Purpose: CD19 chimeric antigen receptor T-cell (CAR-T) therapy demonstrates remarkable efficacy in patients with B-Cell Acute Lymphoblastic Leukemia (B-ALL), with six US Food and Drug Administration–approved products available. Despite high initial response rates, most patients eventually relapse. Relapse after CD19 CAR T therapy remains a significant challenge to survival outcomes. As outcomes for patients with disease recurrence after CD19 CAR-T therapy are not comprehensively studied, this analysis aims to define optimal treatment strategies.

Methods: We conducted a retrospective multi-institutional study involving 74 patients with B-ALL who relapsed following CD19 CAR-T cell therapy, 67 of whom received salvage treatment. This study analyzed clinical characteristics, salvage regimens, and survival outcomes in relapsed/refractory (R/R) B-ALL patients who experienced relapse following CD19 CAR-T cell treatment. Complete remission (CR), relapse-free survival (RFS), overall survival (OS), and potential influencing factors were analyzed using IBM SPSS Statistics version 27 and R software version 4.4.2.

Results: A total of 67 patients with R/R B-ALL (31 males, 36 females; age range 6 to 67 years) were included in the salvage therapy analysis. At initial diagnosis, 16 patients (23.9%) exhibited high-risk cytogenetic abnormalities, while 51(76.1%) were standard-risk. The BCR::ABL1 fusion gene was detected in 21 patients (31.3%). Twenty-two patients (32.8%) had undergone prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) or umbilical cord blood transplantation before salvage therapy, including 9 who received consolidative transplantation after achieving CR from initial CAR-T therapy.At relapse, leukemic blasts were CD19+ in 46 cases (68.7%), CD19-/dim in 15 (22.4%), and had undetermined CD19 status in 6 (8.9%). Relapse sites included bone marrow (n=48, 71.6%) and extramedullary disease (EMD; n=14, 20.9%): 8 with central nervous system (CNS) involvement and 6 with non-CNS EMD. Half of EMD cases (7/14) had pre-existing extramedullary involvement. Five patients (7.5%) lacked documented relapse site assessments. With a median follow-up of 8.07 months post-progression, 32 patients (47.8%) achieved complete remission (CR/CRi) following salvage therapy. CR rates differed significantly by treatment modality. The response rates were 61% for targeted treatment (CAR-T reinfusion 61%, monoclonal antibodies 71%, chemotherapy combined with TKi 50%), 19% for chemotherapy (P=0.0035). CR/CRi rates showed no significant association with common high-risk factors (age, bone marrow tumor burden, molecular genetics, EMD), BCR::ABL1 status, CD19-negative relapse, or pre-relapse transplantation. However, CNS relapse demonstrated significantly higher CR rates than non-CNS EMD (100% vs. 17%; P=0.003). Median overall survival (OS) was 8.6 months (95% CI: 4.2–13.1), and median relapse-free survival (RFS) was 7.6 months (95%CI: 4.8–10.4). Patients receiving targeted salvage therapies showed superior OS compared to chemotherapy (P=0.004). CNS relapse was associated with superior OS than non-CNS EMD (P=0.043). Multivariate analysis confirmed targeted therapy as an independent predictor of improved OS (HR: 2.63; 95%CI: 1.17–5.92; P=0.019). Seven patients underwent consolidative allo-HSCT post-salvage (first transplant: n=6; second transplant: n=1). Of these, one patient died from transplant-related complications, two experienced relapse, and four remained in CR at final follow-up.

Conclusion:Patients with relapsed B-ALL following CD19 CAR-T therapy exhibit universally poor prognoses. Salvage therapies involving molecular targeting—including CAR-T reinfusion, monoclonal antibodies, and TKIs—demonstrate superior efficacy over salvage chemotherapy. These approaches provide critical opportunities for bridging to transplantation and improving overall survival. Notably, extramedullary relapse involving the central nervous system (CNS) confers a more favorable prognosis compared to non-CNS extramedullary disease.

Trial registration: The source data of this study is from the following registered clinical trials: NCT04532268,NCT02735291,NCT04605666.

Disclosures: No relevant conflicts of interest to declare.

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2025
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