Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL

Abstract

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.

Graphical abstract

Figure 1.

Study flow. Study course for participants from the time of enrollment to treatment.

Figure 2.

Dose intensity of cyclophosphamide impacts lymphodepletion and CAR T-cell expansion. (A) ALC change before and after HD-Cy and LD-Cy before treatment with CAR T cells (n = 23) demonstrates more significant lymphodepletion in the HD-Cy cohort (P < .001). (B) In vivo CAR T-cell expansion (peak CAR T-cell VCN per milliliter) in peripheral blood was greater in the HD-Cy cohort as compared with the LD-Cy cohort (P = .01).

Figure 3.

Disease response and pretreatment disease burden impact CAR T-cell expansion. In vivo CAR T-cell expansion (peak CAR T-cell VCN per milliliter) in peripheral blood was also higher in patients with disease response (responders), compared with nonresponders (P = .01) (A), and in patients with MRD, compared with morphologic pretreatment disease burden (P = .05) (B).

Figure 4.

CAR T-cell detection. CAR T-cell detection in peripheral blood by PCR (VCN per milliliter) including the HD-Cy cohort (solid line; 14/17 patients detected for at least 1 time point measured) and LD-Cy (dotted line, 4 of 8 patients detected for at least 1 time point measured). Detection of CAR T cells following allo-HSCT was not standardized. However, 14 patients had samples taken after allo-HSCT with 4 patients demonstrating 1 positive sample each (median, 121 days after allo-HSCT; range, 44-195 days) without subsequent positive test.

Figure 5.

Overall survival of combined dose intensity and pretreatment disease burden. Low-dose Cy/MRD cohort (n = 2) not shown (1 of 2 patients alive). mOS, median overall survival; NR, not reached.