High pretreatment disease burden as a risk factor for infectious complications following CD19 chimeric antigen receptor T-cell therapy for large B-cell lymphoma.

Infection has emerged as the chief cause of non-relapse mortality (NRM) post CD19-targeting chimeric antigen receptor T-cell therapy (CAR-T) therapy. Even though up to 50% of patients may remain infection-free, many suffer multiple severe, life-threatening, or fatal infectious events. The primary aim of this study was to explore severe and life-threatening infections post licensed CAR-T therapy in large B-cell lymphoma, with a focus on the role of disease burden and disease sites in assessing individual risk. We sought to understand the cohort of patients who experience ≥2 infections and those at the highest risk of infectious NRM. Our analysis identifies a higher disease burden after bridging therapy as associated with infection events. Those developing ≥2 infections emerged as a uniquely high-risk cohort, particularly if the second (or beyond) infection occurred during an episode of immune effector cell-associated neurotoxicity syndrome (ICANS) or while on steroids and/or anakinra for ICANS. Herein, we also describe the first reported cases of "CAR-T cold sepsis," a phenomenon characterized by the lack of an appreciable systemic inflammatory response at the time of detection of infection. We propose a risk-based strategy to encourage heightened clinician awareness of cold sepsis, with a view to reducing NRM.

Mucormycosis after CD19 chimeric antigen receptor T-cell therapy: results of a US Food and Drug Administration adverse events reporting system analysis and a review of the literature.

Chimeric antigen receptor (CAR) T-cell therapy leads to durable remissions in relapsed B-cell cancers, but treatment-associated immunocompromise leads to a substantial morbidity and mortality risk from atypical infection. Mucormycosis is an aggressive and invasive fungal infection with a mortality risk of 40-80% in patients with haematological malignancies. In this Grand Round, we report a case of mucormycosis in a 54-year-old patient undergoing CAR T-cell therapy who reached complete clinical control of Mucorales with combined aggressive surgical debridement, antifungal pharmacotherapy, and reversal of underlying risk factors, but with substantial morbidity from extensive oro-facial surgery affecting the patient's speech and swallowing. For broader context, we present our case alongside an US Food and Drugs Administration adverse events reporting database analysis and a review of the literature to fully evaluate the clinical burden of mucormycosis in patients treated with CAR T-cell therapy. We discuss epidemiology, clinical features, diagnostic tools, and current frameworks for treatment and prophylaxis. We did this analysis to promote increased vigilance for mucormycosis among physicians specialising in CAR T-cell therapy and microbiologists and to illustrate the importance of early initiation of therapy to effectively manage this condition. Mucormycosis prevention and early diagnosis, through targeted surveillance and mould prevention in patients at highest risk and Mucorales-specific screening assays, is likely to be key to improving outcomes in patients treated with CAR T-cell therapy.

Supportive care for chimeric antigen receptor T-cell patients.

PURPOSE OF REVIEW: The purpose of this review is to provide clear guidance to health professionals delivering chimeric antigen receptor T-cell (CAR-T) therapy on the best supportive management throughout the CAR-T pathway, from referral to long-term follow-up, including psychosocial aspects. RECENT FINDINGS: CAR-T therapy has changed the treatment landscape for relapsed/refractory (r/r) B-cell malignancy. Approximately 40% of r/r B-cell leukaemia/lymphoma patients receiving CD19-targeted CAR-T therapy achieve durable remission following a single dose. The field is rapidly expanding to encompass new CAR-T products for indications such as multiple myeloma, mantle cell lymphoma and follicular lymphoma, and the number of patients eligible to receive CAR-T therapy is likely to continue to grow exponentially. CAR-T therapy is logistically challenging to deliver, with involvement of many stakeholders. In many cases, CAR-T therapy requires an extended inpatient hospital admission, particularly in older, comorbid patients, and is associated with potentially severe immune side effects. Further, CAR-T therapy can lead to protracted cytopenias that can last for several months accompanied by a susceptibility to infection. SUMMARY: For the reasons listed above, standardised, comprehensive supportive care is critically important to ensure that CAR-T therapy is delivered as safely as possible and that patients are fully informed of the risks and benefits, as well as the requirement for extended hospital admission and follow-up, to fully realise the potential of this transformative treatment modality.

Hypotension and short-term anaesthesia induce ERK1/2 phosphorylation in autonomic nuclei of the brainstem.

The aims of this study were: first, to investigate the effects of anaesthesia on phosphorylated extracellular signal-regulated kinase (p-ERK)1/2-immunoreactivity (-ir) in the brainstem; second, to choose the best anaesthetic for p-ERK1/2 studies; and third, to determine the effect of short-term hypotension on p-ERK1/2-ir in the brainstem. Rats were anaesthetized with halothane, sodium pentobarbital or 100% CO2 narcosis, or were cervically dislocated and within 5 min perfused and the brains processed immunohistochemically for pERK1/2-ir. p-ERK1/2-ir was primarily observed in regions associated with cardiovascular and/or respiratory control. Several regions consistently showed dense p-ERK1/2 labelling, including a restricted region of the ventrolateral medulla (VLM). In contrast, other regions showed differential labelling depending on the mode of death. Cervical dislocation showed the least VLM labelling, limited to a discrete area approximately 0.6-1.4 mm caudal to the facial nucleus. Anaesthetics induced labelling throughout the VLM, with halothane inducing the most. Many p-ERK1/2-ir VLM neurons were catecholaminergic following halothane or sodium pentobarbital anaesthesia, but no double labelling was seen following cervical dislocation. Of the anaesthetics, sodium pentobarbital induced the least labelling and was used subsequently. Intravenous hydralazine was used to induce a 20-min period of hypotension, whereas arterial pressure did not change in vehicle-treated animals. Hydralazine evoked more pERK-ir neurons in specific regions, including the VLM, nucleus tractus solitarius (NTS), parabrachial nuclei, Kolliker-Fuse nucleus and locus coeruleus. Approximately twice as many p-ERK1/2-positive neurons were seen in the intermediate NTS and rostral VLM following hydralazine compared with the vehicle. In conclusion, p-ERK1/2-ir identifies neurons in central autonomic regions, and their number and distribution are markedly affected by anaesthetics, and are increased in some regions by short-term hypotension.