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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.

Chimeric antigen receptor T-cell therapy with axicabtagene ciloleucel (axi-cel) has considerably improved survival in adults with relapsed/refractory large B-cell lymphoma. This study reports patient-reported outcomes (PROs) such as quality of life (QOL) and toxicity in the first 90 days after treatment. Hematologic cancer patients treated with axi-cel (N = 103, mean age = 61, 39% female) completed SF-36 or PROMIS-29 QOL questionnaires prior to treatment and 90 days after. PRO-Common Terminology Criteria for Adverse Events toxicity items were completed by patients at baseline and 14, 30, 60, and 90 days after treatment. Mixed models examined change in PROs over time. From preinfusion to 90 days later, patients reported improvements in physical functioning, pain, and fatigue (ps < 0.01), but worsening of anxiety (p = 0.02). Patient-reported toxicities worsened by day 14 with improvement thereafter. The five most severe symptoms at day 14 included fatigue, decreased appetite, dry mouth, diarrhea frequency, and problems with concentration. Results indicate improvement in some domains of QOL over time with transient patient-reported toxicities., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel)., Experimental Design: Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression., Results: We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity., Conclusions: These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality., (©2020 American Association for Cancer Research.)

High metabolic tumor volume (MTV) predicts worse outcomes in lymphoma treated with chemotherapy. However, it is unknown if this holds for patients treated with axicabtagene ciloleucel (axi-cel), an anti-CD19 targeted chimeric antigen receptor T-cell therapy. The primary objective of this retrospective study was to investigate the relationship between MTV and survival (overall survival [OS] and progression-free survival [PFS]) in patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axi-cel. Secondary objectives included finding the association of MTV with response rates and toxicity. The MTV values on baseline positron emission tomography of 96 patients were calculated via manual methodology using commercial software. Based on a median MTV cutoff value of 147.5 mL in the first cohort (n = 48), patients were divided into high and low MTV groups. Median follow-up for survivors was 24.98 months (range, 10.59-51.02 months). Patients with low MTV had significantly superior OS (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.10-0.66) and PFS (HR, 0.40; 95% CI, 0.18-0.89). Results were successfully validated in a second cohort of 48 patients with a median follow-up for survivors of 12.03 months (range, 0.89-25.74 months). Patients with low MTV were found to have superior OS (HR, 0.14; 95% CI, 0.05-0.42) and PFS (HR, 0.29; 95% CI, 0.12-0.69). In conclusion, baseline MTV is associated with OS and PFS in axi-cel recipients with LBCL., (© 2020 by The American Society of Hematology.)

Chimeric antigen receptor T-cell (CAR-T) therapy has proven to be a very effective cancer immunotherapy. Axicabtagene ciloleucel and tisagenlecleucel are the first-in-class anti-CD19 CAR-T currently available for relapsed/refractory adult large B-cell lymphoma. Tisagenlecleucel is also available for pediatric and young adult (up to age 25 years) patients with relapsed/refractory B-acute lymphoblastic leukemia. Cytokine release syndrome (CRS) and CAR-T-associated encephalopathy syndrome (neurotoxicity) are the most common adverse effects associated with CAR-T therapy. They can lead to significant morbidity and preclude widespread use of this treatment modality. Treatment-related deaths from severe CRS and cerebral edema have been reported. There is a significant heterogeneity in the side-effect profile of different CAR-T products under investigation and there is a need to develop standardized guidelines for toxicity grading and management. Here, we summarize the current literature on pathogenesis, clinical presentation, and management of CRS and neurotoxicity. The different grading systems of CRS and management protocols used in different trials have made it difficult to compare the outcomes of different CAR-T therapies. Several prevention strategies such as predictive biomarkers of CRS and neurotoxicity and modified CAR-T with 'built-in' safety mechanisms are being studied, with the potential to greatly expand the safety and applicability of CAR-T treatment across various malignancies.