Relapse after glofitamab has a poor prognosis and rates of CD20 loss are high.

We reviewed cases with aggressive B-cell non-Hodgkin lymphoma who relapsed or progressed following glofitamab. The prognosis was poor, with low rates of response to subsequent salvage therapies, and a median overall survival of 4.1 months from the time of progression. There were high rates of CD20 loss (59%) at the time of relapse. In a field where CD20 × CD3 bispecific antibodies are entering routine clinical use, our experience highlights a potential means of resistance. It illustrates both the need to further characterise mechanisms of CD20 loss, and to pursue clinical trials of novel non-CD20-directed treatments in this cohort.

Paediatric medication incident reporting: a multicentre comparison study of medication errors identified at audit, detected by staff and reported to an incident system.

OBJECTIVES: To compare medication errors identified at audit and via direct observation with medication errors reported to an incident reporting system at paediatric hospitals and to investigate differences in types and severity of errors detected and reported by staff. METHODS: This is a comparison study at two tertiary referral paediatric hospitals between 2016 and 2020 in Australia. Prescribing errors were identified from a medication chart audit of 7785 patient records. Medication administration errors were identified from a prospective direct observational study of 5137 medication administration doses to 1530 patients. Medication errors reported to the hospitals' incident reporting system were identified and matched with errors identified at audit and observation. RESULTS: Of 11 302 clinical prescribing errors identified at audit, 3.2 per 1000 errors (95% CI 2.3 to 4.4, n=36) had an incident report. Of 2224 potentially serious prescribing errors from audit, 26.1% (95% CI 24.3 to 27.9, n=580) were detected by staff and 11.2 per 1000 errors (95% CI 7.6 to 16.5, n=25) were reported to the incident system. Although the prescribing error detection rates varied between the two hospitals, there was no difference in incident reporting rates regardless of error severity. Of 40 errors associated with actual patient harm, only 7 (17.5%; 95% CI 8.7% to 31.9%) were detected by staff and 4 (10.0%; 95% CI 4.0% to 23.1%) had an incident report. None of the 2883 clinical medication administration errors observed, including 903 potentially serious errors and 144 errors associated with actual patient harm, had incident reports. CONCLUSION: Incident reporting data do not provide an accurate reflection of medication errors and related harm to children in hospitals. Failure to detect medication errors is likely to be a significant contributor to low error reporting rates. In an era of electronic health records, new automated approaches to monitor medication safety should be pursued to provide real-time monitoring.

Web-based cognitive rehabilitation intervention for cancer-related cognitive impairment following chemotherapy for aggressive lymphoma: protocol for a randomised pilot trial.

INTRODUCTION: Cancer-related cognitive impairment is common among people diagnosed with and treated for cancer. This can be a distressing and disabling side effect for impacted individuals. Interventions to mitigate cognitive dysfunction are available, but, to date, most have been trialled in samples that are largely or exclusively composed of people with solid tumours. Intervention strategies to support cognitive functioning are needed, but there is a paucity of research in this area. The main aim of this study is to test the feasibility and acceptability of methods and procedures intended for use in a definitive trial of a web-based cognitive rehabilitation programme, Responding to Cognitive Concerns (eReCog), in people who have received chemotherapy for aggressive lymphoma. METHODS AND ANALYSIS: The proposed study is a single-site, parallel-group, pilot randomised controlled trial, with one baseline and one follow-up (or postintervention) assessment. 38 people from the target population with low perceived cognitive function based on the Cognitive Change Screen will be recruited from a specialist cancer centre between July 2023 and June 2024. After baseline assessment, participants will be randomised one-to-one to receive usual care only (a factsheet about changes in memory and thinking for people with cancer) or eReCog plus usual care. The 4-week eReCog intervention consists of four online modules offering psychoeducation on cognitive impairment associated with cancer and its treatment, skills training for improving memory, and attention and relaxation training. Study outcomes will include the feasibility of recruitment and retention at follow-up assessment (primary outcomes), as well as adherence to, usability of and intrinsic motivation to engage with eReCog, and compliance with study measures. The potential efficacy of eReCog will also be evaluated. ETHICS AND DISSEMINATION: Ethical approval was granted by the Peter MacCallum Cancer Centre Human Research Ethics Committee in Victoria, Australia (HREC/97384/PMCC). Study findings will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12623000705684.

Machine learning reveals the control mechanics of an insect wing hinge.

Insects constitute the most species-rich radiation of metazoa, a success that is due to the evolution of active flight. Unlike pterosaurs, birds and bats, the wings of insects did not evolve from legs1, but are novel structures that are attached to the body via a biomechanically complex hinge that transforms tiny, high-frequency oscillations of specialized power muscles into the sweeping back-and-forth motion of the wings2. The hinge consists of a system of tiny, hardened structures called sclerites that are interconnected to one another via flexible joints and regulated by the activity of specialized control muscles. Here we imaged the activity of these muscles in a fly using a genetically encoded calcium indicator, while simultaneously tracking the three-dimensional motion of the wings with high-speed cameras. Using machine learning, we created a convolutional neural network3 that accurately predicts wing motion from the activity of the steering muscles, and an encoder-decoder4 that predicts the role of the individual sclerites on wing motion. By replaying patterns of wing motion on a dynamically scaled robotic fly, we quantified the effects of steering muscle activity on aerodynamic forces. A physics-based simulation incorporating our hinge model generates flight manoeuvres that are remarkably similar to those of free-flying flies. This integrative, multi-disciplinary approach reveals the mechanical control logic of the insect wing hinge, arguably among the most sophisticated and evolutionarily important skeletal structures in the natural world.

Primary gastric diffuse large B-cell lymphoma: A multicentre retrospective study.

Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) accounts for the majority of extra-nodal DLBCL. Even so, literature is lacking on early, localised presentations. We studied a cohort of patients with stage I disease, diagnosed between 2006 and 2018, from six centres between Australia, Canada and Denmark. Our goal was to characterise outcomes, review treatment and investigate the role of interim positron emission tomography (iPET). Thirty-seven eligible patients were identified. The median duration of follow-up was 42.2 months. All received chemoimmunotherapy with 91.9% (n = 34) given rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 35.1% (n = 13) underwent consolidative radiotherapy. Eighteen patients were H. pylori positive and 11 had the documentation of H. pylori eradication therapy. The 4-year progression-free survival and overall survival of R-CHOP was 88% (95% CI: 71-95) and 91% (95% CI: 75-97) respectively. All patients who achieved a partial metabolic response or complete metabolic response on iPET went on to achieve complete response at the end of treatment. R-CHOP-based therapy with iPET assessment appears to offer favourable outcomes, with radiotherapy and H. pylori eradication therapy implemented on a case-by-case basis.

The impact of unilateral pulmonary artery stenosis on right ventricular to pulmonary arterial coupling in patients with transposition of the great arteries.

BACKGROUND: Unilateral pulmonary artery (PA) stenosis is common in the transposition of the great arteries (TGA) after arterial switch operation (ASO) but the effects on the right ventricle (RV) remain unclear. AIMS: To assess the effects of unilateral PA stenosis on RV afterload and function in pediatric patients with TGA-ASO. METHODS: In this retrospective study, eight TGA patients with unilateral PA stenosis underwent heart catheterization and cardiac magnetic resonance (CMR) imaging. RV pressures, RV afterload (arterial elastance [Ea]), PA compliance, RV contractility (end-systolic elastance [Ees]), RV-to-PA (RV-PA) coupling (Ees/Ea), and RV diastolic stiffness (end-diastolic elastance [Eed]) were analyzed and compared to normal values from the literature. RESULTS: In all TGA patients (mean age 12 ± 3 years), RV afterload (Ea) and RV pressures were increased whereas PA compliance was reduced. RV contractility (Ees) was decreased resulting in RV-PA uncoupling. RV diastolic stiffness (Eed) was increased. CMR-derived RV volumes, mass, and ejection fraction were preserved. CONCLUSION: Unilateral PA stenosis results in an increased RV afterload in TGA patients after ASO. RV remodeling and function remain within normal limits when analyzed by CMR but RV pressure-volume loop analysis shows impaired RV diastolic stiffness and RV contractility leading to RV-PA uncoupling.

Epicardial adipose tissue and pericardial constraint in heart failure with preserved ejection fraction.

AIMS: Obesity and epicardial adiposity play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), and both are associated with increased filling pressures and reduced exercise capacity. The haemodynamic basis for these observations remains inaccurately defined. We hypothesize that an abundance of epicardial adipose tissue (EAT) within the pericardial sac is associated with haemodynamic signs of pericardial constraint. METHODS AND RESULTS: HFpEF patients who underwent invasive heart catheterization with simultaneous echocardiography were included. Right atrial pressure (RAP), right ventricular end-diastolic pressure, and pulmonary capillary wedge pressure (PCWP) were invasively measured. The presence of a square root sign on the right ventricular pressure waveform and the RAP/PCWP ratio (surrogate parameters for pericardial constraint) were investigated. EAT thickness alongside the right ventricle was measured on echocardiography. Sixty-four patients were studied, with a mean age of 73 ± 10 years, 64% women, and a mean body mass index (BMI) of 28.6 ± 5.4 kg/m2. In total, 47 patients (73%) had a square root sign. The presence of a square root sign was associated with higher BMI (29.3 vs. 26.7 kg/m2, P = 0.02), higher EAT (4.0 vs. 3.4 mm, P = 0.03), and higher RAP (9 vs. 6 mmHg, P = 0.04). Women had more EAT than men (4.1 vs. 3.5 mm, P = 0.04), despite a comparable BMI. Women with a square root sign had significantly higher EAT (4.3 vs. 3.3 mm, P = 0.02), a higher mean RAP (9 vs. 5 mmHg, P = 0.02), and a higher RAP/PCWP ratio (0.52 vs. 0.26, P = 0.002). In men, such associations were not seen, although there was no significant interaction between men and women (P > 0.05 for all analyses). CONCLUSIONS: Obesity and epicardial adiposity are associated with haemodynamic signs of pericardial constraint in patients with HFpEF. The pathophysiological and therapeutic implications of this finding need further study.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Impact and utility of follicular lymphoma GELF criteria in routine care: an Australasian Lymphoma Alliance study.

Follicular Lymphoma (FL) treatment initiation is largely determined by tumor burden and symptoms. In the pre-rituximab era, the Group d'Etude des Lymphomes Folliculaires (GELF) developed widely adopted criteria to identify high tumor burden FL patients to harmonize clinical trial populations. The utilization of GELF criteria (GELFc) in routine therapeutic decision-making is poorly described. This multicenter retrospective study evaluated patterns of GELFc at presentation and GELFc utilization in therapeutic decision-making in newly diagnosed, advanced stage rituximab-era FL. Associations between GELFc, treatment given, and patient survival were analyzed in 300 eligible cases identified between 2002-2019. 163 (54%) had ≥1 GELFc at diagnosis. The presence or cumulative number of GELFc did not predict PFS in patients undergoing watch-and-wait (WW) or those receiving systemic treatment. Of interest, in patients with ≥1 GELFc, 16/163 (10%) underwent initial watch-and-wait (comprising 22% of the watchand- wait cohort). In those receiving systemic therapy +/- radiotherapy, 74/215 (34%) met no GELFc. Our data suggest clinicians are using adjunctive measures to make decisions regarding treatment initiation in a significant proportion of patients. By restricting FL clinical trial eligibility only to those meeting GELFc, reported outcomes may not be applicable to a significant proportion of patients treated in routine care settings.

Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update.

ABSTRACT: Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.

Comparative efficacy and safety of tisagenlecleucel and axicabtagene ciloleucel among adults with r/r follicular lymphoma.

Regulatory approvals of tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) have established the feasibility of chimeric antigen receptor T-cell therapies for the treatment of adults with relapsed or refractory follicular lymphoma (r/r FL). This study used individual patient data from ELARA (tisa-cel) and aggregate published patient data from ZUMA-5 (axi-cel) to compare efficacy and safety outcomes in r/r FL using matching-adjusted indirect comparison methods. After adjustment for baseline differences in the trial populations, the results suggested that tisa-cel (n = 52), compared with axi-cel (n = 86), had similar effects on overall response rate (91.2% vs. 94.2%; p = .58), complete response rate (74.0% vs. 79.1%; p = .60), progression-free survival (HR [95% CI]: 0.8 [0.4, 1.9]; p = .67), and overall survival (HR [95% CI]: 0.5 [0.2, 1.5]; p = .21). Tisa-cel (n = 53) was associated with better safety outcomes than axi-cel (n = 124), reflected by lower rates of any grade and grade ≥3 cytokine release syndrome and neurological events.

Descending control and regulation of spontaneous flight turns in Drosophila.

The clumped distribution of resources in the world has influenced the pattern of foraging behavior since the origins of locomotion, selecting for a common search motif in which straight movements through resource-poor regions alternate with zig-zag exploration in resource-rich domains. For example, during local search, flying flies spontaneously execute rapid flight turns, called body saccades, but suppress these maneuvers during long-distance dispersal or when surging upstream toward an attractive odor. Here, we describe the key cellular components of a neural network in flies that generate spontaneous turns as well as a specialized pair of neurons that inhibits the network and suppresses turning. Using 2-photon imaging, optogenetic activation, and genetic ablation, we show that only four descending neurons appear sufficient to generate the descending commands to execute flight saccades. The network is organized into two functional units-one for right turns and one for left-with each unit consisting of an excitatory (DNae014) and an inhibitory (DNb01) neuron that project to the flight motor neuropil within the ventral nerve cord. Using resources from recently published connectomes of the fly, we identified a pair of large, distinct interneurons (VES041) that form inhibitory connections to all four saccade command neurons and created specific genetic driver lines for this cell. As predicted by its connectivity, activation of VES041 strongly suppresses saccades, suggesting that it promotes straight flight to regulate the transition between local search and long-distance dispersal. These results thus identify the key elements of a network that may play a crucial role in foraging ecology.

Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy.

ABSTRACT: Bispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in patients with heavily pretreated disease, and 3 drugs have so far received regulatory approvals in various countries. However, BsAbs can potentially lead to severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy has been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies, yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3×CD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3×CD20 BsAb-related toxicities.

Increased disparities in waitlist and post-heart transplantation outcomes according to socioeconomic status with the new heart transplant allocation system.

BACKGROUND: The study objective was to assess disparities in outcomes in the waitlist and post-heart transplantation (HT) according to socioeconomic status (SES) in the old and new U.S. HT allocation systems. METHODS: Adult HT candidates in the United Network for Organ Sharing database from 2014 through 2021 were included. Old or new system classification was according to listing before or after October 18, 2018. SES was stratified by patient ZIP code and median household income via U.S. Census Bureau and classified into terciles. Competing waitlist outcomes and post-transplantation survival were compared between systems. RESULTS: In total, 26,450 patients were included. Waitlisted candidates with low SES were more frequently younger, female, African American, and with higher body mass index. Reduced cumulative incidence (CI) of HT in the old system occurred in low SES (53.5%) compared to middle (55.7%, p = 0.046), and high (57.9%, p < 0.001). In the new system, the CI of HT was 65.3% in the low SES vs middle (67.6%, p = 0.002) and high (70.2%, p < 0.001), and SES remained significant in the adjusted analysis. In the old system, CI of death/delisting was similar across SES. In the new system, low SES had increased CI of death/delisting (7.4%) vs middle (6%, p = 0.012) and high (5.4%, p = 0.002). The old system showed similar 1-year survival across SES. In the new system, recipients with low SES had decreased 1-year survival (p = 0.041). CONCLUSIONS: SES affects waitlist and post-transplant outcomes. In the new system, all SES had increased access to HT; however, low SES had increased death/delisting due to worsening clinical status and decreased post-transplant survival.

Machine learning reveals the control mechanics of an insect wing hinge.

Insects constitute the most species-rich radiation of metazoa, a success due to the evolution of active flight. Unlike pterosaurs, birds, and bats, the wings of insects did not evolve from legs 1 , but are novel structures attached to the body via a biomechanically complex hinge that transforms tiny, high-frequency oscillations of specialized power muscles into the sweeping back-and-forth motion of the wings 2 . The hinge consists of a system of tiny, hardened structures called sclerites that are interconnected to one another via flexible joints and regulated by the activity of specialized control muscles. Here, we imaged the activity of these muscles in a fly using a genetically encoded calcium indicator, while simultaneously tracking the 3D motion of the wings with high-speed cameras. Using machine learning approaches, we created a convolutional neural network 3 that accurately predicts wing motion from the activity of the steering muscles, and an encoder-decoder 4 that predicts the role of the individual sclerites on wing motion. By replaying patterns of wing motion on a dynamically scaled robotic fly, we quantified the effects of steering muscle activity on aerodynamic forces. A physics-based simulation that incorporates our model of the hinge generates flight maneuvers that are remarkably similar to those of free flying flies. This integrative, multi-disciplinary approach reveals the mechanical control logic of the insect wing hinge, arguably among the most sophisticated and evolutionarily important skeletal structures in the natural world.

Patterns of neurotoxicity among patients receiving chimeric antigen receptor T-cell therapy: A single-centre cohort study.

BACKGROUND AND PURPOSE: Immune effector cell-associated neurotoxicity syndrome (ICANS) is an important complication of chimeric antigen receptor T-cell (CAR-T) therapy. This study aims to identify the patterns of neurotoxicity among patients with ICANS at a tertiary referral centre in Australia. METHODOLOGY: This single-centre, prospective cohort study included all consecutively recruited patients who underwent CAR-T therapy for eligible haematological malignancies. All patients underwent a comprehensive neurological assessment and cognitive screening before CAR-T infusion, during the development of ICANS, and 1 month after treatment. Baseline demographic characteristics, incidence, and neurological patterns of neurotoxicity management were evaluated. RESULTS: Over a 19-month period, 23% (12) of the 53 eligible patients developed neurotoxicity (10/12 [83%] being grade 1). All patients showed changes in handwriting and tremor as their initial presentation. Changes in cognition were manifested in most of the patients, with a more substantial drop noted in their Montreal Cognitive Assessment compared to immune effector cell-associated encephalopathy scores. All manifestations of neurotoxicity were short-lived and resolved within a 1-month period, with a mean duration of 8.2 days (range = 1-33). CONCLUSIONS: The patterns of CAR-T-related neurotoxicity often include change in handwriting, tremor, and mild confusional state, especially early in their evolution. These may remain undetected by routine neurological surveillance. These features represent accessible clinical markers of incipient ICANS.

CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study.

ABSTRACT: CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.

Death from mantle cell lymphoma limits sequential therapy, particularly after first relapse: Patterns of care and outcomes in a series from Australia and the United Kingdom.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterised by a heterogeneous clinical course. Patients can often receive sequential treatments, yet these typically yield diminishing periods of disease control, raising questions about optimal therapy sequencing. Novel agents, such as chimeric antigen receptor T-cell therapies and bispecific antibodies, show promise in relapsed MCL, but are often reserved for later treatment lines, which may underserve patients with aggressive disease phenotypes who die early in the treatment journey. To assess the problem of patient attrition from lymphoma-related death limiting sequential treatment, we performed a multicentre retrospective cohort analysis of 389 patients treated at Australian and UK centres over a 10-year period. Deaths from MCL increased after each treatment line, with 7%, 23% and 26% of patients dying from uncontrolled MCL after first, second and third lines respectively. Patients with older age at diagnosis and early relapse after induction therapy were at particular risk of death after second-line treatment. This limitation of sequential treatment by lymphoma-related death provides support for the trial of novel therapies in earlier treatment lines, particularly in high-risk patient populations.