Reinfusion of CD19 CAR T Cells for Relapse Prevention and Treatment in Children with Acute Lymphoblastic Leukemia

Relapse after CD19-directed chimeric antigen receptor (CAR)-modified T-cells remains a substantial challenge. Short CAR T-cell persistence contributes to relapse risk, necessitating novel approaches to prolong durability. CAR T-cell reinfusion (CARTr) represents a potential strategy to reduce the risk of, or treat, relapsed disease after initial CAR infusion (CARTi). We conducted a retrospective review of reinfusion of murine (CTL019) or humanized (huCART19) anti-CD19.4-1BB CAR T-cells across 3 clinical trials or commercial tisagenlecleucel for relapse prevention [peripheral B-cell recovery (BCR) or bone marrow hematogones ≤6 months after CARTi], minimal residual disease (MRD) or relapse, or nonresponse to CARTi. The primary endpoint was complete response (CR) at day 28 after CARTr, defined as complete remission with B-cell aplasia. Of 262 primary treatments, 81 were followed by ≥1 reinfusion (investigational CTL019, n=44; huCART19, n=26; tisagenlecleucel, n=11), representing 79 unique patients. Of 63 reinfusions for relapse prevention, 52% achieved CR (BCR, 15/40, 38%; hematogones, 18/23, 78%). Lymphodepletion was associated with response to CARTr for BCR (OR 33.57, P = 0.015), but not hematogones (OR 0.30, P = 0.291). The cumulative incidence of relapse was 29% at 24-months for CR versus 61% for nonresponse to CARTr (P=0.259). For MRD/relapse, CR rate to CARTr was 50% (5/10), but 0/8 for nonresponse to CARTi. Toxicity was generally mild, with the only grade ≥3 cytokine release syndrome (n=6) or neurotoxicity (n=1) observed in MRD/relapse treatment. Reinfusion of CTL019/tisagenlecleucel or huCART19 is safe, may reduce relapse risk in a subset of patients, and can reinduce remission in CD19-positive relapse.