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.

Administration of chimeric-antigen receptor T-cell (CAR-T) therapy is complex and associated with unique toxicities. Identifying patients at risk for inferior outcomes is important for individualized management. The Glasgow-prognostic score (GPS) is a simple score shown to be highly prognostic of outcomes in the setting of traditional chemotherapy or checkpoint inhibitor administration. We sought to evaluate the value of the GPS to predict outcomes of patients with relapse refractory multiple myeloma (RRMM) receiving anti-BCMA CAR-T therapy. We included all patients treated with commercial CAR-T therapy for RRMM between 5/1/2021 - 2/1/2023 at the Moffitt Cancer Center. The GPS (CRP >1 mg/dL, 1 point; albumin <3.5, 1 point) was calculated for all patients at lymphodepletion (day -6) and patients were grouped as high-risk GPS (score=2) or low-risk GPS (0 or 1). The primary endpoint was overall survival (OS) at day 100. A total of 139 pts were included, with a median follow up of 6.7 months (95% CI, 6.2 to 8.9 months). Pts were treated with either idecabtagene vicleucel (83%) or ciltacabtagene autoleucel (17%). In total, 14% were classified with high-risk GPS, with significantly increased risk for grade 3 CRS (p=0.003) and ICANS of any grade (p<0.001). Patients in the high-risk GPS group had significantly lower day-100 OS (68.4% vs 97.3%, p<0.001), OS at 6 months (56% vs 91.8% p=0.0019) and PFS at 6 months (38.3% vs 72.3%, p=0.03). The association of GPS with day-100 OS remained significant in a multivariable model. In conclusion, the GPS identifies a group of high-risk patients with RRMM receiving CAR-T therapy who experience increased rates of immune-mediated toxicity and are at higher risk for early mortality.

Jain A, et al. Int J Heart Fail. 2023 Jun;5:e13. https://doi.org/10.36628/ijhf.2023.0015

Purpose: Sarcopenia is a hallmark of cancer cachexia. Chimeric antigen receptor (CAR) T-cell therapy is associated with an inflammatory state that may exacerbate sarcopenia. The relationship among CAR T-cell therapy, sarcopenia, and metabolism is poorly understood. Experimental Design: In 83 patients with large B-cell lymphoma, the skeletal muscle index was measured from clinical images obtained at baseline and days 30 and 90 after therapy. Serum metabolomics (n = 57 patients) was performed in the first 4 weeks. Results: Baseline sarcopenia was present in more than half of patients and associated with shorter median overall survival than for non-sarcopenic patients (10.5 vs. 34.3 months; P = 0.006). This reduction was due to increased nonrelapse mortality with all six nonrelapse mortality events occurring in patients with baseline sarcopenia. In the first 30 days after CAR T-cell therapy, one of three patients experienced skeletal muscle loss greater than 10%. Muscle loss was associated with higher tumor burden and neurotoxicity but was not significantly associated with long-term survival. Serum metabolomics revealed an early (weeks 1–2) increase in purine metabolites, followed by a later (weeks 3–4) increase in triglyceride levels. The serum metabolite with the highest fold-increase from baseline was adipic acid, attributed to the inpatient hospital menu of jello and other tart beverages. Conclusions: Skeletal muscle loss after CAR T-cell therapy is common and is associated with fatty acid catabolism. Patients with baseline sarcopenia have poor tolerance and reduced survival. Future studies of dietary and exercise interventions may improve CAR T-cell therapy outcomes.

Axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor T-cell therapy, has significantly improved clinical outcomes in adult patients with relapsed/refractory large B-cell lymphoma. However, few studies have examined patient-reported outcomes (PROs) or neurocognitive performance in patients treated with axi-cel. Moreover, no longitudinal PRO study has reported on patients treated with axi-cel as standard of care in the United States, to our knowledge. This paper reports on real-world changes in PROs (i.e., quality of life [QOL] and perceived cognition) and objective neurocognitive performance before treatment with axi-cel and in the first year after. Patients scheduled to receive axi-cel as standard of care were recruited from a single cancer center between March 2020 and June 2022. QOL was assessed using the EORTC QLQ-C30 and EQ-5D-5L at baseline recruitment (ie, prior to conditioning chemotherapy before axi-cel), and at 7, 14, 30, 60, 90, 180, and 360 days after receiving axi-cel. Perceived cognition was assessed using the Patient-Reported Outcomes Measurement Information System Cognitive Function 4a scale. Objective neurocognitive performance was assessed using a battery of tests at baseline, and 30, 90, and 360 days after receiving axi-cel. Random-effects mixed models evaluated changes in QOL, perceived cognition, and neurocognitive performance using all available data. Clinically meaningful change in QOL was defined as a difference of 10 points on the EORTC QLQ-C30. Clinically meaningful change in perceived cognition or neurocognitive performance was defined as a difference of 5 points. On average, participants (N = 53) were 63 years of age (SD = 13), and predominantly male (62%), White (92%), and college graduates (60%). Participants reported statistically significant improvements from baseline to day 360 in overall QOL, physical functioning, role functioning, and social functioning (Ps < .05) after axi-cel, despite clinically significant worsening in the first 14 days. For role functioning and social functioning, improvements also met criteria for clinical significance. There were no statistically (Ps > .05) or clinically significant changes in perceived cognition over time. Despite some transient declines, neurocognitive performance generally returned to or exceeded baseline levels by day 360 (Ps < .01). However, visuospatial ability worsened by day 90 and did not recover to baseline levels by day 360 (P < .0001). These real-world data suggest that axi-cel is associated with significant improvements in overall QOL in the first year after infusion. These data are generally consistent with, or exceed, improvements in QOL reported from clinical trials of axi-cel therapy. Despite transient worsening in the acute period after treatment, neurocognitive performance in most domains also recovered to pretreatment levels by 1 year after infusion. These findings extend previous research by reporting on patients' perspectives on axi-cel therapy received as standard of care in the real-world setting and neurocognitive changes after treatment with axi-cel.

Objectives The first goal of the study is to provide a descriptive overview of the utilization of left ventricular assist device (LVAD) for the treatment of congestive heart failure (CHF) and determine the rates of LVAD use stratified by patients' demographic and hospitals' characteristics in the United States. Next, is to measure the hospitalization outcomes of length of slay (LOS) and cost in inpatients managed with LVAD. Methods We conducted a cross-sectional study using the nationwide inpatient sample and included 184,115 patients (age >= 65 years) with a primary discharge diagnosis of hypertensive and non-hypertensive CHF and was further classified by inpatients who were managed with LVAD. We compared the distributions of demographic and hospital characteristics in CHF inpatients with versus without LVAD by performing Pearson's chi-square test for categorical variables, and independent sample t-test for continuous variables. Results The inpatient utilization of LVAD was 0.93% (1690 out of 184,115) in CHF patients. The LVAD cohort were younger compared to non-LVAD group (mean age, 69.9 years vs. 79.4 years). The utilization rate of LVAD was also almost four times higher in males (1.50%) compared to females (0.36%). Although whites (78.5%) accounted for majority of LVAD recipients, the rate of LVAD utilization was highest in blacks (1.04%) and lowest in Hispanics (0.58%) with whites having utilization rate of 0.89%. Medicare was the dominant primary payer to cover the LVAD inpatients (91.1%), though the rate of LVAD utilization is highest in private (2.22%) and lowest in those covered by public insurance (medicaid/medicare). CHF patients in public hospitals (1.79%) were more than twice more likely to receive LVAD than in private hospitals (0.83%) due to higher utilization rate. LVAD utilization rate was approximately 55 times higher in teaching hospitals (1.67%) compared to non-teaching hospitals (0.03%), and 20 times higher in large bed hospitals (1.41%) compared to small bed-size hospitals (0.07%). CHF patients that received LVAD had a significantly longer LOS (34.6 days vs 9.8 days) and higher inpatient treatment costs ($802,118 vs. $86,302) compared to non-LVAD group. Conclusion The inpatient utilization of LVAD was in CHF patients is higher in males, blacks and private health insurance beneficiaries. In terms of hospital characteristics, the utilization of LVAD for CHF management was higher in large bed sized, and public type and teaching hospitals compared to their counterparts. This data will allow us to devise strategies to improve LVAD utilization and increase its outreach for heart failure patients, especially those on the transplant waiting list. Despite its effectiveness, awressive usage of LVAD is restricted due to cost-effectiveness and lack of technical confidence among medical professional due to complications.