Abstract For younger, fit patients with mantle cell lymphoma (MCL), first-line therapy includes high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). HDCT-ASCT demands considerable healthcare resources and costs and causes acute and long-term complications. The phase 3 TRIANGLE trial found clinically beneficial improvements in overall survival and safety when HDCT-ASCT was replaced with an ibrutinib regimen without ASCT. This study aimed to develop a comprehensive ASCT treatment clinical pathway model for patients newly diagnosed with MCL and assess the impact on hospitalization duration, healthcare resources, and cost. The clinical pathway was modeled using ClipMed®PPM software-based process analysis. Data were sourced from the IWiG® reference model for quantitative activity-based health economic evaluation and validated by clinical experts alongside standard operating procedures. Cost inputs were obtained using reimbursement sources and tariff publications in Germany. The total clinical pathway, from ASCT-eligibility assessments, induction therapy, HDCT-ASCT consolidation, and up to 100 days post-ASCT, covered: 49 patient-clinician interaction days; 346 patient services (inpatient and outpatient settings); 1653 processes. HDCT-ASCT involved 23 days’ hospitalization. Healthcare professionals’ time associated with apheresis and HDCT-ASCT, which could be spared with the TRIANGLE ibrutinib regimen without ASCT, totaled 214 h. Costs associated with the total clinical pathway, excluding those associated with severe adverse events, other comorbidities, and long-term complications, amounted to €50,815 per patient. For newly diagnosed ASCT-eligible patients with MCL, HDCT-ASCT is associated with at least 23 hospitalization days, considerable costs, and substantial healthcare resources – assets that could be redirected with adoption of the TRIANGLE ibrutinib regimen without ASCT.

Brexucabtagene-autoleucel (brexu-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) product approved for relapsed/refractory Mantle Cell Lymphoma (MCL) after two prior treatment lines, including Bruton tyrosine kinase inhibitors (BTKi). Patients with high-risk (hr) disease—defined by high-intermediate or high-risk MIPI-c, p53 overexpression, or TP53 alterations—have a poor prognosis, underscoring the need for improved first-line strategies. The European Mantle Cell Lymphoma Network therefore designed a phase II trial to investigate the incorporation of brexu-cel into first-line therapy for hr MCL. CARMAN is a randomized controlled, international, multicenter, open-label phase II trial evaluating efficacy, safety, and tolerability of an abbreviated induction followed by first-line brexu-cel and 6 months Ibrutinib maintenance (Arm A) as compared to standard of care induction and maintenance (Arm B). In Arm A, induction consists of two cycles of ibrutinib plus rituximab (I + R) followed by two cycles of R-CHOP plus ibrutinib (I). R-CHOP + I may be omitted in patients achieving complete or partial remission after two cycles of I + R, who then receive one additional I + R cycle before brexu-cel infusion and I maintenance. Arm B comprises a TRIANGLE-like regimen based on age, fitness, and investigator choice (alternating R-CHOP plus ibrutinib/R-DHAP or IR-bendamustine), followed by IR maintenance. Overall, 150 patients from five European countries are randomized 1:1. The primary endpoint is failure-free survival from randomization, with failure event defined as the earliest of stable disease at the end of induction (Arm B, or Arm A if brexu-cel is not infused) or within 12 weeks from CAR-T-cell infusion (Arm A), disease progression after induction, or death from any cause. Secondary endpoints include efficacy (overall and complete response rates and PET-negative CR rate 6 months from randomization as assessed according to Lugano criteria, molecular remission rate as measured by MRD), safety and tolerability (adverse events graded according to CTCAE), and patient-reported quality of life as measured by the EORTC-QLQ-C30 and EORTC-QLQ-NHL-HG29 questionnaires. When complete, CARMAN will provide important information on efficacy and safety in first-line CAR-T cell therapy in hr MCL and has the potential to prepare a practice changing confirmatory trial for these difficult-to-treat patients. Recruitment is ongoing. EU clinical trial number: 2022-502405-15-00.

Mantle cell lymphoma (MCL) is a rare B-cell Non-Hodgkin-lymphoma that predominantly affects elderly patients. While younger and fit patients receive an intensive first-line treatment, older or comorbid patients have limited options of chemo-immunotherapy (CIT) alone followed by anti-CD20-antibody maintenance. Targeted oral agents as Bruton`s tyrosine kinase inhibitors (BTKi, e.g. ibrutinib) - and B-cell lymphoma 2 (Bcl2) – inhibitors (e.g. venetoclax) have revolutionized the treatment especially for relapsed patients, with apparent synergistic effects. The MCL elderly III trial of the European MCL Network is an international phase II trial evaluating the efficacy of the combination of ibrutinib, venetoclax and rituximab as well as the CIT bendamustine and rituximab in combination with ibrutinib in elderly patients with untreated MCL. The primary trial objective is to evaluate efficacy in both treatment arms as measured by failure-free survival at 30 months separately in both treatment arms. Secondary endpoints include progression-free survival, response rates, overall survival, adverse events as well as quality of life and impact of frailty and sarcopenia on treatment outcome through geriatric and body composition assessments via imaging. Exploratory endpoints comprise the rate of minimal residual disease negativity and kinetics of immune reconstitution. The first patient was included in May 2023, with full site activation achieved in Q1 2025. Until May 15th 2025, 75 of 150 planned patients were enrolled in 27 German and Italian trial sites. This is the first randomized trial to exploratively compare a BTKi-Bcl2i-anti-CD20 triplet to a BTK-CIT combination in older MCL patients. The trial is registered on EU Clinical Trial Register (20225018089600).

Background: Patient-reported outcomes (PROs) are important for assessing drug benefits. The Federal Joint Committee (G-BA) in Germany has introduced a new instrument, the so-called application-related data collection (in German: Anwendungsbegleitende Datenerhebung, AbD), which requires availability of data from registries for PRO comparisons. Research question: How can PROs be successfully implemented in a European registry? Methods: As part of the AbD for a CAR T-cell product, the European Mantle Cell Lymphoma Network (EMCL) introduced recording of PROs in its registry in fall 2023. Solutions had to be found for issues such as contract design, data protection, data collection logistics, workload for the centers, and data transfer. This article reports on initial experiences with implementation. Results and conclusion: Collection of PROs in medical registries is possible, but involves a great deal of effort. Public funding of PRO ascertainment in registries is advised, for example within AbD.

Zusammenfassung Hintergrund Patientenberichtete Endpunkte („patient-reported outcomes“ [PRO]) sind wichtige Zielgrößen für die Bewertung des Nutzens eines Medikaments. Für das vom Gemeinsamen Bundesausschuss (G-BA) in Deutschland neu eingeführte Instrument der Anwendungsbegleitenden Datenerhebungen (AbD) wird gefordert, dass Vergleichsdaten für PRO aus Registern zur Verfügung stehen. Fragestellung Wie kann es gelingen, PRO in einem europäischen Register zu implementieren? Methode Im Rahmen der AbD für ein CAR-T-Zell-Produkt hat das europäische Mantelzell-Lymphom-Netzwerk (European Mantle Cell Lymphoma Network, EMCL) im Herbst 2023 die Erfassung von PRO in seinem Register eingeführt. Dabei mussten Lösungen für Fragen unter anderem der Vertragsgestaltung, des Datenschutzes, der Logistik der Datenerhebung, der Arbeitsbelastung für die Zentren und des Datentransfers gefunden werden. Dieser Beitrag berichtet über die ersten Erfahrungen bei der Implementierung. Ergebnisse und Schlussfolgerung Die PRO-Erfassung im Rahmen von medizinischen Registern ist möglich, aber mit hohem Aufwand verbunden. Eine Regelfinanzierung der PRO-Erfassung in Registern erscheint sinnvoll, beispielsweise im Rahmen von AbD.

Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from the initial MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are established standard treatment at first relapse, but their effectiveness as compared to chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes amongst patients at first, late-POD beyond 24 months. Patients treated upfront with BTKi were excluded. The primary objective was progression-free survival from time of second-line therapy (PFS-2) of BTKi versus CIT. After accrual, all patients were prospectively followed-up. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 (range:19-70) years and 77% were males. Median follow-up from time of first relapse was 53 months (range:12-144). Overall, 114 patients had second-line BTKi, while 271 had CIT, consisting of rituximab-bendamustine (R-B, n=101), R-B and cytarabine (R-BAC, n=70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone-CHOP- or platinum-based, n=100). The two groups were balanced for clinicopathological features, and median time to first relapse (48 months for both). Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT [not reached-NR vs 26 months, respectively, P=.0003], and overall survival [NR and 56 months, respectively, P=.03]. Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio-HR, 0.41 for R-B, 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in BTKi-naïve MCL patients.

Mantle cell lymphoma (MCL) is a rare but challenging B-cell-lymphoma affecting predominantly elderly patients. While fit patients traditionally receive an intensive first-line treatment followed by autologous stem cell transplantation, elderly or unfit patients are often treated by chemo-immunotherapy alone followed by anti-CD20-antibody maintenance. In recent years, potential long-term sequelae of chemotherapy have become a concern. At the same time, the advent of effective targeted agents has opened new therapeutic opportunities. Venetoclax, a bcl-2 inhibitor, has shown substantial efficacy in relapsed MCL. In order to prolong duration of remission, the combination with the Bruton tyrosinkinase inhibitor (BTKi) Ibrutinib has successfully been investigated in various clinical trials in the relapsed setting. We initiated a trial to determine the feasibility of a chemo-free combination therapy in elderly patients with newly diagnosed MCL. MCL-Elderly III is an international, randomized phase II trial assessing efficacy and safety of the combination Venetoclax, Ibrutinib and Rituximab for 6 cycles followed by 24-months maintenance treatment of Venetoclax, Ibrutinib and Rituximab (EU CT registration number 2022-501808-96-00). As a comparative arm serves the combination Bendamustine, Rituximab and Ibrutinib for 6 cycles followed by 24-months maintenance of Rituximab and Ibrutinib, as adopted from the SHINE trial. In the maintenance period in both arms, Rituximab is administered every second cycle. A total of 150 adult patients (≥60 years, ECOG ≤ 2) with previously untreated stage II-IV MCL and at least 1 measurable tumor lesion (>1.5 cm x >1.0 cm) will be enrolled and allocated at a 1:1 ratio. Main inclusion criteria are an adequate hematopoietic reserve as well as sufficient liver and renal function. Patients with serious cardiovascular disease or bleeding disorders are excluded. Patients will be recruited in 40 sites in Germany and Italy. The duration of this study is estimated to be 66 months (5.5 years). The primary endpoint is efficacy as measured by failure-free survival (FFS) at 30 months. FFS will be reported separately for the two trial arms. For each treatment arm, a separate exact binomial hypothesis test will be performed using the null hypothesis 30-month FFS ≤ 60%. The significance level will be set to 10%, accounting for the phase 2 design with a limited sample size. Secondary endpoints comprise other efficacy endpoints such as overall survival (OS) and overall response rate (ORR) as well as safety endpoints such as the rate of adverse events. Notably, a geriatric assessment will be performed within the screening period. Quality of life during induction and maintenance therapy will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life core questionnaire (EORTC QLQ-C30) along with its module for high-grade non-Hodgkin lymphoma (EORTC QLQ-NHL-HG29). Importantly, the accompanying scientific program will evaluate genetic subclassification, minimal residual disease (MRD) based on next-generation sequencing (NGS), and immune-reconstitution. The first patient was included in May 2023. As of July 18th, 34 German trial sites are activated and 32 patients were enrolled. The activation of Italian sites is planned for September 2024.

Mantle cell lymphoma (MCL) is a rare lymphoma subtype that accounts for 8% of Non-Hodgkin lymphomas and is still considered incurable. Prognostic parameters such as TP53 alterations, high Ki-67 proliferation index, blastoid or pleomorphic morphologic characteristics and/or high-risk combined MCL International Prognostic Index (MIPI-c) are associated with poor outcome. Chemoimmunotherapy and targeted therapies such as Bruton's tyrosine kinase inhibitors (BTKi) may induce remission in such high-risk patients, but early relapses frequently occur and actually there is a unmet need for improved treatment. The anti-CD19 chimeric antigen receptor T-cell (CAR-T) product brexucabtagene autoleucel has demonstrated encouraging efficacy in relapsed or refractory aggressive MCL, failing to previous BTKi therapy after up to 5 prior regimens. However, restricting CAR-T cell therapy to subsequent treatment lines increases the risk of disease evolution causing potentially limited treatment efficacy. Thus, applying CAR T cells in first line, targeting more susceptible malignant cells, seems reasonable. The combination with Ibrutinib is likely to induce synergistic effects with CAR-T-cells by increasing the viability and expansion of T-cells while inhibiting T-cell exhaustion. The European Mantle Cell Lymphoma (EMCL) Network has developed a phase II study concept exploring early treatment intensification through the integration of brexucabategene autoleucel into the first line treatment of high-risk MCL patients. In the control arm, patients are treated analogous to the TRIANGLE study (EudraCT#: 2014-001363-12), which recently has established the use of Ibrutinib in combination with intensive induction and maintenance in younger patients with MCL. CARMAN is a randomized controlled, international, multicenter, open-label phase II trial (clinicaltrials.gov: NCT06482684) evaluating the efficacy and safety of brexucabtagene autoleucel following an abbreviated induction (3 cycles of Ibrutinib + Rituximab (IR) and 2 cycles of Ibrutinib + R-CHOP in patients not achieving at least a PR to IR), and 6 months Ibrutinib maintenance starting 3 months post CAR-T-treatment (Arm A) as compared to standard of care chemoimmunotherapy combined with Ibrutinib induction (patients ≤ 65 years will receive 3 cycles R-CHOP+Ibrutinib/ 3 cycles R-DHAP alternating, followed by ASCT if appropriate and Ibrutinib/Rituximab maintenance. Patients ≥65 years will receive 6 cycles of Bendamustine and Rituximab + Ibrutinib or R-CHOP + Ibrutinib without ASCT) and 2 years maintenance with Ibrutinib with or without Rituximab maintenance, according to national guidelines (Arm B). The maximum duration of the study will be 7 years, with up to 2 years recruitment, 2.5 years of treatment (Arm B) and up to 2.5 years additional follow-up. The primary endpoint is the failure-free survival from randomization to stable disease or progressive disease after end of induction, or death from any cause. A total number of 150 patients (18-75 years, ECOG ≤2) with previously untreated stage II-IV MCL, at least one high-risk feature (MIPI-c high intermediate or high risk and/or TP53-mutation and/or p53-overexpression by immunohistochemistry) and at least 1 measurable lesion according to the Lugano Response Criteria will be enrolled (approx. 75 in each arm) in about 40 sites in 5 countries: Germany, France, Spain, Czech Republic and The Netherlands. The primary statistical evaluation aims to reject the null hypothesis of equal FFS-probabilities in the two trial arms on a two-sided significance level of 10% and is planned to have 90% power to reject the null hypothesis if the true FFS-hazard ratio is 0.558 for A vs. B. One efficacy interim analysis is planned after the observation of half of the projected events. The scientific program includes analysis for MRD, molecular risk profiling, immune reconstitution and quality of life. As of July 31st, the first patients have been recruited in Germany and activation of all sites is planned until end of 2024.

The SCHOLAR-2 retrospective study highlighted poor overall survival (OS) with standard of care (SOC) regimens among patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who failed a covalent Bruton tyrosine kinase inhibitor (BTKi). In the ZUMA-2 single-arm trial, brexucabtagene autoleucel (brexu-cel; autologous anti-CD19 CAR T-cell therapy) demonstrated high rates of durable responses in patients with R/R MCL who had previous BTKi exposure. Here, we compared OS in ZUMA-2 and SCHOLAR-2 using three different methods which adjusted for imbalances in prognostic factors between populations: inverse probability weighting (IPW), regression adjustment (RA), and doubly robust (DR). Brexu-cel was associated with improved OS compared to SOC across all unadjusted and adjusted comparisons. Hazard ratios (95% confidence intervals) were 0.38 (0.23, 0.61) for IPW, 0.45 (0.28, 0.74) for RA, and 0.37 (0.23, 0.59) for DR. These results suggest a substantial survival benefit with brexu-cel versus SOC in patients with R/R MCL after BTKi exposure.

Background: Chimeric antigen receptor T-cells have revolutionized treatment in many B-cell neoplasias. In MCL, brexucabtagene autoleucel (brexu-cel) has been the first product approved based on results of the ZUMA-2 trial for patients failing prior chemoimmunotherapy and BTK-inhibitor. However, in ZUMA-2, strict criteria have been used for patient selection, e.g. no use of intensive bridging/holding treatment was allowed, excluding patients with high treatment needs. In contrast to this, in the real-world scenario patient selection is much more diverse questioning whether the results of controlled trials can be reproduced in the regular treatment landscape. In this intent, we have analyzed the results obtained with brexu-cel as standard-of-care treatment (SOC) of r/r MCL in Germany and Switzerland. Patients/methods: Eligible for this first analysis of an ongoing registry study were all German and Swiss patients with r/r MCL who have been treated with SOC brexu-cel since 09/2020 and were registered with the German Stem Cell Registry (DRST) and the Registry of the European Mantle Cell lymphoma (EMCL), respectively. Of note, some patients have received more than one CAR-T-treatment. Data were analyzed for patient and disease characteristics, prior treatment history, response to treatment, and complications as well as post treatment outcomes. Due to the character of this analysis based on real world data, with heterogeneous surveillance strategies we have used primarily time to next treatment (TTNT) instead of progression-free survival, due to the potential biases for the latter. While still adding patients to the analysis, an additional follow-up data cut is planned 10/2023. Results: 111 patients have been identified: median age at diagnosis was 64.3 years (range 42.3-79.5; 19/99 patients ≥ 70), 18% female (not known (nk) 2.7%); ethnicity 66.7% Caucasian (nk 30.6%). Disease characteristics: 80/88 had stage 3/4 (91%), histology was classical in 34/57 cases (60%) and blastoid in 19/57 (33%), respectively. MIPI score was low 14/53 (26%), intermediate 17 (32%), high 21 (40%). TP53 alteration was present in 13/58 (22%), Ki67-expression was ≤ 30% in 18/50 (36%). TTNT for last treatment preceding CAR-T-treatment was 7.7 months. Overall survival (OS) for the entire patient population from diagnosis was 12.8 years. Preceding CAR-T, median number of treatments was 3 (range 1-9), all patients had prior Rituximab and Ibrutinib, 62 patients (56%) had received autologous stem cell transplantation (SCT) and 11 patients had received an allogeneic SCT. Median age at this time point was 68.1 years (range 49-82y). 50/110 patients were >70 years. Bridging treatment had been used in 88/112 (79%) preceding CAR. Based on investigator evaluation ORR was 86%, best response to CAR-T was CR in 47/76 patients (62%) and PR in 18/76 (24%). Time to death or new treatment after CAR-T was 8 months (mo) for patients ≤ 70y and 12 mo for patients > 70y. There was no difference for the number of prior lines (≤ 3 vs. > 3). The estimated median OS was 1.9 years. 26 patients have received at least 1 additional line of treatment after progression. Safety: Post-CAR CRS was seen in 95/114 (83%), Grade 1/2 77/95 (81%), Grade 3/4 (18%), Grade 5 (1%); ICANS was noted in 57/111 (51%), Grade 1/2 43/57 (75%), all other Grade 3/4. The rate of ICU admissions was 25/106 (24%). However, within 28 days after CAR-T-cell treatment 9/98 (9%) patients have died. Overall, in the post CAR-T-period 20 patients died of reasons other than progression: 4 CAR-related, 11 infections, 5 other/unknown. Discussion: In this real-world analysis, we could demonstrate, despite a more heterogeneous pre-treated patient population, a high overall and complete response rate. Median post CAR-T-cell survival was promising with 1.9 years. While CRS and ICANS risks seem to be comparable to trial data, the high non-relapse mortality (NRM) observed after SOC brexu-cel for r/r MCL is a concern and warrants refinement of anti-infectious surveillance and prophylaxis. Further work focusses on the identification of potential risk factors, e.g. using risk scores such as CAR-HAEMATOTOX, EASIX, and Severe4.

Data on outcome of patients with mantle cell lymphoma (MCL) and COVID-19 infection are limited. The European MCL (EMCL) registry is a centralized registry of the EMCL network, collecting real-world information about treatments and disease courses. During the COVID-19 pandemic, additional data on MCL patients with COVID-19 infection were collected, aiming to identify risk factors for mortality from COVID-19. In our retrospective, multicenter, international study, we collected data from 63 MCL patients with a median age of 64 years (range, 44-84) in 9 countries with evidence of a COVID-19 infection between February 2020 and October 2021. The overall mortality rate was high (44.4%), especially in hospitalized patients (61%) and in patients with need for intensive care unit care (94%). Patients receiving rituximab had significantly poorer survival than patients not receiving rituximab (P = 0.04). Our data highlight the importance of prevention strategies and underline the need for effective vaccination in this vulnerable cohort.

IntroductionIn the pre-chimeric antigen receptor [CAR] T-cell therapy era, patients with R/R MCL typically faced a poor prognosis after failing BTKi with no established standard of care (SOC). In a phase 2, multicenter, single-arm trial (ZUMA-2; NCT02601313), brexu-cel demonstrated long-term overall survival (OS) benefit in patients with R/R MCL who had 1–5 prior therapies, including a BTKi (Wang et al. JCO 2022). The European retrospective observational study, SCHOLAR-2, showed poor OS in 288 patients with R/R MCL who failed a BTKi due to disease progression or intolerance (Hess et al. BJH 2023). SCHOLAR-2 data reflects clinical practice (excluding CAR T-cell therapies), providing a benchmark for indirect treatment comparisons (ITCs) of brexu-cel to historical SOC. We present results of an updated ITC of OS of brexu-cel versus non-CAR T-cell SOC using individual patient data from ZUMA-2 and SCHOLAR-2.MethodsLong-term follow-up data from ZUMA-2 were used for brexu-cel (data cut-off: July 23, 2022). Real-world evidence on the effectiveness of non-CAR T-cell SOC was from the subset of the SCHOLAR-2 post-BTKi treated population that better resembled patients in ZUMA-2 (i.e., ECOG performance status 0–1 and ≥1 year of follow-up). Comparisons of OS were made using three different statistical methods which adjusted for imbalances in pre-specified key prognostic factors between the study populations: 1) inverse probability weighting (IPW) with ZUMA-2 as the target population, 2) multivariable regression (MVR), and 3) doubly robust (DR). Variables included in the final models are in Table 1. Relative treatment effects were shown as hazard ratios (HRs) with 95% confidence intervals (CIs).ResultsMedian follow-up times were 46.1 and 27.6 months for ZUMA-2 and SCHOLAR-2 cohort, respectively. At baseline, the study populations were well balanced (i.e., absolute standardized difference <10%) in terms of prior BTKi duration/response, while other characteristics were imbalanced (Table 1); after weighting in the base-case analysis (IPW approach), all the key prognostic factors were well-balanced between the two populations.Median OS was 46.4 months (95% CI: 24.9–58.7) with brexu-cel and 15.4 months (95% CI: 9.99–30.9) with non-CAR T-cell SOC. The IPW-adjusted median OS with non-CAR T-cell SOC was 14.0 months (95% CI: 6.8–30.9). Brexu-cel was associated with improved OS compared to non-CAR T-cell SOC in the unadjusted and adjusted comparisons (Figure 1). The adjusted HRs were 0.38 (95% CI: 0.24–0.62; p<0.001) for IPW, 0.46 (95% CI: 0.28–0.74; p=0.001) for MVR, and 0.38 (95% CI: 0.24–0.60; p<0.001) for DR.Conclusion/SummaryDespite the inherent limitations of an unanchored ITC, these updated results continue to suggest significant OS benefit with brexu-cel versus non-CAR T-cell SOC in patients with R/R MCL post-BTKi and may help inform treatment choices in this high unmet need population.

SummaryMantle cell lymphoma (MCL) after relapse is associated with poor prognosis. No standard of care exists and available evidence for treatments is limited, particularly in patients who fail Bruton tyrosine kinase inhibitor (BTKi) therapy. This multicentre retrospective chart review study, SCHOLAR‐2, addresses this knowledge gap and reports on data collected from 240 patients with relapsed/refractory MCL in Europe who were treated with BTKi‐based therapy between July 2012 and July 2018, and had experienced disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. The median overall survival (OS) from initiation of first BTKi therapy was 14.6 months (95% confidence interval [CI] 11.6–20.0) in the overall cohort, 5.5 months (95% CI 3.9–8.2) in 91 patients without post‐BTKi therapy, and 23.8 months (95% CI 18.9–30.1) in 149 patients who received post‐BTKi therapy (excluding chimeric antigen receptor T‐cell treatment). In the latter group, patients received a median of one (range, one to seven) line of post‐BTKi therapy, with lenalidomide‐containing regimens and bendamustine plus rituximab being the most frequently administered; the median OS from initiation of first post‐BTKi therapy was 9.7 months (95% CI 6.3–12.7). These results provide a benchmark for survival in patients with R/R MCL receiving salvage therapy after BTKi failure.

Despite the neurodegenerative disorder Alzheimer’s disease (AD) is the most common form of dementia in late adult life, there is currently no therapy available to prevent the onset or slow down the progression of AD. The progressive cognitive decline in AD correlates with a successive accumulation of cerebral amyloid-β (Aβ) due to impaired clearance mechanisms. A significant percentage is removed by low-density lipoprotein receptor-related protein 1 (LRP1)-mediated transport across the blood–brain barrier (BBB) into the periphery. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to members of the low-density lipoprotein receptor protein family at the cell surface and targets them for lysosomal degradation, which reduces the number of functional receptors. However, the adverse impact of PCSK9 on LRP1-mediated brain Aβ clearance remains elusive. By using an established BBB model, we identified reduced LRP1-mediated brain-to-blood Aβ clearance due to PCSK9 across different endothelial monolayer in vitro. Consequently, the repetitive application of FDA-approved monoclonal anti-PCSK9 antibodies into 5xFAD mice decreased the cerebral Aβ burden across variants and aggregation state, which was not reproducible in brain endothelial-specific LRP1−/− 5xFAD mice. The peripheral PCSK9 inhibition reduced Aβ pathology in prefrontal cortex and hippocampus–brain areas critically involved in memory processing—and prevented disease-related impairment in hippocampus-dependent memory formation. Our data suggest that peripheral inhibition of PCSK9 by already available therapeutic antibodies may be a novel and easily applicable potential AD treatment.

The prognosis of elderly patients diagnosed with diffuse large B cell lymphoma (DLBCL) is considered to be clearly inferior to that of younger patients. Besides tumor biology and comorbidities, treatment selection due to an assumed reduced tolerability may contribute to this difference. With increasingly more patients diagnosed at advanced age, current treatment selections need to be reviewed carefully. Hence, we analyzed the results of patients above the age of 70 in whom a diagnosis of DLBCL was made. Whereas patients up to 80 were frequently selected for and were able to tolerate standard treatment (86% intended use, 74% completion), patients above the age of 80 years were not only treated more cautiously (67 and 60%, respectively) but did show inferior response to treatment with standard treatment (CR rate for intended R-CHOP use 64% vs. 43%). However, on an individual level, patients receiving and completing standard treatment obtained results that resemble the results of younger patients, irrespective if aged more than 80 and impose superior to prior reports in this age cohort. Median PFS for the entire group of patients was 3.44 years, with 4.83 years for patients below 80 and only 1.09 years for patients above the age of 80. The corresponding figures for OS were 7.38 years (estimated); after 2 years, OS was 81% in the younger cohort in contrast to 68% in patients > 80 years. However, for patients not planned to receive or not tolerating R-CHOP, results remain poor; tailored approaches for these patients are required.

The metalloprotease meprin β (Mep1b) is capable of cleaving cell-adhesion molecules in different tissues (e.g. skin, kidney and intestine) and is dysregulated in several diseases associated with barrier breakdown (Alzheimer´s disease, kidney disruption, inflammatory bowel disease). In this study, we demonstrate that Mep1b is a novel regulator of tight junction (TJ) composition and blood-brain barrier (BBB) integrity in brain endothelium. In Mep1b-transfected mouse brain endothelial cells (bEnd.3), we observed a reduction of the TJ protein claudin-5, decreased transendothelial electrical resistance (TEER) and an elevated permeability to paracellular diffusion marker [14C]-inulin. Analysis of global Mep1b knock-out (Mep1b-/-) mice showed increased TJ protein expression (claudin-5, occludin, ZO-1) in cerebral microvessels and increased TEER in cultivated primary mouse brain endothelial compared to wild-type (wt) mice. Furthermore, we investigated the IgG levels in cerebrospinal fluid (CSF) and the brain water content as additional permeability markers and detected lower IgG levels and reduced brain water content in Mep1b-/- mice compared to wt mice. Showing opposing features in overexpression and knock-out, we conclude that Mep1b plays a role in regulating brain endothelial TJ-proteins and therefore affecting BBB tightness in vitro and in vivo.