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Background Chimeric antigen receptor (CAR) T-cell therapies have recently been established as an important option for the management of relapsed/refractory (R/R) DLBCL. However, real-world studies suggest that approximately half of all patients (pts) receiving commercial CAR-T therapies will relapse within 6 months. These pts have a poor prognosis, with estimated overall survival (OS) of only 5 months, indicating a significant unmet need. Odronextamab is a novel, off-the-shelf, CD20×CD3 bispecific antibody that has demonstrated activity in both R/R follicular lymphoma and R/R DLBCL. We have previously reported encouraging results with odronextamab from the Phase 1 ELM-1 study (NCT02290951) in pts with R/R DLBCL post CAR-T therapy (Bannerji R, et al. Lancet Haematol. 2022). These results were consistent with the antitumor activity seen in pts with R/R DLBCL from the Phase 2 ELM-2 study (Kim WS, et al. ASH 2022). Here, we present an updated analysis of outcomes in a prespecified cohort of post CAR-T patients from ELM-1. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Revisions to the step-up regimen were reported previously (Bannerji R, et al. Lancet Haematol. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 160 mg on Days (D) 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg every 2 weeks until disease progression or unacceptable toxicity. Those pts who achieved a complete response (CR) that was durable for ≥9 months transitioned to dosing with 320 mg every 4 weeks. The primary endpoint was objective response rate (ORR), assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DoR), progression-free survival (PFS), and OS. Immune biomarker assessment was an exploratory endpoint. Results As of Dec 20, 2022, 46 pts were treated (safety-evaluable), with 44 pts evaluable for efficacy. For safety-evaluable pts, median age was 63 years (range 27-82), 67% male, 74% Ann Arbor stage III-IV, and 72% were refractory to CAR-T therapy administered in any prior line. 44 pts were evaluable for efficacy after 4.9 months median duration of follow-up. The ORR and CR rate by ICR were 48% (21/44) and 30% (13/44), respectively. Responses were durable, and both median DoR and median duration of CR were not reached. The probability of maintaining a response for 12 months was 62% and the probability of maintaining a CR for 9 months was 86%.A responder analysis of the subgroup of pts who achieved a CR will be presented. The CAR-T treated pts with DLBCL who were evaluable for biomarker analysis (n=10) had lower T-cell counts at baseline compared with CAR-T naive DLBCL pts (n=41 comparable pts who received odronextamab in ELM-2), yet the fold-change of T-cell expansion at C4D15 was greater in CAR-T treated pts versus CAR-T naive pts. T-cell dynamics, such as changes in activation, exhaustion, and memory subsets, will be presented. Safety was generally consistent with that previously reported. Six (13%) pts permanently discontinued odronextamab due to a treatment-emergent AE (device-related infection, pneumonia, dysphagia, gait disturbance, leukemia, and encephalopathy [n=1 each]). The most common treatment-emergent AE was CRS (any grade, 52%). The highest grade of CRS reported was Grade 2, and low-grade CRS events occurred in 46% of pts with the 0.7/4/20 mg step-up regimen. No cases of ICANS were reported in pts with the 0.7/4/20 mg regimen. Grade ≥3 infections occurred in 10 (22%) pts, with no Grade 5 events. No cases of tumor flare were reported. Conclusions Odronextamab monotherapy demonstrates encouraging antitumor activity in heavily pretreated pts who have progressed after CAR-T therapy, with a generally manageable safety profile. Durable CRs were achieved in this difficult-to-treat setting. These data support the potential role of odronextamab in the treatment paradigm for R/R DLBCL. Further studies to evaluate the optimal sequencing and combinations of odronextamab with CAR-T therapy are warranted.

Background The class of CD20×CD3 bispecific antibodies (BsAbs) has emerged as an important anti-lymphoma modality for patients (pts) with R/R B-cell non-Hodgkin lymphoma. Odronextamab, a novel, off-the-shelf, CD20×CD3 BsAb, has previously demonstrated compelling efficacy in both R/R diffuse large B-cell lymphoma and R/R FL. In pts with R/R FL, odronextamab monotherapy achieved 75% complete response (CR) rates and encouraging durability of responses, and showed generally manageable safety, in the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. ASH. 2022). Here, we report the results of a second, pre-specified interim analysis of ELM-2. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Optimization of the step-up regimen to further mitigate cytokine release syndrome (CRS) was reported previously (Kim TM, et al. ASH. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1, followed by 80 mg on Days 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 160 mg every 2 weeks until disease progression or unacceptable toxicity. Pts who achieved a durable CR for ≥9 months transitioned to dosing every 4 weeks. A pre-specified interim analysis was performed when 80 pts had completed ≥12 months follow-up. The primary endpoint was objective response rate (ORR), assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included CR rate, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and changes in scores of patient-reported outcomes. Minimal residual disease (MRD) was included as an exploratory endpoint. Results At data cut off (Jan 31, 2023), the global study was fully enrolled and included 140 safety-evaluable pts with FL; 128 pts were efficacy-evaluable and 85 pts had ≥12 months follow-up. The median duration of study follow-up for efficacy was 26.6 months. In the safety-evaluable FL population, median age was 60.5 years (range 22-84), 53% were male, and pts had received a median of 3 (range 2-13) prior lines of therapy. 73% of pts were refractory to their last therapy, 41% were double refractory, and 74% were refractory to an anti-CD20 antibody. 50% of pts had progression of disease within 2 years (POD24) and 29% had a prior autologous hematopoietic stem cell transplant. ORR and CR rate by ICR were 80% (102/128) and 72% (92/128), respectively, and were consistent across pts with high-risk features. Responses were durable, with both median DoR and duration of CR of 21.7 months; the probability of maintaining CR for 24 months was 48%. Median PFS was 20.7 months (95% CI: 16.7-26.5) and median OS was not reached; the probability of survival at 3 years was 63%. Patient-reported overall quality of life (QoL) scores were maintained during the course of treatment. MRD status at 12 weeks was highly predictive of PFS. Safety was generally consistent with previous reports, and no new treatment-related Grade (Gr) 5 events were recorded since the first interim analysis. The most common treatment-emergent AEs (>30% all grades) were CRS (55%), anemia (34%), neutropenia (34%), and pyrexia (33%). With the optimized 0.7/4/20 mg step-up regimen (n=72), 98% of CRS events were Gr 1/2, and only one pt had Gr 3 CRS. All CRS events resolved with supportive measures; 13 pts received tocilizumab for CRS management with the optimized regimen. Only one low-grade ICANS event was reported with the optimized regimen. Gr ≥3 infections occurred in 50 (36%) pts (Gr 5, n=14 [10%]); COVID-19 infections were reported in 46 (35%) pts (Gr 5, n=8 [6%]). Conclusions The results of this pre-specified analysis of the Phase 2 ELM-2 study continue to demonstrate deep and durable responses with odronextamab in heavily pretreated, refractory pts with R/R FL. 90% of responders were complete responders, with a 48% probability of maintaining CR for 2 years. High CR rates appear to translate to favorable, long-term survival outcomes in the setting of incurable disease. The incidence of AEs was consistent with earlier reports, with no new treatment-related Gr 5 events. Importantly, continued treatment with odronextamab had no detrimental effects on overall QoL. These data underscore the promise of odronextamab as a potentially effective agent for the management of R/R FL. Updated data will be presented.

Background: Goals of patient-centered care for management of relapsed or refractory follicular lymphoma (R/R FL) are to improve clinical outcomes while maintaining or improving health-related quality of life (HRQoL). In ELM-2 (NCT03888105), a Phase 2, open-label, multicohort, multicenter study, odronextamab monotherapy demonstrated high and durable complete response rates and generally manageable safety in patients with R/R FL. We report here, for the first time, patient-reported outcome (PRO) results from ELM-2 in patients with R/R FL. Methods: Patients with R/R FL Grade 1-3a received odronextamab IV at 80 mg weekly in 21-day cycles in Cycles (C) 1-4. Optimization of the step-up regimen to mitigate cytokine release syndrome (CRS) was reported previously. Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg in C1, then 80 mg on Days 1, 8, and 15 of C2-4. After C4, odronextamab maintenance continued at 160 mg every 2 weeks until disease progression or unacceptable toxicity. Patients with durable complete response (≥9 months) switched to dosing every 4 weeks. Patients completed EORTC QLQ-C30, FACT-Lym, and EQ-5D-3L questionnaires at Weeks 1 (baseline), 2, 3, 4, and 10, then every 8 weeks for the remainder of the first year and every 12 weeks in the second year. Results here focus on six key PRO scales: EORTC QLQ-C30 Global Health Status/Quality of Life (GHS/QOL), physical functioning (PF), role functioning (RF), and fatigue; FACT-Lym lymphoma subscale (LymS); and EQ-5D-3L visual analog score (VAS). Longitudinal analyses using mixed models for repeated measures (MMRM) were conducted through Week 50 (the last visit with ≥10 patients with PRO data). Changes from baseline were considered statistically significant if the 95% confidence interval did not contain zero. No adjustment for multiplicity was performed, hence all statistical significance is nominal. Published ranges for minimum important difference (MID) to define clinically meaningful changes are: EORTC QLQ-C30 scales, 10 points; FACT-Lym LymS, 2.9-5.4 points; and EQ-5D-3L VAS, 7-12 points. For responder and time to definitive deterioration (TTDD) analyses, the upper end of these published MID ranges was used to define deterioration or improvement. Results: At the ELM-2 interim data cutoff on 31-Jan-2023, 140 patients with R/R FL Grade 1-3a had received at least 1 dose of odronextamab. Median age was 60.5 years (range: 22-84), with 38.6% ≥65 years, 52.9% male, 57.1% White, 32.1% Asian, 52.2% ECOG=0, and 47.1% ECOG=1. Median duration of follow-up was 26.6 months (range: 6.2-37.5). PRO completion rates for EORTC-QLQ-C30, FACT-Lym, and EQ-5D-3L were high at baseline and remained high for all assessments through Week 50. At baseline, moderate levels of general health (GHS/QoL) and high levels of functioning (PF and RF) were observed that were higher (better) than reference values for general cancer or non-Hodgkin's Lymphoma (NHL). Fatigue scores at baseline were lower (less symptoms) than reference values for general cancer or NHL. EORTC QLQ-C30 GHS/QOL, PF, RF, and fatigue scores were maintained from baseline through Week 50 (Table). For EQ-5D-3L VAS, the overall estimated mean changes from baseline improved statistically significantly but did not reach MID thresholds (Table). For FACT-Lym LymS, overall estimated mean change from baseline statistically significantly improved, and scores improved statistically significantly from Weeks 10 to 42 (except Week 34), with clinically meaningful improvements at Weeks 26 and 42 (Figure). The proportion of patients reporting meaningful improvement or stability across the six scales was higher than the proportion reporting meaningful worsening through Week 50 (Table). The median TTDD for EORTC-QLQ-C30 GHS/QoL was 22.41 (95% CI: 14.59 to not yet reached) months, corresponding to the median PFS. Median TTDD was not reached for EORTC QLQ-C30 PF, FACT-Lym LymS, and EQ-5D-3L VAS scales. Conclusions: For patients with R/R FL, patient-reported HRQoL results were favorable during odronextamab treatment until disease progression, with no detriments on patient-reported symptoms, functioning, and overall quality of life. These results complement encouraging clinical efficacy, durability of responses, and tolerability observed in this highly refractory patient population and support the future role of odronextamab in the management of patients with R/R FL.

Abstract Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Abstract Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis–associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1–4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation–associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. Significance: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.

Background Acute pericarditis (AP) is considered a cardiovascular complication in patients with COVID‐19. We aimed to ass‐ess the incidence, associated complications, and clinical impact of AP on hospitalized patients with COVID‐19. Methods and Results In this retrospective cohort study, International Classification of Diseases, Tenthth Revision, Clinical Modification ( ICD‐10 ) codes were used to identify patients with COVID‐19 with or without AP in the National Inpatient Sample 2020 database. We compared outcomes between AP and non‐AP groups before and after propensity‐score matching for patient and hospital demographics and relevant comorbidities. A total of 211 619 patients with a primary diagnosis of COVID‐19 were identified, including 983 (0.46%) patients who had a secondary diagnosis of AP. Before matching, patients with COVID‐19 with AP were younger (59.93±19.24 years old versus 64.29±16.82 years old) and more likely to have anemia (40.5% versus 19.9%), cancer (6.7% versus 3.6%), and chronic kidney disease (29.3% versus 19.6%) (all P <0.05). After matching, patients with COVID‐19 with AP (n=980), when compared with the matched non‐AP group (n=2936), had higher rates of mortality (21.3% versus 11.1%, P <0.001), cardiac arrest (5.0% versus 2.6%, P <0.001), cardiogenic shock (4.2% versus 0.5%, P <0.001), ventricular arrhythmia (4.7% versus 1.9%, P <0.001), acute kidney injury (38.3% versus 28.9%, P <0.001), acute congestive heart failure (14.3% versus 4.8%, P <0.001), and longer length of stay (7.00±10.00 days versus 5.00±7.00 days, P <0.001) and higher total charges ($75066.5±$130831.3 versus $44824.0±$63660.5, P <0.001). Conclusions In hospitalized patients with COVID‐19, AP is a rare but severe in‐hospital complication and is associated with worse in‐hospital outcomes.

AbstractObjectivesAlthough hemispheric surgeries are among the most effective procedures for drug‐resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1‐, 2‐, and 5‐years post‐hemispherectomy.MethodsRetrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time‐to‐seizure recurrence. A multivariate Cox proportional‐hazards regression model was developed to predict the likelihood of post‐hemispheric surgery seizure freedom at three time points (1‐, 2‐ and 5‐ years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops‐calculator.com/).ResultsThe selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non‐hemispheric resective surgery, and contralateral fluorodeoxyglucose–positron emission tomography [FDG‐PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time‐to‐seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG‐PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non‐lesional MRI, non‐stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%.SignificanceOnline calculators are useful, cost‐free tools that can assist physicians in risk estimation and inform joint decision‐making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.