Citations

526 Background: The PALLAS trial (NCT02513394) investigated the efficacy of the addition of palbociclib (palbo) to standard adjuvant endocrine therapy (ET) to reduce breast cancer recurrence. Previous analyses of this trial have not shown significant benefit of combination palbo+ET over ET alone. Given prior data showing that extent of neutropenia is associated with response to palbo and other cell cycle-specific therapies, we evaluated whether extent of neutropenia could identify responders to palbo in the adjuvant setting. Methods: PALLAS is a global, open-label, phase III trial that randomized patients (pts) with stage II-III hormone-receptor positive, HER2-negative breast cancer to receive ET for ≥5 years with or without standard-dose palbo for 2 years in 28-day cycles. The primary endpoint is invasive disease-free survival (iDFS). For this exploratory analysis, the palbo population was classified into pts with treatment-emergent high-grade neutropenia (HGN) with maximum grade ≥3 (absolute neutrophil count <1000), or low-grade/no neutropenia (LGN) with maximum grade <2; these groups were compared to each other and to the ET alone group for 5-year iDFS outcomes. Logistic regression examined individual baseline characteristics associated with HGN during the first 3 cycles within the palbo group. Impact of HGN during the first 3, 6, and 12 cycles on iDFS was tested using univariate and multivariable landmark Cox regression. Results: The safety population included 5736 pts, 2840 allocated to palbo+ET, 2896 to ET alone. Prior publications reported no new safety signals, low rates of serious infection, and no grade 5 treatment-related events. The palbo+ET group consisted of 1006 (35.4%) LGN and 1834 (64.6%) HGN. 5-year iDFS results are shown in the table. Pts who received palbo+ET and developed HGN by the end of cycle 6 had significantly improved 5-year iDFS compared to those who received ET alone (p=0.04), which remained statistically significant when adjusting for body mass index (BMI), prior chemotherapy, and race. Multivariable logistic regression showed lower BMI, prior chemotherapy, Asian race, and prior mastectomy were significantly associated with HGN (all p<0.05). Conclusions: In this exploratory analysis of the phase III PALLAS adjuvant trial, addition of palbo to ET appeared to be superior to ET alone in pts who developed HGN in the first 6 cycles of treatment but not in those who had LGN. These findings are consistent with observations in the metastatic setting suggesting that neutropenia could be a useful biomarker for palbo concentration and efficacy. Clinical trial information: NCT02513394 . Maximum grade neutropenia measured at end of cycle: 5-year iDFS Palbo+ET HGN (%) Palbo+ET LGN (%) ET alone (%) Hazard Ratio p-value 3 84.9 84.4 1.06 0.54 84.9 82.9 1.17 0.06 6 85.6 84.9 1.08 0.44 85.6 83.4 1.19 0.04 12 86.3 85.9 1.06 0.57 86.3 85.0 1.12 0.20

e13574 Background: AL (amyloid light chain) amyloidosis is associated with poor prognosis especially if diagnosis occurs with cardiac involvement. Current AL treatments target the plasma cell clone producing the light chains that misfold, aggregate and deposit in various tissues. The multi-organ manifestations of AL amyloidosis require a multidisciplinary care team of hematologist-oncologists, cardiologists, and other healthcare providers (HCPs) for comprehensive, patient-centric management. Since 2022, Amyloidosis Stakeholder Partnerships for Impact, Reach & Equity (ASPIRE), facilitated by Amyloidosis Research Consortium (ARC) has been bringing together biotech and pharmaceutical companies with the shared goal of optimizing amyloidosis patient care. Through this study, ARC-ASPIRE sought to document and share the current best practices and key barriers to patient-centric amyloidosis care at US specialized amyloidosis centers (SACs). A broad range of stakeholders in amyloidosis care – healthcare providers at SACs, patients, referring physicians, and patient advocacy group representatives – were interviewed for this study. This abstract presents findings relevant to the management of patients with AL amyloidosis. Methods: Structured interviews were conducted between December 2023 and February 2024 with 77 amyloidosis stakeholders (physicians, advanced practice providers, registered nurses from 17 SACs, patients, referring physicians, and patient advocacy group representatives), including 12 hematology-oncologists and 8 AL patients. SACs were selected to be representative of current US amyloidosis care, based on geography, amyloidosis patient volume, years since establishment, and types of amyloidosis treated. Results: Three-quarters of participating SACs treat AL patients under a single multidisciplinary amyloidosis program. Multidisciplinary care is facilitated by regular team meetings, dedicated clinic days, and informal communications across specialties. At diagnosis, collaboration between cardiology and hematology-oncology ensures AL patients are accurately diagnosed and promptly treated. Sixty percent of SACs have a centralized intake system, and patients suspected with AL are prioritized to ensure an appointment within 1 week of referral. Key barriers were delayed or missed diagnosis due to low awareness of AL amyloidosis within community oncologists, travel burden to SACs, lack of seamless medical records sharing and telehealth regulations. Conclusions: The best practices outlined in this study serve to educate AL amyloidosis and non-AL amyloidosis HCPs for better multidisciplinary collaboration and early diagnosis. The key barriers identified should be addressed to improve patient care.

Abstract Background: Leukocyte immunoglobulin-like receptor B2 (LILRB2) suppresses immune cell activation, particularly within myeloid cells in the tumor microenvironment (TME), while the PD-1/PD-L1 axis serves as a key immune checkpoint that inhibits T-cell function. SPX-303 is a novel bispecific antibody designed to simultaneously block LILRB2 and PD-L1, thereby revitalizing antitumor immune responses. Here, we present initial findings from the ongoing first-in-human Phase 1 trial of SPX-303 in patients with advanced solid tumors, including safety, pharmacokinetics (PK), and receptor occupancy (RO). Methods: This is an open-label, multicenter Phase 1 study for patients with advanced solid malignancies with 3+3 dose-escalation design, followed by an expansion cohort at the recommended Phase 2 dose (RP2D). SPX-303 is administered intravenously every three weeks and safety is assessed through CTCAE v5.0 criteria. Primary Objectives of this study are to determine the safety, tolerability, and RP2D of SPX-303. Secondary endpoints include antitumor activity as well as characterization of the PK and PD of SPX-303. This study is currently open and enrolling in escalation cohorts. Citation Format: Justin Moser, Hao Xie, Yujie Zhao, Yousef Zakharia, Dongdong Li, Brandon William, Dinh-Duc Nguyen, Jack Hovey, Tiffany Li, Robert Cai, Jichun Ma, Jingdong Qin, Martin Siekierzycki, Anthony Haight, Hua Jin, Weiwei Mao, Kevin Bin Li, Gui-Dong Zhu. A first-in-human phase 1 study on the safety, PK, receptor occupancy, and pharmacodynamic markers of SPX-303, a first-in-class LILRB2×PD-L1 bispecific antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT116.

ABSTRACT Ventricular arrhythmias (VA), including ventricular tachycardia and fibrillation, are critical cardiac conditions that are often managed by catheter ablation among those unresponsive to pharmacologic therapy. The choice of anesthesia and sedation regimens for VA ablations may impact arrhythmia inducibility and hemodynamic stability, which can affect procedural success and complication rates. This systematic review and meta-analysis aimed to compare the efficacy and safety of sedation versus general anesthesia (GA) among patients undergoing VA ablation. The review was prospectively registered on PROSPERO (CRD42023441553). Database searches were conducted across five major databases from inception to March 9, 2024 to identify randomized trials or observational studies including adult patients undergoing ablations for VA. Screening and data extraction were completed in duplicate. Risk-of-bias assessments were conducted using ROBINS-I as all included studies were observational, and the quality of evidence was evaluated using the GRADE framework. Six observational studies (N = 16,435) were included. No significant differences were found between sedation and GA for total procedure time (MD: −14.16 minutes; 95%CI: −38.61 to 10.29 minutes), arrhythmia non-inducibility (RR: 0.73; 95% CI: 0.33–1.58), acute ablation success (RR: 1.06; 95% CI: 0.65–1.71), or procedural complications (RR: 0.72; 95% CI: 0.28–1.85). However, sedation was associated with significantly lower intraprocedural hemodynamic instability (RR: 0.28; 95% CI: 0.12–0.70). These findings indicate that while sedation and GA have comparable outcomes, sedation may be associated with less hemodynamic instability during VA ablation. However, more high-quality studies are needed to confirm these results.

AbstractThe immune system and sleep are inextricably linked in both health and pathological conditions. Tightly regulated neuroimmune processes are critical for the physiological maintenance of healthy sleep. Reciprocally, sleep disturbances can detrimentally affect immune homeostasis and predispose to increased risk of autoimmune conditions, which themselves are bidirectionally associated with a higher risk of sleep disturbances. Autoimmune diseases of the central nervous system (CNS), particularly conditions that affect neuroanatomical regions involved in sleep homeostasis and nocturnal respiration, are associated with an increased risk sleep disorders that may impact diagnosis, clinical course, and management. This review summarizes the bidirectional relationship between sleep and immunity and highlights several exemplar autoimmune conditions of the CNS that include sleep disorders as a consequence or diagnostic feature of the disorder.

Abstract Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. In vivo spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in ∼400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence in vitro . Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.

Abstract Context Research and scholarship are core drivers of medicine in the modern era. Evidence-based practice continues to replace expert opinion and long-held practice beliefs. Involvement in the development and writing of these guidelines is critical for Doctors of Osteopathic Medicine (DOs) to maintain a seat at the academic table. According to the American Osteopathic Association (AOA), 11 % of practicing physicians in the US are DOs. This number is growing, as nearly 25 % of current medical students attend an osteopathic medical school. Without involvement in guideline development, DOs risk giving up control of their own practice of medicine. Objectives To quantify the contribution of DOs to the body of literature guiding practice, author information was extracted from all US-based guidelines published in the years 2021, 2022, and 2023 listed in the Emergency Care Research Institute (ECRI) Guidelines Trust database. Methods Authors of US-based guidelines listed in the ECRI Trust database from the years 2021–2023 were counted and categorized into one of three groups based on terminal degree: MD holders, DO holders, and Other-degree holders. Authors whose degrees could not be identified were counted as “Unidentifiable.” Additional data including sponsoring organization, organization type, and specialty were collected. Results A total of 674 guidelines were published by US organizations in 2021, 2022, and 2023, with 604 reporting author information. A total of 9,376 authors were counted. Of that, 7,253 held an MD (77 %), 110 held a DO (1.2 %), and 1,848 held another terminal degree (19.7 %); meanwhile, 1.66 % of counted authors did not have an identifiable degree. A total of 604 guidelines published by US organizations were identified. Of these, 88 (14.6 %) contained at least one DO author in their author list. Sixty-two unique specialties were identified, along with 130 unique sponsoring organizations. Of those specialties, 28 (44.4 %) had at least one DO author of at least one guideline. Of 130 sponsoring organizations, 44 (33.8 %) developed at least one guideline with at least one DO author. No osteopathic sponsoring organizations were identified. Conclusions Based on these results, we conclude that DOs are underrepresented in the development of guidelines.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and comprehensive care of patients with MDS based on a review of recent clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts is convened at least on an annual basis. During the annual meeting, the panel evaluates new and emerging data to inform their recommendations. These NCCN Guidelines Insights review the recent updates, including treatment recommendations both for lower-risk and higher-risk MDS, preference stratification of therapeutic agents, and emerging data on novel therapeutics.