1. Clonal hematopoiesis is associated with increased toxicity in large B-cell lymphoma patients treated with chimeric antigen receptor T cell therapy
- Author
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Neeraj Y. Saini, David M. Swoboda, Uri Greenbaum, Jungsheng Ma, Romil Patel, Kartik Devashish, Kaberi Das, Mark R. Tanner, Paolo Strati, Ranjit Nair, Luis E. Fayad, Sairah Ahmed, Hun Ju Lee, Swaminathan Iyer, Raphael Steiner, Nitin Jain, Loretta Nastoupil, Sanam Loghavi, Guilin Tang, Preetesh Jain, Michael Wang, Jason Westin, Michael R. Green, David Sallman, Eric Padron, Marco Davila, Frederick L. Locke, Richard Champlin, Elizabeth Shpall, Partow Kebriaei, Christopher R. Flowers, Michael Jain, Feng Wang, Andrew Futreal, Nancy Gillis, Sattva S. Neelapu, and Koichi Takahashi
- Subjects
medicine.medical_specialty ,Myeloid ,business.industry ,Context (language use) ,medicine.disease ,Gastroenterology ,Chimeric antigen receptor ,Lymphoma ,Cytokine release syndrome ,medicine.anatomical_structure ,Internal medicine ,medicine ,Cumulative incidence ,Chimeric Antigen Receptor T-Cell Therapy ,B-cell lymphoma ,business - Abstract
To explore the role of clonal hematopoiesis (CH) on chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep-sequencing on 114 large B-cell lymphoma patients treated with anti-CD19 CAR T-cells. We detected CH in 42 (36.8%) pre-treatment patient samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. The incidence of grade ≥3 immune-effector cell-associated neurotoxicity syndrome (ICANS) was higher in CH-positive patients compared to CH-negative patients (45.2% vs. 25.0%, p=0.038). Higher toxicities with CH were primarily driven by three CH genes, DNMT3A, TET2 and ASXL1 (DTA mutations). The incidence of grade ≥3 ICANS [58.9% vs. 25%, p=0.02] and grade ≥3 cytokine release syndrome [17.7% vs. 4.2%, p=0.08] were higher in patients with DTA mutations than those without CH. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR-T therapy was higher in patients with CH than those without CH (19% [95%CI: 5.5-38.7] vs. 4.2% [95%CI: 0.3-18.4], p=0.028).Statement of SignificanceOur study reveals that clonal hematopoiesis mutations, especially those associated with inflammation (DNMT3A, TET2, ASXL1), are associated with severe grade toxicities in lymphoma patients receiving anti-CD19 chimeric antigen receptor therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted.
- Published
- 2021