CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study
- Author(s)
- Minson, A; Hamad, N; Cheah, CY; Tam, C; Blombery, P; Westerman, D; Ritchie, D; Morgan, H; Holzwart, N; Lade, S; Anderson, MA; Khot, A; Seymour, JF; Robertson, M; Caldwell, I; Ryland, G; Saghebi, J; Sabahi, Z; Xie, J; Koldej, R; Dickinson, M;
- Details
- Publication Year 2024-02-22,Volume 143,Issue #8,Page 673-684
- Journal Title
- Blood
- 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.
- Keywords
- Adult; Humans; *Lymphoma, Mantle-Cell/drug therapy; *Receptors, Chimeric Antigen/therapeutic use; Neoplasm Recurrence, Local/drug therapy; T-Lymphocytes; Immunotherapy, Adoptive/methods; Antigens, CD19; Adenine/*analogs & derivatives; *Piperidines
- Department(s)
- Clinical Haematology; Pathology; Parkville Cancer Clinical Trials Unit; Cancer Imaging; Biostatistics and Clinical Trials
- Publisher's Version
- https://doi.org/10.1182/blood.2023021306
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-04-09 12:09:08
Last Modified: 2024-04-09 12:09:16