Efficacy and safety of CD-19 CAR-T cells in the treatment of B-cell acute lymphoblastic leukemia with CNSL

Patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) have poor prognosis after salvage chemothera.
Central nervous system (CNS) relapse occurs in approximately 1% of patients, and there are few treatment options for CNS leukemia (CNSL), which is refractory to conventional regime.
Chimeric antigen receptor (CAR) T cell therapy represents one of the most promising immunotherapy approaches for hematological malignanci.
Multiple clinical trials of CD19-specific CAR-T cell therapy have demonstrated complete remission (CR) rates of 70-90% in children and adults with R/R B-A.
However, due to the adverse effects and treatment-related neurotoxicity of CAR-T therapy, CNSL has rarely been the focus of CAR-T cell therapy clinical tria.
In recent years, some studies have reported that patients with refractory secondary CNS diffuse large B-cell lymphoma (DLBCL) received CD19 CAR-T cell therapy and achieved CR with controllable and reversible neurotoxicity, confirming the entry of CAR-T cells into Efficient transport in the central nervous syst.
There are clinical reports showing that CD19 CAR-T cell-mediated cerebrospinal fluid (CSF) leukemia cell clearance has fully reversible toxicity, further suggesting that R/R B-ALL patients with CNSL may benefit from CAR-T cell therapy with a safety profi.
Acce.
The team of Professor Xu Kailin from the Institute of Hematology, Xuzhou Medical University conducted a clinical trial to explore the efficacy and safety of CD-19 CAR-T in the treatment of B-ALL patients with CN.
Methods: From November 2016 to April 2021, a total of 52 patients with R/R-B-ALL with CNSL were enrolled in 2 clinical trials from 5 centers in Chi.
CNS disease status in patients with B-ALL was defined as follows: CNS-1 (no blasts detected by cytology in CSF specimens), CNS-2 (<5/μL WBC, blasts positive), or CNS-3 (≥5/μL WBC) , blast-positive or solid tumor.
CNSL was confirmed with CNS-3 status at the time of the most recent relapse or within 30 days prior to screeni.
4 patients who did not receive CAR-T cell infusion (failure of CAR-T cell preparation [n=1], serious infection [n=1], withdrawal of consent [n=1], death [n=1]) were exclud.
A total of 48 patients received CAR-T cell infusion and were included in the analys.
After leukocyte collection, 27 patients received CNS-directed bridging therapy, and 21 patients received CNS-directed bridging therapy until after CAR-T cell injecti.
At the last assessment before CAR-T cell injection, patients were divided into CNS-1 status (3 cases), CNS-2 status (15 cases), and CNS-3 status (30 cases) (Figure
Figure 1 Study Results >>>> Treatment Response At day 30 assessment, 42 of 48 patients (85%; 95% CI, 73-91) achieved BM disease CR/C.

Forty-one patients (84%; 95% CI, 78-98) achieved CNSL remissi.

One patient achieved BM disease remission, and 4 patients did not respond to treatme.

Two patients died on days 13 and 14 after CAR-T cell infusion, respective.

Patients who received CNS-directed bridging therapy had higher CNSL remission rates than those who did not receive bridging therapy (93% vs 74%; p = 034)
>>>> Survival median follow-up 15 months (range 3 to 3
Among the 42 patients who achieved CR/CRi, the 12-month cumulative recurrence rate (CIR) for bone marrow and central nervous system disease was 31% and 13%, respectively (p=04
The median duration of response (DOR) in patients with BM disease was 10 months (95% CI, 8-22), and the median DOR in CNSL patients was not reached (NR) (Figure 2.

The 48 patients had a median overall survival (OS) of 10 months (95% CI, 15-21) and a median event-free survival (EFS) of 7 months (95% CI, 7-18) (F.

2.

The 6-month OS rate and EFS rate were 70% (95% CI, 56-81) and 53% (95% CI, 35-61), respective.

Patients with CNS-3 status before CAR-T cell infusion had worse EFS than patients with CNS-1/2 status (1 months .

NR .

10 months, p = 049) (F.

2C), but there were differences in OS among the 3 groups of patients Not statistically significant (NR, 18, and 14 for CNS-1, CNS-2, and CNS-3, respectively; p = 54
Ph+ B-ALL patients had significantly shorter median OS compared with patients without BCR/ABL rearrangement (0 months .

18 months, p=014) (F.

2D), as was EFS analysis (5 months) months .

16 months, p=008) (Figure 2.

Figure 2 >>>> Common adverse events (AEs) within the first 30 days of safety are summarized in Table
Nine patients (18%) developed grade 3-5 cytokine release syndrome (CR.

Multivariate logistic regression model data showed higher peak CAR DNA copies (OR 230, 95% CI 043-1425, p=002) and increased sIL-6 levels (OR 355, 95% CI 430-026, p=002 ) is an independent risk factor for severe CRS (grades 3-
Serious neurotoxic events (NEs) (grades 3-4) occurred in 11 (29%) patien.

Common neurotoxic events were encephalopathy (29%), decreased consciousness (28%), delirium (17%), headache (16%), and epilepsy (3%) (Table
Multivariate analysis found that higher peak CAR DNA copies, elevated sIL-6 levels, higher percentage of CNS blasts, and CNS-3 status in peripheral blood (PB) were independent risk factors for the development of severe NE (Table
Table 1 Table 2 Severe CRS was effectively managed according to guidelines, and 6 of 9 patients with severe CRS (67%) received the IL-6 receptor antagonist tocilizumab, with (n=3) or without glucocorticoids Hormone therapy (n=
Of the 11 patients with grade 3-4 NE, 10 (99%) received systemic glucocorticoid therapy, and other treatments included tocilizumab (3 cases), mannitol (7 cases), antiepileptic drugs (6 cases) ), levetiracetam prophylaxis (1 case), and intensive care (2 case.

No patient developed fatal diffuse cerebral ede.

Spearman analysis showed that neurotoxicity was significantly correlated with the incidence and severity of CRS (r=553, p=02In addition, despite receiving tocilizumab, high-dose corticosteroids, and plasma exchange, 2 patients experienced fatal AEs within 30 days of CAR-T cell infusion, 1 of whom died of grade 5 CRS, manifested as refractory hypotension/hypoxia and grade 4 organ toxicity; 1 death from refractory.

coli seps.

CONCLUSIONS: CD19-specific CAR-T cell-based therapy can induce similar high response rates in bone marrow and central nervous system diseases, with longer duration of remission in CNSL than in BM disea.

CD19 CAR-T cell therapy offers a potential treatment option for those previously excluded CNSL patients with manageable neurotoxici.

However, this study is limited by the incomplete and retrospective nature of CAR-T cell kinetic information in the C.

Prospective studies with larger high-burden CNSL cohorts are warranted to optimize strategies for the treatment of R/R-B-ALL with CN.

References Yuekun Qi, Mingfeng Zhao, Yongxian Hu, et .

Efficacy and safety of CD19-specific CAR T-cell-based therapy in B-cell acute lymphoblastic leukemia patients with CN.

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2022 Mar 25;blo.

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