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.

  • Currently, there is no standard indication for CAR-T cells in CLL.

  • 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

/

  1. RT Richter transformation, R/R relapsed/refractory, TP53 alt. TP53 mutation and/or 17p deletion, CRS cytokine release syndrome, NT neurotoxicity, allG all grades, G ≥ 3 grade ≥ 3, na not available, CK complex karyotype (≥3 abnormalities), BM bone marrow, MRD(−) BM negative bone marrow minimal residual disease, NRM non relapse mortality
  2. aTranscend CLL 004 study with lisocabtagene maraleucel
  3. bAssessment limited to evaluable patients

Key Points

  • 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.

  • However, more data, including clinical trials with a longer follow-up time, are required before adding CAR-T cells to clinical practice.