Chanan‐Khan, Asher

Abstract Introduction: Plamotamab (XmAb13676) is a humanized bispecific antibody that binds both CD20 and CD3 to recruit cytotoxic T cells to kill CD20 expressing malignant cells. Interim results of an ongoing first-in-human (FIH), dose-escalation study (XmAb13676-01; NCT02924402) in subjects with relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL) are reported. Methods: The study is an FIH, multi-center, open-label, phase 1, dose-escalation study in subjects with R/R NHL with a standard 3 + 3 design. The primary objectives are to determine safety, tolerability, and the maximum tolerated dose (MTD) or recommended dose of plamotamab. Secondary objectives include preliminary anti-tumor activity and pharmacokinetics/pharmacodynamics of plamotamab. This study has 3 Parts: Part A, escalating dose cohorts that establish an initial priming dose as part of repeated weekly infusions at a fixed, weight-based dose in a 28-day cycle; Part B, with a dosing schedule consisting of a priming dose on Cycle 1 Day 1, established in Part A, followed by step-up dosing (SUD) on subsequent weeks; and Part C is an SUD regimen with flat and less frequent dosing. Cytokine release syndrome (CRS) prophylaxis with dexamethasone, antihistamine, and acetaminophen was mandated prior to each administration of plamotamab. Treatment was continued for 2 cycles or longer if there was evidence of therapeutic benefit. Results: At data cut-off (01Jul2021), 80 subjects with NHL have been treated. Subjects had a median age of 62 years (range 32-89), a median of 4 prior therapies (range 1-10), and had been diagnosed a median of 28 months (range 6-353) prior to treatment in the study. The most common treatment-related adverse event was CRS. Overall, 50 subjects (62.5%) experienced CRS, with 4 (5.0%) experiencing Grade ≥ 3 CRS. No related neurotoxicity >Grade 2 has been observed. Treatment responses for NHL were assessed by the Lugano criteria or International Working Group criteria for Waldenström Macroglobulinemia. There have been 23 objective responses (43.4% overall response rate [ORR]) and 13 (38.2%) at doses of ≥ 80 µg/kg or flat dosing in all evaluable subjects with NHL and diffuse large cell B-cell lymphoma, respectively. In the efficacy-evaluable, follicular lymphoma population, at doses of 80-360 µg/kg or flat dosing, objective responses were observed in 8/10 (80%) subjects. After implementation of flat dosing, as opposed to weight-based dosing, a 50% ORR (4/8 evaluable subjects) has been observed in NHL subjects in that cohort. An MTD has not been reached, and dose escalation is ongoing. Overall, 4 out of 16 (25%) evaluable subjects with prior CAR-T therapy responded to plamotamab. Conclusions: Plamotamab demonstrated evidence of clinical activity in heavily pretreated subjects with R/R NHL. CRS was generally manageable with premedication. The study is ongoing with further optimization of dose and schedule. Figure 1 Figure 1. Disclosures Patel: Kite Pharma: Consultancy, Speakers Bureau; Genentech: Consultancy; Morphosys: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; ADC Therapeutics: Consultancy; Lilly: Consultancy. Michot: GSK: Honoraria; Celgene: Honoraria; MSD: Consultancy, Honoraria; Innate Pharma: Research Funding; Incyte: Research Funding; H3 biomedecine: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Gamamabs: Research Funding; Forma: Research Funding; Exelixis: Research Funding; Eos: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo,: Research Funding; Clovis: Research Funding; Chugai: Research Funding; Boeringer Ingelheim: Research Funding; Celgene: Research Funding; Blueprint: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Aduro: Research Funding; Abbvie: Research Funding; ASTEX: Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Research Funding; Roche: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chanan-Khan: Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Ascentage: Research Funding; 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. Ghesquieres: Janssen: Honoraria; Mundipharma: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Honoraria; Gilead Science: Consultancy, Honoraria. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Portell: Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; SeaGen: Research Funding; Targeted Oncology: Honoraria; Aptitude Health: Honoraria; Abbvie: Research Funding; Pharmacyclics: Honoraria; Kite: Honoraria, Research Funding; Merck: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Morphosys: Honoraria; TG Therapeutics: Honoraria, Research Funding; Genentech: Research Funding; VelosBio: Research Funding. Solh: Jazz Pharmaceuticals: Consultancy; Partner Therapeutics: Research Funding; BMS: Consultancy; ADCT Therapeutics: Consultancy, Research Funding. Wierda: Loxo Oncology, Inc.: Research Funding; GSK/Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; Gilead Sciences: Research Funding; KITE Pharma: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma Inc.: Research Funding; Xencor: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Karyopharm: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Johnson: Xencor: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Garcha: Xencor: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Promedim: Ended employment in the past 24 months. Ribrag: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. Liebowitz: Xencor: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Phillips: Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding.

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 Background: The phase 3 head-to-head trial of acalabrutinib (acala) vs ibrutinib (ibr) (NCT02477696) demonstrated noninferior efficacy and improved tolerability with acala in previously treated CLL (Byrd J Clin Oncol 2021). We now report additional data to further characterize BTKi-related adverse events (AEs) and the safety profile of acala and ibr, including measures of AE burden that account for frequency, duration, and drug exposure, which are not captured by incidence alone. Methods: Patients (pts) received oral acala 100 mg BID or ibr 420 mg QD until disease progression or unacceptable toxicity. Overall incidence, exposure-adjusted (exp-adj) incidence, and exp-adj time with event (sum of event durations [all grades]*100/sum of treatment-emergent period [for all pts in each arm]) were assessed for the most common BTKi-related AEs. Atrial fibrillation (afib)/flutter, hypertension (htn), and bleeding events were further characterized by time to onset, cumulative incidence by Kaplan-Meier method, pt subgroup, and AE management. Results: A total of 533 pts (acala, n=268; ibr, n=265) were randomized; median treatment exposures were 38.3 and 35.5 mo, respectively. Incidence and exp-adj incidence and time with event are reported for the most common AEs and events of clinical interest (ECIs) (Table). Among cardiovascular (CV) ECIs, incidences of any-grade afib/flutter, htn, and bleeding were statistically higher with ibr, with higher exp-adj incidence (2.0-, 2.8-, and 1.6-fold, respectively) and exp-adj time with event (2.8-, 3.7-, and 1.8-fold). Ventricular arrhythmias were reported in 3 ibr-treated pts vs 0 pts in the acala arm. Among other BTKi-related AEs, incidences of any-grade diarrhea, arthralgia, contusion, urinary tract infection (UTI), back pain, muscle spasms and dyspepsia were statistically higher with ibr, with a 1.5- to 4.1-fold higher exp-adj incidence, and a 1.4- to 13.1-fold higher exp-adj time with event (except for UTI, which had a 1.4-fold lower exp-adj time with event for ibr). Incidences of headache and cough were statistically higher with acala, with a 1.6- and 1.2-fold higher exp-adj incidence, respectively, and a 1.4- and 1.1-fold higher exp-adj time with event. The total exp-adj time with event for all any-grade AEs was 37% higher with ibr (234 [acala] vs 320 [ibr] mo/100 person-mo). For any-grade afib/flutter, median time to onset was longer for acala vs ibr (28.8 vs 16.0 mo), and cumulative incidence was lower for acala at 6 mo (2% vs 6%), 12 mo (3% vs 8%), 18 mo (4% vs 10%), and 24 mo (5% vs 12%). Afib/flutter also occurred less frequently with acala vs ibr in subgroups of age (<65 y: 3% vs 7%; ≥65 y: 15% vs 23%), prior line of therapy (1-3: 10% vs 16%; ≥4: 7% vs 19%), and among pts without prior history (6% vs 15%). Cox proportional-hazards (PH) analysis of new-onset afib/flutter showed a 63% rate reduction favoring acala (Figure 1). Among all pts, concomitant medication use for afib/flutter was less common for acala (8%) vs ibr (14%), with antithrombotic use reported in 5% vs 9% of pts, respectively. For any-grade htn, median time to onset was similar for acala and ibr (8.1 vs 7.0 mo), but cumulative incidence was lower for acala at 6 mo (5% vs 12%), 12 mo (6% vs 16%), 18 mo (8% vs 20%), and 24 mo (8% vs 23%). Htn also occurred less frequently with acala vs ibr in subgroups of age (<65 y: 9% vs 23%; ≥65 y: 10% vs 23%), prior line of therapy (1-3: 10% vs 25%; ≥4: 4% vs 11%), and among pts without prior history (7% vs 23%). Cox PH analysis of new-onset htn showed a 77% rate reduction favoring acala (Figure 2). No dose reductions or treatment discontinuations due to htn occurred in either arm. Concomitant medication use for htn was less common for acala (5%) vs ibr (19%). For any-grade bleeding events, the median time to onset was similar for acala vs ibr (1.2 vs 1.2 mo), and cumulative incidence was lower for acala at 6 mo (29% vs 42%), 12 mo (32% vs 45%), 18 mo (34% vs 49%), and 24 mo (38% vs 51%). Bleeding events also occurred less frequently with acala vs ibr in most subgroups of age (<65 y: 26% vs 47%; ≥65 y: 49% vs 55%) and prior line of therapy (1-3: 39% vs 54%; ≥4: 32% vs 30%). Bleeding events were associated with dose reduction in 3 vs 2 pts in the acala vs ibr arms, respectively, and led to treatment discontinuation in 2 vs 4 pts. Conclusions: In this head-to-head trial of BTKis in CLL, event-based analyses demonstrated a higher BTKi-related toxicity burden with ibr, with a lower impact of CV-related toxicity with acala across subgroups. Figure 1 Figure 1. Disclosures Seymour: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. 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; BeiGene, Jansen, Ascentage: Honoraria; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BieGene, Jansen, Ascentage: Consultancy. Furman: Genentech: Consultancy; Sanofi: Consultancy; Morphosys: Consultancy; Incyte: Consultancy; Beigene: Consultancy; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; X4 Pharmaceuticals: Consultancy; Sunesis: Consultancy; Acerta/AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; Pharmacyclics: Consultancy; Oncotracker: Consultancy; Janssen: Consultancy, Honoraria; Verastem: Consultancy; AstraZeneca: Honoraria. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. Mato: Genmab: Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; MSKCC: Current Employment; Acerta/AstraZeneca: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Kuptsova-Clarkson: AstraZeneca: Current Employment, Current equity holder in publicly-traded company; AbbVie: Current holder of individual stocks in a privately-held company. Miranda: ASTRAZENECA: Current Employment; ASTRAZENECA: Current equity holder in publicly-traded company. Wagner: AstraZeneca: Current Employment. Higgins: AstraZeneca: Current Employment; PROMETRIKA, LLC: Ended employment in the past 24 months. Sohoni: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Revolution Medicines: Current Employment, Current equity holder in publicly-traded company; Theravance: Current equity holder in publicly-traded company. Jurczak: AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months; European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy.

Abstract INTRODUCTION Sparse data exist regarding I+V in an off-trial setting, particularly in patients (pts) with progression of disease on either I or V as single agent treatment. The 1-year overall survival (OS) rates with V monotherapy following I range from 75%-91% (Eyre et al, BJH 2019; Jones et al, Lancet Oncol 2018); however, longer-term follow-up of these or other patient cohorts treated with V after I has not yet been reported. Effective options in double-refractory pts are lacking when a clinical trial is not feasible. Here, we report our experience with I+V in these patient groups. METHODS After IRB approval, we reviewed the records of pts seen at Mayo Clinic (between 4/2012-1/2021) who received I+V therapy off-trial for CLL progression. Pts treated with I+V for Richter's transformation were excluded. Time to next treatment (TTNT) was measured from I+V treatment start date to the date of next treatment start or last known treatment status with death as a competing risk. OS was measured from I+V start date until date of death or when the patient was last known alive; OS was analyzed using the Kaplan-Meier method and Cox proportional hazards model. RESULTS Thirty-three pts with progressive CLL were treated with I+V (median duration 13.3 months [95% CI: 7.1 months-not estimable (NE)]). The median age was 70 years (range 47-86), 6 (18%) were women, and 20 (65%) had del(17p) or TP53 mutation. The median number of prior lines of therapy was 3 (range 1-15). Additional characteristics at the time of I+V start are shown in Table 1. Median follow-up from start of I+V was 23.8 months. Among 22 pts with prior progression on I only (V-naïve), the median duration of I+V was 14.8 months (95% CI 7.6 months-NE). The median duration on either I or V from the start of combination was 20.3 months (95% CI 8.3 months-NE). The median TTNT was 25.1 months (Figure 1A). Four pts proceeded to cellular therapy (alloSCT [n=3], CAR-T [n=1]) while on I+V. Next therapy (n=9) consisted of Richter transformation treatment (n=2), chemotherapy plus continued I+V (n=1), anti-CD20 plus continued I+V (n=1), duvelisib + I (n=1), TP-0903 + I (n=1), reintroduction of I at disease progression after previously stopping I during I+V therapy (n=1), and reintroduction of I (n=1) or V (n=1) at disease progression after previously stopping I+V. Of 9 pts who did not receive subsequent therapy, 4 pts remain on I+V (median duration 16.4 months), 4 pts continued V after discontinuing I (median duration on V from start of I+V was 21.5 months), and 1 pt discontinued I+V following a second cancer diagnosis and died without receiving additional CLL-directed treatment. Eleven pts received I+V in the double-refractory setting; 9 pts had prior disease progression on sequential I then V and 2 pts had prior disease progression on sequential V then I. The median duration of I+V was 7.5 months (95% CI 4.3 months-NE), and the median duration of either agent from I+V start was 10.8 months (95% CI 7.1 months-NE). The median TTNT was 14.0 months (Figure 1A). Eight pts required additional treatment, consisting of PI3K inhibitor (n=2), anti-CD20 added to I+V (n=1), CAR-T (n=1), anti-CD20 with (n=1) or without (n=1) bendamustine added to continued I, and Richter transformation treatment (n=2). One pt continues I+V (17.4 months ongoing) without further treatment. Two pts died from disease progression without receiving additional treatment. The median OS of all 33 pts was 27.4 months (95% CI 25.9 months-NE; Figure 1B). The median OS of the 22 pts with prior progression on I (V-naïve) was 47.1 months (95% CI 27.7 months-NE), and the median OS of the 11 pts with prior progression on I and V separately was 27.0 months (95% CI 15.5 months-NE). In univariate analyses, prior progression on V was a predictor of shorter OS (HR=3.9; 95% CI 1.4-11.2; p=0.01). CONCLUSIONS Combination I+V therapy in heavily pre-treated CLL pts who have disease progression after I provides durable benefit with a median OS approaching 4 years. In the double-refractory setting, repurposing both drugs as combination I+V therapy can be a useful strategy, despite the short-term disease control, for pts where clinical trial options are limited or not available. Further examination of these approaches in larger cohorts and understanding the operative resistance mechanisms in pts with double-refractory disease are key next studies. Figure 1 Figure 1. Disclosures Ding: Octapharma: Membership on an entity's Board of Directors or advisory committees; DTRM: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chanan-Khan: BeiGene, Jansen, Ascentage: Honoraria; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage: Research Funding; 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. Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding. Wang: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Novartis: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees. Ailawadhi: Pharmacyclics: Consultancy, Research Funding; Xencor: Research Funding; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; Sanofi: Consultancy; BMS: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Ascentage: Research Funding; Medimmune: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Research Funding; Beigene: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Genentech: Consultancy. Koehler: AbbVie: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Kay: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Combination ibrutinib and venetoclax in patients with relapsed CLL.

Abstract Background: BCL-2 inhibition with venetoclax has proved to be highly effective treatment for patients with CLL. However, when administered to patients with CLL who have a high tumor burden, venetoclax is associated with an elevated risk of tumor lysis syndrome (TLS). Because of this risk, venetoclax is initiated with a gradual, 5-week dose ramp-up, requiring close laboratory monitoring over an extended period. Lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor under clinical development for hematologic malignancies (HMs). Preliminary data in 18 patients with CLL treated in a first-in-human study suggested the feasibility of an abbreviated ramp-up of lisaftoclax that might also result in a lower incidence of neutropenia (Ailawadhi et al, J Clin Oncol 39, 2021; abstr 7502). Methods: This new study is a global, open-label, multicenter, two-part phase 1b dose escalation and dose expansion study to assess the safety and tolerability of lisaftoclax (Part 1) and lisaftoclax combined with rituximab or acalabrutinib (Part 2), including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). The trial is enrolling adults with (1) histologically confirmed CLL/SLL (by 2018 iwCLL criteria) that is relapsed or refractory to ≥ 1 prior therapy and requires treatment (also by 2018 iwCLL criteria); (2) adequate bone marrow function (in the absence of growth factors), including absolute neutrophils ≥ 1.0 × 10 9/L in patients without bone marrow involvement (not required in CLL/SLL patients with bone marrow involvement); and (3) adequate renal and hepatic function. Exclusion criteria: (1) recent history of allogeneic stem cell transplantation or CAR T-cell therapy (< 90 days); (2) prior treatment with a BCL-2 inhibitor (unless patient discontinued such therapy without disease progression); (3) treatment with vitamin K anticoagulants or previous discontinuation of treatment due to acalabrutinib toxicity (in acalabrutinib plus lisaftoclax cohort); (4) active Richter's syndrome; (5) infection (e.g. HIV, hepatitis); (6) CNS involvement; (7) prior cancer that has recurred within 2 years of screening and requires treatment (apart from adequately treated cervical or breast carcinoma in situ); (8) uncontrolled and other serious concomitant illnesses, including cardiovascular disease and diabetes; (9) failure to recover adequately after surgical procedures; and (10) active graft-vs-host disease or a requirement for immunosuppressive treatment. In a standard "3+3" dose escalation design (Part 1), lisaftoclax is being administered orally once daily in a 28-day cycle, with full doses of 200 to 1,200 mg (by 200-mg increments at 4 dose levels (400, 600, 800, and 1,000 mg) in parallel. The ramp-up is performed in the hospital with close monitoring for TLS and consists of the following doses and days of lisaftoclax treatment: 20 mg on Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5, 600 mg on Day 6, 800 mg on Day 7, and 1,000 mg on Day 8. Patients who experience TLS on any of these days have their dose held until resolution of TLS before proceeding to the next dose. Part 2 includes a further standard 3+3 dose escalation of lisaftoclax combined with rituximab or acalabrutinib (in separate cohorts), with a further planned dose expansion at recommended phase 2 doses of these combination regimens. Primary outcome measures are (1) DLTs observed during cycle 1; and (2) MTD (measured over the same interval). DLT criteria are defined as grade 4 thrombocytopenia or neutropenia lasting > 7 days, grade 3 ≥ thrombocytopenia with bleeding, grade 4 febrile neutropenia, or grade 3 ≥ non-hematologic toxicities. As of July 19, 2021, 71 patients have been enrolled (of 144 planned). Clinicaltrial.gov identifier: NCT04215809. Disclosures Davids: Ascentage Pharma: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Pagel: Gilead: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Incyte/MorphoSys: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy; Actinium Pharmaceuticals: Consultancy; MEI Pharma: Consultancy; Pharmacyclics/AbbVie: Consultancy. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Usenko: Abbvie: Honoraria; Acerta: Honoraria; Ascentage: Honoraria; AstraZeneca: Honoraria; Celgene: Honoraria; Il Yang: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Oncopeptides: Honoraria; Rigel: Honoraria; Takeda: Honoraria; UCB: Honoraria. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Huang: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Li: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Ahmad: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Mudenda: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

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: Prognostic testing, including immunoglobulin heavy-chain variable region gene (IgHV) mutation status, cytogenetic abnormalities by fluorescence in situ hybridization (FISH), and immunophenotyping has been recommended in all newly diagnosed patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) prior to treatment initiation, and even in previously treated patients in some settings. Recent data have shown that disease with high-risk genetic features is better managed with novel agents than traditional chemoimmunotherapy. As such, the need for testing has become more relevant for disease management. However, there is limited recent data on real-world patterns of testing for risk factor assessment and in-turn, patterns of evidence-based treatment selection. This study aimed to examine: (1) the frequency and results of testing, (2) timing of testing by line of therapy, and (3) factors associated with the receipt of testing. Methods: De-identified data from the Flatiron Health EHR-derived database was used to identify patients who were ≥18 years old with newly-diagnosed CLL/SLL, who had ≥6-month continuous enrollment, and no prior treatment from January 2014 to May 2021. Testing evaluated included IgHV mutation status, FISH cytogenetic (11q deletion [del(11q)], 13q deletion [del(13q)], 17p deletion [del(17p)], Trisomy 12 [+12]) and other biomarkers (including CD38 and ZAP-70) by immunophenotyping. Descriptive analyses were conducted to examine the frequency and results in the overall population, and compared by patient characteristics and across sociodemographic groups. Multivariable logistic regression was conducted to examine factors associated with the likelihood of receiving testing. Statistical significance was determined as a p-value of <0.05. Results: A total of 3,037 CLL patients were included (median age=73, 62.3% male, 74.6% white). The majority of patients (92%) received treatment in community practices, with 54.1% commercially-insured. We observed over half of CLL patients did not receive risk factor testing (Figure 1): IgHV mutation analyses (76.2%, n=2,315), FISH (61.5%, n=1,868) and immunophenotyping (72.1%, n=2,190). Of those who had testing, the majority (99%) had it done once prior to starting first-line therapy. Significant differences in the receipt of testing were observed between different age, gender, race/ethnicity, and regional subgroups (Table 1). Among patients who received testing, the presence of high-risk biomarkers was as follows: unmutated IgHV (56.1%), del(17p) present (14.4%), del(11q) present (16.9%), and CD38 present (30.8%). Compared to patients <65 years, testing results in elderly patients ≥65 years showed a lower presence of unmutated IgHV (53.8%) and del(11q) (15.7%) while higher del(17p) (14.7%) and +12 (28.1%). No significant disparity was observed in white vs. non-white patients except for a lower incidence of mutated IgHV and del(13q) presence. Compared to tested men, tested women had a lower presence of unmutated IgHV (53.9%), del(11q) (11.4%) and CD38+ (25.8%) while higher del(17p) (18.2%). We then investigated the impact of risk testing on therapy selection, and noted that patients with del(17p) had a higher likelihood than those who tested negative (73.6% vs. 48.4%) of being treated with novel agents (ibrutinib, acalabrutinib, or venetoclax). In contrast, 26.4% of those who tested del(17p) present and 39.8% among those who did not get tested received chemotherapy. Multivariable regression showed that patients who were older (≥65 years), female or those living in the west of U.S. were significantly less likely to receive testing. Conclusions: The NCCN guidelines recommend novel agents for patients with high-risk CLL/SLL. Thus, all patients are advised to complete risk-factor testing for both prognostication and selection of optimal, evidence-based therapy. Our real-world data highlights not only a significant gap in testing, but that this suboptimal testing is more common in vulnerable populations. We observed that despite identification of del(17), a quarter of CLL patients failed to receive novel agents in the frontline setting. Our analysis identified an unmet need for further education and refinement of clinical practice. This is necessary to achieve the best clinical outcome in CLL patients through robust risk-assessment testing and optimal therapeutic triaging. Figure 1 Figure 1. Disclosures Chanan-Khan: BieGene, Jansen, Ascentage: Consultancy; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage: Research Funding; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BeiGene, Jansen, Ascentage: Honoraria. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Zimmerman: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Ascentage: Research Funding; Medimmune: Research Funding; Pharmacyclics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Xencor: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Cellectar: Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; AbbVie: Consultancy; Beigene: Consultancy; Takeda: 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.