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Chimeric antigen receptor (CAR) T-cell therapy has improved treatment for young patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL), with 1-year relapse-free survival rates reaching 60%. However, central nervous system (CNS) involvement is seen in 20% of all relapses; CNS disease is associated with a reduced overall survival (OS) after relapse and is difficult to treat. Safety and efficacy data of CD19-directed CAR T-cell therapy for CNS relapse remains scarce, as most trials have excluded patients with active CNS disease. Therefore, Leahy et al. performed a post hoc analysis that evaluated the safety and activity of CAR T-cell therapy in patients with a history of CNS R/R B-cell ALL.1
This study included a total of 195 patients with R/R CD19-positive ALL or lymphocytic lymphoma from five clinical trials (Pedi CART19 [NCT01626495], 13BT022 [NCT02374333], 16CT022 [NCT02906371], ENSIGN [NCT02228096], and ELIANA [NCT02435849]) from the Children’s Hospital of Philadelphia, Philadelphia, US. The participants of these studies received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019.
A total of 154 patients from the Pedi CART19, ELIANA, ENSIGN, and 16CT022 trials received tisagenlecleucel, and 41 patients from the 13BT022 trial received huCART19 (humanized CD19-directed CAR-T cells).
Patients were included if they had a positive control of CNS disease at enrolment and infusion; and patients were excluded if they required treatment for acute neurological toxic effects (greater than Grade I in severity) or had parenchymal lesions that were likely to increase the risk of neurotoxicity.
Patients were categorized according to CNS status at relapse or within the 12 months preceding CAR T-cell infusion—either CNS-positive or CNS-negative disease (Table 1).
Patients with CNS-positive disease were further subcategorized based on the morphological bone marrow involvement—defined as either combined bone marrow and CNS involvement, or isolated CNS involvement.
Endpoints were the number of patients with complete response 28 days following infusion, incidence of cytokine release syndrome and neurotoxicity in the first 8 weeks after infusion, and Kaplan-Meier analysis of relapse-free survival (RFS) and OS.
Table 1. Baseline characteristics by subgroup*
Characteristic, n (%) (unless otherwise specified) |
All patients |
CNS stratification |
CNS categorization by BM involvement |
||||
---|---|---|---|---|---|---|---|
CNS-neg |
CNS-pos |
p value |
BM or combined BM and CNS involvement |
Isolated CNS involvement† |
p value |
||
Median age at infusion, years (IQR) |
11.3 (7.7–16.5) |
12.4 (7.6–17.0) |
10.2 (7.9–15.0) |
0.63 |
12.3 (7.8–17.0) |
10.2 (8.0–13.7) |
0.35 |
Age group, years |
|
|
|
|
|
|
|
<3 |
8 (4) |
4 (3) |
4 (6) |
0.76 |
4 (3) |
4 (9) |
0.29 |
3 to <10 |
72 (37) |
47 (36) |
25 (38) |
— |
57 (38) |
15 (35) |
— |
10 to <18 |
82 (42) |
56 (43) |
26 (39) |
— |
64 (42) |
18 (42) |
— |
≥18 |
33 (17) |
22 (17) |
11 (17) |
— |
27 (18) |
6 (14) |
— |
Sex |
|
|
|
0.94 |
|
|
0.80 |
Female |
85 (44) |
56 (43) |
29 (44) |
— |
67 (44) |
18 (42) |
— |
Previous HSCT |
94 (48) |
59 (46) |
35 (53) |
0.33 |
73 (48) |
21 (49) |
0.93 |
Disease status at referral |
|
|
|
<0.0001 |
|
|
0.0002 |
Primary refractory |
27 (14) |
26 (20) |
1 (2) |
— |
27 (18) |
0 (0) |
— |
First relapse |
59 (30) |
44 (34) |
15 (23) |
— |
50 (33) |
9 (21) |
— |
Second or greater relapse |
109 (56) |
59 (46) |
50 (76) |
— |
75 (49) |
34 (79) |
— |
Neurological comorbidity |
|
|
|
|
|
|
|
Stroke |
4 (2) |
3 (2) |
1 (2) |
>0.99 |
3 (2) |
1 (2) |
>0.99 |
Seizure |
26 (13) |
14 (11) |
12 (18) |
0.15 |
18 (12) |
8 (19) |
0.25 |
Methotrexate toxicity |
15 (8) |
11 (9) |
4 (6) |
0.54 |
12 (8) |
3 (7) |
>0.99 |
Neurological deficit |
13 (7) |
7 (5) |
6 (9) |
0.37 |
8 (5) |
5 (12) |
0.17 |
BM disease burden before infusion |
|
|
|
<0.0001 |
|
|
<0.0001 |
<0.01% |
74 (38) |
30 (23) |
44 (67) |
— |
39 (26) |
35 (81) |
— |
0.01–4.99% (M1) |
30 (15) |
22 (17) |
8 (12) |
— |
24 (16) |
6 (14) |
— |
5–25% (M2) |
19 (10) |
17 (13)‡ |
2 (3) |
— |
19 (13) |
0 (0) |
— |
>25% (M3) |
72 (37) |
60 (47)‡ |
12 (18)‡ |
— |
70 (46) |
2 (5)§ |
— |
CNS status before infusion¶ |
|
|
|
0.021 |
|
|
0.054 |
CNS1 |
177 (91) |
120 (93)‡ |
57 (86)‡ |
— |
139 (91) |
38 (88) |
— |
CNS2 |
14 (7) |
9 (7)‡ |
5 (8) |
— |
12 (8) |
2 (5) |
— |
CNS3# |
4 (2) |
0 (0) |
4 (6) |
— |
1 (1) |
3 (7) |
— |
Seizure prophylaxis |
64 (33) |
22 (17) |
42 (64) |
<0.0001 |
33 (22) |
31 (72) |
<0.0001 |
BM, bone marrow; CAR, chimeric antigen receptor; CNS, central nervous system; CSF, cerebrospinal fluid; HSCT, hematopoietic stem cell transplant; IQR, interquartile range; neg, negative; pos, positive; WBC, white blood cells. |
Table 2. Disease outcomes following CAR T-cell therapy*
Outcome |
All patients |
CNS stratification |
CNS categorization by BM involvement |
||||
---|---|---|---|---|---|---|---|
CNS-neg |
CNS-pos |
p value
|
BM or combined BM and CNS involvement |
Patients with isolated CNS involvement |
p value |
||
Disease response at Day 28, n (%) |
|
|
|
|
|
|
|
Complete response |
185 (95) |
121 (94) |
64 (97) |
0.74 |
143 (98) |
42 (98) |
0.35 |
No response |
7 (4) |
6 (5) |
1 (2) |
|
7 (5) |
0 (0) |
|
Not evaluable† |
3 (2) |
2 (2) |
1 (2) |
|
2 (1) |
1 (2) |
|
Patients with relapse, n/N (%) |
72/185 (39) |
45/121 (37) |
27/64 (42) |
0.51 |
56/143 (39) |
16/42 (38) |
0.90 |
CNS status at relapse, n/N (%)‡ |
|
|
|
0.0066 |
|
|
0.0062 |
CNS1 |
45/72 (63) |
33/45 (73) |
12/27 (44) |
|
38/56 (68) |
7/16 (44) |
|
CNS2 |
4/72 (6) |
1/45 (2) |
3/27 (12) |
|
1/56 (2) |
3/16 (19) |
|
CNS3 |
7/72 (10) |
1/45 (2) |
6/27 (22) |
|
3/56 (5) |
4/16 (25) |
|
Unknown |
16/72 (22) |
10/45 (22) |
6/27 (22) |
|
14/56 (25) |
2/16 (12) |
|
Median follow-up (IQR), months |
37 (21–49) |
36 (18–49) |
39 (25–49) |
0.73 |
36 (18–49) |
40 (29–52) |
0.38 |
BM, bone marrow; CAR, chimeric antigen receptor; CNS, central nervous system; CSF, cerebrospinal fluid; IQR, interquartile range; neg, negative; pos, positive; WBC, white blood cells. |
There was no difference in the incidence or severity of cytokine release syndrome or neurotoxicity between the CNS-negative and the CNS-positive disease subgroups (Table 3).
Table 3. Cytokine release syndrome and neurotoxic adverse events by CNS status*†
Adverse event |
CNS-negative disease |
CNS-positive disease |
p value |
---|---|---|---|
Cytokine release syndrome, % |
|
|
0.26 |
Grade 0 |
15 |
20 |
|
Grade 1 |
9 |
3 |
|
Grade 2 |
47 |
58 |
|
Grade 3 |
14 |
11 |
|
Grade 4 |
15 |
9 |
|
Any neurotoxicity, % |
|
|
0.20 |
Grade 0 |
59 |
41 |
|
Grade 1 |
19 |
30 |
|
Grade 2 |
11 |
15 |
|
Grade 3 |
9 |
9 |
|
Grade 4 |
2 |
3 |
|
CNS, central nervous system. |
In summary, the two CAR-T cell therapies, tisagenlecleucel and huCART19, show promising efficacy in reducing CNS disease and maintaining durable remissions in young patients with CNS R/R B-cell ALL or lymphocytic lymphoma. As CNS involvement in the multiple-relapsed setting, particularly following radiation and hematopoietic stem cell transplantation, is difficult to treat and has a poor outcome, the durable remissions observed in this patient population represent a major advance in the treatment of patients with CNS relapse ALL. The overall incidence of CNS relapse was low, and the results indicate that patients with CNS disease that is adequately controlled before infusion can benefit from CD19 CAR T-cells, without increasing the risk of severe neurotoxicity.
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