Abstract
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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Clinical Development of CAR-T Cells for CLL
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.
Current Indications for CAR-T Cells in the Treatment Landscape of CLL
In the absence of studies with informative sample sizes and follow-up and without an approved CAR-T cell preparation available, there is currently no indication for CAR-T cells in CLL outside of a clinical trial. However, if a suitable trial is available, CAR-T cells can be proposed as an alternative in patients with high-risk-2 CLL who have a high transplant risk according to the EBMT-ERIC recommendations (Dreger et al. 2018). In patients with a low transplant risk, allogeneic haematopoietic cell transplantation (alloHCT) still appears to be the more promising approach in terms of long-term disease control (Tournilhac et al. 2020; Roeker et al. 2020; Mato et al. 2020). The advent of more effective CAR-T cell therapies for CLL is eagerly awaited and may rapidly change this algorithm.
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Currently, there is no standard indication for CAR-T cells in CLL.
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CAR-T cells may be an alternative to alloHCT in high-risk patients in clinical trials.
Prospective Studies of Autologous Anti-CD19 CAR-T Cell Therapy for CLL
Porter et al. (2015) | Frey et al. (2020) | Gill et al. (2018) | Turtle et al. (2017) | Gauthier et al. (2020) | Siddiqi et al. (2020) | Wierda et al. (2020) | |
---|---|---|---|---|---|---|---|
Patients (n) | 14 | 38 | 19 | 24 (5RT) | 19 (4RT) | 22 (1RT) | 19 |
CAR-T with ibrutinib | CTL019 No | CART-19 No | CTL119 Yes | JCAR014 No | JCAR014 Yes | JCAR017a No | JCAR017a Yes |
Age (years) | 66 (51–78) | 61 (49–76) | 62 (42–76) | 61 (40–73) | 65 (40–71) | 66 (50–80) | 60 (50–77) |
Previous lines (n) | 5 (1–11) | 3.5 (2–7) | 2 (1–16) | 5 (3–9) | 5 (1–10) | 4 (2–11) | 4 (2–11) |
Ibrutinib (R/R) | 1 (1) | 9 (?) | 5 (0) | 24 (19) | 19 (19) | 23 (17) | 19 (19) |
Venetoclax (R/R) | 0 | 1 | 0 | 6 (6) | 11 (6) | 13 (11) | 11 (na) |
CK (%) | Na | Na | Na | 67 | 74 | 48 | 42 |
TP53 alt. (%) | 43 | 39b | 58 | Del = 58 | Del = 74 | Mut = 61 Del = 35 | Mut = 32 Del = 42 |
ORR (%) | 57 | 44b | 71b | 70 | 83b | 82b | 95 |
CR (%) | 29 | 28b | 43b | 17 | 22b | 46b | 63 |
MRD(−) BM (%) | 29 | na | 78b | 50b | 61b | 65b | 79 |
CRS (all/G3) (%) | 64/43 | 63/24 | 95/16 | 83/8 | 74/0 | 74/9 | 74/5 |
NT (all/G3) (%) | 36/7 | na/8 | 26/5 | 33/25 | 26/26 | 39/22 | 32/16 |
FU (m) | 19 (6–53) | 32 (2–75) | 19 (8–28) | NA | 12 (4–17) | 24 | 10 |
PFS (m) PFS >24 m (n) | 28% @18 m 3 | 1 m 7 | na na | 8.5 m na | 38% @12 m na | 50% @18 m na | na na |
NRM (n) cause | 1 (infection) | 0 / | 1 (cardiac) | 1 (CRS/NT) | 1 (cardiac) | 0 / | 0 / |
Key Points
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Autologous CAR-T cells for CLL have been in development for almost 10 years, with interesting results in poor-risk disease, including patients double refractory to both BTKi and BCL2i.
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However, more data, including clinical trials with a longer follow-up time, are required before adding CAR-T cells to clinical practice.
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Tournilhac, O., Dreger, P. (2022). Chronic Lymphocytic Leukaemia. In: Kröger, N., Gribben, J., Chabannon, C., Yakoub-Agha, I., Einsele, H. (eds) The EBMT/EHA CAR-T Cell Handbook. Springer, Cham. https://doi.org/10.1007/978-3-030-94353-0_14
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