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

Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma

CD19 CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with >= grade 3 neutropenia seen in 21/70 (30-0%) patients at day 30 and persisting in 3/31 (9-7%) patients at 1 year. B cells were undetectable in 30/34 (88-2%) patients at day 30, but were detected in 11/19 (57-9%) at 1 year. Median IgG levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/μl at 1 year after axi-cel (n=19, range 33 – 269). In total, 23/85 (27-1%) patients received IVIG after axi-cel, and 34/85 (40-0%) received G-CSF. Infections in the first 30 days occurred in 31/85 (36-5%) patients, of which 11/85 (12-9%) required intravenous antibiotics or hospitalization (“severe”) and were associated with cytokine release syndrome (CRS), neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, 7 severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T cell immunosuppression without severe infection

Association between vitamin D supplementation and mortality: systematic review and meta-analysis.

OBJECTIVE: To investigate whether vitamin D supplementation is associated with lower mortality in adults. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, and the Cochrane Central Register from their inception to 26 December 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing vitamin D supplementation with a placebo or no treatment for mortality were included. Independent data extraction was conducted and study quality assessed. A meta-analysis was carried out by using fixed effects and random effects models to calculate risk ratio of death in the group receiving vitamin D supplementation and the control group. MAIN OUTCOME MEASURES: All cause mortality. RESULTS: 52 trials with a total of 75 454 participants were identified. Vitamin D supplementation was not associated with all cause mortality (risk ratio 0.98, 95% confidence interval 0.95 to 1.02, I2=0%), cardiovascular mortality (0.98, 0.88 to 1.08, 0%), or non-cancer, non-cardiovascular mortality (1.05, 0.93 to 1.18, 0%). Vitamin D supplementation statistically significantly reduced the risk of cancer death (0.84, 0.74 to 0.95, 0%). In subgroup analyses, all cause mortality was significantly lower in trials with vitamin D3 supplementation than in trials with vitamin D2 supplementation (P for interaction=0.04); neither vitamin D3 nor vitamin D2 was associated with a statistically significant reduction in all cause mortality. CONCLUSIONS: Vitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment. Vitamin D supplementation reduced the risk of cancer death by 16%. Additional large clinical studies are needed to determine whether vitamin D3 supplementation is associated with lower all cause mortality. STUDY REGISTRATION: PROSPERO registration number CRD42018117823

Body Composition Assessment Provides Prognostic Information in Patients With Cancer Affected by Chronic Graft vs. Host Disease

ABSTRACT Background Additional tools are needed to assess mortality risk among patients with cancer. Patients with chronic graft vs. host disease (cGVHD) after allogeneic haematopoietic cell transplantation (HCT) represent a high‐risk cancer population with mortality risk explained by cGVHD severity, but also informed by baseline comorbidities, functional status before and after HCT, and cumulative toxicity from the procedure and its complications. Radiographic body composition metrics from CT scans have previously shown association with complications in other populations. Methods We examined a single‐centre consecutive series (2005–2016) of HCT recipients with cGVHD and CT‐scans immediately proximal to cGVHD diagnosis to investigate association of radiographic body composition measures and mortality. Skeletal muscle index (SMI) and fat index (FI) were quantified on CT imaging at the 3rd lumbar (L3) and 4th thoracic (T4) vertebra. SM Hounsfield units (HU) were obtained to evaluate SM density. Cut points for SMI were from literature and cut points for FI were established by sex‐specific optimal stratification. Results A total of n = 113 patients met the inclusion criteria for this analysis, aged 51.2 ± 10.5(SD) years and predominantly male (n = 71, 63%) and diagnosed with NHL (n = 110, 97%). Onset cGVHD NIH overall severity was mild in N = 56 (49%), moderate in 44 (38%) and severe in 15 (13%), with median time to cGVHD onset after HCT of 173 days [IQR 122;295]. A CT scan at 77 days [IQR 33;202] post HCT was selected for analysis. In multivariate analysis, CT‐defined body fat ≥ 35% was independently associated with increased mortality (HR 2.094 (95% CI 1.060, 4.136), p = 0.033) overall. Patients of male sex had higher FI than females and showed a more prominent association between high FI and mortality. SMI as well as other indices of adiposity were not associated with survival in multivariable analysis including BMI, sarcopenic obesity and low skeletal muscle radiodensity. In exploratory analyses, we demonstrated similar results per CT chest at T4, suggesting possible future application to a larger HCT population. Conclusions These data support that radiographic body composition measures provide prognostic information among patients with cancer affected by cGVHD post‐HCT and suggest that high body fat % is a promising candidate for future study. These findings suggest that low skeletal muscle mass alone does not predict for poor outcomes in HCT patients with cGVHD as previously described in other cancers. Independent validation of this work is needed, including further studies based on CT chest to enhance application to a larger HCT population

Oxygen-free resistance heating with nitrogen and silane as an energy-efficient heating process for hot stamping

Hot stamping is a process for the production of ultra-high-strength components used in the automotive industry for passenger protection. In this process, cut blanks are heated in a roller hearth furnace, which is operated with gas, to approx. 950 °C in 8 to 10 min and then formed and quenched in a water-cooled tool. This extends the yield strength of the components up to 1500 MPa. The long heating time is caused by the coating of aluminium and silicon (AlSi) with a thickness of 70 μm. During the 8 to 10 min, an intermetallic phase forms and ensures that the blank does not scale. Due to the long heating time and the energy carrier gas, the process is very energy inefficient and can only be controlled slowly. Resistance heating provides an energy-efficient alternative. Due to the direct current flow through the sheet, up to 68% of the energy can be saved compared to roller hearth furnace heating. The process is a high-speed heating process that can heat sheets to 950 °C in less than 10 seconds. The heating time is not sufficient for conventional coatings to bond sufficiently with the base material, which means that there are currently no suitable coatings for resistance rapid heating. A new approach is to suppress scale formation by reducing the oxygen during heating. By lowering the oxygen partial pressure to the XHV level, scale formation is not possible. At the same time, this absence of oxygen is an ideal condition for applying coatings. Due to the developed resistance heating device, sheets can be heated within a very short time without scale and without the need for fossil fuels