HemaSphere最新文献

Hematotoxicity and infections are the main drivers of non-relapse mortality after chimeric antigen receptor (CAR)-T therapy. Consequently, reliable predictive biomarkers are highly needed to improve risk assessment and optimize patient management. In this study, we applied the immune-related adverse outcome pathway concept to delineate key events and risk factors of CAR-T-associated hematotoxicity. To identify predictive biomarkers, we performed flow cytometry and multiplex assays before and early after CAR-T infusion on 78 patients (ide-cel n = 31; axi-cel n = 24; and cilta-cel n = 23) undergoing CAR-T therapy. Severe hematotoxicity was linked to endothelial dysfunction, as evidenced by reduced levels of ANG1, soluble selectins, and increased soluble VCAM-1 (sVCAM-1) early after CAR-T infusion. Increased sVCAM-1, reflecting endothelial dysfunction, elevated soluble IL-2R (sIL-2R), indicating a proinflammatory state, and high tumor burden before lymphodepletion were key risk factors for CAR-T-associated hematotoxicity. Patients with elevated sVCAM-1 and sIL-2R at baseline (pre-lymphodepletion) exhibited significantly reduced overall survival (OS) (sVCAM-1; P = 0.0009), prolonged Grade 4 neutropenia (sVCAM-1; 12.1 vs. 6.0 days; P = 0.0016), more aplastic neutrophil recovery (5% vs. 30%; P = 0.007), and more severe infections (22.4% vs. 55%; P = 0.011). Baseline sIL-2R and sVCAM-1 demonstrated robust predictive value for prolonged neutropenia, severe infections, and mortality independently of key clinical variables such as the underlying disease and CAR-T product. Integration of these markers improves existing models and can help to refine risk assessment and guide individualized patient management in CAR-T therapy.

Despite advances in targeted therapies, treatment of chronic lymphocytic leukemia (CLL) remains challenging, highlighting the urgent need for effective new therapeutic strategies. Although chimeric antigen receptor (CAR) T-cell therapy dramatically improved outcomes in acute lymphoblastic leukemia (ALL), its efficacy in CLL is limited. We hypothesize that this disparity results from pronounced CAR T-cell exhaustion and the immunosuppressive tumor microenvironment (TME) in CLL. We utilized an autologous 3D TME co-culture model to investigate the functionality of CAR T cells derived from CLL and ALL patients within physiologically relevant conditions. Our results revealed increased exhaustion levels and diminished cytotoxicity of CAR T cells from CLL patients compared to those from ALL patients. Importantly, combining CAR T-cell treatment with interleukin-10 (IL-10) or CXCR4 blockade effectively improved cytotoxicity against CLL cells, even in stromal-protected regions within the 3D model. These findings offer insights into CAR T-cell dysfunction in CLL and support novel TME-targeted combination strategies to improve clinical outcomes.

Corticosteroids are commonly used to manage cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor (CAR) T-cell therapy, and yet, their dose-specific impact on outcomes remains uncertain. We retrospectively evaluated 276 adults with large B-cell lymphoma (LBCL) treated with CD19-directed CAR-T therapy (axi-cel, tisa-cel, or liso-cel) between 2016 and 2023 at a single institution. Cumulative corticosteroid dose was defined as the total dose administered within 21 days of infusion. Corticosteroids were administered to 105 patients (38%), initiated at a median of 5 days post-infusion (interquartile range [IQR] 3–7) for CRS (38%), ICANS (15%), or both (47%). Use was more frequent with axi-cel (P < 0.001), although the cumulative dose and duration were similar across products. To assess the impact of corticosteroid exposure, we carried out a 21-day landmark analysis. Corticosteroid exposure, modeled as a time-dependent covariate, was not significantly associated with infection risk, non-relapse mortality, or inferior overall survival (OS) or progression-free survival (PFS). However, in a landmark analysis, patients receiving above-median cumulative corticosteroid doses had a significantly higher risk of infection compared to those receiving below-median corticosteroid doses or no corticosteroids (P = 0.042). In a landmark multivariable analysis, corticosteroid cumulative dose was associated with increased late hematologic toxicity (adjusted hazard ratio [HR] 1.02, 95% CI 1.02–1.03). Finally, in a sensitivity analysis excluding patients with Grade ≥4 CRS/ICANS, corticosteroid cumulative dose remained unassociated with OS or relapse, but was linked to shorter PFS (adjusted HR 1.04, 95% CI 1.01–1.06). These findings support the safe yet judicious use of corticosteroids to manage CAR-T toxicities in LBCL.

Advancements in the rapidity, cost efficacy, and sensitivity of next-generation sequencing (NGS) have facilitated molecular risk stratification and precision medicine-based treatment for pediatric leukemia. The benefit of uniform cytomolecular analyses for clinical trial risk assignment is clear. However, the clinical impact of comprehensive NGS for pediatric leukemias at an institutional level is not well described. We report the genomic spectrum of one of the largest cohorts of pediatric and adolescent/young adult (AYA) acute leukemias examined to date (n = 1442) via institutional NGS testing from our large tertiary care center. We evaluated the clinical utility of genomic results for informing prognosis and treatment. We identified high utility of the comprehensive DNA-based mutational panel and RNA-fusion panel, which detected leukemia-associated variants in 99% of specimens. We observed 65% of B-cell acute lymphoblastic leukemia cases and 69% of patients with acute myeloid leukemia harbored a prognostic molecular alteration. In total, 325 of 1134 patients (29%) harbored potentially targetable molecular biomarkers, and 23% of cases with follow-up data received precision medicine-based therapy. Paired diagnostic and relapsed leukemia samples aided in differentiation between treatment-related leukemia versus lineage drift/switch. These findings demonstrate the broad utility of comprehensive molecular sequencing for pediatric/AYA leukemia at an institutional level to improve outcomes.