Has the shortage of fludarabine altered the current paradigm of lymphodepletion in favor of bendamustine?

The most common lymphodepletion regimen used prior to infusion of chimeric antigen receptor-T cells (CAR-T) is cyclophosphamide (CY) in combination with fludarabine (Flu) (CY-FLU). While cyclophosphamide (CY) possesses lymphotoxic effects, it concurrently preserves regulatory T cell activity, potentially affecting the efficacy of CAR-T cells. Moreover, the use of fludarabine (FLU) has been linked to neurotoxicity, which could complicate the early detection of immune effector cell-associated neurotoxicity syndrome (ICANS) observed in CAR-T cell therapy. Given the ongoing shortage of FLU, alternative lymphodepleting agents have become necessary. To date, only a limited number of studies have directly compared different lymphodepleting regimens, and most of these comparisons have been retrospective in nature. Herein, we review the current literature on lymphodepletion preceding CAR-T cell therapies for lymphoid hematologic malignancies, with a specific focus on the use of bendamustine (BEN). Recent evidence suggests that administering BEN before CAR-T cell infusion yields comparable efficacy, possibly with a more favorable toxicity profile when compared to CY-FLU. This warrants further investigation through randomized prospective studies.

Intracerebral hemorrhage in COVID-19: A narrative review.

Coronavirus Disease 19 (COVID-19) pandemic affects the worldwide healthcare system and our understanding of this disease grows rapidly. Although COVID-19 is a mainly respiratory disease, neurological manifestations are not uncommon. The aim of this review is to report on the etiology, clinical profile, location, and outcome of patients with intracerebral hemorrhage (ICH) and COVID-19. This review includes 36 studies examining ICH in the clinical presentation of COVID-19. Overall, 217 cases with intracranial hemorrhage, of which 188 ICHs, were reported. Generally, a low incidence of both primary and secondary ICH was found in 8 studies [106 (0.25%) out of 43,137 hospitalized patients with COVID-19]. Available data showed a median age of 58 years (range: 52-68) and male sex 64%, regarding 36 and 102 patients respectively. Furthermore, 75% of the patients were on prior anticoagulation treatment, 52% had a history of arterial hypertension, and 61% were admitted in intensive care unit. Location of ICH in deep structures/basal ganglia was ascertained in only 7 cases making arterial hypertension an improbable etiopathogenetic mechanism. Mortality was calculated at 52.7%. Disease related pathophysiologic mechanisms support the hypothesis that SARS-CoV2 can cause ICH, however typical ICH risk factors such as anticoagulation treatment, or admission to ICU should also be considered as probable causes. Physicians should strongly suspect the possibility of ICH in individuals with severe COVID-19 admitted to ICU and treated with anticoagulants. It is not clear whether ICH is related directly to COVID-19 or reflects expected comorbidity and/or complications observed in severely ill patients.