Liu, Sizhu

Abstract Introduction: Mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL) and chronic lymphocytic leukemia (CLL) are subtypes of non-Hodgkin's lymphoma. Collectively, these subtypes constitute a large proportion of all B-cell malignancies; however, they are typically associated with survival spanning several years with multiple interspersed treatment periods due to frequent relapses. This can predispose patients to repeated hospitalization resulting in significant economic impact. The objectives of this study were to examine real-world treatment patterns, costs and healthcare resource utilization for patients with these lymphomas, as well as identify disparities and risk factors associated with costs incurred in US hospitals. Methods: A retrospective study was conducted using the Premier Healthcare Database, a geographically diverse all-payer, hospital administrative database containing more than one billion inpatient and hospital-based outpatient encounters. Patients aged ≥18 years with at least 1 inpatient or 2 hospital-based outpatient visits with a MCL, WM, CLL, or MZL diagnosis, and who received treatment for these conditions from 1/1/2014 to 10/31/2019 were included in the study. Descriptive analysis was conducted to examine patient sociodemographic and hospital characteristics, all-cause and lymphoma-related healthcare resource utilization and costs. Costs were obtained from patients' discharge files and hospital billing records. Multivariable analysis was performed using generalized linear models to examine risk factors associated with costs and LOS for each lymphoma type. Treatment evaluated including any use of supportive care (blood transfusion, granulocyte colony stimulating factors [GCSF]), and by regimen (steroids alone, chemotherapy alone, chemo-immunotherapy, rituximab alone, targeted therapy alone, targeted therapy in combination with chemotherapy, other). Statistical significance was determined as a p-value of <0.05. Results: The study population included 23,952 CLL, 3,387 MCL, 2,655 MZL, and 1,811 WM patients in the US hospital database. Patients with WM were statistically significantly older (77 ± 58.5 years) compared to patients with CLL (74.2 ± 30.2 years), MCL (70.7 ± 37.3 years) or MZL (69.3 ± 33.8 years). More male (71.7%) and white (87.8%) patients were identified in the MCL cohort compared to the general lymphoma cohorts (Males: 58.7%; whites: 86.3). The most common comorbidities included chronic pulmonary disease (27.1%), gastroesophageal reflux disease (17.6%), moderate-severe renal disease (16.6%), congestive heart failure (15.7%) and diabetes without chronic complications (15.2%). Overall, more than two-thirds of patients in each lymphoma group received treatment with steroids alone during hospitalizations. While the use of steroids alone was higher among whites compared to non-white patients (69.5% vs. 60.4%), the use of chemo-immunotherapy was lower in whites compared to non-whites (11.9% vs. 16.2%). The average LOS of inpatient hospitalization ranged from 6.3 days for CLL to 7.4 days for MCL, with the mean costs per hospitalization from $19,566 (CLL) to $24,439 (MCL). Non-white patients have significantly longer mean LOS days compared with white patients (CLL: 18.3 vs. 14.8; MCL: 21.7 vs. 18.3; MZL: 21.6 vs. 18.5; WM 19.0 vs. 14.5). Across the 4 lymphoma types, multivariable regression confirmed the descriptive results and demonstrated that higher hospitals costs were associated with patients who were non-white, Hispanic/Latino, treated in hospitals located in the Northeast or West, or had Medicaid; statistically significant increased cost of care was also noted for patients who received targeted therapy or supportive care, such as blood transfusion or GCSF (Table 1). Conclusions: Real-world data demonstrated the significantly high total hospital costs once patients with MCL, WM, MZL, and CLL patients were hospitalized, with significantly higher impact to minority populations. Given the increased availability of effective oral therapeutics, optimal and timely disease control in the outpatients setting can potentially prevent or decrease hospitalizations and reduce economic burden on healthcare. Future studies are needed to explore the reason for admission, clinical outcomes, and potential preventive interventions. Figure 1 Figure 1. Disclosures Chanan-Khan: Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; Cellectar: Current equity holder in publicly-traded company; Ascentage: Research Funding; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BieGene, Jansen, Ascentage: Consultancy. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Cao: Premier, Inc.: Current Employment; BeiGene, Ltd.: Consultancy. Baumer: BeiGene, Ltd.: Consultancy; Premier, Inc.: Current Employment. Krishnaswami: BeiGene, Ltd.: Consultancy; Premier, Inc.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Abstract Introduction: Clinical availability of highly effective novel agents (including Bruton tyrosine kinase [BTK] and B-cell lymphoma 2 [BCL-2] inhibitors) is rapidly altering the therapeutic landscape of chronic lymphocytic leukemia (CLL) necessitating a review of treatment guidelines. However, there is limited real-world data to validate if the availability of these novel agents has translated to a true shift in treatment paradigm for patients treated in the community. As the majority of CLL patients are treated in non-academic community-based settings, we investigated the clinical adoption trends of commercially available FDA approved novel agents for treatment of CLL patients. In addition, given that the COVID-19 pandemic led to major alteration in clinical oncology practices, we further studied if this contributed to an alteration in the selection of therapeutic agents resulting in changes of CLL treatment patterns and the utilization of novel agents in the real-world setting. Thus, the objectives of this study were to examine the utilization pattern of various CLL therapies, as well as evaluate the pattern of adoption of novel agents for treatment and the impact of COVID. Methods: A retrospective observational study was conducted using the Flatiron Health database that comprised EHR-derived de-identified data. Adult patients (≥18 years) with newly diagnosed CLL from January 2014 to May 2021, with no prior treatment and who were continuously enrolled for at least 6 months before and 3 months after the index date, defined as the first date of CLL/SLL diagnosis were included. Treatment regimens were classified into seven mutually exclusive categories: bendamustine-based chemotherapy, other chemotherapy, anti-CD20-based therapy, ibrutinib, idelalisib, acalabrutinib and venetoclax. Further treatment categorization included chemotherapy vs. targeted therapy, and traditional IV vs. novel oral agents. The impact of the pandemic was examined by comparing the pre- and post-COVID cohorts (defined as 15 months pre- and post- of March 1, 2021). Descriptive analyses were conducted to examine the frequency of use of treatment regimens by quarter in each year, line of therapy and between different age, gender, US geographical region, insurance status, and race/ethnicity subgroups. Multivariable regression was conducted to examine factors associated with the likelihood of adoption of novel and oral agents. Statistical significance was determined at a p-value of less than 0.05. Results: A total of 3,037 newly diagnosed CLL patients (median age =73) were included in the study. Over half were male (62.3%), white (74.6%) and commercially-insured (54.1%). Patients were primarily treated in community practices (92%). Overall, a significant trend in adoption of novel agents was observed throughout the years following their approval (Figure 1A). Across the evaluation period, a significant decrease in chemotherapy use was observed from 61.3% (quarter 1, 2014) to 20% (quarter 2, 2021) in favor of targeted therapy as first-line therapy (Figure 1B). In contrast, the utilization of novel oral agents (vs. traditional IV agents) for first-line therapy increased from 9.5% to 70.9% for the same period (Figure 1C). Similar trends were observed for second-line and third-line therapies. Encouragingly, this change in treatment patterns was adopted comparably in all sociodemographic subgroups with no evidence of disparity. While there was no statistically significant difference between the pre- and post-COVID treatment landscape, the adoption of target and novel oral agents has been more pronounced with the COVID pandemic. Conclusions: Results from real-world data suggest that there is a clear shift towards the adoption of novel therapies with preference given to targeted agents and oral therapies in the US since 2014. Further research examining real-world outcomes associated with treatment regimens are needed to inform decision makers. Figure 1 Figure 1. Disclosures Chanan-Khan: Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Ascentage: Research Funding; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; BieGene, Jansen, Ascentage: Consultancy. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Zimmerman: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Abstract Introduction: The impact of cancer care and management beyond treatment is significantly high for cancer patients. Due to the complexities of cancer treatment, patients are heavily reliant upon ancillary support often rendered by friends and family. One significant yet unquantifiable impact of cancer on society is productivity loss of both patients and their caregivers. Non-Hodgkin lymphoma is considered largely incurable with a protracted clinical course punctuated with multiple remission and relapses, warranting repeated treatment and intensive clinical testing, which necessitates significant engagement of patients and caregivers. Many patients are members of the workforce at the age of diagnosis. Both working patients and caregivers need time for medical care, which translates to indirect economic impact due to lost productivity. The objectives of this analysis were to evaluate the productivity loss and indirect costs in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenström macroglobulinemia (WM) and their caregivers. Methods: The MarketScan Commercial and Health and Productivity Management databases were used to identify patients with CLL, MCL, MZL, and WM (using ICD-9/ICD-10 codes) who were continuously enrolled for ≥6 months pre- and ≥1 month post-diagnosis (index date) from 1/1/2010 to 12/31/2019. The final study cohort included patients aged 18-64 who were full-time workers with eligibility of absentee, or short-/long-term disability on index date and for ≥1 month in follow-up. Those who were pregnant during the study period were excluded. Adult, full-time employed caregivers, defined as family members covered under the same health plan as the patient, and continuously enrolled ≥6 months pre- and ≥1 month post-index, were also identified. Among those with eligibility, the percentage with a claim of absentee, short- or long-term disability (patients only), and associated productivity time loss and indirect costs during follow-up were examined. Lost wages were calculated using the US Bureau of Labor Statistics 2019 report. For short- or long-term disabilities, mean daily wages were reduced to 70% of typical wages. Productivity time loss and costs were reported per-patient-per-month (PPPM) for each lymphoma. Results: The final patient cohort included 3,450 CLL, 448 MCL, 1,052 MZL and 394 WM patients; the caregiver cohort included 1,435 CLL, 171 MCL, 437 MZL and 190 WM caregivers. Among eligible patients, there were higher proportions of patients that had absentee claims (CLL, 76%; MCL, 72%; MZL, 72%; WM, 82%), followed by short-term disability (CLL, 16%; MCL, 36%; MZL, 18%; WM, 17%) and long-term disability (CLL, 3%; MCL, 10%; MZL, 3%; WM, 3%) (Figure 1A). The proportions of caregivers with absentee claims (CLL, 78%; MCL, 90%; MZL, 69%; WM, 75%) were also higher than those with short-term disability (CLL, 7%; MCL, 10%; MZL, 4%; WM, 8%) (Figure 1B). For all 4 lymphoma types, average illness-related absentee hours were higher in patients than caregivers (CLL, 9.5 vs 6.9; MCL, 44.5 vs 3.6; MZL, 17.0 vs 5.0; WM, 18.2 vs 8.1). A similar pattern was observed for short-term disability days (CLL, 6.9 vs 4.2; MCL, 10.8 vs 3.4; MZL, 7.0 vs 2.2; WM, 6.7 vs 4.8). Average PPPM indirect costs were higher for patients with long-term disability (CLL, $1,433; MCL, $1,233; MZL, $1,302; WM, $2,056) than with short-term disability (CLL, $1,203; MCL, $1,950; MZL, $1,145; WM. $1,177) or absentee claims (CLL, $365; MCL, $1,606; MZL, $612; WM, $662), except for patients with MCL (Figure 2A). Similar trends were observed among caregivers, though the indirect costs due to absenteeism and short-term disability were higher in patients than caregivers (Figure 2B). Conclusions: This real-world evidence study uncovered patients with CLL, MCL, MZL and WM and their caregivers incur substantial disease burden as shown by their productivity loss and indirect costs. Effective treatments that can offer a cure or better remission rates and shorter duration with less toxicity may not only enhance the patients and caregivers' quality of life but also reduce work loss. The availability of oral, targeted therapies has resulted in higher remission rates, durable responses, manageable toxicities and improved quality of life in trials. Future studies are needed to understand the impact of these oral, targeted therapies on patients' and caregivers' productivity. Figure 1 Figure 1. Disclosures Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Irwin: IBM Watson Health: Current Employment; BeiGene, Ltd.: Consultancy. Packnett: IBM Watson Health: Current Employment; BeiGene, Ltd.: Consultancy. Lew: BeiGene, Ltd.: Consultancy; IBM Watson Health: Current Employment. Noxon: BeiGene, Ltd.: Consultancy; IBM Watson Health: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Chanan-Khan: BieGene, Jansen, Ascentage: Consultancy; BeiGene, Jansen, Ascentage: Honoraria; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Cellectar: Current equity holder in publicly-traded company; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Ascentage: Research Funding.

Abstract Introduction: Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) are the most common types of leukemia in adults in the United States. The US veteran population, predominantly older males, are at high risk for CLL/SLL, especially with prior exposure to Agent Orange or other herbicides during military service. With the increasing availability of novel agents and associated improved survival, there is a need to assess the real-world evidence of CLL/SLL burden in US veterans, as well as the clinical and economic outcomes associated with current treatments. The objective of this retrospective cohort study was to examine the clinical burden, costs and healthcare resource utilization of CLL/SLL in veterans. Methods: Adults who were newly diagnosed with CLL/SLL were identified in the Veteran Health Administration dataset from October 2014 to September 2019. Eligible patients were required to have at least 2 visits with CLL/SLL diagnosis, and continuous enrollment of 6 months pre- and 3 months post-index date, defined by the first diagnosis date. The study population was further required to have at least 1 CLL/SLL treatment on or after the index date. Treatment regimens were identified by line of therapy and categorized mutually exclusively as: bendamustine-based (alone or in combination) therapy, other chemotherapies, ibrutinib, rituximab-monotherapy, or other regimen. Descriptive analyses were conducted to examine patient sociodemographic characteristics, comorbidities, concurrent medications, and treatment patterns including the frequency and duration of each treatment regimen. Adherence was measured by discontinuation and switching rates. Discontinuation was defined as no treatment for 90 days from the last day of supply during the study period. To ensure only patients who prematurely discontinued chemotherapy treatment and not those who completed their treatment cycles are captured, premature discontinuation was defined as a treatment duration of <90 days for bendamustine-based and <120 days for rituximab monotherapy. Costs and healthcare resource utilization were examined by first-, second-, and third-line therapy. Healthcare resource utilization examined included hospitalization and length-of-stay (LOS). Total costs were reported for all-cause and CLL/SLL-related, and calculated as the sum of inpatient, outpatient and pharmacy costs per-patient-per-month (PPPM). Multivariable logistic regression was conducted to examine factors associated with costs, frequency and LOS of hospitalizations. Results: Among the 13,664 veteran patients diagnosed with CLL/SLL, 79% were in watch-and-wait and the final study population consisted of 2,861 patients who received at least 1 line of CLL/SLL therapy (mean duration=465 days). Most patients were elderly (median age =70 years), white (83%), and male (98%). Approximately 39% of veterans had concurrent use of proton pump inhibitors at baseline. Average time to treatment initiation from diagnosis to first-line therapy was 315 days. A total of 770 (26.9%) patients further received second-line therapy (mean duration of treatment=318 days) and 199 (7.0%) patients received third-line therapy (mean duration of treatment=229 days). Ibrutinib was the most common treatment regimen across all lines of therapy (first-line: 39%; second-line: 55%; third-line: 43%) with discontinuation rates at 59.6%, 60.1%, and 55.2% in first-, second-, third-line therapy respectively (Figure 1 and 2). The CLL/SLL-related hospitalization rate was 39% with an average LOS of 7 days. Total PPPM all-cause and CLL/SLL-related costs were $26,709 and $17,233, respectively; these costs were increased by line of therapy. Controlling for patient clinical and demographic covariates, treatment discontinuation and treatment switching were statistically significant predictors of higher inpatient admissions, LOS of hospitalizations, and costs. Conclusions: This real-world data demonstrated significant clinical and economic burden associated with CLL/SLL among the US veterans. Furthermore, the suboptimal adherence, as reported by high treatment discontinuation rates and its impact on increasing costs and healthcare resource use, highlights the real-world unmet needs of CLL/SLL management in the veteran population. Future studies are needed to further understand the long-term outcomes of each treatment regimen. Figure 1 Figure 1. Disclosures Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Chanan-Khan: Ascentage: Research Funding; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BieGene, Jansen, Ascentage: Consultancy.

Abstract Introduction: Chronic lymphocytic leukemia (CLL) is the most frequently diagnosed hematologic cancer, with many patients diagnosed at a later stage in life and typically with comorbidities that often complicate CLL management. Atrial fibrillation (AF) is the most common arrhythmia in the United States and is associated with high hospitalization and mortality rates. While the relationship between CLL and AF has been reported, there is limited real-world evidence on the clinical and economic impact of AF in CLL patients. The objectives of this study were to examine the impact of AF on cardiovascular (stroke, bleeding events, heart failure) and economic (costs and healthcare resource utilization [HRU]) outcomes among patients with CLL. Methods: This retrospective observational study used the IBM MarketScan Research Databases in Treatment Pathways that includes at least a 10-million sample of the commercial and Medicare supplemental claims database. Patients who were at least 18 years, diagnosed with CLL (identified by ICD-9/ICD-10) and continuously enrolled from January 2009 to July 2020 were included. CLL patients were followed up for one year after their first CLL diagnosis date to examine the incidence of AF. Cardiovascular outcomes were evaluated as the incidence of stroke, bleeding events, and heart failure among the CLL patients with and without AF. Costs and HRU were assessed following up until 1 year after the first date of AF, stroke, bleeding events, and heart failure. HRU was evaluated for outpatient, emergency room (ER), inpatient, and pharmacy visits, and by length of stay (LOS) for hospitalizations. Costs were evaluated in overall population and by HRU type. Statistical differences in clinical outcomes between patients with and without AF were compared using chi-square tests. The Mann Whitney Wilcoxon test was used to compare the medians for the HRU and cost outcomes. The associations between AF and hospitalizations as well as costs were evaluated by multivariable logistic regression and generalized linear model, respectively. Statistical significance was determined at a P-value of less than 0.05. Results: Among the total of 23,756 newly diagnosed CLL patients (median age 68 years, 57.83% male) included in the study, 11% had AF within 1 year of the CLL diagnosis. CLL patients who had AF were significantly older (median age: 67 vs 82 years) and had more male patients (56.9% vs 65.1%) compared to CLL patients without AF. Significantly higher rates of stroke (12.67% vs. 4.97%), bleeding events (17.45% vs. 8.53%), and heart failure (31.14% vs. 4.70%) were observed in CLL patients with AF than those without (Figure 1). Compared to the CLL cohort without AF, adjusted regression analysis indicated that overall, CLL cohort with AF was twice as likely to be hospitalized (odds ratio [OR]=2.03) and incurred 44% higher total costs (cost ratio [CR]=1.44). Further examining the impact of AF-related cardiovascular outcomes, we observed that CLL patients with AF who developed stroke, bleeding events, and heart failure had statistically significant higher HRU (outpatient, ER, inpatient, and pharmacy visits), longer LOS, and costs (total, outpatient, pharmacy) than CLL patients without AF. After adjusting for demographic and clinical confounders, significantly higher hospitalization rates and costs were also reported in the CLL cohort who had AF with further stroke (OR=2.59; CR=1.36), bleeding events (OR=3.27; CR=2.03), and heart failure (OR=5.47; CR=2.07) compared to the CLL cohort without AF. Conclusions: The findings of this real-world study demonstrated significantly higher hospitalizations, cardiovascular events, and economic burden incurred by CLL patients who had AF than those without. The presence of stroke, bleeding events, heart failure among CLL patients with AF further increased the HRU and costs. This study highlighted the importance of better disease management, more intentional monitoring for AF and improved CLL therapeutics with a lower risk of AF or cardiovascular toxicity to prevent or minimize the incidence of AF in CLL patients. Figure 1 Figure 1. Disclosures Mohan: BeiGene, Ltd.: Current Employment. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Dick: IBM Watson Health: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Chanan-Khan: Ascentage: Research Funding; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; BieGene, Jansen, Ascentage: Consultancy.