CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study.

Autor:	Minson A; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia., Hamad N; Department of Haematology, St Vincent's Hospital, Sydney, Australia., Cheah CY; Department of Haematology, Sir Charles Gairdner Hospital, Perth, Australia.; School of Medicine, University of Western Australia, Crawley, Australia., Tam C; Clinical Haematology, Alfred Hospital, Melbourne, Australia., Blombery P; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia., Westerman D; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia., Ritchie D; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia., Morgan H; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia., Holzwart N; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia., Lade S; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia., Anderson MA; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia.; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia., Khot A; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia., Seymour JF; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia., Robertson M; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia., Caldwell I; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia., Ryland G; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia., Saghebi J; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia., Sabahi Z; Department of Haematology, St Vincent's Hospital, Sydney, Australia., Xie J; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia., Koldej R; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia., Dickinson M; Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.; Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Feb 22; Vol. 143 (8), pp. 673-684.
DOI:	10.1182/blood.2023021306
Abstrakt:	Abstract: CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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