Citations

Background: Although Covalent BTKis have revolutionized treatment of CLL/SLL, cardiotoxicity is a known side effect, which can increase the total costs to the healthcare system. This study evaluated the real-world healthcare resource utilization (HCRU) and costs in patients who did and did not experience incident cardiovascular adverse events (CVAEs) during cBTKi treatment. Methods: Adult patients diagnosed with CLL/SLL who initiated ibrutinib or acalabrutinib treatment (index date) between 2020-2023 in the United States were identified using claims data from Optum's de-identified Clinformatics® Data Mart Database and followed up to 36 months post-index. Patients were stratified into two cohorts based on the presence of an incident CVAE during treatment with index cBTKi, defined as the occurrence of a CVAE not present in a patient's medical history. HCRU and costs were evaluated on a per 1,000 patient-months basis. Z tests and univariate gamma general linear models were used to compare HCRU and cost rates. HCRU between those who received ibrutinib or acalabrutinib were also assessed. Results: Overall, 2,069 eligible patients were identified with a mean ± SD age of 73.7 ± 9.1 years, and 40.4% were female. The mean ± SD [median] treatment-specific observation period was 11.4 ± 9.5 [8.5] months. Of the total cohort, 442 (21.4%) experienced at least one incident CVAE, while 1,627 patients (78.6%) experienced no CVAEs. Among those without a pre-index history of the specific CV AE of interest, the proportion of patients with incident events were 21.4% for hypertension, 9.8% for atrial fibrillation, 9.2% for atrial flutter, and 9.6% for ventricular arrhythmias. Patients who experienced an incident CVAE had 4,334 total days with medical service compared to 3,138 days in those who did not (p<0.001). The drivers of differences in total medical service days between those with and without CVAEs were inpatient days (690 vs 230), followed by outpatient days (2,798 vs 2,425), other visits (e.g., hospice; 662 vs 375), and emergency room (ER) visits (184 vs 109). Total days with medical service were 3,458 in those who received ibrutinib and 3,410 with acalabrutinib. Total healthcare cost rates in those who experienced an incident CVAE were $20,250,560 compared to $17,413,460 in those without CVAEs (p<0.001). Inpatient costs drove differences in total costs between those with CVAEs and those without ($3,417,948 vs $915,839, p<0.001), followed by outpatient ($2,415,060 vs $1,769,628, p<0.01) and ER costs ($186,820 vs $87,585, p<0.001). Pharmacy costs were the largest contributor to total cost rates for both cohorts ($14,016,900 for those with a CVAE vs $14,473,270 without any CVAEs, p<0.001). Regarding specific incident CVAEs, the cost difference in total costs between those with and without the event were $3,789,820 for atrial fibrillation (higher in those with the event), $3,867,160 for atrial flutter, $3,674,860 for ventricular arrhythmias, and $721,840 for hypertension. Inpatient costs were the largest driver in total cost differences between those with and without the specific CVAE of interest; inpatient cost differences were $3,255,699 higher in those with atrial fibrillation, $3,436,913 with atrial flutter, and $3,299,371 with ventricular arrhythmia. For hypertension, pharmacy costs drove differences in total costs and were $346,570 higher in those with the CVAE. Summary/Conclusion: Overall, the economic burden remains high in patients treated for CLL/SLL, especially in cBTKi patients experiencing an incident CVAE. These findings highlight the importance of careful treatment selection, safety monitoring, and early management of CVAEs in order to improve patient outcomes and reduce the downstream impacts on healthcare resources and costs.

Background: Mosunetuzumab (Mosun), a CD20xCD3 bispecific antibody, received accelerated approval for the intravenous treatment of patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) who have received ≥2 prior lines of systemic therapy. Mosun can be administered in the outpatient setting with a fixed treatment duration. In an ongoing Phase I/II study, Mosun administered subcutaneously (SC) induced durable responses with a manageable safety profile in pts with previously untreated low-tumor burden FL (LTB; Flinn et al. ASH 2023). Efficacy, safety and pharmacodynamic profiles of Mosun SC are being evaluated in an open-label, multicenter, Phase II study (MorningSun; NCT05207670) in pts with B-cell non-Hodgkin lymphomas, including previously untreated FL. Here we present >8-month follow-up efficacy, safety and biomarker data for Mosun SC in first-line, LTB FL. Methods: Pts had untreated Grade (Gr) 1 or 2 FL, LTB by Groupe d'Etude des Lymphomes Folliculaires criteria, Ann Arbor stage III/IV disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Mosun SC injection was administered with step-up dosing in Cycle (C) 1 (Day [D] 1, 5mg; D8, 45mg; D15, 45mg), then 45mg on D1 of each 21-day cycle. Hospitalization was not mandatory. Pts with a complete metabolic response (CMR) after C8 could complete therapy. Pts with a partial metabolic response (PMR) or stable disease continued treatment for up to 17 cycles. Dexamethasone premedication was mandatory in C1 and C2 and optional thereafter. The primary endpoint was progression-free survival at 24 months. Exploratory analyses assessed cytokine levels in pts with versus without cytokine release syndrome (CRS) and pharmacodynamic changes in T and B cells in a subgroup of pts. Results: As of February 7, 2024, 65 pts were enrolled in US community (n=41) and academic (n=24) centers. At baseline, median age was 63 years (range: 34-82). Most pts had an ECOG PS of 0 (83.1%) or 1 (15.4%); 29 pts (44.6%) had extranodal involvement and 3 pts (4.6%) had B symptoms. Median duration of follow-up was 8.6 months (95% confidence interval [CI]: 5.7-10.9). Median number of cycles was 8 (range: 1-17). Among 60 pts with ≥1 post-baseline tumor assessment, the objective response rate was 95.0% (95% CI: 86.1-99.0; n=57) and CMR was 83.3% (95% CI: 71.5-91.7; n=50). Median time to response was 2.8 months (range: 2.3-8.3). At data cut-off, responses were ongoing in 48 pts with a CMR and in 5 pts with a PMR. In 64 safety-evaluable pts, the most common adverse event (AE) was injection-site reaction (70.3%; Gr 1, 65.6%; Gr 2, 4.7%). CRS by ASTCT occurred in 30 pts (46.9%; Gr 1, 39.1%; Gr 2, 7.8%); CRS events presented early in C1 (53.1%; Gr1, 45.3%; Gr2, 7.8%) and C2 (Gr1, 1.6%). Nineteen pts received CRS treatment (tocilizumab, 7.8%; steroids, 7.8%; tocilizumab + steroids, 4.7%; fluids, 3.1%; low-flow oxygen, 1.6%); 8 pts had a serious AE and were hospitalized. All CRS events resolved. Other common AEs included headache (45.3%; Gr 1, 29.7%; Gr 2, 15.6%), fatigue (45.3%; Gr 1, 35.9%; Gr 2, 9.4%), maculo-papular rash (31.3%; Gr 1, 14.1%; Gr 2, 15.6%; Gr 3, 1.6%), and increased alanine aminotransferase (28.1%; Gr 1, 21.9%; Gr 2, 4.7%; Gr 3, 1.6%). Gr 3/4 AEs in ≥5% of pts were neutropenia without fever (12.5%; Gr 3, 4.7%; Gr 4, 7.8%) and lymphopenia (7.8%; Gr 3, 1.6%; Gr 4, 6.3%). Suspected immune effector cell-associated neurotoxicity syndrome occurred in 2 pts (confusional state, Gr 1, n=1; Gr 2, n=1); all events resolved. Infections occurred in 30 pts (46.9%; Gr 1, 7.8%; Gr 2, 31.3%; Gr 3, 7.8%) with the most common (≥10%) being COVID-19 (17.2%; Gr 1, 7.8%; Gr 2, 7.8%; Gr 3, 1.6%) and upper respiratory tract infections (12.5%; Gr 1, 3.1%; Gr 2, 9.4%). One pt had a Gr 5 (fatal) AE 13.7 months after treatment was completed (reported as unrelated to Mosun; cause unknown). After the first Mosun dose, cytokine levels significantly increased on C1D2 (interleukin-6, n=44, p≤0.001; interferon-γ and tumor necrosis factor-α, n=41, p≤0.001). This spike in cytokine levels did not differ in pts with (n=19) versus without (n=25) CRS events in C1. Conclusions: Mosun SC monotherapy shows encouraging high efficacy as a fixed-duration treatment in first-line LTB FL. A manageable safety profile was reported, supporting ease of access for patients with drug administration in outpatient settings. Longer follow-up is needed to confirm long-term durability of response and safety.

Introduction: Red blood cell (RBC) transfusion is a lifesaving intervention with a low but persistent risk of transfusion-transmitted infection. Amustaline/glutathione RBC pathogen-reduction (PR) technology is designed to proactively inactivate a broad spectrum of viruses, bacteria, protozoa and leukocytes by chemically crosslinking nucleic acids and preventing replication and transcription. The Red Cell Pathogen Inactivation (ReCePI) trial was a Phase III, double-blinded, randomized non-inferiority study comparing PR and conventional RBCs for the support of acute anemia. Methods/Study Design: Complex cardiac or thoracic-aorta surgery patients received conventional (Control) or PR RBCs (Test) during and for 7 days after surgery. The protocol was conducted with ethics committee approval at all participating centers and written informed consent from all participants. Hemoglobin levels, blood utilization and serum creatinine were assessed as indicators of efficacy and oxygenation of tissues (Karkouti et al. Br J Anaesth. 2012; 109 Suppl 1: i29-i38). The primary endpoint was the incidence of acute kidney injury (AKI) measured as change in serum creatinine from baseline within 48 hours of surgery, a predictor of adverse postoperative outcomes including mortality by Day 30 post-surgery (Lassnig et al. Am Soc Nephrol 2004; 1597-1605). Secondary endpoints included AKI occurring up to 7 days post-surgery (KDIGO Clinical Practice Guideline for AKI, Kidney Inter, Suppl. 2012;2:1-138); death or the need for renal replacement therapy by 30 days post-surgery; PR RBC-specific antibodies; and death by day 75 post-surgery. With >292 subjects enrolled, the study had 80% power to demonstrate non-inferiority, assuming an AKI incidence of 30% with conventional RBCs and a non-inferiority margin of half the conventional RBC rate. Under these circumstances, an absolute treatment increase of 5% in the AKI rate in the PR RBC arm would fail the non-inferiority test. This work was supported by a contract with the US Biomedical Advanced Research and Development Authority (HHS010020160009c) with Cerus Corporation. Results: Five-hundred and eighty-one subjects were randomized and 321 (55%) transfused in 18 US hospitals. In the modified intent-to-treat analysis subjects receiving Test and Control RBCs had similar median [IQR] total blood loss (1500 [940-2475] mL Test, 1733 [1060-2880] mL Control, p=0.310) and comparable median hemoglobin levels at baseline and immediately post-surgery (9.8 [8.9-10.9] g/dL Test, 9.6 [8.6-10.6] g/dL Control, p=0.157) and for 7 days after surgery, The PR RBC arm was transfused with fewer RBCs, measured as total RBC Hb transfused over 7-days (169.0 [102.0-240.0] g Hb PR arm, 188.0 [126.0-295.0] g Hb, conventional RBC arm, p=0.008). The incidence of AKI was 29.3% (46/157) for Test and 28.0% (45/161) for Control. The treatment difference was 0.74% (95% CI -8.9, 10.4%, non-inferiority margin 14.0%, p=0.001 for non-inferiority). Non-inferiority was also achieved by the per protocol analysis. Average mean change in serum creatinine within 48 hours of surgery was comparable (Test 0.020, Control 0.23 mg/dL, P=0.515). Adverse events, serious adverse events and deaths on study were not different. Five of 159 (3.1%) PR RBC recipients developed low titer PR RBC-specific antibodies without clinical signs of hemolysis. Flow cytometry analysis revealed persistent circulating PR RBCs with uniform antigen loss (modulation). Low level human IgG antibody binding was demonstrated in 3 of 5 subjects. Conclusions: PR RBCs showed equivalent hemoglobin support for acute bleeding patients undergoing cardiac or thoracic-aorta surgery while using less transfused total RBC Hb over 7 days. The incidence of AKI in patients transfused with PR RBCs was non-inferior to that observed with conventional RBCs, indicative of effective tissue oxygenation. Treatment-related antibodies to PR-RBC were observed only in Test subjects, the antibodies were low titer, transient, without clinical hemolysis, and persistent circulating PR RBCs were detected with modulated low level acridine antigen expression (www.clinicaltrials.gov #NCT03459287).

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Rosai–Dorfman Disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-Langerhans cell histiocytic neoplasm. Although the disease classically presents as massive painless lymphadenopathy in young adults, RDD can also involve the central nervous system in some patients. CNS lesions, can cause headaches, neurologic deficits, and even neurologic deficits. The imaging appearance of CNS RDD typically mimics that of meningiomas: well-circumscribed dural-based lesions that often have dural tails. However, some imaging clues also exist that might help a radiologist recognize RDD, even before histopathologic confirmation. This radiology-pathology report of a patient with CNS RDD highlights the most pertinent clinical, imaging, and pathologic features of CNS RDD, and discusses what the neuroradiologist needs to know about the disease.

BACKGROUND AND OBJECTIVES: A typical workflow for deep brain stimulation (DBS) surgery consists of head frame placement, followed by stereotactic computed tomography (CT) or MRI before surgical implantation of the hardware. At some institutions, this workflow is prolonged when the imaging scanner is located far away from the operating room, thereby increasing workflow times by the addition of transport times. Recently, the intraoperative O-arm has been shown to provide accurate image fusion with preoperative CT or MR imaging, suggesting the possibility of obtaining an intraoperative localization scan and postoperative confirmation. In this article, we aim to evaluate the compatibility of the stereotactic frame system with the intraoperative O-arm system regarding lead accuracy and surgical flow. METHODS: A total of 17 patients undergoing DBS surgery for movement disorders were evaluated. One patient underwent both the stereotactic CT and O-arm localization, while 16 patients underwent only intraoperative O-arm localization. Following lead placement, intraoperative O-arm imaging was obtained to evaluate the accuracy of the lead placement. Accuracy was defined as the error measured as the distance from the center of the planned trajectory to the cannula. RESULTS: Less than 0.1 mm difference was found between the O-arm imaging technique and CT image localization of the NaviNetics stereotactic head frame in DBS surgery. Of the 16 patients who underwent the intraoperative O-arm imaging alone, the targets included bilateral ventral intermediate nucleus (16 leads), bilateral globus pallidus internus (4 leads), and subthalamic nucleus (12 leads). The mean ± SD radial error in the probe's eye view was 0.71 ± 0.33 mm for n = 32 leads. No tract hemorrhage was observed. CONCLUSION: Intraoperative O-arm imaging can be used safely and effectively for stereotactic registration and lead placement confirmation with the stereotactic system in both awake and asleep DBS surgery.

Abstract Task Group (TG) 314 of the American Association of Physicists in Medicine (AAPM) was charged to develop guidance for recovering from fault states in radiation therapy, specifically regarding the delivery of photon or electron beams using a linear accelerator (linac) including ancillary systems. The fault conditions addressed may involve software, hardware, or a combination of causes. The report provides detailed recommendations for the proactive steps to be taken before a fault, the actions to be taken at the time of a fault, and the safety steps before returning a linac to clinical service, as well as the activities that device manufacturers and standard organizations can do to prevent and resolve the faults. A user‐maintained log of prior faults; establishment of remote access by the vendor; and user training in emergency gantry, couch, and door motions are all useful proactive steps. At the moment of downtime and after ensuring the safety of the patient, the report stresses the importance of capturing fault information, prompt contact with the service engineer after the initial assessment, and considerations for communicating the estimated duration before the linac is returned to service. The medical physicist has a critical responsibility to assess the impact of the fault on patient care. Before resuming clinical use, the medical physicist must both determine the level of testing required to ensure safe operation of the linac and ensure any partially or totally delivered treatments have been correctly saved for accurate completion of the treatment fraction. The report stresses the roles of the radiation therapist, medical physicist, and service engineer to efficiently and safely address linac downtime. The appendices contain a description of the efforts of several organizations regarding linac safety: Integrating the Healthcare Enterprise—Radiation Oncology, International Standards Organization/International Electrotechnical Commission, Radiation Oncology Safety Stakeholder Initiative, and the AAPM Vendor Relations and Product Usability Subcommittee. Disclaimer: The recommendations of this TG should not be used to establish regulations. These recommendations are guidelines for Qualified Medical Physicists and others to use and appropriately interpret for their institution and clinical setting. Each institution may have site‐specific or state‐mandated needs and requirements which may modify their usage of these recommendations.

Introduction: Metabolic pharmacotherapies [Glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i)] have shown benefit in patients with heart failure and preserved ejection fraction (HFpEF). It remains unclear whether the two classes would have additive effects. Methods: We performed a retrospective study using a de-identified federated database with 89 contributing health care organizations (HCO), including over 126 million patients (TriNetX Research Network, Cambridge, MA; date of data access: May 23, 2024). TriNetX regularly aggregates clinical data directly from participating HCOs, and performs extensive data quality and accuracy assessment. While TriNetX obfuscates institutional information relating to participating HCOs, a typical HCO includes a large academic health center with inpatient, outpatient, and specialty care services. We identified all patients with a diagnosis of Heart failure with preserved ejection fraction (HFpEF, ICD-10: I50.3), and SGLT2i usage. We then categorized this patient population into two cohorts, including patients with concomitant GLP1RA use, and patients without GLP1RA use. For both cohorts, we collected data on patient demographics, and the outcomes of all-cause mortality, and all-cause hospitalization, occurring up to 10-years after the index diagnosis. We evaluated differences in outcome risk using hazards ratios and 95% confidence intervals. Results: Prior to propensity score matching, we identified 114,329 patients, with 7931 patients receiving SGLT2i +GLP1RA vs 106398 receiving SGLT2i-alone. Majority (55.7%) identified as white and 24.4% as African Americans and >90% of the patients had a diagnosis of type 2 diabetes mellitus. After propensity matching, the rate of all-cause hospitalization within the combination group was lower than SGLT2i group (29.6% vs 32.4%, HR 0.76 [0.73- 0.79], P<0.001). All-cause mortality for the combination group was 6.8% versus 10.6% within the SGLT2i-alone group (HR 0.52 [0.47-0.56], P<0.001)). Conclusion: In this propensity-matched cohort, patients with HFpEF receiving GLP1RA and SGLT2i had lower rates of hospitalizations and all-cause mortality compared with those receiving SGLT2i alone. Large randomized controlled trials are warranted to corroborate these findings.

Abstract Up to 70% of patients with non-muscle invasive bladder cancer (NMIBC) experience disease recurrence, making it one of the most prevalent cancers in the US. The purpose of this study was to test the performance of Oncuria®-Monitor, a multiplex urinary biomarker assay for the monitoring of voided urine for recurrent bladder cancer. This cross-sectional, multicenter study included a total of 283 subjects with a history of bladder cancer. Voided urine specimens were collected prior to any procedures for multiplex analysis. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC) and descriptive statistical values (e.g., sensitivity and specificity) and compared with the patients’ clinical data and final diagnosis as defined by the results of cystoscopy. Oncuria®-Monitor achieved an overall sensitivity of 94.3%, specificity of 83.6% and negative predictive valuer (NPV) of 96.2% for the detection of recurrent bladder cancer. Patient summary: We conducted a large cross-sectional clinical study for detecting recurrent bladder cancer with a novel, simple urine test (Oncuria®- Monitor), which measures 10 bladder cancer associated proteins in a single voided urine and can be used to detect recurrent bladder cancer. We analyzed urines from 283 patients and demonstrated that Oncuria®-Monitor can detect recurrent bladder cancer with a high degree of accuracy, specifically in patients with high grade or high stage disease. In conclusion, the novel Oncuria®-Monitor urine test can be used to surveil patients with a history of bladder cancer. Citation Format: Zhen Zhang, Florence Le Calvez-Kelm, Makito Miyake, Ian Pagano, Takuto Shimizu, Sergei Tikhonenkov, Sunao Tanaka, Charles J Rosser, Steve Goodison, Hideki Furuya. Oncuria®-Monitor, a non-invasive test for the detection of recurrent bladder cancer: Cross sectional performance evaluation from a multicenter study [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A072.