Citations

Abstract Introduction: The introduction of the Bruton tyrosine kinase inhibitor acalabrutinib combined with bendamustine and rituximab (ABR) as first-line (1L) therapy for mantle cell lymphoma (MCL) in older patients (pts) is reshaping the approach to treatment sequencing in this disease. The primary analysis of the phase 3 ECHO trial (NCT02972840) with data cutoff Feb 15, 2024 (median time on study 44.9 mo) demonstrated improved progression-free survival (PFS) with ABR vs placebo plus BR (PBR; hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57–0.94; P=0.0160) in pts ≥65 y with treatment-naive (TN) MCL. Here we present updated results after 50 mo of follow-up, including time to next treatment 2 (TTNT2; ie, initiation of third-line [3L] therapy). Methods: Pts aged ≥65 y with TN MCL and ECOG performance status ≤2 were randomly assigned 1:1 to receive ABR or PBR. Randomization was stratified according to geographic region and simplified MIPI score. BR was given for 6 cycles followed by rituximab maintenance for 2 y in pts achieving a partial or complete response (CR). Acalabrutinib (100 mg twice daily) or placebo was administered at study start until progressive disease (PD) or unacceptable toxicity. Crossover to acalabrutinib was permitted at PD. The primary endpoint was PFS per independent review committee. TTNT2, which was used as a surrogate for PFS2 (time from initial treatment to second disease progression), was defined as time from randomization to second subsequent (3L) antilymphoma therapy after discontinuation of randomized treatment or death. Results: In total, 299 pts were randomized to each arm; median age was 71 y. At data cutoff (February 15, 2025), median (range) time on study was 51.86 (0.03–93.04) mo and median (range) follow-up through reverse Kaplan-Meier method for PFS was 60.8 (0–88.5) mo. Median TTNT2 was not reached (NR) in the ABR arm and 73.8 mo in the PBR arm, establishing a 24% reduction in the risk of initiating 3L therapy or death with ABR vs PBR (stratified HR 0.76; 95% CI 0.59–0.98). In total, 33 (11.0%) and 100 (33.4%) pts received second-line [2L] treatment (median time to 2L therapy, 26.3 vs 19.6 mo) and 10 (3.3%) and 37 (12.4%) received 3L treatment in the ABR and PBR arms, respectively. When COVID-19 deaths were censored (in alignment with prespecified analyses from the primary study), the HR further improved (stratified HR 0.67; 95% CI 0.50–0.89; median TTNT2 NR in any arm). In total, 71.6% and 78.3% of pts discontinued acalabrutinib and placebo, respectively; the most common reasons (>5%) for discontinuation were adverse events (AEs; 44.5%, ABR; 32.4%, PBR) and objective PD (12.7%, ABR; 30.8%, PBR). Median PFS was 72.5 and 47.8 mo in the ABR and PBR arms, respectively (stratified HR 0.68; 95% CI 0.53–0.87; P=0.002). In total, 108 (36.1%) and 116 (38.8%) pts in each arm died; median overall survival (OS) was NR in both arms (stratified HR 0.87; 95% CI 0.67–1.13), with a 36-mo OS rate of 73.8% with ABR vs 68.3% with PBR. With 1 additional year of follow-up since the primary analysis, rates of grade ≥3 AEs and serious AEs in the ABR arm were comparable to previously reported rates, indicating that prolonged acalabrutinib exposure does not appear to result in cumulative toxicities. Three new cases of grade 3/4 neutropenia were reported, with no marked changes in the rates of grade ≥3 or serious infections. The rate of grade ≥3 cardiac events remained consistent with the primary analysis. In the ABR arm, 1 new case of grade 3/4 atrial fibrillation and 1 new case of grade 3/4 hypertension were reported. Rates of thrombocytopenia, major hemorrhage, and ventricular tachyarrhythmia remain unchanged. Conclusion: In this updated analysis of the ECHO trial, despite crossover to acalabrutinib being permitted in the PBR arm, fewer pts in the ABR arm were in need of subsequent treatment (2L and 3L), with longer TTNT2 in the ABR arm. These results suggest that 1L treatment with ABR provides a 24% reduction in risk of initiating 3L therapies or death. Further follow-up has demonstrated that ABR offers improved efficacy (ie, PFS) vs PBR, with no long-term safety concerns with acalabrutinib maintenance. The updated safety findings further support the favorable benefit–risk profile of acalabrutinib in TN MCL. Altogether, these data support the potential of acalabrutinib in combination with BR as 1L treatment, rather than in later lines, to modify long-term treatment outcomes in pts with TN MCL.

Abstract Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non–tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK− ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.

Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

Introduction: The use of intravascular ultrasound (IVUS) to guide lower extremity deep venous stent placement is associated with improved identification of the degree of maximal vessel stenosis, vessel obstruction, and thrombus burden, compared to venography alone. As the US medical system moves towards value-based care, the financial impact of interventional tools requires close consideration. Currently, there are limited evaluations of the cost effectiveness of IVUS during venous procedures. Research Question: This study seeks to examine the cost-effectiveness of IVUS in lower extremity deep venous interventions. Methods: Medicare fee-for-service claims data from 2016 through 2021 for beneficiaries aged ≥ 65 years undergoing lower extremity venous interventions with stent placement, thrombolysis, and/or thrombectomy were analyzed. Cost ratios between IVUS-guided and non-IVUS-guided procedures were assessed using gamma regression, adjusting for demographic and clinical variables. Results: A total of 52,610 patients were included, with 42.6% undergoing IVUS-guided procedures. IVUS utilization varied by setting, with higher usage in hospital-based outpatient centers (75.3%) and ambulatory surgical centers/outpatient-based laboratories (ASC/OBL; 86.4%) compared to inpatient hospitalizations (10.4%). Among inpatient procedures, IVUS-guided venous intervention was associated with greater cost than non-IVUS procedures at 90 days, with an adjusted cost ratio of 1.04 (95% CI 1.01-1.07), yet was associated with an average 0.6-day shorter hospitalization (p < 0.001; Figure 1, Figure 2 ). There were marginal increased costs associated with use of IVUS in inpatient procedures persisting through one- and three-years follow-up, with adjusted cost ratios of 1.05 (95% CI 1.02-1.08) and 1.05 (95% CI 1.02-1.09), respectively. In contrast, IVUS use was associated with significant cost savings in outpatient settings, with adjusted cost ratios of 0.71 (95% CI 0.69-0.73) in hospital-based outpatient settings and 0.75 (95% CI 0.73-0.78) in ASC/OBL at 90 days. These cost savings persisted at one- and three-year follow-up. Conclusions: IVUS-guided venous intervention was associated with cost savings in outpatient and ASC/OBL settings, while maintaining near cost equivalence in inpatient settings. These findings suggest that in addition to the clinical benefit of IVUS for venous intervention, IVUS is a cost-effective strategy, particularly in the outpatient setting.

Introduction: Semaglutide 2.4 mg has been shown to reduce the risk and severity of cardiometabolic comorbidities (CMCs) and to improve cardiometabolic biomarkers in patients with overweight or obesity in clinical trials. However, real-world evidence in these areas is limited. Research Question: This study compared the incidence rates of CMCs and 12-month changes in biomarkers between adults with overweight/obesity with and without once-weekly subcutaneous semaglutide 2.4 mg use. Methods: A retrospective cohort study using a large U.S. claims database linked with clinical data evaluated patients with semaglutide 2.4 mg use for ≥12 months (June 2021–June 2023) and those without. For each CMC, including hypertension, T2D, dyslipidemia, HF, prediabetes, ASCVD, and CVD, patients were excluded from analysis of each individual CMC if they had claims indicating the corresponding CMC during the 12-month baseline. For each biomarker, patients were required to have the corresponding biomarker measurements at both baseline and 12-month follow-up. For each CMC and biomarker, propensity score weighting was used to balance patient characteristics between semaglutide 2.4 mg users and non-users. Time to CMCs were compared using weighted Cox proportional hazards models and biomarker changes were compared using weighted linear regression. Results: Sample sizes ranged from 14,067 to 25,490 in semaglutide 2.4 mg users and 4,271,926 to 8,578,948 in non-users across CMCs. After balancing, baseline characteristics were similar between users and non-users. Mean age ranged from 44.4 to 47.2 years among users and 44.4 to 47.4 years among non-users; 77%–83% of users and 75%–82% of non-users were women. Compared to non-users, semaglutide 2.4 mg users had significantly lower risk of incident hypertension (Hazard ratio [HR]: 0.62, 95% confidence intervals [CI]: 0.57; 0.68), T2D (HR: 0.45, 95% CI: 0.39; 0.51), HF (HR: 0.48, 95% CI: 0.38; 0.61), prediabetes (HR: 0.75, 95% CI: 0.70; 0.80), ASCVD (HR: 0.65, 95% CI: 0.58; 0.72), and CVD (HR: 0.69, 95% CI: 0.64; 0.75) (all p<0.001). The risk of dyslipidemia was similar between users and non-users (HR: 1.05, 95% CI: 1.00; 1.11, p=0.05). Semaglutide 2.4 mg use was also associated with significant improvements in cardiometabolic biomarkers specified in Table 1 and slower decline in eGFR. Conclusion: In adults with overweight/obesity, semaglutide 2.4 mg was associated with lower risk of specified CMCs and greater improvements in cardiometabolic biomarkers.

Treatment-induced ovarian function loss is a significant concern for many young patients with breast cancer. Accurately predicting this risk is crucial for counselling young patients and informing their fertility-related decision-making. However, current risk prediction models for treatment-related ovarian function loss have limitations. To provide a broader representation of patient cohorts and improve feature selection, we combined retrospective data from six datasets within the FoRECAsT (Infertility after Cancer Predictor) databank, including 2679 pre-menopausal women diagnosed with breast cancer. This combined dataset presented notable missingness, prompting us to employ cross imputation using the k-nearest neighbours (KNN) machine learning (ML) algorithm. Employing Lasso regression, we developed an ML model to forecast the risk of treatment-related amenorrhea as a surrogate marker of ovarian function loss at 12 months after starting chemotherapy. Our model identified 20 variables significantly associated with risk of developing amenorrhea. Internal validation resulted in an area under the receiver operating characteristic curve (AUC) of 0.820 (95% CI: 0.817–0.823), while external validation with another dataset demonstrated an AUC of 0.743 (95% CI: 0.666–0.818). A cutoff of 0.20 was chosen to achieve higher sensitivity in validation, as false negatives—patients incorrectly classified as likely to regain menses—could miss timely opportunities for fertility preservation if desired. At this threshold, internal validation yielded sensitivity and precision rates of 91.3% and 61.7%, respectively, while external validation showed 92.9% and 60.0%. Leveraging ML methodologies, we not only devised a model for personalised risk prediction of amenorrhea, demonstrating substantial enhancements over existing models but also showcased a robust framework for maximally harnessing available data sources.

Background Antibiotic use may alter gut microbiota, which could be associated with various diseases, including cardiovascular disease (CVD). Accordingly, further epidemiological evidence is needed to clarify the potential risk of CVD associated with antibiotic exposure. We evaluated the association between long‐term antibiotic exposure and CVD risk in South Korea. Methods and Results This nationwide retrospective cohort study used data from the Korean National Health Insurance Service database. A total of 2 159 965 individuals aged 40 to 79 years who had no history of antibiotic prescriptions from 2004 to 2005 were included and followed through December 31, 2021. Antibiotic exposure was defined as the cumulative days of antibiotic prescriptions from 2006 to 2010. The primary end point was incident CVD with 2 or more days of hospitalization from 2011 to 2021. Adjusted hazard ratios (aHR) and 95% CIs for CVD according to antibiotic exposure were estimated using multivariable Cox proportional hazards models, adjusting for a range of covariates. Longer cumulative antibiotic prescription days were associated with an increased risk of CVD. The aHRs for CVD associated with 1 to 14, 15 to 90, 91 to 180, 181 to 364, and ≥365 days of antibiotic exposure were 0.98 (95% CI, 0.96–1.01), 1.01 (95% CI, 0.99–1.03), 1.05 (95% CI, 1.03–1.08), 1.06 (95% CI, 1.04–1.09), and 1.10 (95% CI, 1.07–1.13) compared with those with no antibiotic prescriptions. Conclusions In this large population‐based cohort study of Korean adults, long‐term antibiotic exposure may be associated with a higher risk of CVD. Further research is warranted to establish causality and elucidate the underlying mechanisms for this association.