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This document discusses the feasibility of using CD19 CAR T-cell therapy in patients with cardiac lymphoma. The article highlights that cardiac non-Hodgkin lymphoma is not well-represented in medical literature, and the exact incidence is unknown. The authors present three cases of patients with cardiac lymphoma who received CAR T-cell therapy. The first two patients had successful outcomes with no significant cardiac events, while the third patient experienced severe cardiotoxicity after CAR T infusion. The authors suggest that a multidisciplinary approach and preventive measures for severe cytokine release syndrome are important in optimizing the safety and efficacy of CAR T-cell therapy in patients with cardiac lymphoma. [Extracted from the article]

Simple Summary: CAR T-cell therapy became standard of care for patients with relapsed or refractory large B-cell lymphoma. However, their administration can be accompanied by toxicities, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. It is important to identify patients at risk for these toxicities in order to start an early intervention in high-risk patients and guide outpatient CAR T-cell treatment. As a consequence, several easy-to-use risk scores including the EASIX and its derivatives were developed. However, in the available studies, disparities existed among the used endpoints and cutoff values, hampering the utility of these tools in practice. This study aims to validate these EASIX scores in a population-based cohort. This can be used to select the best predictive model and to further guide optimization of the proposed risk scores. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: CAR T-cell therapy has emerged as the new standard of care for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), but real-world outcomes differ across countries. Additionally, real-world data on health-related quality of life (HR-QoL) are scarce but important, as they reflect the direct experience of patients. In the Netherlands, patients can be referred to the CAR-T tumorboard, a national CAR-T expert panel, who decide whether CAR-T is a feasible treatment option. This multicenter study reports on the favorable outcomes, including the HR-QoL, of axicabtagene ciloleucel (axi-cel) for patients with R/R LBCL after ≥2 lines of systemic therapy in the Netherlands. On the other hand, we show that a substantial proportion of patients are still in need of alternative treatments, including improved CAR-T strategies, as they are unfit for or do not respond to axi-cel. Comparing real-world outcomes between cohorts could help to select best practices and further optimize CAR-T treatment. The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020–May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need. [ABSTRACT FROM AUTHOR]

PURPOSE Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell–mediated toxicities is crucial because adequate and timely management can prevent or reverse potential life-threatening complications. In the outpatient setting, patients and informal caregivers have to recognize and report signs and symptoms marking these acute toxicities. This study provides a core set of patient- and caregiver-reported signs and symptoms (outcomes, P/CROs) and definitions of red flags warranting immediate action to include in a daily checklist for support at home, with the goal to make outpatient post–CAR T-cell care safer, optimize patient and caregiver support, and thereby facilitating an early discharge/hospital visit reduction strategy. METHODS We performed a systematic review of phase II/III trials of US Food and Drug Administration–approved CAR T-cell products and selected all common and severe adverse events that could be translated into a P/CRO for inclusion in a two-round modified Delphi procedure. Eleven CAR T-cell–dedicated hematologists from the Dutch CAR T-cell tumorboard representing all treating centers selected P/CROs for inclusion in the core set and defined red flags. The final core set was evaluated with patients and caregivers. RESULTS From nine clinical trials, 457 adverse events were identified of which 42 could be used as P/CRO. The final core set contains 28 items, including five signs for measurement via wearables and two signs for caregiver-performed assessments. CONCLUSION This study provides a core set of P/CROs that can serve as a framework for (eHealth) tools that aim to enable patients and caregivers to more effectively recognize and report signs and symptoms of acute toxicities after CAR T-cell therapy, which will enhance safe outpatient treatment monitoring. [ABSTRACT FROM AUTHOR]

Dear Sirs, Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary and effective treatment of hematological malignancies, in particular diffuse large B-cell lymphoma (DLBCL) [[1]-[3]]. The cortical myoclonic tremor resolved over the course of one to three months in three patients, and progressively improved until last follow-up (i.e., death nine months after CAR T-cell therapy) in one patient. There were also electrophysiological features compatible with myoclonus (i.e., absence of a clear peak in the EMG power spectrum) of cortical origin (i.e., EEG-EMG coherence in a frequency range and presence of cortical drive), like has been demonstrated in patients with familial cortical myoclonic tremor with epilepsy (FCMTE) [[4]]. These cases illustrate that treatment of cortical myoclonic tremor after CAR T-cell therapy is probably dependent on the clinical setting. [Extracted from the article]

During morning rounds, the hematologist on call noticed confusion in a 49-year-old female patient. She had been admitted 5 days earlier for CD19-directed chimeric antigen receptor T.cell ((JAR-T) therapy with infusion of axicabtagene ciloleucel for relapsed diffuse large B-cell lymphoma. Although the patient had been able to have a normal conversation the previous day, on this morning the hematologist found her to have bradyphrenia and to be disoriented to time and place. She had difficulty writ ing and Counting backward. No signs of headache, vomiting, focal deficits, vision abnormalities, hallucinations, pain, changes in bowel or bladder function, cough, or shortness of breath were noticed. No trauma or seizure was observed. Vital signs, including temperature, were normal. A neurologic examination was notable only for disorientation and for slow speech with difficulty in putting words together, with no focal abnormalities. The rest ofher physical examination was normal. [ABSTRACT FROM AUTHOR]

Background: People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study. Methods and Results: This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1- 8.0.], p = 0.034). The risk for SCA in epilepsy was particularly increased in young and females. Conclusion: Epilepsy in the general population seems to be associated with an increased risk for SCA. [ABSTRACT FROM AUTHOR]

Aims: To evaluate changes in QT duration during low-dose haloperidol use, and determine associations between clinical variables and potentially dangerous QT prolongation. Methods: In a retrospective cohort study in a tertiary university teaching hospital in The Netherlands, all 1788 patients receiving haloperidol between 2005 and 2007 were studied; ninety-seven were suitable for final analysis. Rate-corrected QT duration (QTc) was measured before, during and after haloperidol use. Clinical variables before haloperidol use and at the time of each ECG recording were retrieved from hospital charts. Mixed model analysis was used to estimate changes in QT duration. Risk factors for potentially dangerous QT prolongation were estimated by logistic regression analysis. Results: Patients with normal before-haloperidol QTc duration (male ≤430 ms, female ≤450 ms) had a significant increase in QTc duration of 23 ms during haloperidol use; twenty-three percent of patients rose to abnormal levels (male ≥450 ms, female ≥470 ms). In contrast, a significant decrease occurred in patients with borderline (male 430-450 ms, female 450-470 ms) or abnormal before-haloperidol QTc duration (15 ms and 46 ms, respectively); twenty-three percent of patients in the borderline group, and only 9% of patients in the abnormal group obtained abnormal levels. Potentially dangerous QTc prolongation was independently associated with surgery before haloperidol use (ORadj 34.9, p = 0.009) and before-haloperidol QTc duration (ORadj 0.94, p = 0.004). Conclusion: QTc duration during haloperidol use changes differentially, increasing in patients with normal before-haloperidol QTc duration, but decreasing in patients with prolonged before-haloperidol QTc duration. Shorter before-haloperidol QTc duration and surgery before haloperidol use predict potentially dangerous QTc prolongation. [ABSTRACT FROM AUTHOR]

Background Ventricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions (PVCs). Presence of SCN5A mutation increases the risk of PVCs upon exposure to sodium channel blockers (SCB) in patients with baseline type-1 ECG. In patients without baseline type-1 ECG, however, the effect of SCN5A mutation on the risk of SCB-induced arrhythmia is unknown. We aimed to establish whether presence/absence, type, and topology of SCN5A mutation correlates with PVC occurrence during ajmaline infusion. Methods and results We investigated 416 patients without baseline type-1 ECG who underwent ajmaline testing and SCN5A mutation analysis. A SCN5A mutation was identified in 88 patients ( S + ). Ajmaline-induced PVCs occurred more often in patients with non-missense mutations ( S non-missense ) or missense mutations in transmembrane or pore regions of SCN5A -encoded channel protein ( S missense-TP ) than patients with missense mutations in intra-/extracellular channel regions ( S missense-IE ) and patients without SCN5A mutation ( S − ) (29%, 24%, 9%, and 3%, respectively; P < 0.001). The proportion of patients with ajmaline-induced BrS was similar in different mutation groups but lower in S − (71% S non-missense , 63% S missense-TP , 70% S missense-IE , and 34% S − ; P < 0.001). Logistic regression indicated S non-missense and S missense-TP as predictors of ajmaline-induced PVCs. Conclusions SCN5A mutation is associated with an increased risk of drug-induced ventricular arrhythmia in patients without baseline type-1 ECG. In particular, S non-missense and S missense-TP are at high risk. [ABSTRACT FROM AUTHOR]