Although chronic lymphocytic leukaemia (CLL) was one of the first two entities in which CAR-T cells were evaluated, it has not yet arrived in the clinical routine. Since the landmark study by Porter et al. (2011), only six CLL-specific clinical trials have been published, altogether comprising no more than 155 patients (Porter et al. 2015; Gill et al. 2018; Turtle et al. 2017; Gauthier et al. 2020; Siddiqi et al. 2020; Wierda et al. 2020; Frey et al. 2020). All six of these studies investigated CD19-directed CAR-T constructs in heavily pretreated patients, mostly having failed BTKi+/− venetoclax therapy. Despite overall response rates of 60–95%, including MRD clearance in a large proportion of patients, the CR rates appear to be relatively low, and only a few durable responses have been reported in patients achieving a CR (Porter et al. 2015; Frey et al. 2020; Cappell et al. 2020). While toxicity includes 5–20% grade 3 cytokine release syndrome and 5–25% grade 3 neurotoxicity and appears manageable, long-term efficacy remains an unresolved issue. CLL-specific efficacy barriers for CD19 CAR-T cells could include a reduced capacity for sustained T cell expansion in extensively pretreated elderly CLL patients (Lemal and Tournilhac 2019), along with impaired T cell motility, impaired T cell mitochondrial fitness, and T cell exhaustion (Bair and Porter 2019). Concurrent use of ibrutinib might reduce the CRS rate and severity (Gauthier et al. 2020; Gill et al. 2018; Wierda et al. 2020) without impairing CAR-T cell expansion.
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