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7510 Background: FL is the most common type of indolent non-Hodgkin lymphoma. Approved treatment options are limited for pts with R/R FL. In a phase 1b trial ( Blood Adv. 2020;4(19):4802-4811), ZO was found to be tolerable and associated with early signal of efficacy. ROSEWOOD (BGB-3111-212) is a phase 2, randomized study designed to assess efficacy and safety of ZO vs O in pts with R/R FL. Methods: Pts with R/R FL who received ≥2 lines of therapy, including an anti-CD20 antibody and an alkylating agent, were randomized 2:1 to receive either ZO or O. O was given in both arms on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycles 2-6, and then every 8 weeks up to 20 doses maximum. Z (160 mg twice daily) was given until progressive disease (PD) or unacceptable toxicity; Pts with confirmed PD in the O arm were allowed to crossover to ZO. Primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoint included ORR by investigator after crossover. Primary analysis cutoff was October 8, 2021. Results: A total of 217 pts were randomized to ZO (n = 145) or O (n = 72). Median study follow-up was 12.5 mo; median age was 64 yrs. Incidence of high FL International Prognostic Index score was 53% (ZO) and 51% (O). Pts received a median of 3 prior lines of therapy, with 28% (ZO) and 25% (O) of pts receiving > 3 lines. Proportion of pts refractory to rituximab, refractory to the most recent line of therapy, or with PD within 24 mo of initiation of first-line immunochemotherapy was 54%, 32% and 28% with ZO and 50%, 40% and 32% with O, respectively. The study met its primary endpoint: ORR was 68.3% with ZO vs 45.8% with O ( p= 0.0017). CRR was 37.2% (ZO) vs 19.4% (O); 18-mo DOR rate was 70.9% (ZO) vs 54.6% (O); and median PFS was 27.4 mo (ZO) vs 11.2 mo (O; hazard ratio [HR], 0.51 [95% CI, 0.32-0.81], p= 0.0040). Median time to new anti-lymphoma therapy or crossover was not evaluable (NE; ZO) vs 12.1 mo (O; HR, 0.37 [95% CI, 0.23-0.60], p< 0.0001). ORR for 29 pts who crossed over to ZO was 24.1%. Median OS was NE; 18-mo OS probability was 85.4% (ZO) vs 72.6% (O). Most common any grade AEs in the ZO arm were thrombocytopenia (34.3%), neutropenia (27.3%), diarrhea (16.1%), fatigue (14.0%), constipation (13.3%), cough (11.9%), pyrexia (11.2%), and dyspnea (10.5%). Grade ≥3 AEs with incidence > 5% with ZO were neutropenia (22.4%) and thrombocytopenia (14.0%); incidence of atrial fibrillation was 0.7% and major bleeding was 1.4%. Incidence of treatment-emergent AEs leading to death was 5.6% (ZO) and 9.9% (O). Conclusions: ZO demonstrated superior efficacy to O in treatment of pts with R/R FL. ZO had a favorable benefit-risk profile and represents a potential combination therapy for pts with R/R FL. Clinical trial information: NCT03332017.

TPS7591 Background: Patients (pts) with refractory or relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes with standard treatment. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca), an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin, is approved in R/R DLBCL based on data from the phase 2 LOTIS-2 trial (Caimi et al. Lancet Oncol 2021). Rituximab (R) is part of standard immunochemotherapy for DLBCL, both as frontline therapy and in subsequent treatments. Preclinical evidence suggests that the addition of rituximab to anti-CD19 ADC therapy may result in prolonged tumor control (Ryan et al. Blood 2017). LOTIS-5 aims to evaluate Lonca-R vs. standard immunochemotherapy of R + gemcitabine + oxaliplatin (R-GemOx) in pts with R/R DLBCL. Methods: This is a phase 3 randomized open-label, two-part, two-arm multicenter study of Lonca-R in pts with R/R DLBCL (NCT04384484). A review of safety data from the nonrandomized safety run-in (Part 1), comparing the safety of Lonca-R to previous Lonca safety data, was completed in January 2022. The trial is now continuing to the randomized phase (Part 2). In Part 2, approximately 330 pts will be randomized 1:1 to receive Lonca-R or R-GemOx. The primary objective of the study is to evaluate the efficacy of Lonca-R versus R-GemOx. The primary endpoint is progression-free survival by independent central review (ICR). Secondary endpoints include overall survival, overall response rate (by ICR using 2014 Lugano classification), complete response rate by ICR, duration of response by ICR, frequency and severity of adverse events, changes from baseline in safety laboratory and clinical variables, concentration and pharmacokinetic parameters of Lonca (conjugated and total antibody and unconjugated warhead), immunogenicity, and changes in patient-reported outcomes. The time to event endpoints will be analyzed based on the intent-to-treat population using a stratified log-rank test. The dosing regimen for Lonca-R: Lonca at 0.15 mg/kg + rituximab at 375 mg/m2 every 3 weeks (Q3W) for 2 cycles and then Lonca at 0.075 mg/kg + rituximab at 375 mg/m2 Q3W for up to 6 cycles. The dose regimen of R-GemOx: rituximab at 375 mg/m2, gemcitabine at 1000 mg/m2 Gem, and oxaliplatin at 100 mg/m2 every 2 weeks for up to 8 cycles. Key inclusion criteria include age ≥18 years, pathologic diagnosis of DLBCL (including pts with DLBCL transformed from indolent lymphoma) or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, ≥1 line of prior systemic therapy, not being a candidate for stem cell transplantation, and measurable disease per the 2014 Lugano classification. The randomized part of LOTIS-5 commenced in January 2022, and recruitment is ongoing. Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group. Clinical trial information: NCT04384484.

e19506 Background: Many patients (pts) with B-cell malignancies require continuous treatment with Bruton tyrosine kinase inhibitors (BTKi). Adverse events (AEs) are a common reason for ibrutinib (ibr) or acalabrutinib (acala) discontinuation. Early data from BGB-3111-215 showed zanubrutinib (zanu) was well tolerated in pts with B-cell malignancies intolerant to ibr or acala. We report preliminary results with a median follow-up of 4.2 mo. Methods: Pts meeting protocol criteria for intolerance to ibr, acala or both (without documented progressive disease) were given zanu monotherapy (160 mg twice daily or 320 mg once daily). Recurrence of AEs that led to intolerance of prior BTKi and additional safety measures were assessed based on the Common Terminology Criteria for AEs v5.0. Investigators determined responses using disease status at study entry as baseline. Results: As of November 1, 2020 (cutoff), 44 pts (n=34 chronic lymphocytic leukemia/small lymphocytic lymphoma, n=6 Waldenström macroglobulinemia, n=2 mantle cell lymphoma, n=2 marginal zone lymphoma) were enrolled, received ≥1 dose of zanu, and analyzed for safety. Median age was 70.5 y (range, 49-91); median duration of treatment was 4.2 mo (range, 0.1-12.6). Median number of prior regimens was 2 (range, 1-12). Regarding prior BTKi, 39 pts received ibr only, 4 received ibr and acala, and 1 received acala only. The median number of ibr- or acala-intolerant AEs per pt was 2 (range, 1-5). 83% of ibr and 78% of acala intolerant events did not reccur on zanu; Table. At data cutoff, 43 pts remained on treatment; 1 withdrew consent due to zanu-unrelated grade 3 syncope. Overall, 34 pts (77.3%) reported any AE; most commonly reported AEs were myalgia (n=9; 20.5%), contusion (n=8; 18.2%), dizziness (n=7; 15.9%), fatigue (n=7; 15.9%), and cough (n=5; 11.4%). Grade ≥3 AEs were reported in 6 pts (13.6%), serious AEs in 1 pt (2.3%, febrile neutropenia and salmonella infection), AEs requiring dose interruptions in 6 pts (13.6%), and AEs leading to dose reduction in 2 pts (4.5%). No AEs led to zanu discontinuation. No deaths were reported. All efficacy evaluable pts (26/26 [100%]) maintained (10 [38.5%]) or achieved deepening (16 [61.5%]) of their response. Conclusions: Zanu provides an additional treatment option after intolerance to other BTKi, demonstrating tolerability and sustained or improved efficacy. Updated results will be presented. Recurrence and Severity Change of AEs Leading to Ibr or Acala Intolerance. Clinical trial information: NCT04116437. [Table: see text]

Sodium valproate is hepatotoxic in both humans and rat hepatocytes. The toxicity is dose related and frequently associated with simultaneous ingestion of drugs which induce the drug metabolizing system. For these reasons, metabolites of sodium valproate were tested for toxicity using rat hepatocyte cultures. The sodium salts of three metabolites, 2-propylpent-4-enoate, 4-hydroxyvalproate, and perhaps 5-hydroxyvalproate, were toxic in this system. In addition, 2-propylpent-4-enoate was toxic in a dose-related fashion. All are omega and omega-1 oxidation products in the microsome-mediated pathway of valproate metabolism.