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Novel agents, including Bruton tyrosine kinase inhibitors (BTKis), have become the standard of care for patients with chronic lymphocytic leukemia (CLL). We conducted a real-world retrospective analysis of CLL patients treated with acalabrutinib vs ibrutinib to compare outcomes utilizing the Flatiron Health Database. Patients with CLL were included if they initiated acalabrutinib or ibrutinib between 1/1/2018-2/28/2021. The primary outcome of interest was time to treatment discontinuation (TTD). Average treatment effect among the treated weighting was used to balance key baseline characteristics between cohorts. Kaplan-Meier analysis was used to estimate unweighted and weighted median TTD. A weighted Cox proportional-hazards model was used to compare TTD between cohorts. Out of 2509 patients included in the analysis, 89.6% received ibrutinib and 14.1% received acalabrutinib. TTD was not significantly different between cohorts in the unweighted analysis. After weighting, the cohorts were balanced on all baseline characteristics except cardiovascular risk factors and baseline medications use. The median (95% CI) TTD was not reached (NR; 25.1, NR) for the acalabrutinib cohort and was 23.4 months (18.1, 28.7) for the ibrutinib cohort. The discontinuation rate at 12 months was 22% for the weighted acalabrutinib cohort vs 31% for the weighted ibrutinib cohort (P = .005). After additional adjustments for prior BTKi use, the acalabrutinib cohort had a 41% lower risk of discontinuation vs. ibrutinib (HR 0.59; 0.43, 0.81; P = .001). In the largest available study comparing two BTKis, patients with CLL receiving acalabrutinib demonstrated lower rates of discontinuation and a prolonged time to discontinuation vs ibrutinib.

Hannah Le,1 Kellie Ryan,1 Svea K Wahlstrom,2 Martine C Maculaitis,3 Oliver Will,4 Emily Mulvihill,5 Thomas W LeBlanc6 1US Medical Affairs, AstraZeneca, Gaithersburg, MD, USA; 2US Patient Safety, AstraZeneca, Wilmington, DE, USA; 3Kantar, Health Division, New York, NY, USA; 4Kantar, Health Division, Horsham, PA, USA; 5Kantar, Health Division, St. Louis, MO, USA; 6Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC, USACorrespondence: Martine C Maculaitis Email Martine.Maculaitis@kantar.comPurpose: Treatment for chronic lymphocytic leukemia (CLL) has changed dramatically with the approval of novel agents. Information regarding how patients and oncologists make trade-offs across attributes of novel therapies is limited. The purpose of this study was to understand how variations in attributes impact treatment choice among patients and oncologists.Patients and Methods: In this study, 371 participants (patients [n=220] and oncologists [n=151]) completed an online discrete choice experiment (DCE) to quantify preferences for first-line (1L) CLL treatment with novel agents; participants chose between hypothetical treatment profiles consisting of eight attributes with varying levels taken from published literature. Hierarchical Bayesian models were used to estimate attribute level preference weights. The weights were used to compute relative importance, a measure of how influential an attribute is to treatment choice.Results: Increasing 2-year progression-free survival (PFS) from 75% to 95% had the greatest impact on preferences in 1L CLL treatment, accounting for 40% and 30% of the variation in preferences among patients and oncologists, respectively. Risk differences in atrial fibrillation (AF), infection, and discontinuation due to adverse events (AEs) were also important to patients and oncologists. Among both groups, risk differences in tumor lysis syndrome (TLS) and bleeding were least influential in treatment choice. Oncologists required 2– 4 times higher increases in 2-year PFS than patients to accept increased risks of AF, discontinuation due to AEs, bleeding, TLS, and arthralgia/myalgia.Conclusion: Patient–oncologist communication may be improved by a more focused discussion on the risks of AEs, relative to treatment outcomes, with patient goals in mind.Keywords: leukemia, lymphocytic, chronic, B-cell, progression-free survival, tumor lysis syndrome, oncologists

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 >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.

Introduction: Treatment for chronic lymphocytic leukemia (CLL) has changed with the approval of novel agents, which have different toxicity profiles. The aim of the current analysis was to determine how incremental changes in efficacy and toxicity profile impact treatment selection among patients with CLL and oncologists. Methods: In this US-based study, oncologists and CLL patients completed an online survey that included a discrete choice experiment (DCE) to quantify preferences for first line (1L) treatment with novel agents. Self-reported data on oncologist and patient characteristics were also collected. In the DCE, respondents selected between hypothetical treatment profiles consisting of 8 attributes with varying levels. The attributes were selected based on the findings of qualitative interviews assessing treatment priorities among oncologists and patients. The attribute levels were abstracted from clinical trials and published literature (Table 1). Hierarchical Bayesian regression models were used to estimate preference weights for each attribute level. The preference weights were used to generate a base case hypothetical treatment profile, against which other hypothetical profiles varying in adverse event (AE) risk and 2-year progression-free survival (PFS) were evaluated to understand which attributes and levels drive treatment selection. The overall mean summed preference weight for the collective set of alternative profiles was then compared with the base case, with higher positive values indicating the more preferred profile. Results: Oncologists (N=151) reported a mean of 16.3±7.0 years in practice (Table 2). Most practiced in a community setting (72%) and in a major metropolitan/urban area (64%). Among patients (N=220), median age was 56.0 years, with a mean disease duration of 2.0±3.1 years at time of study (Table 2). Most patients were in or had completed at least 1L therapy (68%). Figure 1 illustrates the impact of changing various attribute levels on the overall preference of an alternative profile, relative to a base case profile. Decreasing 2-year PFS from 95% to 75% (Profile A) and reducing the risks of atrial fibrillation (A-fib) from 20% to 5% (Profile B) and infection from 30% to 7% (Profile C) had the greatest influence on treatment preferences for oncologists when holding all other attribute levels constant. Oncologists preferred the profile with reduced 2-year PFS and reduced risk of AEs (Profile G) to the base case profile, corresponding to a 45% difference in preference share. Similarly, for patients, reducing 2-year PFS from 95% to 75% (Profile A) and reducing the risks of infection from 30% to 7% (Profile C) and A-fib from 20% to 5% (Profile B) were most influential in treatment choice when all other attribute levels were held constant (Figure 1). However, patients preferred the base case profile with higher PFS and higher risk of AEs to Profile G, corresponding to a 38% difference in preference share. Conclusions: For oncologists and patients, decreasing 2-year PFS and reducing the risks of either A-fib or infection had the most influence on 1L treatment preference, relative to the base case in which 2-year PFS was the highest and the AE risks were set to the worst levels reported in literature for novel therapies. The pattern and direction of treatment preferences were generally consistent among oncologists and patients, relative to the base case, across all alternative profiles when individually examined. However, for patients, the positive impact of reducing the risk of AEs was outweighed by the negative impact of reducing PFS. Consequently, all other things being equal, patients preferred a 1L profile with higher PFS even if it came with higher AE risks. In contrast, oncologists were willing to accept a treatment with less efficacy in exchange for the most favorable safety profile. This difference may be due to a patient's lack of understanding of the potential severity of AEs or a physician's lack of awareness of the patient's treatment priorities. This is an area for future research and highlights the importance of oncologists explicitly communicating the known efficacy benefits and AE risks associated with each treatment option because these factors may influence patients' treatment choice in a way that differs from their own. Disclosures Ryan: AstraZeneca: Current Employment, Current equity holder in private company. Le:AstraZeneca: Current Employment, Current equity holder in private company. Wahlstrom:AstraZeneca: Current Employment, Current equity holder in private company. Beusterien:Kantar: Other: Employee of Kantar, which received funding from AstraZeneca to conduct this study. Will:Kantar: Other: Employee of Kantar, which received funding from AstraZeneca to conduct this study. Maculaitis:Kantar: Other: Employee of Kantar, which received funding from AstraZeneca to conduct this study. Leblanc:UpToDate: Patents & Royalties: Royalties; Agios, AbbVie, and Bristol Myers Squibb/Celgene: Speakers Bureau; AstraZeneca: Research Funding; AbbVie, Agios, Amgen, AstraZeneca, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Helsinn, Heron, Otsuka, Medtronic, Pfizer, Seattle Genetics, Welvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; American Cancer Society, BMS, Duke University, NINR/NIH, Jazz Pharmaceuticals, Seattle Genetics: Research Funding.

148 Background: CLL treatment has changed dramatically with the approval of novel agents, but data to guide treatment decisions are still lacking. How patients (PTs) and oncologists (ONCs) prioritize treatment attributes is unknown. Methods: ONCs and PTs completed an online survey to quantify preferences for first-line (1L) CLL treatment with novel agents via a discrete choice experiment; ONCs and PTs chose between hypothetical treatment profiles with varying attribute levels taken from product labels, registrational trials, and real-world studies. Hierarchical Bayes models were used to estimate attribute level preference weights, which were used to compute relative importance (RI), a measure of how influential an attribute is in treatment choice out of a total of 100%. Results: For ONCs (N=151), 72% were in community practice. PTs (N=220) had a median age of 56 years; 32% were in active surveillance, 36% were in/had completed 1L treatment, and 32% were relapsed/refractory. Increasing 2-year progression-free survival (PFS) from 75% to 95% had the greatest impact on preferences, with a mean RI of 40% for PTs and 30% for ONCs (Table). When assessing trade-offs between 2-year PFS and other attributes, ONCs required the largest increase in PFS (11%) to compensate for an increased risk of atrial fibrillation (AF) from 5% to 20%. PTs required the largest increase in PFS (6%) to compensate for an increased risk of infection from 7% to 20%. ONCs (vs PTs) required 2–4-times higher increases in PFS to accept an increased risk of AF, discontinuation due to adverse events (AEs), bleeding, tumor lysis syndrome (TLS), and arthralgia/myalgia. Conclusions: ONCs and PTs valued PFS most when selecting a novel CLL agent. While both groups accepted potential risks in exchange for increased PFS, ONCs were less likely to accept a higher risk of AEs. ONCs and PTs may perceive the risks and benefits of novel agents differently. ONC–PT communication may be improved by a more focused discussion on the risks of AEs, relative to treatment outcomes, with patient goals in mind. [Table: see text]

Introduction: Chronic lymphocytic leukemia (CLL) is an indolent disease most common in elderly adults. While chemo-immunotherapy is a standard first-line (1L) therapy for physically fit patients, treatment options for all CLL patients have greatly increased with the approval of novel agents. Thus, treatment decision-making in CLL has become more challenging, as physicians and patients must consider the risk-benefit trade-offs inherent to treatment options. Yet, little is known about the attitudes, beliefs, and preferences that underlie treatment decision-making in real-world settings for CLL. We aimed to elucidate oncologist/hematologist (ONC) and patient (PT) preferences about key attributes associated with novel CLL treatments using qualitative methods. Methods: In May 2019, we conducted in-depth interviews with 10 ONCs who each manage ≥20 CLL PTs with systemic therapy, prescribe novel agents for CLL, and spend at least 50% of their time in direct PT care. In addition, we interviewed 10 adult PTs with CLL. A commercial healthcare database was used to recruit ONCs, and PTs were recruited via advocacy groups. A trained moderator used a semi-structured interview guide to facilitate interviews focused on attributes influencing CLL treatment decision-making; for ONCs, interviews also asked about factors used to decide whether to treat a PT (vs. active surveillance [AS]). A standardized qualitative coding procedure (content analysis) was used to identify key themes emerging from interview responses. Descriptive statistics are reported to summarize the results. Results: ONCs had a median of 10.5 (range: 7-30) years in practice; most (n=7, 70%) reported working in an academic setting. The decision on whether or not to initiate treatment (vs. AS) depended on multiple factors, primarily symptoms, with patient motivation, health status, and treatment goals playing a lesser role. All ONCs prioritized efficacy when selecting a CLL treatment; progression-free survival (PFS; n=9) and overall survival (OS; n=7) were the top 2 metrics considered. Shorter treatment duration was considered when preferred by the PT or where adherence was a concern. ONCs perceived novel CLL therapies to be effective and well-tolerated; tumor lysis syndrome (TLS; n=8), atrial fibrillation (n=7), and diarrhea (n=7) were among the adverse events (AEs) most often cited as being a concern. ONCs perceived dose reduction as a way to mitigate certain types of AEs. All non-academic ONCs (n=3, 100%) presented one specific treatment to their PTs, but most academic ONCs (n=5, 71%) also discussed options with PTs, even if one specific treatment was recommended. Among PTs, the median age was 62.5 (range: 54-78) years, and most (n=7, 70%) were female. Four (40%) PTs were in 1L, with 4 (40%) in second/later lines (2L+), of treatment for their CLL; 2 (20%) PTs were in AS. Efficacy (described in terms of long-term remission) and concern about the impact of AEs on quality of life (QoL) were of greatest importance to PTs in choosing a treatment. Half reported that their ONC presented a specific recommendation for 1L treatment. Among 1L and 2L+ PTs (n=8), most (n=6, 75%) reported that ONCs did not provide detailed information about AEs associated with their CLL treatment. Across all PTs, cardiac issues and TLS (each, n=7) were the serious AEs most frequently reported as being of concern; other potential AEs, including joint pain (n=5) and brittle fingernails (n=2), were also cited as being of concern. Most PTs (n=9, 90%) expressed their preference for the convenience of oral over intravenous therapy. PTs who had a dose reduction (n=3) reported less apprehension about the potential impact on treatment efficacy than those who never had a dose reduction (n=7). Conclusions: While there was overlap between ONCs and PTs in the most concerning AEs, some PTs cited additional AEs due to the potential impact to their QoL. Regarding treatment preferences, PTs placed high importance on the impact of AEs on QoL, although this was of less importance to ONCs. Unlike ONCs, who viewed dose reductions as a means of resolving certain AEs, some PTs tended to question whether a dose reduction would diminish treatment efficacy. A better understanding of factors that influence treatment preferences may help facilitate ONC-PT communication when selecting novel CLL therapies. Future research should verify if these findings generalize to a representative PT population. Disclosures Le: AstraZeneca: Employment, Other: Stocks. Pendergraft:AstraZeneca: Employment, Equity Ownership. Wahlstrom:AstraZeneca: Employment, Equity Ownership. Ryan:AstraZeneca: Employment, Equity Ownership. Mulvihill:Kantar: Employment. Campbell:Kantar: Employment. Maculaitis:Kantar: Employment. LeBlanc:Helsinn: Consultancy; Jazz Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Duke University: Research Funding; Flatiron: Consultancy; Celgene: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; CareVive: Consultancy; Astra Zeneca: Consultancy, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; NINR/NIH: Research Funding; Pfizer Inc: Consultancy; American Cancer Society: Research Funding; Heron: Membership on an entity's Board of Directors or advisory committees; Medtronic: Membership on an entity's Board of Directors or advisory committees.

It has been suggested that cocaine acts directly in the brain to enhance central sympathetic outflow. However, some studies suggested that the cardiovascular effects of cocaine are related to a peripheral action. To characterize further the site of cocaine's cardiovascular effect, we compared the hemodynamic effects of cocaine (2 mg/kg, i.v. bolus) with those observed after administration of an equimolar dose (2.62 mg/kg, i.v. bolus) of cocaine methiodide, a quaternary derivative of cocaine that does not penetrate the blood-brain barrier, by using sufentanil-sedated dogs. Cocaine produced significant (p < 0.05) increases in heart rate (+37+/-11 beats/min), mean arterial pressure (+55+/-11 mm Hg), left ventricular end-diastolic pressure (+5.3+/-1.0 mm Hg), and cardiac output (+2.4+/-0.9 L/min). Cocaine methiodide produced increases in heart rate (+57+/-11 beats/min), mean arterial pressure (+45+/-11 mm Hg), left ventricular end-diastolic pressure (+3.4+/-1.0 mm Hg), and cardiac output (1.1+/-0.9 L/min), which were not significantly different from those observed with cocaine. Because opiate sedation potentially might have attenuated central sympathetic outflow, we further confirmed the qualitative similarity of the actions of cocaine and cocaine methiodide on heart rate and blood pressure in unsedated, conscious dogs. Our data suggest that the cardiovascular effects of cocaine result primarily from a peripheral site of action.