ALBERT

Description: Background: Sickle Cell Disease (SCD) describes a group of inherited hemolytic disorders caused by structurally abnormal variants of hemoglobin, which result in the sickle-shaped red blood cells (RBCs) that are characteristic of the disease. In patients with SCD, overexpression of adhesion molecules such as P-selectin bind sickled RBCs to endothelial cells; this contributes to hemolytic anemia and vaso-occlusive crises (VOCs), which are associated with severe acute and chronic pain. Patients with sickle cell disease often experience disease-related complications, affecting a diverse range of organs, thought to be due to the systemic impact of chronically inflamed vasculature, ongoing hemolysis and ischemic damage as a result of vaso-occlusive events. Many of these SCD-related complications are associated with significant morbidity and poor quality of life. The relationship between VOC frequency and the incidence of these complications is still being assessed. This study aimed to assess the relationship between the number of VOC experienced in the previous year and the occurrence of complications using real world evidence from the UK, specifically the Hospital Episode Statistics (HES) database. OBJECTIVE: To examine the relationship between the number of VOCs reported in the previous 12 months and the presence of SCD-related complications using a mixed modelling approach. METHODS: All patients reported with a diagnosis of SCD between 2008 and 2017 in the NHS England's HES database were identified. Detailed follow-up data on the number of vaso-occlusive crisis events and occurrence of complications was evaluated using ICD-10 diagnosis codes. Assuming no unmeasured confounding, the causal effect of VOCs, categorized into 3 groups (0, 1-2, 3+), was estimated using marginal structural models (MSM) for the complications reported in the dataset. To obtain inverse probability of treatment and censoring weights (IPTW and IPCW), the probability of being in each VOC category was estimated with a multinomial logistic model, and subsequently, the probability of being censored was estimated with a binary logistic model. The two models were adjusted for age, gender, ethnicity, and the occurrence in the previous 12 months of the 20 most common SCD complications and comorbidities in the dataset. Pooled logistic regressions were used to approximate the IPW-MSM Cox model. E-values were used to assess the minimum strength of association that an unmeasured confounder would have to have with both exposure (VOC) and outcome in order to fully explain away the observed relationship. Uncertainty in the magnitude of the E-value required to explain observed associations was explored by calculating values for both the point estimate and the lower bound of the confidence interval. RESULTS: A total of 15,076 patients were identified with a diagnosis of SCD in the HES database for this analysis. Patients had a median age of 30 and a female-male ratio of 1.7:1. A broad range of SCD related-complications were experienced by patients in the UK as shown in Table 1. Rates of some complications were observed less frequently than expected, in particular, leg ulcers, pulmonary hypertension, osteomyelitis, priapism and acute kidney injury, reported at

Description: Abstract 4048 Introduction: Chemotherapy + GCSF mobilization and GCSF alone are the most common mobilization regimens for autologous stem cell transplant (ASCT). We examined the benefits and limitations of both regimens in terms of mobilization success, predictability and costs. Methods: A retrospective, multi-center chart review was conducted of multiple myeloma (MM) and lymphoma patients mobilized between January 1, 2006 and December 31, 2007 for ASCT. Patients were excluded if they were mobilized with plerixafor (Mozobil®) or enrolled in a clinical trial of mobilization regimens. Data collected included demographics, disease and treatment history, mobilization regimen, blood counts, aphaeresis, remobilization, cells transplanted, time to engraftment and resource use. Stem cell collection practices and related clinical outcomes were analyzed separately for patients that were mobilized with chemotherapy + GCSF vs. GCSF alone. Resource use was evaluated using US unit cost data. Results: Data were collected for 227 consecutive patients from 11 centers (143 patients that received a chemotherapy + GCSF mobilization regimen and 84 patients who received GCSF alone). Total cells collected were significantly higher in the chemotherapy + GCSF mobilization group compared to GSF alone (18.6 × 106/kg vs.7.0 × 106/kg, p

Description: Introduction: Pain is the top concern of individuals with sickle cell disease (SCD). Acute painful vaso-occlusive episodes are the leading cause of emergency department (ED) encounters and frequent hospital admissions. There are well-documented disparities for patients with SCD, including significant delays in starting therapy and under treatment of pain in the ED. An acute care observation unit (ACOU) staffed with SCD specialists can help to address these disparities. Here we study the service impact of increasing the hours of operation of a dedicated sickle cell ACOU on utilization and hospital admissions at the University of Illinois at Chicago (UIC), a regional sickle cell resource. We hypothesized that increased hours of operations will lead to decreased ED utilization and inpatient hospitalizations. Methods: The outcomes of individuals 〉16 years of age presenting with an acute painful episode to the sickle cell ACOU at UIC were assessed for the 12 months before and the 12 months after increasing the hours of operation from 9 hours/day to 15 hours/day Monday through Friday in February 2014. The outcomes of SCD patients presenting to the ED during the 12-month period following expanding hours in the ACOU were also assessed. The main outcome measures were ACOU and ED utilization and hospital admission rates. Results: There were 344 encounters in the sickle cell ACOU in the 12 months before expansion of service hours compared to 796 in the 12 months after expanding the hours, an increase of 131%. This represents 0.15 patients treated per hour before increasing the hours versus 0.2 per hour after increasing the hours. Seventy-two percent of the patients treated at the sickle cell ACOU were discharged home in the 12 months prior to expanding hours versus 75% after. During the comparative 12-month period following expansion of hours in the ACOU, there were 1074 encounters for SCD acute painful episodes in our ED, representing 0.12 patients treated per hour of operation. Only 35% of SCD patients treated in the ED for an acute painful episode were discharged home. Conclusion: The sickle cell ACOU at UIC more than doubled its patient volume following the expansion of operation from 9 to 15 hours/day during weekdays. Based on the hours of operation, during a comparative 12-month period the sickle cell ACOU treated twice as many SCD patients with an acute painful compared to the ED while discharging rather than hospitalizing twice as often. These observations suggest that allocating resources to a dedicated sickle cell ACOU can decrease ED utilization and subsequent inpatient hospitalizations. Disclosures No relevant conflicts of interest to declare.

Description: The classical myeloproliferative neoplasms (MPNs) are a group of disorders characterised by activation of the JAK/STAT signalling pathway. A large proportion of patients with MPNs have an acquired mutation, JAK2V617F, which causes constitutive kinase activity. Patients with wild-type JAK2 show gene expression patterns characteristic of JAK/STAT activation, and the majority have mutations in other genes associated with increased pathway activation. Inhibition of JAK/STAT activation represents an attractive therapeutic approach for these disorders. In myelofibrosis, treatment with a JAK inhibitor reduces spleen volume, improves quality of life and prolongs life expectancy, whereas there is evidence that other therapies are no better than placebo. This study aimed to find new treatments for MPNs by identifying compounds that suppress JAK/STAT activation. We screened a small-molecule library consisting of FDA approved drugs, cytotoxic drugs, agrochemicals, and pure natural products to identify modulators of STAT-responsive transcription in the low complexity Drosophila model. We independently identified methotrexate (z-score -8.72) and the chemically similar aminopterin (z-score -8.2) as strong inhibitors of Drosophila JAK/STAT activation. The suppression of transcriptional reporter activity was dose dependent and was observed following activation of the pathway with the Drosophila JAK/STAT ligand Upd and by the gain of function Drosophila JAK HopTuml. To examine whether these results translated to the more complex JAK/STAT signalling pathway of humans we examined the effect of methotrexate in the Hodgkin Lymphoma cell line HDLM-2, which shows constitutive phosphorylation of several JAK/STAT family members. Immunoblotting for phosphorylated pathway components showed that methotrexate produced a dose dependent reduction in levels of tyrosine phosphorylated STAT5 (Y694), without affecting total STAT5 levels. Methotrexate did not affect phosphorylated proteins in other signalling pathways, including pAKT, p c-Jun or pMAPK. To examine the potential of methotrexate as a treatment for MPNs, we used the HEL cell line, which is homozygous for JAK2V617F and shows STAT5 phosphorylation that is dependent on JAK2 activity. Immunoblotting showed that methotrexate produced a dose dependent reduction in levels of pSTAT5. Significant suppression of STAT5 phosphorylation was seen following treatment with methotrexate at concentrations equivalent to those measured in the serum of patients taking low dose oral methotrexate (0.4 – 0.8 mM, p

Description: Abstract 1925 After mobilization, the timing of aphaeresis can be highly variable, often depending on rise in peripheral blood stem cell levels. Some centers that conduct autologous stem cell transplant (ASCT) do not conduct aphaeresis for stem cell collection on weekends. We examined stem cell collection practices and related outcomes in centers that do and do not conduct weekend aphaeresis. Methods: A retrospective, multi-center chart review was conducted of multiple myeloma (MM) and lymphoma patients mobilized between January 1, 2006 and December 31, 2007 for ASCT. Patients were excluded if they were mobilized with plerixafor (Mozobil®) or were enrolled in a clinical trial of mobilization regimens. Data collected included demographics, disease and treatment history, mobilization regimen, blood counts, aphaeresis, remobilization, cells transplanted, time to engraftment, and resource use. Stem cell collection practices and related clinical outcomes were analyzed separately for sites that did and did not conduct weekend aphaeresis. Results: Data were collected for 292 consecutive patients in the different centers (91 patients from 4 sites that performed weekday only aphaeresis and 201 patients from 7 sites who performed aphaeresis on weekends and weekdays). Weekday only aphaeresis sites were more likely to conduct GCSF alone mobilization compared to weekend sites (42% vs. 21%, p

Description: OBJECTIVES: Vaso-occlusion is a hallmark feature of sickle cell disease (SCD) that promotes ischemia-reperfusion injury and leads to acute pain episodes, known as vaso-occlusive crises (VOCs). VOCs are disabling and frequently impact on the ability of the patient to attend work or school and participate in activities of daily living. VOCs are the primary reason for medical facility visits amongst SCD patients and are associated with increased morbidity and mortality. The acute pain of a VOC often requires parenteral opioid administration in hospital emergency departments and inpatient units. Patients are also frequently prescribed oral opioids to aid in home management of VOCs. The development of new SCD therapies that have been shown to reduce or prevent VOCs has generated interest in their potential as opioid sparing agents. This study evaluated the effect of crizanlizumab-a humanized monoclonal antibody indicated in the US for reduction of VOCs in SCD-on opioid use for managing VOC related pain. METHODS: In this post hoc analysis, subject-level data from the SUSTAIN (NCT01895361) trial were analyzed to determine the number of days of opioid use by patients in both the 5.0 mg/kg crizanlizumab and placebo arms during the 52-week follow-up period. Opioid use captured in case report forms was retrospectively assessed. Due to the common use of "as needed" (PRN) dosing for analgesics, a decision tree was developed in conjunction with clinical advice to guide classification of the opioid as being taken or not taken on a given day based on clinically plausible assumptions. Assumptions considered dose frequency (fixed vs. PRN), route of administration (parenteral vs. oral), and concomitant medications (anti-emetics and anti-histamines). Opioid record start dates, end dates, and dose frequencies were used to determine the number of unique days during the trial that each patient had taken at least one opioid. The annualized days with opioid use was calculated for each patient by dividing their number of unique days on opioids by their duration (days) in the trial. The distribution of annualized days with opioid use was compared between patients from the 5.0 mg/kg crizanlizumab and placebo arms. Mann-Whitney U tests with p-values were used to test differences between arms. A four-step analysis was planned to incorporate an increasing number of assumptions to define whether the opioid had been taken on a given day (see footnote of Table 1). Analyses were performed primarily in the per-protocol (PP) population considering all routes of administration and parenteral use only. Outcomes in the intention-to-treat (ITT) population were also assessed. RESULTS: The PP population included 40 patients in the 5.0 mg/kg crizanlizumab arm and 41 patients in the placebo arm. A comparison of the baseline demographics (age, sex, genotype, hydroxyurea use, crisis frequency, and opioid use) showed no statistically significant differences between the two arms. Results of the final step of each analysis are presented as the primary analysis (see Table 1); results of Step 1 were considered a sensitivity analysis (not shown). The median annualized days with opioid use in the PP population was lower in the crizanlizumab arm compared with the placebo arm (absolute reduction: 4.00 days; relative reduction: 57%; p=0.162). The median annualized days with parenteral opioid use was lower in the crizanlizumab arm compared with the placebo arm (absolute reduction: 2.01; relative reduction: 50%; p=0.047). Results in the ITT population (see Table 1) and for sensitivity analyses (not shown) showed similar trends of reduced annualized days with opioid use for patients in the crizanlizumab group compared to the placebo group. CONCLUSIONS: These findings indicate that crizanlizumab, compared with placebo, may reduce the annual number of days where opioids are used to manage pain from VOCs. Importantly, the benefit was observed for parenteral and oral opioids, demonstrating clinical and patient relevance. These findings are concordant with the tendency for crizanlizumab to reduce the number of VOCs experienced by SCD patients annually; the primary finding of the SUSTAIN trial. The reduction in opioid use with crizanlizumab requires exploration in future studies, but the findings of this study translate into positive clinical and patient-relevant outcomes beyond reducing the frequency of VOCs. Disclosures Smith: Shire: Research Funding; Imara: Research Funding; Novo Nordisk: Consultancy; Ironwood: Consultancy; Pfizer: Consultancy; Incyte: Other: Investigator; Health Resources and Services Administration: Other: Investigator, Research Funding; Patient-Centered Outcomes Research Institute: Other: Investigator, Research Funding; NHLBI: Research Funding; Shire, Inc.: Other: Investigator, Research Funding; Global Blood Therapeutics, Inc.: Consultancy, Research Funding; Novartis, Inc.: Consultancy, Other: Investigator, Research Funding; Emmaeus Pharmaceuticals, Inc.: Consultancy; GlycoMimetics, Inc.: Consultancy. Ataga:Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Research Funding; Editas Medicine: Honoraria; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Forma Therapeutics: Consultancy; Modus Therapeutics: Honoraria; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding. Saraf:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Boards, Speakers Bureau; Novartis, Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer, Global Blood Therapeutics, Novartis: Research Funding. Adisa:Novartis Pharmaceuticals Corporation: Current Employment. Bailey:Novartis Pharmaceuticals Corporation: Current Employment. Ramscar:Novartis Pharma AG: Current Employment. Bonner:Eversana: Current Employment. Brown:Eversana: Current Employment. Pastor:Eversana: Current Employment.