Robert Bosch Hospital,Robert Bosch Stiftung

ABSTRACT:Beyond cure, major goals in patients with Hodgkin lymphoma (HL) are tailoring treatment to a patient's individual risk for relapse to reduce acute and late toxicities, identifying candidates for early incorporation of novel agents, and making treatment affordable on a global level. Minimal residual disease (MRD) assessment by circulating tumor DNA (ctDNA) sequencing emerged as a promising strategy to achieve these goals; however, previous studies differed in sampling time points, assay validation, and definitions for MRD negativity. Here, we applied LymphoVista, a validated ctDNA sequencing assay for genotyping and MRD monitoring in lymphoma, to samples obtained from the German Hodgkin Study Group (GHSG) HD21 trial after 2 cycles of treatment (MRD-2) using a case-cohort design. Patients with positive MRD-2 result were at higher risk for relapse, progression, or death compared with MRD-2-negative patients (4-year progression-free survival [PFS], 36.7% vs 82.2%; hazard ratio, 5.3; 95% confidence interval, 2.0-13.8; P = .0008). After inverse probability weighting accounting for the number of events in the full reference set, patients with positive and negative MRD-2 results had 4-year PFS rates of 72.2% vs 95.3%. Combining MRD-2 with positron emission tomography after 2 cycles of BrECADD/eBEACOPP (PET-2) can identify patients at very low and patients at very high risk of relapse, progression, or death. In summary, these results suggest that MRD-2 assessment by LymphoVista allows for early outcome prognostication in patients with HL and could be used as a tool to improve treatment guidance on its own or in conjunction with PET-2.

Abstract INTRODUCTION The German Hodgkin Study Group (GHSG) HD21 trial for adult patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (AS-cHL) was designed to reduce treatment-related morbidity (TRMB) and improve efficacy by comparing the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to the standard eBEACOPP protocol. Here, we report the final efficacy and safety including long-term progression-free survival (PFS), overall survival (OS), and late toxicity outcomes. METHODS This open-label, international, randomized phase III trial included adults aged 18-60 with newly diagnosed AS-cHL, randomized 1:1 to treatment with 4–6 cycles of eBEACOPP or BrECADD, guided by positron emission tomography after two cycles (PET2). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Co-primary objectives were reduction of TRMB and superiority of PFS with BrECADD vs. eBEACOPP, both of which were met previously. The final analysis focused on long-term PFS, overall survival (OS), and second primary malignancies (SPMs). Kaplan-Meier estimates and Cox regression were used for time-to-event analysis in the intention-to-treat (ITT) population. Additionally, we describe prognostic factors for PET2 response among baseline characteristics including metabolic tumor volume (MTV) and the prognostic value of international prognostic score (IPS) variables and MTV at baseline for PFS, respectively, in the BrECADD arm. Univariate logistic regressions were used to identify associations with interim PET response (p<=.001), which were then compared using multivariate analyses. RESULTS A total of 1,500 patients were enrolled between July 2016 and August 2020 across 233 sites in nine countries. Baseline demographics and disease characteristics were well balanced between arms. After 2 cycles of BrECADD, 235/664 patients (35%) with centrally reviewed PET2 were classified as PET-positive. ECOG > 0 (Odds Ratio [OR] 1.62, 95% CI 1.03-2.55) and higher MTV (OR 1.14 per 100 mL, 95% CI 1.06-1.22) at baseline were associated with positive PET after 2x BrECADD in multivariate analysis. Median follow-up for this final analysis was 60 months and seven new PFS-events occurred after the previous analysis at 48 months: Five in the eBEACOPP arm and two in the BrECADD arm. Confirming earlier analysis, the hazard ratio (HR) for PFS was 0.64 (95% CI 0.44–0.93) favoring BrECADD. The absolute 5-year PFS for BrECADD was 93.6% (95% CI 91.7–95.5) vs. 90.6% (95% CI 88.4-92.8) with eBEACOPP, with a particularly pronounced 5y PFS benefit in PET2-negative patients of 96.2% vs. 92.4% (HR 0.46, 95% CI 0.25–0.83;). Among the IPS variables, male sex (HR 2.68, CI 95% 1.37-5.27) and hemoglobin < 10.5 g/dL (HR 2.41, 95% CI 1.25-4.68) were associated with higher risk for PFS events in multivariate cox regression, whereas MTV at baseline in univariate cox regression was not (HR 0.95 per 100 mL, 95% CI 0.81-1.11). Salvage therapies were similar across treatment arms: most patients with progression or relapse received autologous stem cell transplantation (52/61 (82%) after eBEACOPP vs 29/38 (76%) after BrECADD). With four (two in each treatment group) new death events since the previous analysis, OS remained at 98% in both arms. The cumulative incidence of SPMs at 60 months was 2.1% after eBEACOPP and 2.8% after BrECADD, with differing patterns: more secondary MDS/AML occurred in the eBEACOPP arm (six vs. one), while more secondary NHL cases were observed in the BrECADD arm (two vs. eight). No new sMDS/AML events occurred beyond the primary analysis. CONCLUSION With 5 years follow-up, this analysis confirms the unprecedented primary cure-rate and long-term safety profile of BrECADD. While higher baseline lymphoma burden associates with incomplete remission at PET2, the risk for treatment failure seems mitigated through response-adaptation. Taken together, our results establish individualized BrECADD as a standard treatment option for adult patients with newly diagnosed AS-cHL.

Our objective was to examine the association between the time and number of stops during the 400-meter walk test (400MWT) and average daily steps and walking cadence in a German cohort of frail and sarcopenic community-dwelling older adults at first observation (FO) and individual last observation (LO) after at least 11 months. Stops during the 400MWT led to a longer time. Time in the 400MWT was significantly associated with average daily steps and walking cadence at FO and LO (24.5 ± 8.5 months). Stops alone were not associated with average daily steps and walking cadence. Gait speed under laboratory conditions can be used to estimate daily physical activity, represented by average daily steps and walking cadence, in frail and sarcopenic older adults. Physical activity (PA) is recommended for frail and sarcopenic older adults as an essential means of preventing negative health outcomes and decline in functional abilities. Our objective was to examine the association between the time and/or stops during the 400-m walk test (400MWT) and average daily steps and walking cadence in a German cohort of frail and sarcopenic community-dwelling older adults. For this sub-study the German cohort of 104 frail and sarcopenic older adults (i.e., SPRINTT) aged 80.8 ± 5.2 years was divided into participants having made none or one stop or more than one stops, referred to as non-stoppers and multi-stoppers. The characteristics and general health state (physical function, disease state, concerns about falling) at first observation (FO) and individual last observation (LO) after at least 11 months (mean 24.5 ± 8.5 months) were examined. Daily PA represented by average daily steps and walking cadence was assessed over three to seven days at FO and LO using the activPAL3 micro. Time and stops made during the 400MWT and their association with daily PA were investigated using regression with bootstrapping. Out of 104 frail and sarcopenic older adults, 84 non-stoppers (female: n = 54; 64.3

Drug recalls occur regularly with some resulting in medication switches for patients. Limited research into this topic suggests that drug recalls can lead to anxiety and unrest for patients which in turn can affect confidence in and use of medication. In this context, a better understanding of patient perceptions and communication preferences is essential to adequately handle drug recalls and ensure continued medication adherence and trust. The aim of this study was to elucidate patients’ experiences, perceptions, and preferences regarding drug recalls. This qualitative study comprised focus group discussions with patients that experienced a drug recall, recruited through pharmacies from distinct locations in the Netherlands. We aimed to conduct at least two focus groups, each comprising a minimum of six participants. Audio recordings were transcribed verbatim and analyzed using a thematic analysis approach. It was found that patients had limited knowledge of drug recall procedures, often confused them with shortages, and struggled to interpret associated risks. Communication was frequently perceived as unclear, triggering varied emotional responses and, in some cases, reduced trust in and use of medications. Patients preferred pharmacist-led, personalized communication tailored to recall urgency, and emphasized the importance of shared decision-making, particularly during medication substitutions. Drug recalls cause a range of emotions in patients, leading to reduced confidence and use of medication in some patients. Preferences centered on understandable, transparent, and personalized communication led by pharmacists. The findings of this study emphasize the importance of embedding patient engagement and tailored communication within pharmacovigilance systems to maintain trust and support shared decision-making during drug recalls.

The clinical and molecular heterogeneity of diffuse large B cell lymphoma (DLBCL) is incompletely understood. By integrating proteomic, transcriptomic, and genomic data from 478 DLBCL tumors, we identify seven DLBCL proteogenotypes (PGs) reflecting specific pathophysiological features that span known molecular subtypes. PG4 is associated with poor outcome independent of established risk factors such as cell-of-origin, international prognostic index, or genetic features. PG4 contains activated B cell-like and germinal center B cell-like tumors and genetically unclassified cases. It shares a dark-zone-related B cell phenotype and shows enrichment for BTG1 mutations that can activate MYC. Single-cell sequencing and spatial transcriptomics reveal enhanced MYC and TCF3/4 transcriptional activity irrespective of MYC translocations. The PG4 tumor microenvironment is characterized by exhausted CD8+ T cells. Our study identifies common oncogenic themes underlying high-risk DLBCL tumors and provides a proteogenomic framework for future diagnostic and therapeutic approaches.