Event-free survival was 68.3% at 6 months, 48.3% at 12 months, and 48.3% at 24 months in patients treated with AUTO1.
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The cell therapy AUTO1, consisting of autologous CAT19-41BB-Z chimeric antigen receptor (CAR) T-cells, 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).
Data from the ALLCAR19 study were published in the Journal of Clinical Oncology and included findings from 20 patients that received an AUTO1 infusion. Of these patients, 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. 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.
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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.