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

Abstract

Few studies have described chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoblastic leukemia (B-ALL) patients with central nervous system leukemia (CNSL) due to concerns for poor response and treatment-related neurotoxicity. Our study included 48 relapsed/refractory B-ALL (R/R B-ALL) patients with CNSL to evaluate the efficacy and safety of CD19-specific CAR T-cell-based therapy. The infusion resulted in overall response rate of 87.5% (95% confidence interval [CI], 75.3-94.1) in bone marrow (BM) disease and remission rate of 85.4% (95% CI, 72.8-92.8) in CNSL. With a median follow-up of 11.5 months (range, 1.3-33.3), the median event-free survival (EFS) was 8.7 months (95% CI, 3.7-18.8), and the median overall survival (OS) was 16.0 months (95% CI, 13.5-20.1). The cumulative incidences of relapse (CIR) in BM and CNS diseases were 31.1% and 11.3%, respectively, at 12 months (p=0.040). The treatment was generally well tolerated with 9 patients (18.8%) experiencing grade ≥3 cytokine release syndrome. Grade 3-4 neurotoxic events (NEs), which developed in 11 patients (22.9%), were associated with a higher pre-infusion disease burden in CNS and were effectively controlled under intensive management. Our results suggested that CD19-specific CAR T-cell-based therapy could induce similar high response rate in both BM and CNS diseases. The duration of remission in CNSL was longer than that in BM disease. CD19 CAR T-cell therapy may provide a potential treatment option for those previously excluded CNSL patients with manageable neurotoxicity. Clinical trials were registered at www.clinicaltrials.gov as # NCT02782351 and www.chictr.org.cn as # ChiCTR-OPN-16008526.

Prognostic significance of CNSL at diagnosis of childhood B-cell acute lymphoblastic leukemia: A report from the South China Children’s Leukemia Group

“…Recently, Qi et al. ( 31 ) found that CD19-specific chimeric antigen receptor T-cell-based therapy might provide a potential treatment option for B-cell ALL patients with CNSL. Alternately, Tang et al.…”

“…However, it has been reported that intrathecal chemotherapy is much more likely to cause catastrophic consequences (28)(29)(30). Recently, Qi et al (31) found that CD19-specific chimeric antigen receptor T-cell-based therapy might provide a potential treatment option for B-cell ALL patients with CNSL. Alternately, Tang et al reported results from the CCCGALL-2015 trial, where they found that upfront dexamethasone might reduce leukemic blasts in the blood and CNS before diagnostic lumbar puncture and general anesthesia might reduce the risk of TLP, while CSF flow cytometry might allow a more accurate diagnosis (32).…”

Relapse after CAR-T cell therapy in B-cell malignancies: challenges and future approaches

“…CAR-T cells lacking CXCR4 exhibit poor migration and retention in the bone marrow, let alone trafficking into the CNS with its physical barrier, the blood-brain barrier (BBB). However, recent clinical trials proved the safety and efficacy of CD19 CAR-T cell therapy with a high response rate in patients with CNS leukemia and lymphoma (Siddiqi et al, 2021;Tan et al, 2021;Qi et al, 2022). This suggests that there may be other possible mechanisms for the CNS infiltration of CAR-T cells.…”

Chimeric antigen receptor engineered T-cell therapy for central nervous system lymphoma

“…To our knowledge, Xu et al [52] have conducted the largest clinical trial to date exploring the efficacy and safety of CD19 CAR-T-cell therapy for R/R B-cell acute lymphoblastic leukemia (ALL) with CNS invasion. Severe CRS (grade ≥3) and ICANS (grade ≥3) were observed in 9 (18.8%) and 11 patients (22.9%), respectively.…”