Poor outcome of patients with COVID-19 after CAR T-cell therapy for B-cell malignancies: results of a multicenter study on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party and the European Hematology Association (EHA) Lymphoma Group

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Càncer hematològic; Malalties infecciosesCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cáncer hematológico; Enfermedades infecciosasCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Haematological cancer; Infectious diseasesCOVID-19 is posing a significant threat to health in vulnerable patients, such as immunocompromised patients. For hematopoietic cell transplantation (HCT) recipients and patients with hematologic malignancies it is known that COVID-19 leads to severe morbidity and high mortality as compared to the general population [1–3]. For patients treated with Chimeric Antigen Receptor T-cell (CAR-T-cell) therapy for B-cell malignancies however, descriptions of the clinical course and outcome are still limited to small case series and case reports [4–8]. CAR-T-cell therapy recipients are believed to be at high risk of poor outcomes from COVID-19 due to their severely immunocompromised state, caused by prior lymphodepleting immunochemotherapy and CAR-T-cell therapy related side effects such as B-cell depletion, hypogammaglobulinemia, and cytopenias. In order to rapidly inform the medical field on the impact of COVID-19 on CAR-T-cell therapy recipients, the EBMT Infectious Diseases Working Party and the EHA Lymphoma Group joined forces and present the clinical course of COVID-19 in the largest European cohort to date

Health-related quality of life in cancer immunotherapy: a systematic perspective, using causal loop diagrams.

PURPOSE: System science offers a unique set of tools, including causal loop diagrams (CLDs), for stakeholders to better grasp the complexity of factors surrounding quality of life. Because the health-related quality of life (HRQoL) of cancer immunotherapy patients exists within an intricate system affected by and affecting many factors across multiple dimensions, the development of a systems-level model can provide a powerful framework to aid the understanding of this complexity. We developed a CLD for HRQoL of cancer immunotherapy patients. METHODS: We first applied a literature-based approach to construct a CLD for patients following immunotherapy. We then iteratively reviewed and enhanced the CLD through interviews with subject matter experts. RESULTS: Based on the reviewed literature and subject matter expert input, we produced a CLD representing the system surrounding cancer immunotherapy patients' HRQoL. Several feedback loops are identified that span clinical experiences, oncology teams' perceptions about immunotherapy, social support structures, and further research and development in cancer immunotherapy, in addition to other components. The CLD enables visualization of thought experiments regarding how a change anywhere in the system can ultimately worsen or improve patients' HRQoL. CONCLUSION: The CLD illustrates the valuable contribution of a systems perspective to quality-of-life research. This systems-based qualitative representation gives insight on strategies to inhibit harmful effects, enhance beneficial effects, and inherent tradeoffs within the system. The CLD identifies gaps in the literature and offers a communication tool for diverse stakeholders. Our research method provides an example for studying the complexities of quality of life in other health domains

SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers

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 (Snon-missense) or missense mutations in transmembrane or pore regions of SCN5A-encoded channel protein (Smissense-TP) than patients with missense mutations in intra-/extracellular channel regions (Smissense-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% Snon-missense, 63% Smissense-TP, 70% Smissense-IE, and 34% S−; P < 0.001). Logistic regression indicated Snon-missense and Smissense-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, Snon-missense and Smissense-TP are at high risk

Differential Changes in QTc Duration during In-Hospital Haloperidol Use

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 (OR(adj) 34.9, p = 0.009) and before-haloperidol QTc duration (OR(adj) 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 prolongatio

CD19-directed CAR T-cell therapy in B-cell NHL

PURPOSE OF REVIEW: CD19-directed chimeric antigen receptor (CAR) T-cell therapy is a valuable new treatment option for patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. The aim of this review is to give an overview of the pivotal phase I/II trials, emerging real-world evidence and ongoing trials. RECENT FINDINGS: For decades, attempts at improvement of the poor prognosis of patients with R/R large B-cell lymphoma with new treatment regimens have been disappointing. Since the first report of CD19-directed CAR-T-cell therapy in 2010, three constructs have been tested in large phase I/II trials and resulted in 30-40% durable responses. This has led to Food and Drug Administration and European Medicines Agency approval for axicabtagene ciloleucel and tisagenlecleucel and filing of the biologics license application for lisocabtagene maraleucel. Emerging real-world evidence seems to confirm the promising results. However, considerable toxicity, mainly cytokine release syndrome and neurotoxicity limits their general applicability and not all patients intended to be treated can be bridged during the manufacturing period due to kinetics of the disease. Randomized phase III clinical trials are being conducted to test anti-CD19 CAR-T-cell therapy in the second-line and several phase II trials are aiming to improve efficacy and decrease toxicity. SUMMARY: CD19-directed CAR-T-cell therapy has become standard of care for aggressive R/R diffuse large B-cell non-Hodgkin lymphoma (DLBCL), but challenges still remain

Health-related quality of life in cancer immunotherapy: a systematic perspective, using causal loop diagrams

Purpose: System science offers a unique set of tools, including causal loop diagrams (CLDs), for stakeholders to better grasp the complexity of factors surrounding quality of life. Because the health-related quality of life (HRQoL) of cancer immunotherapy patients exists within an intricate system affected by and affecting many factors across multiple dimensions, the development of a systems-level model can provide a powerful framework to aid the understanding of this complexity. We developed a CLD for HRQoL of cancer immunotherapy patients. Methods: We first applied a literature-based approach to construct a CLD for patients following immunotherapy. We then iteratively reviewed and enhanced the CLD through interviews with subject matter experts. Results: Based on the reviewed literature and subject matter expert input, we produced a CLD representing the system surrounding cancer immunotherapy patients’ HRQoL. Several feedback loops are identified that span clinical experiences, oncology teams’ perceptions about immunotherapy, social support structures, and further research and development in cancer immunotherapy, in addition to other components. The CLD enables visualization of thought experiments regarding how a change anywhere in the system can ultimately worsen or improve patients’ HRQoL. Conclusion: The CLD illustrates the valuable contribution of a systems perspective to quality-of-life research. This systems-based qualitative representation gives insight on strategies to inhibit harmful effects, enhance beneficial effects, and inherent tradeoffs within the system. The CLD identifies gaps in the literature and offers a communication tool for diverse stakeholders. Our research method provides an example for studying the complexities of quality of life in other health domains

Facilitatory and inhibitory effects of SCN5A mutations on atrial fibrillation in Brugada syndrome

Brugada syndrome (BrS) is associated with increased risk for atrial fibrillation (AFib). However, the role of SCN5A mutations in the occurrence of AFib remains unclear. Cardiac sodium current reduction caused by SCN5A mutations may facilitate AFib by slowing intra-atrial conduction and inducing structural changes, but also prevent it by suppressing atrial ectopic activity. Here, we examined the relation between SCN5A mutations, atrial conduction velocity, atrial structural changes, and atrial ectopic activity in BrS. Data from 214 BrS patients [78 with an SCN5A mutation (patients with an SCN5A mutation, BrSSCN5A+) and 136 without an SCN5A mutation (patients without an SCN5A mutation, BrSSCN5A-)] were collected. Intra-atrial conduction velocity was assessed by measuring P-wave durations at baseline and during sodium channel provocation testing. Atrial structural changes were assessed by measuring atrial dimensions using cardiac magnetic resonance imaging. Atrial ectopic activity was assessed by determining the incidence of atrial ectopic beats using 24 h Holter recordings. Clinical characteristics (including AFib occurrence) did not differ between BrSSCN5A+ and BrSSCN5A-. Baseline P-wave durations were longer in BrSSCN5A+ than in BrSSCN5A-, but lengthened markedly in BrSSCN5A- during provocation testing. Atrial dimensions did not differ. Atrial ectopic beats occurred more often in BrSSCN5A-, and the proportion of patients experiencing one or more atrial ectopic beats was larger in BrSSCN5A- than in BrSSCN5A+. In BrS, the presence of an SCN5A mutation is associated with intra-atrial conduction slowing and suppressed atrial ectopic activity. Intra-atrial conduction slowing may provide a plausible substrate for AFib maintenance, while reduced atrial ectopic activity may constitute inhibition of the trigger for AFib initiatio