Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion

Prolonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with "intermittent" neutrophil recovery (e.g., recurrent neutrophil dips) compared to either "quick" or "aplastic" recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion

Inferior outcomes of EU versus US patients treated with CD19 CAR-T for relapsed/refractory large B-cell lymphoma: association with differences in tumor burden, systemic inflammation, bridging therapy utilization, and CAR-T product use

Real-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use

Asthma and COPD Overlap Syndrome (ACOS): A Systematic Review and Meta Analysis

<div><p>Background</p><p>The combination of asthma and chronic obstructive pulmonary disease (COPD), or ACOS is a recently defined syndrome. The epidemiology of the condition is poorly described and previous research has suggested ACOS is associated with worse outcomes than either condition alone. We therefore decided to complete a systematic review of the published literature.</p><p>Methods</p><p>This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines. A structured search was performed in the PubMed, Embase, and Medline databases up to Feb 2015 to identify studies reporting incidence, prevalence, health care utilization, morbidity, or mortality in COPD and asthma.</p><p>Results</p><p>A total of 19 studies were included in the present study. The pooled prevalence of overlap among COPD was 27% (95% CI: 0.16–0.38, p<0.0001) and 28% (95% CI: 0.09–0.47, p = 0.0032) in the population and hospital-based studies, respectively. We found no significant difference between ACOS and COPD in terms of gender, smoking status, lung function and 6mWD. However, in comparison to subject with only COPD, ACOS subjects were significantly younger, had higher BMI, healthcare utilization, and lower HRQoL.</p><p>Conclusion</p><p>ACOS is a common condition that exists in a substantial proportion of subjects with COPD. ACOS represents a distinct clinical phenotype with more frequent exacerbations, hospitalization, worse health-related quality of life, and higher healthcare costs than either disease alone. There is a critical need to better define the management and treatment of this syndrome.</p></div

Forest Plot: polled prevalence of overlap among COPD patients in population based studies.

<p>Study 1 = Shirtcliffe et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref010" target="_blank">10</a>], study 2 = Menezes et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref011" target="_blank">11</a>], study 3 = Marsh et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref012" target="_blank">12</a>], study 4 = Johannessen et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref016" target="_blank">16</a>], study 5 = Danielsson et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref017" target="_blank">17</a>], study 6 = Methvin et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref018" target="_blank">18</a>], study 7 = Miravitlles et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref019" target="_blank">19</a>], study 8 = Y. Zhou+CESCOPD et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref020" target="_blank">20</a>], study 9 = Jyrki-Tapani al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref021" target="_blank">21</a>].</p

Forest Plot: polled prevalence of overlap among COPD patients in hospital based studies.

<p>Study 1 = Kauppi et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref013" target="_blank">13</a>], study 2 = Hardin et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref014" target="_blank">14</a>], study 3 = Alonso JL et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref015" target="_blank">15</a>], study 4 = Fabbri et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136065#pone.0136065.ref022" target="_blank">22</a>].</p

Characteristics of included studies.

<p>Abbreviations and definitions: COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity, ICD: International Classification of Diseases.</p><p>Characteristics of included studies.</p

Review process (PRISMA Flow Diagram): details of review process.

<p>Review process (PRISMA Flow Diagram): details of review process.</p

Outcome of Outpatient Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma and Relapsed and Refractory Hodgkin Lymphoma. The Experience of King Fahad Specialist Hospital in Dammam, Saudi Arabia

Background: Autologous hematopoietic stem cell transplants (HSCT) is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (MM) and patients with relapsed and refractory Hodgkin lymphoma (R/R-HL) who achieve chemosensitivity after salvage therapy. Although autologous HSCT is routinely performed in an &nbsp;inpatient setting, the procedure can safely be performed in an &nbsp;outpatient setting.Methods and materials: A retrospective study of patients with MM and R/R- HL who received outpatient autologous HSCT at King Fahad Specialist Hospital (KFSH) in Dammam, Saudi Arabia between the first of April 2017 and the 31st of January 2022 was performed.Results: Over the study period of 4 years and 10 months, a total of 90 outpatient autologous HSCTs were performed for 79 patients (54 patients with MM; 4 of them received planned tandem autografts and 7 other myeloma patients received second autologous HSCTs for relapsed or progressive disease; and 25 patients with R/R-HL) at our institution. The median ages of patients with MM and those with R/R-HL at HSCT were 50.4 years and 27.8 years respectively.At the presentation of their MM, the following high-risk (HR) features were encountered: stage II and III diseases according to the revised international scoring system (RISS) in 53.7%; adverse cytogenetics in 42.6% and extensive bone involvement in 53.7% of patients. In patients with HL at presentation, 48% of patients had stage IV disease according to Ann Arbor staging classification and 84% of patients had B symptoms.Survival for 100 days post-HSCT for all patients with MM and HL who received outpatient autologous transplants was 100%. For patients with MM, the overall survival (OS) rates at 3 years and 4 years post-HSCT were 80% and 67%, while the progression-free survival (PFS) rates over 3 years and 4 years were 58% and 38% respectively. For patients with HL, the OS at 6 years post-HSCT was 95% while the PFS rates at 3 years and 6 years post-HSCT were 84% and 62% respectively.Conclusion: Outpatient autologous HSCT for patients with MM and HL is safe, and feasible and can lead to short-term as well as long-term outcomes that are comparable to autologous transplantation performed in an &nbsp;inpatient setting. Additional benefits of outpatient autologous include saving beds and reducing hospital costs

Laboratory Techniques Used to Diagnose Constitutional Platelet Dysfunction

International audiencePlatelets play a major role in primary hemostasis, where activated platelets form plugs to stop hemorrhaging in response to vessel injuries. Defects in any step of the platelet activation process can cause a variety of platelet dysfunction conditions associated with bleeding. To make an accurate diagnosis, constitutional platelet dysfunction (CPDF) should be considered once von Willebrand disease and drug intake are ruled out. CPDF may be associated with thrombocytopenia or a genetic syndrome. CPDF diagnosis is complex, as no single test enables the analysis of all aspects of platelet function. Furthermore, the available tests lack standardization, and repeat tests must be performed in specialized laboratories especially for mild and moderate forms of the disease. In this review, we provide an overview of the laboratory tests used to diagnose CPDF, with a focus on light transmission platelet aggregation (LTA), flow cytometry (FC), and granules assessment. Global tests, mainly represented by LTA, are often initially performed to investigate the consequences of platelet activation on platelet aggregation in a single step. Global test results should be confirmed by additional analytical tests. FC represents an accurate, simple, and reliable test to analyze abnormalities in platelet receptors, and granule content and release. This technique may also be used to investigate platelet function by comparing resting- and activated-state platelet populations. Assessment of granule content and release also requires additional specialized analytical tests. High-throughput sequencing has become increasingly useful to diagnose CPDF. Advanced tests or external research laboratory techniques may also be beneficial in some cases