CD19-Targeted 19-28z CAR-Modified T-Cells in Adult Patients with Relapsed/Refractory B-Cell ALL: Impact of MRD-Negative CR and Allogeneic Stem-Cell Transplant on Outcomes

Targeted immunotherapy with T-cells expressing a CD19-targeting 19-28z chimeric antigen receptor (CAR) has demonstrated high antileukemia activity in adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Park and colleagues reported the long-term safety and antitumor activity of 19-28z CAR T-cells from that phase 1 clinical trial in adult patients with relapsed/refractory ALL; in particular, the roles of posttreatment minimal residual disease (MRD) negativity and allogeneic hematopoietic stem-cell transplant (allo-HSCT) prior to or following CAR T-cell infusion on safety and clinical outcome were reported.

The treatment protocol involved leukapheresis in eligible patients, transduction of T-cells with a retroviral vector encoding 19-28z CARs, administration of lympho-depleting chemotherapy, and infusion of 1 x 10⁶ to 3 x 10⁶ 19-28z CAR T-cells/kg 2 days. A total of 46 patients were treated, of which 18 patients (39%) had undergone prior allo-HSCT. Prior to 19-28z CAR T-cell infusion, 24 of the evaluable patients had morphologic disease and the rest had minimal disease (<5% blasts in bone marrow). Following 19-28z CAR T-cell infusion, 37 (82%) patients achieved complete remission (CR); 83% (30 of 36 evaluable patients) achieved an MRD-negative CR (MRD-CR); median time to CR was 21 days. Median overall survival (OS) was 9.0 months in all patients, and 10.6 months in patients who achieved CR; OS rate at 6 months was 71%. Based on MRD status after CAR T-cell treatment, OS at 6 months was 80% in the MRD-CR cohort, and 43% in the MRD+CR cohort, indicating the predictive value of posttreatment MRD status. By HSCT status CAR T-cell treatment, OS rate at 6 months was 71% in patients who underwent post-CAR allo-HSCT (n = 12) versus 64% in patients who did not receive allo-HSCT after CAR T-cells. Comparing with the patient cohorts who did not undergo prior allo-HSCT before the CAR T-cell treatment, those who had received prior allo-HSCT showed statistically significant difference in MRD CR rates (75% vs 89%), incidences of severe cytokine release syndrome (28% vs 21%), and median OS (Not reached vs 9.0 months). Overall, 24% of patients experienced severe cytokine release syndrome (CRS) and 28% experienced grade 3/4 neurotoxicity; CRS was managed with IL6-inhibitor and/or steroid use. Based on these results, the authors concluded that 19-28z CAR T-cells showed robust antitumor efficacy in adult patients with relapsed/refractory ALL, as previously reported, and that post-CAR T-cell infusion MRD negativity was a strong predictive marker of survival.

1. Park JH, et al. ASH 2014. Abstract 382.
2. Park JH, et al. ASH 2015. Abstract 682.