This multicenter, single-arm, phase 1/2 study evaluated the safety and efficacy of CD19-directed allogeneic chimeric-antigen-receptor (CAR) immunotherapy CTX110 in adult patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL). Patients received 1 or 2 treatment courses: standard lymphodepletion, followed by 1 CTX110 infusion at dose levels (DLs) 1-4 (3-60 × 107 CAR T-cells; dose escalation, N=32), or 2 infusions at DL4 on days 1 and 35 (cohort expansion, N=31). Primary endpoints in dose escalation and cohort expansion were incidence of dose-limiting toxicities and objective response rate, respectively. CTX110 was administered to 63 heavily pretreated patients: 59% primary refractory, 43% with ≥3 prior treatment lines. Among 57 patients whose first infusion was DL≥3, rates of objective and complete response (CR) were 65% and 39%, respectively. Among 22 patients achieving CR, 5 (23%) had ongoing CR at data cutoff, with 15-50 (median 34) months follow-up. The 2-infusion regimen appeared to prolong response duration compared to 1 infusion (hazard ratio 0.65). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 54% and 13% of treated patients, respectively, including 2 grade ≥3 cases each. The most common grade ≥3 adverse events were neutropenia (59%), and anemia and thrombocytopenia (35% each). Serious adverse events occurred in 32% of treated patients, including CRS (14%), ICANS (8%), and febrile neutropenia (6%). In this r/r NHL population, CTX110 was well-tolerated, resulting in clinically meaningful responses at DL≥3, with a second infusion demonstrating evidence of further clinical benefit. This trial (NCT04035434) was registered at www.clinicaltrials.gov.

We performed a retrospective study in patients with febrile neutropenia between 2005 and 2020 to assess the impact of time-to-antibiotics (TTA) on mortality. We included 1089 patients (58% males) aged 58 [46-67] years with hematological malignancies (62% acute leukemias, 20% lymphomas). TTA was 132 [68-271] minutes and hospital mortality was 9.1%. Hourly TTA was not associated with mortality in multivariate logistic regression. Hospital mortality was lower in patients with TTA ≤4 h (8.0% versus 11.9%, p = 0.04) and after propensity score matching based on comorbidities, vital signs and biological parameters at the time of fever, TTA ≤4 h remained associated with decreased mortality (odds ratio 0.55, 95% CI 0.31-0.96, p = 0.038). These findings were not confirmed in subgroups of patients with sepsis or bacteremia. Our study confirmed that TTA >4 h was associated with increased mortality but does not support recommendations of TTA ≤1 h in febrile neutropenia.

Lurbinectedin in combination with irinotecan showed synergistic antitumor activity in preclinical studies. A phase I/II trial (NCT02611024) evaluated this combination in patients with advanced solid tumors. The phase II stage evaluated the antitumor activity of the recommended dose (RD) (lurbinectedin 2.0 mg/m[2] on Day (D)1 plus irinotecan 75 mg/m[2] on D1 and D8 q3wk with primary granulocyte colony-stimulating factor prophylaxis) in five tumor-specific cohorts. This pooled analysis describes the safety profile of this combination from 233 patients with different advanced solid tumors treated at the RD. Adverse events (AEs) and laboratory abnormalities were graded using NCI-CTCAE v.4. The most frequent AEs (any grade) related to treatment were fatigue (71% of patients/25% of cycles), diarrhea (62%/17%), nausea (59%/18%), vomiting (35%/7%) and decreased appetite (32%/6%); the most common grade ≥ 3 AEs were fatigue (14%/2%), diarrhea (14%/2%) and febrile neutropenia (9%/1%). The most common grade ≥ 3 laboratory abnormality regardless of relationship was neutropenia (53%). The rate of discontinuation due to treatment-related AEs was 3% (n = 7 patients). There was one treatment-related death (0.4%) involving a 63-year-old male patient (0.4%) diagnosed with metastatic NEN who died due to grade 5 staphylococcal bacteremia. In conclusion, this pooled analysis shows a predictable and manageable safety profile for lurbinectedin in combination with irinotecan in patients with advanced solid tumors, with myelosuppression, fatigue and gastrointestinal disorders being the main toxicities observed.Trial code: ClinicalTrials.gov identifier: NCT02611024.

Neutrophils contribute to immune surveillance by releasing neutrophil extracellular traps (NETs) through NETosis. While essential, dysregulated NETosis is linked to pathology. We examined its role in salt-sensitive versus salt-resistant hypertension using Dahl rat models. Hypertensive Dahl S rats, but not normotensive Dahl R rats, showed increased NETosis, higher neutrophil counts, and chronic low-grade inflammation. Inhibiting NETosis with DNase I or by the genetic deletion of peptidyl arginine deiminase (Pad4) exacerbated blood pressure (BP) in S rats, suggesting NETosis protects against salt-sensitive hypertension. Pad4 deletion also caused neutropenia, reduced reactive oxygen species, and exaggerated BP elevation under a high-salt diet. In contrast, Pad4 deletion in R rats lowered systolic BP regardless of diet, indicating NETosis supports BP homeostasis in normotension. These findings highlight the context-dependent role of NETosis in BP regulation, with NETs acting as a protective mechanism in salt-sensitive hypertension.

Backgroundand Objectives: Targeted therapies are increasingly used in the management of chronic lymphocytic leukemia (CLL); however, real-world data from routine clinical practice remain limited. Materials and Methods: We performed a retrospective analysis of 47 patients with CLL who received at least one targeted therapy at a tertiary university hospital. Clinical characteristics, treatment responses, and adverse events were assessed. A total of 58 treatment events were included. Results: Obinutuzumab, ibrutinib, and venetoclax were administered in 34.5%, 46.5%, and 19.0% of treatment events, respectively. Numerically higher response rates were observed in treatment events involving obinutuzumab compared with ibrutinib and venetoclax (92.9% vs. 54.5% and 55.6%, respectively); however, treatment allocation was not randomized and these findings should be interpreted descriptively. Median overall survival from initiation of the first targeted therapy was 30.9 months. Adverse events occurred in more than 80% of treatment events. Neutropenia was more frequent with obinutuzumab and venetoclax, whereas bleeding events were more common with ibrutinib. Conclusions: In this real-world cohort, targeted therapies showed response patterns and safety findings consistent with routine clinical practice. Obinutuzumab was more frequently prescribed in older and more comorbid patients, reflecting treatment patterns rather than comparative superiority. These findings should be considered descriptive and hypothesis-generating, given the retrospective and single-center design.