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.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
