Prognosis for adult B-cell acute lymphoblastic leukaemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. In the phase I ALLCAR19 study, Autologous CAT19-41BB-Z CAR-T cells (AUTO1) now demonstrate a tolerable safety profile, high remission rates, and good persistence in adult patients with relapsed/refractory B-ALL and support AUTO1 as a stand-alone treatment in this population.
EXPERT OPINION OF PROF. DR. BARBARA DE MOERLOOSE, HAEMATOLOGIST, UNIVERSITY HOSPITAL GHENT
“The CAR-T cells used in the ALLCAR19 study contain a 4-1BB costimulatory domain and have a long persistence. As such, this therapy can be considered as a stand-alone treatment in adult patients with R/R ALL.”
Despite the fact that CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has been approved for the treatment of paediatric relapsed or refractory B-cell acute lymphoblastic leukaemia (R/R ALL), the role of CD19 CAR-T in adult B-ALL is less clear. For adult patients, CD19 CAR-T trials have shown significant immune-mediated toxicity, relatively short duration engraftment and remission, and a requirement for consolidation with allogeneic stem-cell transplantation (allo-SCT). Therefore, a novel second-generation CD19-CAR, CAT19-41BB-Z, has been generated. The CD19-targeted single-chain variable fragment (scFv) in CAT19-41BB-Z has a lower affinity for CD19 than FMC63, the scFv used in all currently licensed CD19 CAR-T products. This results in a fast off rate, designed for more physiologic T-cell activation with reduced toxicity and improved engraftment. The ALLCAR19 study was designed to investigate whether the safety profile, manufacturing feasibility, and preliminary efficacy outcomes of Autologous CAT19-41BB-Z CAR-T cells (AUTO1), previously demonstrated in the paediatric B-ALL setting, could be reproduced in adults.
This multicentre, non-randomised, open-label phase I study was conducted in three centres, treating 20 adult patients with R/R B-ALL. Following leukapheresis and CAR-T manufacture, patients received lymphodepletion (LD) with intravenous fludarabine (30 mg/m2, 3 doses over 3 days) and cyclophosphamide (60 mg/kg, single dose). CAR-T was administered in a split-dose schedule, titrated to pre-LD bone marrow (BM) disease burden. On day 0, patients with blasts > 20% received 10 x 106 CAR-T and patients with blasts ≤ 20% received 100 x 106 CAR-T cells. At an interval of 9 days (in the absence of grade 3-4 cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity syndrome [ICANS] or grade 1-2 ICANS not fully resolved), dose 2 was administered, to a total dose of 410 x 106 CAR-T cells.
In total, 25 patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. Of the 4 patients who were not infused, one developed CD19-negative relapse following blinatumomab bridging, one developed graft-versus-host-disease (GVHD) and two died from infection in the context of progressive refractory B-ALL. Median age of the 20 infused patients was 41.5 years, 75% had an abnormal disease karyotype and 30% had Ph+ disease. Patients had received a median of three previous lines, including blinatumomab in 25%, inotuzumab ozogamicin (IO) in 50%, and allo-SCT in 65%. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. In total, 18 patients (90%) received bridging therapy. Of them, only 4 had a significant reduction in disease burden to ≤ 5% blasts. The median observed follow-up on all 20 patients from first infusion was 21.7 months.
Eight patients (40%) developed grade 2 cytokine release syndrome (CRS) but no patients experienced ≥ grade 3 CRS. The median onset of CRS was at 6 days post-infusion and the median duration was 4.5 days. ICANS was observed in 4 of 20 (20%) patients and only 3 patients developed grade 3 ICANS, which responded swiftly to corticosteroids, resolving to ≤ grade 1 within 72 hours in all cases. The median onset of ICANS was at 22 days post-infusion and the median duration was 1.5 days. No GVHD was observed on study.
Seventeen of 20 (85%) patients achieved minimal residual disease (MRD)–negative complete response at month 1 and 14 of 20 were in ongoing MRD-negative complete remission at month 3. The event-free survival (EFS) at 6, 12, and 24 months was 68.3%, 48.3% and 48.3% respectively. Corresponding overall survival (OS) rates were 69.1%, 63.8% and 58%, respectively. OS and EFS were not significantly different between patients with and without previous allo-SCT. Three of 17 patients had allo-SCT while in morphologic remission at a median of 9 months post–CAR-T. Four patients experienced CD19-negative relapse at a median of 4.5 months post–CAR-T, with ongoing CAR-T persistence. Two patients developed CD19-positive relapse at month 6 and month 9, with CAR-T loss and B-cell recovery.
The ALLCAR19 study demonstrates the feasibility of manufacturing and administration of AUTO1 to adults with R/R B-ALL. AUTO1 expanded and persisted in most patients with limited immunotoxicity, and remissions were maintained for over 24 months without allo-SCT. ALLCAR19 is a proof of concept that a fast off-rate CD19 CAR can be a stand-alone salvage therapy in adult R/R B-ALL with acceptable toxicity.
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