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