Phase II One Arm Multicenter Study of Early Reinfusion of Tisagenlecleucel to Promote Durable B-cell Aplasia in Pediatric and Young Adult Patients with relapsed/refractory CD19-Positive B-cell Acute Lymphoblastic Leukemia (REFUEL)

Peripheral B-cell aplasia (BCA), defined as low/absent peripheral blood B-cells, is an expected on-target, off-tumor effect of CD19-directed CAR T-cell therapy. BCA serves as a surrogate marker of sustained CAR T-cell persistence and relapse risk, as early B-cell recovery (BCR) following infusion is associated with increased relapse rates. We hypothesized that increased CAR T-cell exposure through early reinfusion (administered 35-60 days after the initial infusion without additional lymphodepletion) may prolong the duration of BCA. A phase II, one arm, multicenter study was conducted to evaluate early reinfusion of tisagenlecleucel (tisa-cel) to promote durable BCA in pediatric and young adult patients with relapsed/refractory (R/R) CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) (NCT05460533). Eligible patients required MRD- complete response (CR) by flow cytometry and ongoing BCA at time of reinfusion. The primary objective was to reduce the rate of peripheral blood BCR to <10% at 6-months post-infusion through early tisa-cel reinfusion, compared to historical control rate of 26%. Between 10/2022 and 01/2025, 30 patients (median age, 14 years; range 2-26) received tisa-cel reinfusion at a median of 37 days (range, 34-57) after their initial infusion. Of these patients, 60% were female, 43% Hispanic, and 33% had a high disease burden prior to initial treatment. Prior therapies included: CAR T-cell therapy (n=3), blinatumumab (n=5), inotuzumab (n=4), TKI (n=5), and allo-HCT (n=3). Toxicities associated with reinfusion were minimal: 6/30 (20%) patients experienced CRS (all grade 1), and no cases of ICANS were observed, compared to 16/30 (53%; all ≤ grade 2) experiencing CRS and 1/30 (3%; grade 2) experiencing ICANS after initial infusion. BCR (absolute B-cell count >50/uL) occurred in 10 patients within 6 months of initial infusion; 2 patients experienced relapse as a competing event, and the remaining 18 maintained BCA at 6 months. The overall rate of early BCR was 33% (90% CI, 19 to 50%). Post-reinfusion peripheral CAR T-cell expansion within 1 month of reinfusion was evaluable in 22 patients and was observed in 17 (77%). Following reinfusion, 10 patients relapsed and 4 died. Ten patients subsequently underwent allo-HCT for either loss of BCA (n=7) or relapse (n=3). The relapse rate was 31% (95% CI,14-48%) at 12 months and 42% (95% CI, 18-67%) at 24 months. OS was 89% (95% CI, 78-100%) at 12 months and 80% (95%CI, 63-100%) at 24 months. Early tisa-cel reinfusion without additional lymphodepletion was safe, with lower rates of CRS and no ICANS. Although reinfusion led to transient CAR T-cell expansion and durable B-cell aplasia in some patients, the primary endpoint of reducing 6-month BCA loss below 10% was not met. These findings suggest that early reinfusion is feasible but may not significantly prolong CAR T-cell persistence in pediatric and young adult patients with R/R B-ALL.