Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features

Abstract

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is effective in patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, efficacy data is sparse in subgroups of patients with high-risk features such as BCR-ABL+, TP53 mutation, extramedullary disease (including central nervous system leukemia) or posttransplant relapse. It is also uncertain whether there is an added benefit of transplantation after anti-CD19 CAR T-cell therapy. We conducted a phase 1/2 study of 115 enrolled patients with CD19+ B-ALL. A total of 110 patients were successfully infused with anti-CD19 CAR T cells. In all, 93% of patients achieved a morphologic complete remission, and 87% became negative for minimal residual disease. Efficacy was seen across all subgroups. One-year leukemia-free survival (LFS) was 58%, and 1-year overall survival (OS) was 64% for the 110 patients. Seventy-five nonrandomly selected patients (73.5%) subsequently received an allogeneic hematopoietic stem cell transplant (allo-HSCT). LFS (76.9% vs 11.6%; P < .0001; 95% confidence interval [CI], 11.6-108.4) and OS (79.1% vs 32.0%; P < .0001; 95% CI, 0.02-0.22) were significantly better among patients who subsequently received allo-HSCT compared with those receiving CAR T-cell therapy alone. This was confirmed in multivariable analyses (hazard ratio, 16.546; 95% CI, 5.499-49.786). Another variate that correlated with worse outcomes was TP53 mutation (hazard ratio, 0.235; 95% CI, 0.089-0.619). There were no differences in complete remission rate, OS, or LFS between groups of patients age 2 to 14 years or age older than 14 years. Most patients had only mild cytokine release syndrome and neurotoxicity. Our data indicate that anti-CD19 CAR T-cell therapy is safe and effective in all B-ALL subgroups that have high-risk features. The benefit of a subsequent allo-HSCT requires confirmation because of nonrandom allocation. This trial was registered at www.clinicaltrials.gov as #NCT03173417.

Conflict of interest statement

Conflict-of-interest disclosure: T.H. and X.-a.-L. are employees of Immunochina Pharmaceuticals Co., Ltd. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

CAR T-cell treatment schedule for enrolled patients.

Figure 2.

Kaplan-Meier plots of OS and LFS of 110 total patients and 102 CR patients after anti-CD 19 CAR T-cell therapy. (A-D) On day 30 after anti-CD19 CAR T-cell infusion, 102 of 110 patients achieved morphologic CR. To show long-term efficacy after CAR T-cell therapy, Kaplan-Meier analysis of OS and LFS were performed for both the 110 total patients and 102 CR patients.

Figure 3.

Long-term efficacy of allo-HSCT after CAR T-cell therapy. (A-B) Of the 102 CR patients, 75 nonrandomly selected patients subsequently were bridged into allo-HSCT (designated the "CAR T bridged into allo-HSCT" group). The remaining 27 patients did not undergo transplantation (designated the "CAR T alone" group). Kaplan-Meier analysis showed that 1-year OS and LFS for patients bridging into allo-HSCT after CAR T-cell therapy were significantly better than those for patients receiving CAR T-cell therapy alone (OS: 79.1% vs 32.0%; P < .0001; hazard ratio [HR], 0.048; 95% CI, 0.016-0.148; LFS: 76.9% vs 11.6%; P < .0001; HR, 35.45; 95% CI, 11.6-108.4).

Figure 4.

Kaplan-Meier plots of OS and LFS of 102 patients with CR vs CRi. (A-B) On day 30 post anti-CD19 CAR T-cell infusion, a total of 102 patients achieved morphologic CR with 60% (61 of 102) achieving CRi. There was a trend toward better OS (85.5% vs 59.7%; log-rank test P = .193; HR, 1.816; 95% CI, 0.739-4.462) and LFS (73.3% vs 57.4%; P = .123; HR, 0.54; 95% CI, 0.25-1.18) for patients with CR vs CRi.

Figure 5.

Kaplan-Meier plots of OS and LFS of 102 patients with MRD-negative CR vs MRD-positive CR. (A-B) For the 102 patients who achieved CR after CAR T-cell therapy, 96 patients were MRD-negative CR. Kaplan-Meier analysis demonstrated a trend toward better OS (69.7% vs 50%; P = .136; HR, 3.85; 95% CI, 0.65-22.61) and LFS (64.8% vs 42.9%; P = .135; HR, 1.62; 95% CI, 0.38-7.0) for patients with MRD-negative CR vs MRD-positive CR, but there was no statistical significance because of the small number of patients in the MRD-positive patient group (n = 6).

Figure 6.

B-ALL patients with TP53 mutation had a lower OS and LFS than those without TP53 mutation. (A-B) The 102 patients were divided into 2 groups based on TP53 mutation status: TP53+ mutation and TP53– mutation. Kaplan-Meier analysis showed that OS and LFS at 6 months were much lower for patients carrying the TP53 mutation when compared with the patients without a TP53 mutation (OS: 51.9% vs 89.0%; P < .0001; HR, 61.75; 95% CI, 11.35-336.1; LFS: 42.4% vs 82.6%; P = .0002; HR, 0.06; 95% CI, 0.014-0.26).

Figure 7.

Long-term efficacy of CAR T-cell therapy in patients who relapsed after transplantation. (A-B) The 102 CR patients who received CAR T-cell therapy were divided into 2 groups: those who relapsed after transplant and those without previous transplant. Patients with a history of previous transplantation had a lower 1-year OS and LFS than the group without previous transplant (OS: 30.5% vs 79.2%; HR, 5.27; P = .009; 95% CI, 1.51-18.48; LFS: 25.4% vs 69.4%; P = .011; HR, 0.23; 95% CI, 0.07-0.71).