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

Claire Roddie, Juliana Dias, Maeve A. O'Reilly, Mahnaz Abbasian, Amaia Cadinanos-Garai, Ketki Vispute, Leticia Bosshard-Carter, Marina Mitsikakou, Vedika Mehra, Harriet Roddy, John A. Hartley, Victoria Spanswick, Helen Lowe, Bilyana Popova, Laura Clifton-Hadley, Graham Wheeler, Joanna Olejnik, Adrian Bloor, David Irvine, Leigh WoodMaria A.V. Marzolini, Sabine Domning, Farzin Farzaneh, Mark W. Lowdell, David C. Linch, Martin A. Pule*, Karl S. Peggs

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

PURPOSE Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 ( NCT02935257 ) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease–negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4%-84.4%) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL.
Original languageEnglish
Pages (from-to)3352-3363
Number of pages12
JournalJournal of Clinical Oncology
Volume39
Issue number30
DOIs
Publication statusPublished - 20 Oct 2021

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