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Relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL), historically characterized by a poor prognosis and increased morbidity, remains a challenge to treat in children. Tisagenlecleucel, an autologous CD-19-directed chimeric antigen receptor (CAR) T-cell therapy, showed significant efficacy and a tolerable safety profile in children with R/R B-ALL in a primary analysis of the ELIANA phase II trial (NCT02435849).1 Preclinical research has also demonstrated that CD19-targeting CAR T cells can downregulate CD22 expression in a subset of tumor cell line models.
Recently, Wang et al. published outcomes from a phase II study of coadministration of CD19- and CD22-directed CAR T-cell therapies in childhood B-ALL in Journal of Clinical Oncology.2 Considering the fundamental treatment principle of ALL that combination therapy prevents drug resistance and a preclinical model demonstrating that simultaneous CD19-/CD22 targeting may reduce the risk of antigen loss, the authors investigated whether coadministration of CD19- and CD22-targeted CAR T cells could improve efficacy.
This was a phase II, open-label, multicenter study in children aged ≤21 years with R/R B-ALL. Patients received CD19-/CD22-CAR T-infusion (n = 225) and were separated into three cohorts (Figure 1).
Figure 1. Study design*
CAR, chimeric antigen receptor.
*Adapted from Wang, et al.2
CD31 T lymphocytes were collected from peripheral blood (1–2 mL/kg) and CAR T cells were manufactured at the Shanghai Children’s Medical Center. CD19-/CD22-specific CAR T cells were cultured separately and pooled together (1:1).
The primary endpoint was recommended phase II dose of combined CD19-/CD22-CAR T cells, CAR T-cell related adverse effects, complete remission rate at Day 28 post-infusion, event-free survival (EFS), and overall survival at Month 12 with or without consolidative transplantation. Exploratory analyses were performed on the effect of sustained B-cell aplasia.
Overall, 225 patients were infused with CD19-/CD22-specific CAR T cells with a median age of 7.6 years. Patient baseline characteristics are summarized in Table 1.
Table 1. Selected baseline and clinical characteristics*
Characteristic, % (unless otherwise stated) |
All patients (N = 225) |
---|---|
Median age (range), years |
7.6 (0.8–19.6) |
Disease status, n |
|
Refractory/hematologic relapse |
194 |
Isolated extramedullary relapsed |
31 |
The median time from enrollment to infusion (range), days |
7 (6–12) |
The median dose of combined CD19- and CD22-CAR T-cell (IQR), per Kg |
5.6 ×106 (4.1–7.6 ×106) |
The median dose of CD19-CAR T cells |
2.7 ×106 (1.9–3.7 ×106), |
The median dose of CD22-CAR T cells |
2.8 ×106(2.1–4.0 ×106) |
CAR, chimeric antigen receptor. |
Toxicities that occurred within 4 weeks of infusion are summarized in Table 2.
Table 2. Safety outcomes in patients with R/R B-ALL infused with CD19-/CD20 CAR T-cells*
Toxicity, % (unless otherwise stated) |
All patients |
R/R disease |
Isolated EM relapse |
---|---|---|---|
CRS |
|
|
|
Any |
88 |
88.1 |
87.1 |
Grade 3 and 4 |
28.4 |
27.3 |
35.5 |
Grade 5† |
0.4 |
0.5 |
0 |
Median time to onset of cytokine release syndrome, days |
1 |
1 |
1 |
Median duration of cytokine release syndrome, days |
5 |
5 |
5 |
Neurotoxicity, |
|
|
|
Any |
20.9 |
21.1 |
19.4 |
Grade 3 and 4 |
4 |
4.1 |
3.2 |
Grade 5‡ |
0.9 |
0.5 |
3.2 |
Median Time to onset of neurotoxicity, days |
4 |
4 |
4 |
Seizure |
14.2 |
15.5 |
6.5 |
Grade 3 and 4 |
|
|
|
Infection |
|
|
|
Grade 3 and 4 |
14.7 |
16.0 |
6.4 |
Fever |
88.0 |
87.6 |
90.3 |
Hypotension |
|
|
|
Grade 3 and 4 |
40.9 |
43.3 |
25.8 |
Hypoxemia |
|
|
|
Grade 3 and 4 |
21.8 |
23.2 |
12.9 |
Grade 5 adverse events |
1.3 |
1.0 |
3.2 |
Received tocilizumab |
74.2 |
76.8 |
58.1 |
Median time to first tocilizumab, |
2 |
2 |
4 |
Received corticosteroids |
79 |
74 |
5 |
Median time to first |
4 |
4 |
4 |
CAR, chimeric antigen receptor; CRS cytokine release syndrome; B-ALL, B-cell acute lymphoblastic leukemia; EM, extramedullary; R/R, relapsed/refractory. ‡One patient with hematologic relapse died of neurotoxicity at 4 days after infusion. One patient with a second isolated CNS relapse died of neurotoxicity at 1.8 months after infusion. |
This study demonstrated encouraging and durable efficacy with CD19-/CD22-CAR T-cell therapy in children with R/R B-ALL. The outcomes were promising in patients with isolated and combined extramedullary relapse, supporting its potential as a therapeutic option for this patient population. A longer follow-up period, combined with deeper analysis afforded by next-generation sequencing technologies, may provide further insights.
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