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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

Authors :
Karl S. Peggs
Bilyana Popova
Claire Roddie
David Irvine
Marina Mitsikakou
Martin Pule
Joanna Olejnik
Graham M. Wheeler
Maria A. V. Marzolini
Mark W. Lowdell
Farzin Farzaneh
Amaia Cadinanos-Garai
Sabine Domning
Harriet Roddy
Victoria J. Spanswick
Ketki Vispute
Leigh Wood
Juliana Dias
Leticia Bosshard-Carter
David C. Linch
John A. Hartley
Maeve A O'Reilly
Adrian Bloor
Mahnaz Abbasian
Vedika Mehra
Laura Clifton-Hadley
Helen Lowe
Source :
Journal of Clinical Oncology. 39:3352-3363
Publication Year :
2021
Publisher :
American Society of Clinical Oncology (ASCO), 2021.

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.

Details

ISSN :
15277755 and 0732183X
Volume :
39
Database :
OpenAIRE
Journal :
Journal of Clinical Oncology
Accession number :
edsair.doi.dedup.....4a9b9fca67a336258e2820d72bc656fe
Full Text :
https://doi.org/10.1200/jco.21.00917