Superior Outcomes in Relapsed/Refractory Childhood B-ALL Than Adult Patients with CD19 CAR-T Cell Therapy: A Single-Center Pilot Prospective Study of 23 Patients

Objective: CD19 CAR-T cell therapy has emerged as a powerful immunotherapy for relapsed/refractory (R/R) B-ALL. The purpose of this study is to compare the efficacy and safety profile of CD19 CAR-T cell therapy for pediatric and adult patients with R/R B-ALL.

Methods: We analyzed 23 pediatric and adult R/R B-ALL patients recruited from April 2016 to November 2018 to the clinical trial with CD19 CAR-T cell therapy (ClinicalTrials.gov, NCT03391739). Patients' high-risk features included ≥3 prior lines of treatment (n=11 ), extramedullary infiltration (n=6) , prior allogeneic hematopoietic stem cell transplantation (allo-HSCT, n = 4), Philadelphia chromosome positivity (n = 8) and other poor prognostic factors (n=8). At the time of CAR-T cell therapy, 20 patients had morphologic disease (≥5% blasts in bone marrow [BM] or measurable extramedullary disease), and 3 patients had minimal residual disease (MRD) (<5% blasts in BM) even after the salvage chemotherapy. All patients received fludarabine (25 mg/m2×3d) and cyclophosphamide (900mg/m2/day×2d) as a preconditioning regimen followed by a single infusion of 0.9-4 × 108/kg autologous CD19 CAR-T cells. The primary efficacy end point was the MRD rate post infusion. Secondary end points included persistence of transferred T cells and anti-CD19 activity response. Treatment-related toxicities, particularly cytokine release syndrome (CRS) and neurological toxicities, were observed during the study.

Results: Among the 23 patients with R/R B-ALL, 13 were male and 10 female, with the median age of 18 years (1-61 years). 9 cases were pediatric (age≤14 years) and 14 adult (age>14 years). The median duration of therapy prior to CAR-T cell therapy was 19 (2-76) months and 17 (1-36) months, respectively. The CAR-T cell products were similar in phenotype and function between the pediatric and adult groups. The overall remission rate(ORR)was 15/23 (65.22%). Pediatric patients have a better ORR than adults (88% vs 50%, p<0.05). In the pediatric group, 6 (66.67%) patients achieved MRD-negative remission, 2 (22.22%) hematological remission and 1 (11.11%) unevaluable, while in the adult group, only 7 (50%) patients reached MRD-negative remission. 5 (20.83%) patients, including 2 pediatrics and 3 adults, with high leukemic burden (blast in BM >60% ) developed reversible severe CRS (grade 2-4) and/or reversible severe neurotoxicity with the IL-6 receptor blockade w/o lymphotoxic corticosteroids , and there were no deaths or instances of cerebral edema attributable to product toxicity. Persistence of transferred T cells (CD62L+ CD45RO+) were still detectable in 1 pediatric patient at the 3-months follow up post CAR-T infusion, who were the most severe case of CRS/neurotoxicity with the highest blast (98% in bone marrow) and reached MRD-negative remission rapidly.

Conclusion: These data demonstrate the superior outcomes in pediatric group compared to that of adult patients, with highly potent antileukemic activity and a tolerable adverse effect profile. Therapeutic failure in most adult patients remains a challenge so far. Severity of CRS may correlate with high disease burden and the treatment response.