Matched donor allogeneic CAR-T for adult B-ALL: toxicity, efficacy, repeat dosing, and the importance of lymphodepletion
Abstract
Abstract We developed an allogeneic matched donor CD19 chimeric antigen receptor (CAR) product (CAR–donor lymphocyte infusion [DLI]) for adult patients with B-cell acute lymphoblastic leukemia (B-ALL) after failure of allogeneic stem-cell transplantation (allo-SCT). We evaluate the risks and benefits of pre–CAR-DLI lymphodepleting chemotherapy (LD) and the efficacy of repeat CAR-DLI dosing per conventional DLI protocols. Primary outcomes were toxicity and feasibility of CAR-DLI manufacture; secondary outcomes included CAR-DLI engraftment, expansion, and persistence. A total of 17 allo-SCT donors received leukapheresis and 14 patients with B-ALL (median age, 43 years) received infusion. Median disease burden at registration was 50.5% bone marrow blasts (range, measurable residual disease [MRD] to 100%). Patients 1 to 7 received CAR-DLI alone (CAR-DLI-alone); patients 8 through 14 received CAR-DLI and LD with fludarabine/cyclophosphamide (CAR-DLI+LD). CAR-DLI+LD vs CAR-DLI-alone was associated with superior peak CAR-DLI engraftment (93 134 vs 8010 copies per μg genomic DNA [gDNA]), expansion (858 101 vs 39 038 copies per μg gDNA per 28 days) and persistence (median, 197 vs 32 days). CAR-DLI+LD was not associated with more immunotoxicity than CAR-DLI-alone, and graft-versus-host disease (GVHD; grade 1, skin) affected only 2 of 14 patients (14%). CAR-DLI+LD vs CAR-DLI-alone conferred superior event-free-survival and overall survival at 12 months (57% vs 29%; 83% vs 29%). Repeat CAR-DLI dosing was administered to 8 of 14 (57%) patients with morphological/MRD+ relapse, but with minimal engraftment/expansion or toxicity/efficacy. CAR-DLI+LD has a tolerable safety profile without significant GVHD and is associated with significantly better outcomes than CAR-DLI-alone. Repeat CAR-DLI dosing beyond dose 1 was not found to be effective in this analysis. This trial was registered at www.clinicaltrials.gov as #NCT02893189.
Article Details
Authors (26)
Claire Roddie
1University College London Cancer Institute, Research Department of Haematology, London, United Kingdom
Juliana Dias
Maeve A. O’Reilly
2Department of Haematology, University College London Hospitals, London, United Kingdom
Mahnaz Abbasian
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Amaia Cadinanos-Garai
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Ketki Vispute
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Leticia Bosshard-Carter
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Marina Mitsikakou
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Eftychia Charalambous
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Vedika Mehra
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Harriet Roddy
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Gordon Weng-Kit Cheung
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
John A. Hartley
Nasir Mahmoud
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Leah Ensell
Yashma Patel
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Maria A. V. Marzolini
2Department of Haematology, University College London Hospitals, London, United Kingdom
Farzin Farzaneh
5Gene Vector Laboratory, King’s College London, London, United Kingdom
Lauren Nickolay
6University College London Institute of Child Health, London, United Kingdom
Nourredine Himoudi
6University College London Institute of Child Health, London, United Kingdom
Farhatullah Syed
1King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Bilyana Popova
5University College London Cancer Institute, CRUK Cancer Trials Centre, London, United Kingdom
Sevasti Galani
7Cancer Research UK and University College London Cancer Trial Centre, University College London Cancer Institute, University College London, London, United Kingdom
Alexander Day
Mark W. Lowdell
1Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom
Karl S. Peggs