Patients with relapsed/refractory adult B-cell acute lymphoblastic leukemia who were treated with AUTO1 experienced durable responses.
Autologous CAT19-41BB-Z CAR T-cells (AUTO1) yielded a good safety profile and long-lasting responses for patients with relapsed/refractory adult B-cell acute lymphoblastic leukemia (ALL), according to results from the phase 1 ALLCAR19 study (NCT02935257) that were published in the Journal of Clinical Oncology.
Out of the 20 patients who received an AUTO1 infusion, 85% achieved minimal residual disease negativity during the first month. Additionally, 3 of these 17 patients underwent allogeneic stem-cell transplantation (allo-SCT) while in remission. The event-free survival (EFS) was 68.3% (95% CI, 42.8%-84.4%) at 6 months, 48.3% (95% CI, 23.1%-69.7%) at 12 months, and 48.3% (95% CI, 23.1%-69.7%) at 24 months.
“Although CD19 CAR T has an established role in pediatric relapsed/refractory B-cell [B-ALL], its role in adult B-ALL is not well- established. Toxicities have been more prohibitive in older patients, and response duration more limited with frequent requirement for consolidation with allo-SCT. Immunotoxicity is a particular challenge in adults,” the investigators wrote.
The median patient age was 41.5 years, and 75% had an abnormal karyotype. Additionally, 30% of patients had Philadelphia chromosome (Ph)–positive disease. Patients received a median of 3 lines prior of therapy, with 25% receiving blinatumomab (Blincyto), 50% receiving inotuzumab ozogamicin (Besponsa), and 65% receiving allo-SCT. Those patients who were Ph-positive received 2 or more Tyrosine kinase inhibitors (TKI) before lymphodepletion, including imatinib (Gleevec), ponatinib (Iclusig), and dasatinib (Sprycel). Four of the 6 patients were either relapsed or refractory, and 2 were intolerant to their last-line TKI. The median follow-up was 21.7 months.
Patients received 100x106 CAR T cells on day 0. The second dose was administered at an interval of 9 days at a dose of 410x106 CAR T cells.
The overall survival was 69.1% (95% CI, 43.6%-84.8%) at 6 months, 63.8% (95% CI, 38.6%-80.8%) at 12 months, and 58% (95% CI, 33.1%-76.4%) at 24 months. At a median of 4.5 months, 20% of patients experienced CD19-negative relapse. At 6 months and 9 months, 10% of patients had a CD19-positive relapse and 3 patients had B-cell recovery without relapse. One patient lost CAR T at 3 months and went to receive allo-SCT, but relapsed at 9 months. Additionally, another patient lost CAR T at 3 months following allo-SCT post CAR T while in remission.
In this cohort, 40% of patients developed grade 2 cytokine release syndrome (CRS), and 15% had grade 1. Investigators reported a median onset of CRS of 6 days follwoing infusion. The median duration of CRS was 4.5 days. Of the patients who developed grade 2 CRS, 35% received tocilizumab (Actemra). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 20% of patients, 15% of which were grade 3 and resolved within 24 to 72 hours to grade 1 or lower with corticosteroids. The median onset was 22 days following infusion with a median duration of 1.5 days.
Other safety findings indicated that 15% of patients developed grade 3 thrombocytopenia and 70% developed grade 4; thrombocytopenia did not resolve to less than grade 4 in 22% of cases by day 28. Additionally, 100% of patients experienced grade 4 neutropenia, and in 7 patients, it did not resolve to less than grade 4 by day 28.
Patients also experienced infectious events 30 days or less following infusion, including 12 bacterial, 17 viral, and 4 fungal infections. For infections that occurred between 30 to 90 days after infusion, 15 were infectious, which included bacterial (n = 5), viral (n = 7), and fungal (n = 3). Patients who received allo-SCT were more likely to have late infectious events compared with those in the non-allo-SCT cohort. Before day 28, 2 patients died due to infections, both of whom were neutropenic and lymphopenic for more than 1 year.
Patients also received intravenous immunoglobulin (IVIG), with 2 patients receiving ongoing IVIG before study registration. Thirteen of 18 patients had immunoglobulin G levels of 4 gl/L or less at a median of 2 months post CAR T, and 5 of 13 patients received IVIG for recurrent infections. Graft versus host disease was not observed in this study, despite 63% of patients having received previous allo-SCT.
Cytokine levels were low when measured between day 6 and day 28. There was a statistically significant difference in interleukin-6 (P = .0007) and serum ferritin (P = .0047) for patients with 20% blasts or greater compared with those who had less than 20% blasts. No association with grade 2 or higher CRS and ICANS was observed.
Roddie C, Dias J, O'Reilly MA, et al. Durable responses and low toxicity after fast off-rate CD19 chimeric antigen receptor-T therapy in adults with relapsed or refractory B-Cell acute lymphoblastic leukemia. J Clin Oncol. 2021;39(30):3352-3363. doi:10.1200/JCO.21.00917