Translational Study of Copy Number Variations in Schizophrenia

Rare copy number variations (CNVs) are part of the genetics of schizophrenia; they are highly heterogeneous and personalized. The CNV Analysis Group of the Psychiatric Genomic Consortium (PGC) conducted a large-scale analysis and discovered that recurrent CNVs at eight genetic loci were pathogenic to schizophrenia, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.23, 15q13.3, distal 16p11.2, proximal 16p11.2, and 22q11.2. We adopted a two-stage strategy to translate this knowledge into clinical psychiatric practice. As a screening test, we first developed a real-time quantitative PCR (RT-qPCR) panel that simultaneously detected these pathogenic CNVs. Then, we tested the utility of this screening panel by investigating a sample of 557 patients with schizophrenia. Chromosomal microarray analysis (CMA) was used to confirm positive cases from the screening test. We detected and confirmed thirteen patients who carried CNVs at these hot loci, including two patients at 1q21.1, one patient at 7q11.2, three patients at 15q13.3, two patients at 16p11.2, and five patients at 22q11.2. The detection rate in this sample was 2.3%, and the concordance rate between the RT-qPCR test panel and CMA was 100%. Our results suggest that a two-stage approach is cost-effective and reliable in achieving etiological diagnosis for some patients with schizophrenia and improving the understanding of schizophrenia genetics.

Acute Burn Treatment and History of Drug and Alcohol Addiction: Treatment Outcomes and Opioid Use

Treating pain in burn patients with a history of opioid or drug abuse is challenging. There is no consensus on pain management for burn patients with a history of drug usage. Our aim was to study the association of previous drug addiction and the treatment of acute burn patients, focusing on daily morphine milligram equivalent (MME) requirements and outcomes. We compared patients with (group 1) and without (group 2) a drug addiction history who were admitted to an American Burn Association verified burn center using the Premier database from 2013 to 2018 (n = 3046). Primary outcome was daily MME usage. Secondary outcomes included mortality, expected mortality rate, length of stay (LOS), and number of surgeries. Linear regression was performed to predict MME usage. In total, 16.6% of patients had history of drug abuse. In unadjusted analysis, group 1 had more males (68.1% vs. 57.3%, p < 0.001) and was younger (median 47 vs. median 53, p < 0.001) compared to group 2. In the adjusted analysis, group 1 required 84.1 additional daily MME usage than group 2 (p < 0.01). Drug addiction was associated with an increased number of surgeries, LOS, and higher daily MME usage. Patients with a history of drug usage required almost 60 mg of additional oxycodone per day.

Neural Decoding of EEG Signals with Machine Learning: A Systematic Review

Electroencephalography (EEG) is a non-invasive technique used to record the brain’s evoked and induced electrical activity from the scalp. Artificial intelligence, particularly machine learning (ML) and deep learning (DL) algorithms, are increasingly being applied to EEG data for pattern analysis, group membership classification, and brain-computer interface purposes. This study aimed to systematically review recent advances in ML and DL supervised models for decoding and classifying EEG signals. Moreover, this article provides a comprehensive review of the state-of-the-art techniques used for EEG signal preprocessing and feature extraction. To this end, several academic databases were searched to explore relevant studies from the year 2000 to the present. Our results showed that the application of ML and DL in both mental workload and motor imagery tasks has received substantial attention in recent years. A total of 75% of DL studies applied convolutional neural networks with various learning algorithms, and 36% of ML studies achieved competitive accuracy by using a support vector machine algorithm. Wavelet transform was found to be the most common feature extraction method used for all types of tasks. We further examined the specific feature extraction methods and end classifier recommendations discovered in this systematic review.

Circulating Lipopolysaccharides and Impaired Antioxidant Status in Patients With Atrial Fibrillation. Data From the ATHERO-AF Study

Objectives: Atrial fibrillation (AF) is characterized by an oxidative imbalance, which is associated with an increased risk of cardiovascular events (CVEs). It is unclear whether low grade endotoxemia may contribute to the impaired antioxidant status in AF patients. We investigated the relationship between circulating lipopolysaccharides (LPS) and antioxidant status in AF patients.Patients and Methods:Post-hoc analysis from the ongoing prospective observational cohort ATHERO-AF study including 907 patients. Antioxidant status was evaluated by the activity of glutathione peroxidase 3 (GPx3) and superoxide dismutase (SOD). Patients were divided into two groups to evaluate the risk of CVEs: (1) LPS below median and GPx3 above median (n = 254); (2) LPS above median and GPx3 below median (n = 263).Results: The mean age was 73.5 ± 8.3 years, and 43.1% were women. Median LPS and GPx3 were 50.0 pg/ml [interquartile range (IQR) 15–108] and 20.0 U/ml (IQR 10.0–34.0), respectively. Patients of Groups 2 were older, with a higher prevalence of heart failure. LPS above the median was associated with reduced GPx3 [Odds Ratio for LPS 1.752, 95% Confidence Interval (CI) 1.344–2.285, p &lt; 0.001] and SOD (OR 0.525, 95%CI 0.403–0.683) activity after adjustment for CHA2DS2VASc score. In a mean follow-up of 54.0 ± 36.8 months, 118 CVEs occurred, 42 in Group 1 and 76 in Group 2 (Log-Rank test p = 0.001). At multivariable Cox regression analysis, Group 2 was associated with a higher risk of CVEs [Hazard Ratio (HR) 1.644, 95%CI 1.117–2,421, p = 0.012], along with age ≥ 75 years (HR 2.035, 95%CI 1.394–2.972, p &lt; 0.001), diabetes (HR 1.927, 95%CI 1.280–2.900, p = 0.002), and previous cerebrovascular disease (HR 1.895, 95%CI 1.251–2.870, p = 0.003) and previous cardiovascular disease (HR 1.708, 95%CI 1.149–2.538, p = 0.008).Conclusions: Our study indicates that circulating LPS may contribute to impaired antioxidant status in patients with AF. Patients with coincidentally high LPS and reduced GPx3 activity showed the highest risk of CVEs.

Cost Effectiveness Analysis of Venetoclax Plus Azacitidine Versus Azacitidine in Newly Diagnosed Adult Patients with Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy from a United States Payer Perspective

Background: The phase 3 VIALE-A trial (NCT02993523) demonstrated that venetoclax plus azacitidine (VEN+AZA) improved overall survival (OS) and led to higher remission rates compared with AZA monotherapy, in patients with newly diagnosed (ND) acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Based on the results from VIALE-A, VEN+AZA received full United States (US) Food and Drug Administration approval in October 2020 for patients with ND AML aged ≥75 years, or who were ineligible for intensive induction chemotherapy due to comorbidities. This study aims to assess the long-term cost-effectiveness value of the VEN+AZA regimen from the VIALE-A trial from a US third-party payer perspective. Methods: A partitioned survival model with a 28-day cycle was developed to estimate costs and outcomes of treatment with VEN+AZA vs. AZA among patients with ND AML, who are ineligible for intensive chemotherapy, over a lifetime time horizon. The model included three health states: event-free survival (EFS), progressive/relapsed disease, and death. Within the EFS state, patients were further partitioned into time spent in complete remission (CR) or CR with incomplete marrow recovery (CRi), and time spent in non-CR/CRi. Efficacy inputs (OS, EFS, and CR/CRi rate) for both treatment arms were estimated using VIALE-A data. Best-fit parametric models per Akaike information criterion (AIC) were used to extrapolate OS until it reached EFS, and extrapolate EFS for each treatment until Year 5. Patients who remained in EFS after Year 5 were considered cured, and were assumed to have the same mortality as the US general population. Mean time on treatment (ToT) for both regimens was based on the time observed in VIALE-A. The costs for drug acquisition, drug administration for initial and subsequent treatments, subsequent stem cell transplant procedures, adverse events (AEs), and healthcare resource utilization (HRU) associated with each health state were obtained from the literature or publicly available data. All costs were inflated to 2021 US dollars. Utilities for each health state were estimated using EuroQol-5 dimension-5 level (EQ-5D-5L) data from VIALE-A, based on the US crosswalk value set. Information on disutilities due to Grade 3/4 AEs were obtained from the literature. Incremental cost-effectiveness ratios (ICERs) per life year (LY) and quality-adjusted life year (QALY) gained were estimated. Deterministic sensitivity analyses (DSA), scenario analyses and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of the results. Results: Over a lifetime time horizon, compared with AZA, VEN+AZA was associated with an increase of 1.89 LYs (1.10 vs. 2.99, respectively) and 1.45 QALYs (0.84 vs. 2.30, respectively). Patients in the VEN+AZA arm incurred higher total costs ($250,486 vs. $110,034 for patients in the AZA arm). The ICER for VEN+AZA vs. AZA was estimated to be $74,141 per LY gained, and $96,579 per QALY gained. Results from the DSA and scenario analyses supported the base-case findings, with ICERs ranging from $60,922 to $138,554 per QALY gained. The results were most sensitive to alternative approaches for ToT estimation, subsequent treatment HRU costs, cure time point, and the extrapolation approach for EFS. Results from PSA showed that compared with AZA, VEN+AZA was cost-effective in 99.9% of cases at a willingness-to-pay (WTP) threshold of $150,000. Conclusions: Compared with AZA monotherapy, VEN+AZA results in a favorable ICER of $96,579 per QALY gained over a lifetime time horizon. The base-case results suggest that, compared with AZA, VEN+AZA is a cost-effective strategy based on a WTP threshold of $150,000 per QALY gained. Sensitivity analyses support the base-case results. Thus, VEN+AZA offers a cost-effective strategy in the treatment of patients with ND AML who are ineligible for intensive chemotherapy from a US third-party payer perspective. Disclosures Pratz: Agios: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; University of Pennsylvania: Current Employment; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding. Chai: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Yin: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Nie: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Montez: Genentech, Inc: Current Employment, Other: May hold equity. Iantuono: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Downs: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Ma: Genentech, Inc.: Current Employment, Other: May hold equity.

Treatment Patterns and Outcomes of Patients with Double-Class Refractory or Triple-Class Refractory Multiple Myeloma: A Retrospective US Electronic Health Record Database Study

Introduction: Patients with relapsed/refractory multiple myeloma (RRMM) resistant to multiple drug classes remain a high unmet need population, despite advances in MM patient care. The objective of this study was to assess real-world treatment patterns and outcomes in patients with RRMM who had failed multiple prior lines of therapy (LOT) and were refractory to multiple drug classes to identify gaps in their treatment pathways. Methods: This longitudinal retrospective cohort study utilized the COTA de-identified real-world database derived from US electronic health records of partnered healthcare providers from Q3 1988 through Q1 2020. Adults with active RRMM previously exposed to a proteasome inhibitor (PI) and an immunomodulatory drug and who received ≥3 prior LOTs were identified. Patients were further categorized as refractory to a PI and an immunomodulatory drug (double-class refractory [DCR]) or additionally to an anti-CD38 monoclonal antibody (i.e. daratumumab; triple-class refractory [TCR]). Determining refractory status was based on International Myeloma Working Group criteria. Index LOT was a new LOT after evidence of DCR or TCR status following ≥3 (DCR) or ≥4 (TCR) prior LOTs. Patient characteristics described included Eastern Cooperative Oncology Group (ECOG) performance status, International Staging System (ISS) stage, cytogenetic risk, age, index date, sex, and follow up time. Treatment pattern assessments included treatments received before/during/after index LOT, reasons for discontinuation, refractory status, and retreatment characteristics. Patient outcomes (overall survival [OS], duration of treatment [DOT], and time to next therapy [TTNT]) were analyzed using Kaplan-Meier survival analysis methods. Results: After excluding patients who were aged &lt;18 years at start of index LOT with no evidence of clinical activity and who participated in a clinical trial during index LOT, 381 (DCR) and 173 (TCR) patients were available for analysis. Median follow-up from index LOT initiation through end of data availability/death was 14 (DCR) and 8 (TCR) months. Demographic characteristics were consistent between DCR and TCR patients. Approximately half were aged ≥65 years (49% DCR; 53% TCR), majority had high-risk cytogenetics (56% DCR; 66% TCR) or prior autologous stem cell transplantation (&gt;62%), and 14-16% had ISS stage III. Patients had a median of 3 (DCR) and 6 (TCR) prior LOTs. Prior to index LOT, bortezomib and lenalidomide were the most commonly received PI and immunomodulatory drug (received by &gt;98% of DCR or TCR patients) and the most common PI and immunomodulatory drugs to which patients were refractory (71% and 84% DCR; 76% and 83% TCR, respectively). At index LOT, PI/immunomodulatory drug-based and daratumumab-based therapies remained the most common therapies. Bortezomib and lenalidomide had the longest time to refractory status and highest retreatment rates among DCR or TCR patients. Approximately 40% of TCR patients were retreated with daratumumab-based therapies after becoming refractory (Table). After index LOT, 70% of DCR and 58% of TCR patients continued to a subsequent LOT. Patients most frequently discontinued index LOT due to disease progression (59% DCR; 60% TCR), toxicity (23% DCR; 25% TCR), or doctor preference (14% DCR; 10% TCR). Median duration of gaps between LOTs generally were shorter than 1 month (Table). Median OS was 22.3 (DCR) and 11.6 (TCR) months. Median DOT was 3.3 (DCR) and 2.8 (TCR) months, and median TTNT was 4.1 (DCR) and 3.2 (TCR) months. In multivariate statistical analyses, inferior baseline ECOG performance scores, and high-risk cytogenetic abnormalities were associated with worse prognosis (higher risk of death, shorter DOT, and shorter TTNT) in DCR and TCR patients. Age was not a significant factor after adjusting for other baseline factors. Conclusions: Treatment options are limited for US patients with DCR and TCR RRMM. DCR and TCR patients were frequently retreated with a PI, an immunomodulatory drug, or daratumumab, despite refractoriness to these agents. Many DCR and TCR MM patients stopped active MM treatment after discontinuing index treatment. Patients with DCR and TCR MM have poor prognosis, especially among high cytogenetic risk and poor performance status patients. This study provides the benchmark for new therapies, like BCMA-targeted agents, to be tested in this population. Funding: GSK (Study 217353). Figure 1 Figure 1. Disclosures Wang: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gorsh: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. DerSarkissian: Analysis Group, Inc.: Current Employment. Paka: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Bhak: Analysis Group, Inc.: Current Employment; GlaxoSmithKline: Research Funding. Boytsov: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Zichlin: GlaxoSmithKline: Research Funding; Analysis Group, Inc.: Consultancy, Current Employment. Sansbury: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Yee: Analysis Group, Inc.: Current Employment; GlaxoSmithKline: Research Funding. Ferrante: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Khanal: GlaxoSmithKline: Research Funding; Analysis Group, Inc.: Current Employment. Noman: Analysis Group, Inc.: Current Employment; GlaxoSmithKline: Research Funding. Duh: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study..

Time and Personnel Costs Associated with Adverse Event (AE) Management Among Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Acalabrutinib, Ibrutinib, or Venetoclax

Introduction Guidelines recommend chemoimmunotherapy and novel agents such as Bruton's tyrosine kinase inhibitors and B-cell lymphoma 2 inhibitors for the treatment of CLL. AE profiles differ across therapies, and management of AEs in patients with CLL treated with novel agents incurs burden on healthcare professionals (HCPs) and oncology practices. Time and personnel costs associated with AE management are not well understood for patients with CLL and are overlooked while assessing the value of oncology drugs. To assess practice burden, this study quantified HCP time and personnel costs related to AE management for patients with CLL who received a novel agent, either acalabrutinib, ibrutinib, or venetoclax. Methods HCPs (i.e., oncologists, pharmacists, physician assistants, nurse practitioners, and registered nurses) who actively treated ≥5 patients with CLL during the past year with &gt;1 patient receiving acalabrutinib, ibrutinib, or venetoclax in the past month were recruited through a physician panel vendor to participate in a longitudinal, observational, prospective survey. This study was conducted in two phases (November 2020-January 2021; April-June 2021). Over the 2-month data collection period, HCPs reported on a daily basis the time spent performing AE management activities for CLL patients receiving a novel agent, which included 1) interactions with patients in-person or via remote consultation (telephone, video, or email), 2) interactions with other HCPs, and 3) other management activities that did not include interactions with patients or other HCPs (e.g., recording notes in patient's charts, ordering lab tests). Mean time and personnel costs per AE management activity were summarized using descriptive statistics. Personnel costs (USD) were calculated by multiplying median wage information reported by the ureau of Labor Statistics Occupational Employment Statistics survey by HCP-reported time spent managing AEs. Results Among 49 HCPs enrolled in the survey, 36 (73%; Table 1) reported managing ≥1 AE during a total of 1,106 AE management activities (229 for acalabrutinib; 500 for ibrutinib; 377 for venetoclax) for 421 patients with CLL during the 2-month study period. Among all patients, 108 (26%), 186 (44%), and 129 (31%) received acalabrutinib, ibrutinib, or venetoclax in any line, respectively (Table 2). Anemia was the most frequently managed AE reported among all patients (19%), but differed by treatment: 11%, 19%, and 26% for patients treated with acalabrutinib, ibrutinib, and venetoclax, respectively (Table 2). Other AEs reported among ≥10% of patients with a reported AE management activity also differed by treatment. For acalabrutinib, this included only headache. For both ibrutinib and venetoclax patients, thrombocytopenia, diarrhea, and myalgia were managed in ≥10% of patients. For venetoclax patients, back pain and arthralgia were also managed in ≥10% of patients. Mean (standard deviation [SD]) time spent managing AEs per activity was 11.8 (7.7) minutes (min) overall, 12.1 (7.4) min for acalabrutinib, 11.6 (6.9) min for ibrutinib, and 11.8 (8.9) min for venetoclax (Table 3). Mean time per AE management activity was numerically similar across the three treatments overall and stratified by type of HCP, treatment duration, and line of therapy. We noted differences in the type of HCP managing AEs by treatment, with a lower proportion of oncologists managing acalabrutinib AEs compared to the other two therapies. Corresponding mean (SD) personnel costs per AE management activity were $16.0 ($10.6) overall, and $14.4 ($9.8) for acalabrutinib, $16.3 ($9.8) for ibrutinib, and $16.7 ($11.9) for venetoclax. Conclusions This study demonstrates the importance of accounting for time and labor costs related to AE management, as results suggest that the burden to HCPs related to AE management for patients with CLL treated with acalabrutinib, ibrutinib, and venetoclax is substantial. During the 2-month study period, almost three-quarters of HCPs reported managing ≥1 AEs and an average of 12 AE management days was observed across these HCPs. While mean time and personnel costs were similar, differences in types of AE and types of HCPs managing AEs were observed across treatments. Future research should confirm our observed differences in types of AE and types of HCPs managing AEs by treatment to comprehensively assess the burden of managing AEs for patients with CLL. Figure 1 Figure 1. Disclosures Wahlstrom: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. DerSarkissian: Analysis Group, Inc.: Current Employment. Kunzweiler: Apellis: Other: Employee of Analysis Group, Inc., Research Funding. Castriota: Analysis Group, Inc.: Ended employment in the past 24 months. Chang: Analysis Group, Inc.: Current Employment. Cheung: Analysis Group, Inc.: Ended employment in the past 24 months. Gu: Analysis Group, Inc.: Current Employment. Guo: Analysis Group, Inc.: Current Employment. Duh: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study.. Ryan: AstraZeneca: Current Employment, Current equity holder in publicly-traded company.

Treatment Patterns and Economic Burden Among Elderly Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents: A SEER-Medicare Analysis

Introduction: Previously, we assessed the economic burden of newly diagnosed acute myeloid leukemia (AML) among Medicare patients and found that the economic burden of relapse is high, at approximately 1.2 and 1.6 times the monthly per-patient costs associated with early and late post-remission therapy, respectively (Tabah A, et al. Blood 2020:136(suppl 1):45). A notably high proportion of patients (55%) received ≥ 1 cycle of a hypomethylating agent (HMA). Therefore, the objective of this study was to assess the economic burden of AML among a subgroup of elderly patients who received only HMA monotherapy during induction and then achieved disease remission. Healthcare resource utilization (HCRU) and costs associated with various phases (ie, induction, post-remission therapy, and post-relapse) were assessed. Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, which comprised Medicare claims (parts A, B, and D from 2007 through 2016) and the US National Cancer Institute's SEER database (cancer diagnoses from 2007 to 2015). Included patients had an AML diagnosis in the SEER registry, were ≥ 65 years of age at the AML diagnosis date, had initiated HMA (and no other active treatment) in the outpatient (OP) setting during the first induction cycle post-AML diagnosis, and had an International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) diagnosis code for AML remission following the initiation of induction therapy. Patients were excluded if they had another blood malignancy (including a history of myelodysplastic syndromes), had received hematopoietic stem cell transplantation, or were enrolled in a clinical trial. The induction therapy period was defined as the first initiation of HMA post diagnosis (index date) to the end of the cycle during which a patient had a code for AML remission. The 6-month period prior to the index date was defined as the baseline period. The post-remission phase ended at the earliest of relapse or end of follow-up (ie, death, end of eligibility, or end of available data [December 31, 2016]). The post-relapse phase was from the date of first AML relapse ICD-9/10 code after remission to the end of follow-up. Patient characteristics during the baseline period were summarized descriptively. HCRU and costs (adjusted to 2019 US dollars) associated with induction and post-remission therapy were assessed during days that were part of a treatment cycle. The average per-patient monthly HCRU and costs were reported for the induction, post-remission, and post-relapse phases. Results: A total of 71 patients with newly diagnosed AML (azacitidine: n = 31; decitabine: n = 40) received HMA induction therapy and achieved remission. The median age at AML diagnosis was 78.8 years, 50.7% of patients were male, and 85.9% were White. The mean ± standard deviation (median) time from index date to the end of follow-up was 16.0 ± 12.3 (14.0) months. A total of 63.4% of patients (n = 45) received post-remission therapy. Among all patients, 43.7% relapsed and 85.9% died by the end of follow-up. OP visits were the most common type of visit across all phases with 95.6% of patients having ≥ 1 OP visit during post-remission therapy and 83.9% during the post-relapse phase. Inpatient (IP) visits were highest in the post-relapse phase with 77.4% of patients having ≥ 1 IP visit. The monthly mean per-patient healthcare costs were highest for the post-relapse phase, followed by post-remission therapy, and induction (Table). Costs associated with the OP setting were the greatest contributor to the induction costs (48.9%) while costs associated with the IP setting were the drivers of the costs in the post-remission therapy (56.2%) and post-relapse (72.8%) phases. Conclusions: The economic burden of AML treated with HMA induction therapy was highest in the post-relapse phase, at approximately 1.7 and 1.6 times the monthly per-patient costs during the induction and post-remission therapy phases, respectively. In addition, IP costs made up nearly two-thirds of total monthly per-patient costs in the post-relapse phase, up from approximately 44% and 56% of the induction and post-remission therapy phases, respectively. Treatment options that extend the post-remission phase would reduce the high economic burden associated with AML relapse. Figure 1 Figure 1. Disclosures Brunner: Celgene, Forty Seven Inc, Jazz: Other: Advisory Board; Novartis, Celgene, Takeda, AstraZeneca: Research Funding. Huggar: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Copher: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zhou: Sanofi: Research Funding; Analysis Group: Current Employment, Other: Employee of Analysis Group which received consulting fees for this project . Zichlin: Analysis Group, Inc.: Consultancy, Current Employment; GlaxoSmithKline: Research Funding. Anderson: Analysis Group, which received consultancy fees from GSK: Consultancy, Current Employment. Downes: nalysis Group (employment), Bristol Myers Squibb (consultancy): Consultancy, Current Employment. McBride: BMS: Current Employment.

Real-World Ravulizumab Dosing Patterns Among Patients with Paroxysmal Nocturnal Hemoglobinuria in a US Population

Introduction: Current management of patients diagnosed with paroxysmal nocturnal hemoglobinuria (PNH) includes C5 complement inhibitors such as ravulizumab. The ravulizumab dosage regimen varies by patient body weight and consists of a single loading dose followed by maintenance doses administered every 8 weeks via intravenous infusion (see Table for label-recommended loading and maintenance dosing regimens by patient body weight category). Given its recent 2018 FDA approval, real-world data on the dosing patterns of ravulizumab are limited. This study investigated the real-world dosing patterns of patients with PNH treated with ravulizumab in a large US population. Methods: This retrospective longitudinal cohort study was conducted using provider-based claims data from the Symphony Health Integrated Dataverse ® (IDV). Patients were ≥12 years of age and received ≥2 infusions of ravulizumab between June 21, 2019 and May 6, 2021. The index date was defined as the 1st medical claim for ravulizumab infusion with ≥6 months of continuous clinical activity prior to the index (the baseline period). Patients with ≥1 diagnosis of atypical hemolytic uremic syndrome (another indication for ravulizumab) during the baseline period or on the index date were excluded to identify those with PNH. Patient baseline demographic and clinical characteristics including PNH-related comorbidities and symptoms were described. Because Symphony IDV does not record patient weight, it was assumed that all patients had a weight ≥60 and &lt;100 kg (ie, "medium body weight"), consistent with mean weights reported in recent clinical trials of ravulizumab (~70 kg) and in the US population (men: 91 kg; women: 77 kg). Mean and mode loading and maintenance doses as well as the proportion of patients with high, label-recommended, and low loading and mean maintenance doses were calculated. To test the weight assumptions, 2 sets of sensitivity analyses were carried out to account for alternative dosing pattern scenarios, with all patients classified as "low body weight" (≥40 and &lt;60 kg) or "high body weight" (≥100 kg). Results: A total of 433 patients with PNH were included in the study; the mean age was 47 years and 52% were female. The mean treatment period was 11.8 months; and 54%, 40%, and 6% of patients initiated ravulizumab in 2019, 2020, and 2021, respectively. Most patients (76%) were insured through a commercial insurance plan. Aplastic anemia and myelodysplastic syndrome were present at baseline in 22% and 5% of patients, respectively. The most frequent comorbidities were coagulopathy (13%), deficiency anemias (12%), and hypertension (11%); and 40% of patients had anemia (other than aplastic anemia) at baseline. Prior to initiating ravulizumab, 42% of patients had previously received ≥1 infusion of eculizumab during the baseline period. The mean (standard deviation [SD]) and mode loading doses were 3,316 (2,932) and 3,300 mg, respectively. The proportion of patients with a high, label-recommended, and low loading dose was 59%, 28%, and 13%, respectively (Table). During the maintenance phase, the mean (SD) and mode doses were 3,404 (1,024) and 3,300 mg, respectively; the proportion of patients with a high, label-recommended, and low mean dose during this phase was 27%, 51%, and 23%, respectively (Table). The sensitivity analyses revealed similar trends: nearly half or more than half of patients received a high loading dose; the proportion with a high mean dose during the maintenance phase was substantial when it was assumed that all patients had "low body weight" and negligible when assuming "high body weight" (Table). Conclusions: Most patients with PNH treated with ravulizumab received a higher than label-recommended loading dose regardless of weight category. Additionally, the mean dose received during the maintenance phase was higher than the label-recommended dose of 3,300 mg in more than one-quarter of patients (≥60 - &lt;100 kg). The deviations from label-recommended dosing regimens-especially dosages exceeding recommendations-suggest that in some patients, PNH is not controlled by ravulizumab. Alternative weight scenarios will be tested in future analyses to account for weight distribution in the US. Future budget impact analyses of ravulizumab in patients with PNH should consider real-world dosing patterns in order to determine cost vs benefit. Figure 1 Figure 1. Disclosures Cheng: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study.. Fishman: Apellis: Current Employment, Current equity holder in publicly-traded company. Sarda: Apellis: Current Employment, Current equity holder in publicly-traded company. Krishnan: Apellis: Current Employment, Current equity holder in publicly-traded company. Kunzweiler: Apellis: Other: Employee of Analysis Group, Inc., Research Funding. Vu: Apellis: Other: Employee of Analysis Group, Inc., Research Funding. Yenikomshian: Apellis: Other: Employee of Analysis Group, Inc., Research Funding. Duh: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study..

853. Real-World Persistency of Patients Receiving Tenofovir-Based Pre-Exposure Prophylaxis for the Prevention of HIV Infection in the US

Background Once-daily oral tenofovir-based combinations as pre-exposure prophylaxis (PrEP) have shown to be an effective biomedical HIV prevention strategy for populations at-risk of acquiring HIV-1. However, low adherence can lead to poor effectiveness. This study described the characteristics of commercially-insured US PrEP users. Methods This retrospective study used IQVIA™ PharMetrics Plus data (1/1/2015–3/31/2020) to identify adults newly initiated (index date) on emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or emtricitabine/tenofovir alafenamide (FTC/TAF) as daily PrEP. Users had ≥6 months of continuous enrollment pre-index (baseline); those diagnosed with HIV or with antiretroviral therapy (ART) use during baseline were excluded. User characteristics were described during the baseline period. For FTC/TDF users, proportion of days covered (PDC), persistence, treatment breaks, and switching were described during the follow-up period, which spanned from index to the earliest of disenrollment or end of data. Non-persistence was defined as a &gt;90-day gap from last day of supply, with re-initiation after this gap indicating treatment break. For PDC and persistence, follow-up was censored at HIV infection, defined by both multi-class ART initiation and HIV diagnosis. Results In total 24,232 FTC/TDF and 1,187 FTC/TAF users were identified. Overall, mean age was 35.1 years and 94.5% were male (Table 1). Mean [median] length of follow-up was longer for FTC/TDF (504 [390] days) than FTC/TDF users (77 [70] days). On average, FTC/TDF users had 9.0 dispensings with 38.3 days of supply per dispensing over follow-up; 11.1% had ≥1 treatment break (mean length, 249 days). Among those initiated on FTC/TDF, 10.8% switched to FTC/TAF. The mean PDC for FTC/TDF users at 6 and 12 months was 0.74 and 0.67, respectively, corresponding to 63.7% and 57.9% of patients with PDC ≥0.70 (Figure 1). Persistence to FTC/TDF at 6 and 12 months was 70.2% and 57.4%, respectively (Figure 2). Table 1. Baseline Demographics and Clinical Characteristics of PrEP Users by Regimen Figure 1. Proportion of Days Covered of FTC/TDF Users Figure 2. Kaplan-Meier Persistence Rates of FTC/TDF Users Conclusion Patient characteristics of PrEP users are broadly similar between regimens, though switching from FTC/TDF to FTC/TAF is common. FTC/TDF users had lower real-world PDC and persistence than in recent clinical trials (DISCOVER and HPTN 083). Disclosures Alan Oglesby, MPH, GlaxoSmithKline (GSK) (Employee, Shareholder) Guillaume Germain, MSc, ViiV Healthcare (Other Financial or Material Support, I am an employee of Groupe d’analyse, Ltée, a consulting company that provided paid consulting services to ViiV Healthcare for the conduct of the present study.) Francois Laliberte, MA, Viiv (Research Grant or Support) Staci Bush, NP, GlaxoSmithKline (GSK) (Employee, Shareholder) Heidi Swygard, MD, ViiV Healthcare (Employee) Sean MacKnight, MScPH, Analysis Group (Employee) Annalise Hilts, BA, Analysis Group, Inc. (Employee) Mei Sheng Duh, MPH, ScD, ViiV Healthcare (Grant/Research Support)