=245), 32.7% were poly-microbial (n=80) and 67.3% were mono-microbial (n=165). In comparison, among culture positive samples (n=183), 33.3% (n=61) were polymicrobial and 65.6% (n=120) monomicrobial. Conclusion Our study demonstrates that multiplex real time PCR-based detection of UTI bacterial pathogens has positive agreement with the traditional urine culture method. PCR based testing has the potential to deliver quick pathogen identification to enable targeted treatment options and medication adjustments. Further studies will correlate semi-quantitative cfu/mL culture values with semi-quantitative copies/mL PCR values to further refine result reporting and test performance. Disclosures Pallavi Upadhyay, PhD, HealthTrackRx: Stocks/Bonds Fahida Surar, B.S., HealthTrackRx: Salaried Employee Geun Kim, M.S., HealthTrackRx: Salaried Employee Jay Reddy, PhD, HealthTrackRx: Stocks/Bonds Barbara D. Alexander, MD, Astellas: Advisor/Consultant|HealthtrackRx: Advisor/Consultant|HealthtrackRx: Grant/Research Support|Scynexis: Grant/Research Support|UpToDate: Advisor/Consultant Kimberly Hanson, MD, MHS, FIDSA, HealthTrackRx: Advisor/Consultant|HealthTrackRx: Clinical Advisory Board Member Vijay Singh, PhD, HealthTrackRx: Stocks/Bonds.

The 5th edition of the WHO classification of lymphoid neoplasms-an overview

The "Blue Book" of the WHO classification of haematolymphoid tumours is the worldwide accepted reference in malignant tumours of the myeloid and lymphoid system. The REAL classification of 1994 [2] laid the foundations for the WHO volumes, with continous development and specification to date [3, 5, 6]. In the 5th edition of the classification to be released this year, new insights concerning the pathogenesis and molecular genetics, and new concepts regarding the taxonomic basis of the classification are included. Overviews of the changes and new aspects of the 5th edition of the classification of haematolymphoid tumours (WHO-HAEM5) have recently been published [1, 4]. Overall, 420 authors participated on the WHO-HAEM5, among them numerous members of the large international societies for haematopathology, the European Association for Haematopathology (EAHP) and the Society for Hematopathology (SH). The WHO-HAEM5 was developed in amultidisciplinary setting in numerous online meetings with haematopathologists, haematologists, oncologists, geneticists, epidemiologists and molecular biologists. In extensive discussions, harmonisation of chapters and with the other volumes of the 5th series was sought. For implementation of clinical aspects, aclinical advisory board was consulted. The new classification constitutes asystematic update of former classifications. As has been implemented earlier, the entities are presented in ahierarchical order: category (e.g. mature B‑cell neoplasm), family/class (e.g. diffuse large B‑cell lymphoma, DLBCL), entity (e.g. DLBCL, not otherwise specified, NOS) and subtype (e.g. DLBCL, NOS, GCB-type). Similar to the 5th editions of other WHO classifications, at the end of each chapter, alist of "essential" diagnostic criteria representing minimal criteria to establish the diagnosis and "desirable" diagnostic criteria are given in order to further confirm and specify the diagnosis.

Microfluidic preparation of spermatozoa for ICSI produces similar embryo quality to density-gradient centrifugation: a pragmatic, randomized controlled trial.

Does processing of spermatozoa for IVF with ICSI by a microfluidic sperm separation device improve embryo quality compared with density-gradient centrifugation? Patients randomized to microfluidic sperm preparation had similar cleavage- and blastocyst-stage embryo quality and clinical and ongoing pregnancy rates to those who underwent standard sperm processing for IVF with ICSI. Microfluidic sperm preparation can isolate spermatozoa for clinical use with minimal DNA fragmentation but with unclear impact on clinical outcomes. A prospective randomized controlled trial of 386 patients planning IVF from June 2017 through September 2021 was carried out. One hundred and ninety-two patients were allocated to sperm processing with a microfluidic sperm separation device for ICSI, while 194 patients were allocated to clinical standard density-gradient centrifugation (control) at an academic medical centre. In an intention to treat analysis, there were no differences in high-quality cleavage-stage embryo fraction [66.0 (25.8)% control versus 68.0 (30.3) microfluidic sperm preparation, P = 0.541, absolute difference -2.0, 95% CI (-8.5, 4.5)], or high-quality blastocyst fraction [37.4 (25.4) control versus 37.4 (26.2) microfluidic sperm preparation, P = 0.985, absolute difference -0.6 95% CI (-6, 5.9)] between groups. There were no differences in the clinical pregnancy or ongoing pregnancy rates between groups. The population studied was inclusive and did not attempt to isolate male factor infertility cases or patients with a history of elevated sperm DNA fragmentation. Microfluidic sperm separation performs similarly to density-gradient centrifugation in sperm preparation for IVF in an unselected population. No external funding to declare. M.P.R. is a member of the Clinical Advisory Board for ZyMōt® Fertility, Inc. NCT03085433. 21 March 2017. 16 June 2017.

Clinical ethics support services during the COVID-19 pandemic in the UK: a cross-sectional survey

BackgroundThe COVID-19 pandemic highlighted the need for clinical ethics support provision to ensure as far as possible fair decision making and to address healthcare workers’ moral distress.PurposeTo describe the availability,...

Cutaneous vascular anomalies associated with a mosaic variant of AKT3: Genetic analysis continues to refine the diagnosis, nomenclature, and classification of vascular anomalies

Cutaneous vascular anomalies associated with a mosaic variant of AKT3: Genetic analysis continues to refine the diagnosis, nomenclature, and classification of vascular anomalies

Addressing Legislation That Restricts Access to Care for Transgender Youth.

* Abbreviations: GAC — : gender-affirmative medical care GnRHa — : gonadotropin-releasing hormone analogue TGD — : transgender and gender-diverse Transgender and gender-diverse (TGD) youth experience barriers to accessing health care and are at risk for poorer overall health compared with cisgender peers. In the last year, dozens of US legislative bills have been proposed to restrict the rights of TGD youth.1 A subset of these bills aims to restrict access to essential treatment of youth diagnosed with gender dysphoria, even when they meet rigorous criteria, as determined by a multidisciplinary evaluation (Table 1).1,2 Other proposed legislation would criminalize clinicians who provide gender-affirmative medical care (GAC) for TGD adolescents, with one bill currently under consideration in Oklahoma classifying providing GAC as a felony punishable by 3 years to life in prison.1 Clinicians and parents fear that legislation eliminating access to GAC will lead to worsening mental health and increased suicidality for their TGD children.3 View this table: TABLE 1 Bills Proposed During the 2021 US State Legislative Session to Date Despite these objections, in December 2020, the Bell versus Tavistock ruling in the United Kingdom mandated … Address correspondence to Jessica Kremen, MD, Division of Endocrinology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: jessica.kremen{at}childrens.harvard.edu

Prognostic Indicators and Outcomes of Hospitalised COVID-19 Patients with Neurological Disease: A Systematic Review and Individual Patient Data Meta-Analysis

Background: Neurological COVID-19 disease has been reported widely, but often without using standard case definitions or detailed diagnostic work up. Several meta-analyses, based on such reports, describe the neurological diagnoses but give little information on outcomes and risk factors.Methods: We conducted an individual patient data meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute, and extracted aggregate data from published reports. We analysed features associated with poor outcome (moderate to severe sequelae or death, 3-6, on the modified Rankin scale) using multivariable models. Findings: We identified 381 studies (31 unpublished) describing 4443 patients with COVID-19 and neurological disease: 83 of these provided IPD for 1979 (45%) patients. Encephalopathy (978 [49%]) and cerebrovascular events (506 [26%]), were the most common diagnoses in the IPD database and aggregate data. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41] overall), and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-Dimer. Overall, 30-day mortality was 30% (27-32). The hazard of death was reduced for patients in the WHO European region, but increased in low- and lower-middle-income countries. Interpretation: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission. Funding This study was funded by the UK Medical Research Council’s Global Effort on COVID-19 Programme (MR/V033441/1); UK National Institute for Health Research (NIHR)-funded Global Health Research Group on Acute Brain Infections (17/63/110); and the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections (NIHR200907), at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (Grant Nos. IS-HPU-1112-10117 and NIHR200907).Declaration of Interests: BS reports a grant from UKRI/DHSC Global Effort on COVID-19 Research (Medical Research Council) and non-financial support from UK National Institute for Health Research Global Health Research Group on Brain Infections. SL and TS are supported by a grant from the EU Zika Preparedness Latin American Network consortium (ZikaPLAN). ZikaPLAN has received funding from the EU's Horizon 2020 research and innovation programme under grant agreement number 734584. LCG reports non-financial support from Pfizer, non-financial support from Gilead. LB reports grants from GlaxoSmithKline, Research England and Wellcome Trust. AMBM reports grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico CNPq/Brazil, and São Paulo Research Foundation FAPESP/Brazil. AP reports personal fees from ZAMBON, UCB , BIOMARIN, and ABBvie pharma. TS was an adviser to the GlaxoSmithKline Ebola Vaccine programme, chaired a Siemens Diagnostics clinical advisory board, and advises the WHO Brain Health Unit Forum on Neurology and COVID-19; TS has also previously filed a patent for a test for bacterial meningitis based on a blood test (GB 1606537.7, April 14, 2016), and has grants from the UK Medical Research Council and National Institute for Health Research. All other authors declare no conflict of interest

COVID-19 as a barrier to attending for gastrointestinal endoscopy: weighing up the risks

COVID-19 as a barrier to attending for gastrointestinal endoscopy: weighing up the risks

The Use of MEK Inhibitors in Neurofibromatosis Type 1-Associated Tumors and Management of Toxicities.

Early‐phase clinical trials using oral inhibitors of MEK, the mitogen‐activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)‐associated tumors, particularly progressive low‐grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side‐effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients.Implications for PracticeNeurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low‐grade gliomas. The use of MEK inhibitors is likely to increase substantially in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1‐related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects.

Contactin-1 Antibodies Link Autoimmune Neuropathies to Nephrotic Syndrome

Background: There is an established association between acquired inflammatory demyelinating neuropathies and nephrotic syndrome, but a common immunopathological mechanism has yet to be determined. Antibodies to known glomerular podocyte antigens occur in up to 90% of patients with nephrotic syndrome due to idiopathic membranous glomerulonephritis (MGN), the majority targeting the phospholipase A2 receptor (PLA2R). In patients with immune-mediated neuropathies, antibodies targeting molecules of the node of Ranvier, such as contactin-1 (CNTN1), are increasingly recognised. Methods: In this study, sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, were tested for CNTN1 antibodies. Topographical binding patterns were determined using teased nerve fibres and live myelinated nerve co-cultures. CNTN1 expression in human kidney was characterised by immunohistochemistry, western blotting and PCR. Findings: A total of 16 patients with an immune-mediated neuropathy and MGN were seropositive for IgG4 anti-CNTN1 antibodies. The onset and resolution of both disorders had a close temporal relationship. The majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Four further patients with isolated MGN were also positive for the same antibodies at lower titres. CNTN1 protein was detected within glomerular deposits in biopsies from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. Interpretation: These data provide evidence that CNTN1 antibodies precipitate both autoimmune neuropathy and MGN. The temporal correlation of these disorders, as well as the presence of CNTN1 protein and antibodies in both peripheral nerve and diseased glomeruli, supports a common antibody-mediated pathological process, and defines a new antigenic target in MGN. CNTN1 antibodies have diagnostic and therapeutic relevance, and may additionally serve as a means of monitoring disease activity in both conditions. Funding Statement: Medical Research Council (MRC), GBS/CIDP Foundation International, MRC and Kidney Research UK. Declaration of Interests: SR runs a not-for-profit diagnostic testing service for nodal/paranodal antibodies. He has received a speaker’s honorarium and/or travel expenses from Fresenius Medical Care, Excemed, Alnylam and argenx. AR has received honoraria from Sarepta, Roche and Sanofi Aventis, is a member of MND Association Clinical Advisory Board, and was a member of NICE MND Guideline Development Group. ASC receives funding from NIHR University College London Hospitals Biomedical research centre. AM is a clinical fellow with grant reference number MR/P001777/1. SPi is was funded by a grant from the Karolinska Institutet during the course of the study. All other authors have nothing to declare. Ethics Approval Statement: Research Ethics Committee approval number 14/SC/0280

Advance care planning for vulnerable older adults within an Accountable Care Organization: study protocol for the IMPACT randomised controlled trial

IntroductionPatients with multimorbidity plus additional impairments (eg, mobility limitations, disability, cognitive impairments or frailty) are at the highest risk for poor healthcare outcomes. Advanced care planning (ACP) provides patients and...

Feasibility and Clinical Outcome Of REBOA in Patients With Impending Traumatic Cardiac Arrest

Introduction: Globally, trauma with massive bleeding is the leading cause of death under the age of 40 years [1]. Those who survive the initial trauma may die within the first few hours because of hemorrhage and cardiac arrest [2]. Hypotension with a decrease in systolic blood pressure (SBP) is a late indicator of shock and occurs when vasoconstriction fails to raise the SBP [3]. Cardiopulmonary resuscitation (CPR) is initiated when the carotid pulse cannot be palpated in an unresponsive patient, in whom SBP would have decreased to 40 mm Hg or less [4]. This does not per se confirm a “true” cardiac arrest but may represent a state of inadequate perfusion with impending cardiac arrest (ICA). If no intervention is performed at this stage, a true cardiac arrest will follow [5, 6]. Resuscitative thoracotomy (RT) is indicated in trauma patients with ongoing CPR (< 15 min) and in patients with profound refractory shock [7]. The aim of the RT is to address intra-thoracic injuries, perform open CPR and compress the thoracic aorta while resuscitating the patient with blood products. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a rapidly evolving technique that can possibly replace the role of RT and temporarily stabilize the hemodynamics of exsanguinating patients [8, 9]. It would, therefore, be of interest to study the subgroup of patients presenting with ICA. We aimed to study the feasibility and clinical outcome of REBOA in patients with ICA using data from the ABOTrauma Registry. Methods: Retrospective and prospective data on the use of REBOA in patients with ICA (SBP ≤40 mmHg upon REBOA inflation) from 16 centers globally were collected and reported to the ABOTrauma Registry. SBP was measured both at pre- and post-REBOA inflation. Data collected included patients' demography, vascular access technique, number of attempts, catheter size, operator, zone and duration of occlusion, and clinical outcome. Results: There were 71 patients in this high-risk patient group. REBOA was performed on all patients, in a majority using a 7Fr catheter placed on the first attempt through blind insertion and inflated in Zone I for a period of 30 to 60 minutes by ER doctors, trauma surgeons or vascular surgeons. SBP significantly improved following the inflation of REBOA and 38% of the patients survived. Conclusion: Our study has shown that REBOA is feasible in patients with ICA, SBP can be elevated in these patients with a 38% survival rate. Disclosure: Author Y. Matsumura is on the clinical advisory board for TOKAII Medical Products.

In Hospital Outcome of CEA And CAS in the German National Carotid Registry 2014-2015

Introduction - The German National Quality Assurance Registry includes the datasets of all procedures (CEA and CAS) performed in German hospitals. The in-hospital outcome is reported by a questionnaire and finally evaluated and monitored by a federal institution (IQTIG) with the assistance of a clinical advisory board. It is the aim of this presentation to report the outcome of CEA vs. CAS as well as of simultaneous procedures combined with cardiac surgery or intracranial endovascular procedures. Methods - Data were collected at discharge on a electronic basis and primarily transferred to local state agencies (n=11) for plausibility check and monitoring. The data sets from 11 agencies were then anonymously compiled and evaluated by a federal institute (IQTIG). The quality of the registry is checked on a yearly basis by random sample analysis of individual charts. Data collection is linked to reimbursement of the procedure. The reports from 2014 and 2015 include the data sets from n= 64.868patients. 12.156 CAS (18,7%) and n=52.712 CEA (81,3%) were performed. 2,3% of CEA and 8,4% of the CAS procedures were special indications, including interventions prior to intracranial interventional procedures or other indications. Emergency procedures were included in the registry (7,44% CEA, 16,98% CAS). Results - 654[KM1] hospitals performed CEA and/or CAS in 2014 and with 648 in 2015). 282 (2015) / 297 (2014)hospitals reported <20 cases CEAs[KM2] per year (51,9% (2015) / 53,1% (2014)). 293 (2015) /280 (2014) hospitals reported < 20 CAS procedures 87,2% (2015) / 85,9% (2014)) The rates of preoperative neurological examination was 68,6% ( CEA) and 79,3% ( CAS, the postoperative rates were 58,2% (CEA) and 71,7% ( CAS). The results for stroke and death were below the AHA limit of 3% for asymptomatic carotid stenosis in both groups, with stroke/death rates of 1.76[KM3] % (2014) and 1.58% (2015) for CAS and 1.12% resp. 1.45% for CEA. In the case of contralateral stenosis the results were: 1.40% resp. 2.77% for CAS and 2.64% resp. 1.61% for CEA. In symptomatic stenosis, stroke/death rates for CAS were 3,5% (2014) and 3.91% (2015). CEA resulted in stroke/death rates of 2.35% resp.2.55%. The ratio observed/expected for severe stroke and death rose from 1.00 to 1.41 in the case of CAS, with values for 1.0 and 1.03 for CEA (2014 vs. 2015). Conclusion - The percentage of CAS (18% ) in the population did not change in the last two years. Both methods resulted in acceptable results for treatment of asymptomatic stenosis on a national scale. Risk adjustement was done to make individual hospitals comparable. There were differences in indications: CAS was more often used in acute stroke and in combination with intracranial procedures. CEA was also performed in combination with ACBG; the results of simultaneous ACBG and CEA were poor and reached unacceptable high stroke/death rates. The interpretation of these registry data is somewhat limited due to missing follow-up data as well as due to the fact the the data sets were pooled, and therefore a detailed statistical comparison was not possible.

Flotetuzumab, an Investigational CD123 x CD3 Bispecific Dart® Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients

Flotetuzumab, an Investigational CD123 x CD3 Bispecific Dart® Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients

Engagement in Cognitive-Behavioral Therapy for Chronic Pain Management Is Associated with Reductions in Healthcare Utilization in Pediatric Sickle Cell Disease

Introduction: Chronic pain in sickle cell disease (SCD) is a multifactorial complication that can contribute to high healthcare utilization. Multidisciplinary treatments going beyond medication alone are needed for the most effective chronic pain management. Cognitive-behavioral therapy (CBT) is effective for youth with chronic pain and focuses on improving daily functioning and coping, but the clinical effectiveness for chronic SCD pain has not been evaluated. This study examined changes in healthcare use over time for youth with chronic SCD pain who participated in CBT compared to controls with chronic SCD pain who never initiated CBT. Methods: Youth receiving care at comprehensive SCD clinics at three tertiary care locations at Children's Healthcare of Atlanta were included if they were aged 6-18 years, any SCD genotype, and referred to a pediatric psychology outpatient clinic for chronic pain management from November 2014-March 2018. Youth were excluded if they received bone marrow transplantation during the study period, had ongoing CBT past the study period, or were not actively followed for ≥1 year of medical care pre- or post-CBT. Patients were grouped based on therapy attendance: Established Care (i.e., attended ≥3 CBT sessions within 3 consecutive months); Early Termination (i.e., attended &amp;lt;3 CBT sessions within 3 consecutive months); or Control (i.e., did not attend any CBT visits). Patient-reported outcomes included typical pain intensity, functional disability, and coping efficacy at pre- and post-treatment. Healthcare utilization outcomes were abstracted from electronic medical records including: number of inpatient admissions for pain, total inpatient days for pain, and emergency department dependency ratio (EDR; ratio of ED visits to sum of ED and outpatient visits). For the treatment groups, utilization outcomes were calculated from 12-months prior to the first CBT visit, and from 12-months following the last CBT visit. For the control group, outcomes were calculated for 12-months prior to the referral date, and from 12-months following the average duration of CBT for treatment groups (i.e., 3.5 months) to account for passage of time. Changes over time in inpatient admissions, hospital days, and EDR were evaluated separately using linear mixed effect models with a random effect for person-specific intercepts and slopes, which were retained based on model contribution determined by Bayesian Information Criterion. Time, patient characteristics, SCD-modifying treatments, therapy attendance, number of CBT sessions, and interaction effects were initially included in the models; the most parsimonious models were chosen based on backward selection. Results: At time of referral, youth (n=101) were on average (M) 13.4 years old (SD=2.92), 56.4% female, 68.1% HbSS or HbSβ0, 63.9% prescribed hydroxyurea, and 12.6% received chronic transfusions. The Control (n=44) and Treatment Groups (n=57) did not significantly differ by age, sex, genotype, or treatment with hydroxyurea or chronic transfusion. Based on therapy attendance, 36.1% Established Care, 21.8% were Early Termination, and 42% Controls. Adjusting for age, genotype, and hydroxyurea, patients who terminated CBT early had increased admissions and total hospital days over time compared to controls; those who established care had a reduction in admissions and hospital days over time compared to controls (F's=3.27-3.61, p's&amp;lt;.05). EDR decreased by 0.1 over time for Established Care; for every 1 completed CBT session, EDR was further reduced by 0.01 (p&amp;lt;.05). Patients who completed CBT (n=18) reported decreases in typical pain intensity (Mpre= 5.47, SD=2.24; Mpost=3.76, SD=2.84; p&amp;lt;.01), functional disability (Mpre=26.24, SD=8.45; Mpost=15.18, SD=10.85; p&amp;lt;.001), and improved coping efficacy (Mpre=8.0, SD=2.21; Mpost=9.65, SD=2.94; p&amp;lt;.05) from pre- to post-treatment. Conclusions: Establishing care in CBT may support reductions in admissions for pain, length of stay, and ED dependency for youth with chronic SCD pain beyond the potential effects of age, genotype, and SCD-modifying treatments. Reductions in utilization may be partially supported by patient-reported improvements in functioning, coping, and lower pain intensity following CBT. Reducing barriers to access and enhancing clinical implementation of multidisciplinary treatments may optimize the health of youth with chronic SCD pain. Disclosures Lane: NHLBI: Research Funding; CDC: Research Funding; GA Dept: Other: Contract for newborn screeninjg follow-up services services; Bio Products Laboratory: Other: Sickle Cell Advisory Board; FORMA Therapeutics: Other: Clinical Advisory Board. Dampier:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Micelle BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Consultancy; Epizyme: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Katz Foundation: Research Funding; Modus Therapeutics: Consultancy; NIH: Research Funding; Merck: Research Funding.

Safety of Intravenous Arginine Therapy in Children with Sickle Cell Disease Hospitalized for Vaso-Occlusive Pain: A Randomized Placebo-Controlled Trial in Progress

Safety of Intravenous Arginine Therapy in Children with Sickle Cell Disease Hospitalized for Vaso-Occlusive Pain: A Randomized Placebo-Controlled Trial in Progress

Social Vulnerability Is Associated with Emergency Department Dependency in Pediatric Sickle Cell Disease Patients

Background: Sickle cell disease (SCD) is a complex genetic disorder characterized by significant, largely unpredictable heterogeneity in disease severity and healthcare utilization. The contribution of socioeconomic status (SES) and other environmental factors to this heterogeneity is poorly understood. In other disorders, SES is a major influence on healthcare quality and access, which can be affected by financial status, social stability, transportation, household overcrowding, and other variables. The multiplicative nature of these factors limits the ability to incorporate them in a single measure. The Social Vulnerability Index (SVI) was created by CDC to assist disaster management officials in identifying the locations of their most socially vulnerable populations (https://svi.cdc.gov/). SVI combines many of the SES factors that may contribute to disease severity and healthcare utilization. SVI has previously been validated for use assessing chronic conditions such as asthma, youth inactivity, and BMI. Thus, we hypothesized that SVI is associated with SCD-related severity and utilization. This analysis explores the relationship between census tract level social vulnerability and healthcare utilization in pediatric SCD patients. Methods: The Children's Healthcare of Atlanta's (CHOA) SCD Clinical Database houses a large, population-based cohort of pediatric sickle cell patients. It includes laboratory-confirmed SCD genotype, treatment history, and healthcare utilization for over 3,500 patients from 2010-2018. The database was queried for patients who had ≥1 SCD-related healthcare encounter from 2016-2018 and whose most recent address was in a metro Atlanta county. Addresses were geocoded and matched to CDC's SVI at the census tract level. The SVI combines 15 measures from the US Census and groups them into four related themes - SES, Household Composition &amp; Disability, Minority Status &amp; Language, and Housing &amp; Transportation , which are combined into a percentile ranking of overall social vulnerability ranging from 0 (lowest) to 1 (highest). Patients were categorized by sickle cell anemia (SCA) genotypes (SS or Sβ0 Thalassemia) vs. other. Healthcare utilization was used to calculate the emergency department dependency ratio (EDR, ratio of ED visits to sum of ED and SCD clinic visits) and total inpatient days for acute illness as a measure of disease severity. As reported in previous studies, EDR was classified as high (&gt;=0.33) or low (&lt;0.33). SVI, age, and annual inpatient days were included as continuous variables. A logistic regression model was used to assess the relationship between SVI and EDR. SCA vs. other SCD genotypes, age, and total inpatient days were included as covariates and a backwards selection was used to find the best model. Results: Of the 2,578 active patients from 2016 to 2018, 1,328 met inclusion criteria. Mean age at the end of each measurement year was 10.0 years (SD=5.6), 47.7% were female, and 62.0% had SCA genotypes. Average inpatient days was 3.2 (SD=8.3). Average SVI was 0.50 (SD=0.28) and average EDR was 0.29 (SD=0.29); 44.8% of which were classified as high. All covariates were significant in the multivariate model. In the crude model, SVI was significantly associated with high EDR (OR=2.08, 95% CI: 1.62, 2.66). After controlling for inpatient length of stay, age, and genotype, SVI remained positively associated with high EDR (OR=1.85, 95% CI: 1.41, 2.44). Of the covariates, total hospital days (OR=1.28, 95% CI: 1.25, 1.32) was associated with a higher EDR. Older age (OR=0.97, 95% CI (0.96, 0.99) and SCA genotype (OR=0.41, 95% CI: 0.35-0.48), were negatively associated with high EDR. After controlling for SCA genotype, age, and length of stay, a 1 unit increase in SVI was associated with 85% greater odds of having a high EDR. Conclusions: The analysis demonstrates a significant relationship between SVI and EDR. Further analyses will assess the effect of distance to emergency department, treatment with hydroxyurea or chronic transfusions, and individual themes within SVI to further elucidate this relationship. A limitation of this analysis is that encounters were limited to those occurring at a CHOA facility. Overall, the results support our hypothesis that high social vulnerability is associated with increased reliance on the emergency department for care and that SVI may be a predictor of disease severity and increased healthcare utilization. Disclosures Lane: NHLBI: Research Funding; CDC: Research Funding; GA Dept: Other: Contract for newborn screeninjg follow-up services services; Bio Products Laboratory: Other: Sickle Cell Advisory Board; FORMA Therapeutics: Other: Clinical Advisory Board.

A Phase 1 Study of Flotetuzumab, a CD123 x CD3 DART® Protein, Combined with MGA012, an Anti-PD-1 Antibody, in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background Acute myeloid leukemia (AML) blasts and leukemic stem and progenitor cells typically express higher levels of CD123 than their normal hematopoietic stem cell counterparts, making CD123 an attractive target. Leukemic CD123 expression is associated with poor prognosis, high-risk disease, and increased risk of induction failure (Vergez et al 2011). Single-agent flotetuzumab, an investigational CD123 x CD3 bispecific DART protein, has shown evidence of clinical activity in a Phase 1 study of relapsed/refractory (R/R) acute myeloid leukemia (AML). In this study, flotetuzumab led to T-cell activation which in turn was associated with PD-1 induction on T lymphocytes, enhanced IFNɣ secretion, and upregulation of PD-L1 expression by AML blasts (ASH 2018 Rutella, ASH 2018 Uy). In vitro studies have shown synergistic T-cell mediated cytotoxicity of an AML cell line (KG1A) with flotetuzumab in the presence of PD-1/PD-L1 axis blockade compared to flotetuzumab alone. MGA012, also known as INCMGA00012, is an investigational anti-PD-1 antibody that has shown clinical activity in a Phase 1 study (SITC 2018 Mehnert). We hypothesize that combined checkpoint inhibition with MGA012 together with redirected T‐cell killing of CD123+ cells with flotetuzumab may show enhanced activity over flotetuzumab alone. Methods This is a Phase 1 dose escalation study designed to characterize the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD) or maximum administered dose (if no MTD is defined), pharmacokinetics, and preliminary anti-leukemic activity of flotetuzumab in combination with MGA012, each administered intravenously (IV) in patients with R/R AML. Response evaluation will be determined by modified ELN 2017 criteria. Activity is measured by complete response (CR) (complete remission [CR], or CR with partial hematologic recovery [CRh], or CR with incomplete hematological recovery [CRi], or morphologic leukemia-free state [MLFS]) rate, relapse-free survival, or mortality rate at 1 and 3 months. The impact of flotetuzumab/MGA012 combination on overall survival and event-free survival will be explored. Eligible patients will consist of adults with relapsed or refractory AML (any subtype except acute promyelocytic leukemia) who have exhausted standard of care options. In Induction Cycle 1, patients will be treated with a step-up lead in dose of flotetuzumab, followed by continuous infusion flotetuzumab, starting at week 2 of Cycle 1 and continuing through each 28-day cycle. MGA012 will be administered every two weeks. Depending on response, patients will transition to either consolidation or second induction. Eligible patients who achieve CR/CRh/CRi can receive maintenance MGA012 alone for up to 12 months. Disclosures Wei: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria. Fong:Novartis: Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Astellas: Consultancy. Montesinos:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Gil:Jazz Pharmaceuticals: Honoraria; Gilead: Honoraria; Daiichi-Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Abbvie: Honoraria. Perez De Oteyza:Celgene: Speakers Bureau. Rowe:BioSight: Consultancy. Wolach:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker. Sun:MacroGenics, Inc.: Employment, Equity Ownership. Baughman:MacroGenics, Inc.: Employment, Equity Ownership. McNulty:MacroGenics, Inc.: Employment, Equity Ownership. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Wigginton:Western Oncolytics: Other: clinical advisory board; MacroGenics, Inc.: Employment, Equity Ownership. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership.