Citations

Abstract Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post–CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ≥3 events). No cases of immune effector cell–associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.

Abstract Genome-wide DNA methylation signatures correlate with and distinguish central nervous system (CNS) tumor types. Since the publication of the initial CNS tumor DNA methylation classifier in 2018, this platform has been increasingly used as a diagnostic tool for CNS tumors, with multiple studies showing the value and utility of DNA methylation-based classification of CNS tumors. A Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) Working Group was therefore convened to describe the current state of the field and to provide advice based on lessons learned to date. Here, we provide recommendations for the use of DNA methylation-based classification in CNS tumor diagnostics, emphasizing the attributes and limitations of the modality. We emphasize that the methylation classifier is one diagnostic tool to be used alongside previously established diagnostic tools in a fully integrated fashion. In addition, we provide examples of the inclusion of DNA methylation data within the layered diagnostic reporting format endorsed by the World Health Organization (WHO) and the International Collaboration on Cancer Reporting. We emphasize the need for backward compatibility of future platforms to enable accumulated data to be compatible with new versions of the array. Finally, we outline the specific connections between methylation classes and CNS WHO tumor types to aid in the interpretation of classifier results. It is hoped that this update will assist the neuro-oncology community in the interpretation of DNA methylation classifier results to facilitate the accurate diagnosis of CNS tumors and thereby help guide patient management.

Introduction: The Mindfulness-Based Stress Reduction program for breast cancer survivors (MBSR [BCs]) is a stress-reducing program designed to increase cognitive functioning through four meditational practices. This randomized clinical trial aimed to determine if improvements in cognitive functioning and perceived cognitive abilities achieved from the MBSR(BC) were mediated through increased mindfulness, decreased rumination, and decreased perceived stress. Methods: Breast cancer survivors (BCSs) who met inclusion criteria of stage I, II, or III BC and received either chemotherapy (CT) or both CT and radiation were randomized to either the 6-week MBSR(BC), or Breast Cancer Education Support (BCES) program, or to a usual care (UC) regimen. Analysis of covariance was first implemented to identify potential mediators, followed by a formal mediational analysis to evaluate the effects of MBSR(BC) on 6-, 12-, and 26-week outcomes. Results: After consent, 212 BCS were randomized to MBSR(BC) ( n = 91), BCES ( n = 90), or UC ( n = 31). The mean age was 56.5 and the majority of the BCS, 73.1%, were White and non-Hispanic. Results showed increases in “observing” as part of mindfulness as a potential mediator of MBSR(BC) effects on impairments on quality of life and logical memory at 6 months relative to UC. No mediation effects were identified for outcomes measured at 6 or 12 weeks and also when MBSR(BC) was compared with the BCES program. Discussion: These results partially supported our hypothesis that improvement in cognitive functioning would occur through increased mindfulness. Although few mediating relationships were identified, results showed a relationship between mindfulness and cognitive functioning. Both mediating relationships occurred through increases in “observing,” a subconcept of “mindfulness,” when compared to the MBSR(BC) with UC at 6 months. This study shows that mediators may help “optimize” clinical therapeutic treatment effects, thus contributing to the advancement of science. Trial Registration: ClinicalTrials.gov, www.ClinicalTrials.gov . Registration Number: NCT02786797.

Background The prevalence and impact of right ventricular dysfunction (RVD) in degenerative mitral regurgitation (DMR) is unknown. We aimed to determine whether RVD assessed by echocardiography in routine clinical practice is independently associated with mortality in patients with DMR. Methods and Results We used data from the MIDA‐Q (Mitral Regurgitation International DAtabase‐Quantitative) registry, which included patients with isolated DMR due to mitral valve prolapse from January 2003 to January 2020 from 5 tertiary centers across North America, Europe, and the Middle East. A cohort of 2917 (mean age: 66 years, 70.8% male patients, follow‐up: 5.2 [3.3–8.3] years) consecutive patients with severe DMR was included and long‐term mortality was analyzed. RVD, identified in 426 (14.6%) patients, was associated with reduced 8‐year survival (55%±3% versus 77%±1%; P <0.001), overall and in all subgroups of patients, even after comprehensive adjustment including left ventricular dilatation and dysfunction, DMR severity, pulmonary pressures, and surgery (adjusted hazard ratio, 1.44 [95% CI, 1.17–1.77]; P <0.001). This excess mortality was observed under medical management (adjusted hazard ratio, 1.57 [95% CI, 1.20–2.05]; P =0.001) and after surgical correction of mitral regurgitation (adjusted hazard ratio, 1.45 [95% CI, 1.02–2.05]; P =0.039). Patients with RVD undergoing surgery within 3 months of diagnosis experienced a better 8‐year survival (73%±4% versus 43%±4%; P <0.001), even after adjustment (adjusted hazard ratio, 0.44 [95% CI, 0.29–0.67]; P <0.001) despite an increase of 1‐month postoperative mortality (7.1% versus 0.5% for patients without RVD; P <0.001). Conclusions RVD is observed in 14.6% of severe DMR and exhibits a powerful and independent association with excess mortality partially attenuated by mitral surgery. Therefore, assessment of right ventricular systolic function should be included in routine DMR evaluation and in the clinical decision‐making process.

The NCCN Guidelines for Survivorship include recommendations for screening, evaluation, and treatment of psychosocial and physical problems resulting from adult-onset cancer and its treatment. They also include recommendations to promote healthy behaviors and immunizations in survivors and provide a framework for care coordination. These NCCN Guidelines Insights summarize the panel’s current recommendations regarding sexual health and fertility.

Abstract Aims To evaluate clinical outcomes, echocardiographic features, and the efficacy and safety of sacubitril/valsartan compared to valsartan across age groups in the PARAGON-HF trial. Methods and results A total of 4796 participants ≥50 years of age with chronic heart failure (HF) and left ventricular ejection fraction (LVEF) ≥45% were divided into three age groups: &lt;65 years (n = 825), 65–74 years (n = 1772), and ≥75 years (n = 2199). Echocardiograms of 1097 patients were analysed in a standardized fashion at a core imaging laboratory. The primary composite outcome was total HF hospitalizations and cardiovascular (CV) death. Older patients were more likely to experience primary composite outcomes (compared to patients &lt;65 years, adjusted rate ratio [aRR] for ≥75 years: 1.39, 95% confidence interval [CI] 1.21–1.61), total HF hospitalization (aRR 1.27, 95% CI 1.09–1.49), and CV death (adjusted hazard ratio [aHR] 2.04, 95% CI 1.44–2.87). Age did not modify the effect of sacubitril/valsartan compared to valsartan on primary composite endpoint (pinteraction = 0.79) in the overall population or in those with LVEF ≤57%. Older adults randomized to sacubitril/valsartan were more likely to develop hypotension compared to those receiving valsartan (pinteraction = 0.026). Older patients had smaller left ventricular chamber sizes, higher LVEF, and were more likely to have abnormal measures of diastolic function. Conclusion Older patients with HF with preserved ejection fraction had higher event rates than younger patients, more adverse events overall, and more hypotension when treated with sacubitril/valsartan; however, the treatment benefits of sacubitril/valsartan were retained in older patients.

Abstract Introduction Limited data currently exist on the role and efficacy of additional series of collagenase clostridium histolyticum (CCH) injections among Peyronie’s disease (PD) men who have previously failed a first series of injections. We sought to evaluate outcomes of a novel protocol for CCH injections among men who had previously failed 6-8 CCH injections using a traditional approach. Objective To evaluate whether additional rounds of CCH using a novel protocol in men previously unresponsive results in greater curve improvements. Methods A randomized, controlled trial (NCT05108558) is ongoing. All participants previously failed to achieve ≥20% curvature improvement with 6-8 prior CCH injections. Men were randomized 3:1 to receive either CCH + traction (RestoreX) + sildenafil (treatment) up front or initial observation followed by treatment (controls). Outcomes were compared between treatment and control groups. Key measures included objective curve improvements and standardized/non-standardized questionnaires, with assessments obtained at baseline, 6-weeks after completion of CCH (treatment arm), after the no treatment period (controls), and at 1 year. Results A total of 38/40 men have been randomized to date, with 22 having fully completed treatment. Mean age was 57 years, with a median PD duration of 22 months. Median composite baseline curvature was 65 degrees, with 40% having hourglass or indentation deformities, 8% calcification, median baseline IIEF-EFD 20, and 58% able to have penetrative intercourse. Median estimated improvement with the prior CCH series was 0% (IQR 0, 18.8), and the median number of prior injections was 8. The majority of men were dissatisfied with their prior series of CCH (58% vs 35% satisfied, 8% neutral). Of the 22 men who had completed the study protocol, 50% required 1 series, 14% 2 series, 29% 3 series, and 7% 4 series. Compared to the no treatment arm, treated men experienced significantly greater improvements (median 60 degrees vs 0, p = 0.01). IIEF-EFD was non-statistically higher in treated men (0 vs -5, p = 0.17). 92% of men reported a subjective major improvement in curvature, with the median subjectively estimated improvement 90%. 42% reported improved sensitivity (58% no change), while 63% reported improved or no change in erectile function, with 9% unsure, and 27% worse. Post-treatment, 92% of men were very satisfied with CCH as a treatment and 8% neutral. Conclusions Repeating CCH using a novel protocol after an initially unsuccessful course of CCH achieves significant improvements in curvature and patient satisfaction. Additional data, including external validation, are warranted. Disclosure Yes, this is sponsored by industry/sponsor: Endo Pharmaceuticals. Clarification: Industry funding only - investigator initiated and executed study. Any of the authors act as a consultant, employee or shareholder of an industry for: PathRight Medical.

Introduction: GOLCA is a potential first-in-class CELMoDTM agent for the treatment of lymphoma, purposefully designed to target the proteins Ikaros/Aiolos to produce dual immunomodulatory and anti-tumor activity, with preferential distribution to lymphoid organs. Pharmacodynamic data in pts with R/R FL show that, combined with RTX, the immunomodulatory effects of GOLCA are significantly increased (Chavez et al, EHA 2024, #1132). GOLCA as monotherapy (mono) and + RTX has been shown to be well-tolerated and effective in pts with R/R DLBCL (Chavez et al, ASH 2023, #4496) and R/R FL (Chavez et al, EHA 2024, #1132). Here, we report 30 mo follow up of pts with R/R FL who received GOLCA mono, and updated safety/efficacy of GOLCA + RTX from the ongoing Phase 1/2 CC-99282-NHL-001 study (NCT03930953). Methods: Pts with R/R FL with ≥ 2 prior lines of therapy (L) received GOLCA mono at different dosing schedules during part A (dose exploration) and GOLCA ± RTX at 0.2 mg or 0.4 mg days (d) 1-14 every 28 d (q28d) in part B (dose expansion). Total treatment duration with GOLCA was up to 2 years or until progressive disease or unacceptable toxicity, whichever occurred first. The efficacy-evaluable population consisted of pts completing ≥ 1 cycle of GOLCA and having baseline tumor assessment and ≥ 1 post-baseline tumor assessment or clinical progression or disease-related death. Results: As of May 31, 2024, 63 pts with R/R FL have enrolled: GOLCA mono (n = 19) at various dosing schedules and GOLCA + RTX at 0.2 mg (n = 22) or 0.4 mg (n = 22) on d1-14 q28d schedule. The median time from diagnosis to first dose of GOLCA was 68 mo (range, 23-136) and 59 mo (range, 15-309) in GOLCA mono and + RTX cohorts, respectively. The median number of prior therapies received was 4 (range, 2-11), and 3 (range, 1-12) in GOLCA mono and + RTX cohorts, respectively. In the GOLCA mono and + RTX cohorts, 9/19 (47%) and 13/43 (30%) pts had received prior lenalidomide (len)-based therapy, with 5/9 and 7/13 having len-refractory disease, respectively. In the GOLCA + RTX cohort, 10/43 (23%) had prior CAR T cell therapy and 6/43 (14%) had prior anti-CD20xCD3 bispecific antibody with or without CAR T cell therapy. In the GOLCA + RTX-treated safety population (n = 43), the incidence of treatment emergent adverse events (TEAEs) was similar across 0.2 and 0.4 mg dose levels (DL). The most frequent grade (G) 3+ TEAEs were neutropenia (44%) and anemia (12%). The incidence of febrile neutropenia was 7%. Serious adverse events occurred in 30% of pts, with febrile neutropenia and pneumonia being the most common, in 2 pts (5%) each, as well as pulmonary embolism in 1 pt. Neutropenia led to GOLCA dose interruption in 4 pts (9%) and dose reduction in 1 pt (2%). No pts discontinued treatment because of GOLCA-related TEAEs. Non-hematological TEAEs (e.g., GI toxicity, rash, fatigue) were all low-grade (except 1 pt with G3 fatigue). There were no new safety signals identified for GOLCA mono (part A) at the 30-mo follow up period. In the efficacy-evaluable population, at a median follow up of 6 mo (range 3-18), the ORR and CRR in the GOLCA + RTX cohort (n = 29) were 57% and 29% at 0.2 mg dose (n = 14) and 93% and 67% at 0.4 mg dose (n = 15), respectively. The median time to response was 2 mo (first response assessment). At the 0.4 mg DL of GOLCA + RTX, consistent responses were seen in pts at 2L/3L and 4L+, including in those with prior exposure to len-based therapies and/or T-cell-redirecting therapy. At the 0.4 mg DL, 12/14 (86%) pts remained in response at the time of data cut-off. In pts receiving GOLCA mono across different dose schedules in part A (n = 12), ORR and CRR were 67% and 42%, respectively. Responses were durable, with median DOR of 22 mo (range, 2-51) at a median follow up of 30 mo. 33% of pts (4/12) have completed 2 yrs of protocol defined GOLCA treatment and remain in response at the 1 yr post-treatment follow-up period, without requiring any intervening treatment. Conclusions: GOLCA 0.4 mg + RTX was well tolerated and highly active in heavily pre-treated pts with R/R FL, including those with prior exposure to len-based therapies and/or T-cell-redirecting therapies. Treatment with fixed-duration GOLCA mono led to durable responses including a subset of pts remaining treatment free, without progression at extended follow up. These data further support development of GOLCA + RTX as a fixed-duration, chemotherapy-free, outpatient treatment option in pts with R/R FL, and also pts with newly diagnosed advanced stage FL (NCT06425302).