CAR19 Therapy Drives Expansion of Clonal Hematopoiesis and Associated Cytopenias

• Published in: Transplantation and cellular therapy 2024-02, Vol.30 (2), p.S3-S4
• Main Authors: Hamilton, Mark P., Sworder, Brian, Alig, Stefan, Good, Zinaida, Boegeholz, Jan, Schroers-Martin, Joseph, Tamaresis, John, Esfahani, Mohammad, Lu, Ying, Olsen, Mari, Liu, Chih Long, Ehlinger, Zachary, Desai, Moksha, Liu-Fei, Felicia, Muffly, Lori S, Negrin, Robert S., Arai, Sally, Johnston, Laura, Lowsky, Robert, Meyer, Everett H., Rezvani, Andrew R., Shizuru, Judith A., Weng, Wen-Kai, Shiraz, Parveen, Sidana, Surbhi, Bharadwaj, Sushma, Smith, Melody, Dahiya, Saurabh, Sahaf, Bita, Diehn, Max, Frank, Matthew J., Mackall, Crystal L., Kurtz, David, Miklos, David B., Alizadeh, Ash A.
• Format: Article
• Language: English
• ISSN: 2666-6367; 2666-6367
• DOI: 10.1016/j.jtct.2023.12.023

For patients with relapsed/refractory large B-cell lymphomas (rrLBCL), CD19-directed chimeric antigen receptor T-cells (CAR19) improve survival compared to autologous hematopoietic cell transplantation (HCT). However, major toxicities of CAR19 therapy include prolonged cytopenias and associated infections. To better understand the impact of CAR19 on such toxicities, we studied a cohort of LBCL patients achieving durable remissions to assess immune recovery after CAR19 treatment. We first profiled bone marrow aspirates from patients requiring biopsy due to prolonged cytopenia and/or clinical concern for myeloid neoplasms. No patient had evidence of lymphoma relapse at the time of biopsy, and all were >60 days from CAR19 infusion. Among 21 biopsied patients with DNA sequencing, 18 (86%) had evidence of ≥1 somatic mutation in genes canonically associated with myeloid clonal hematopoiesis (CH) in the marrow (Fig. 1A), with the most recurrently mutated genes being DNMT3A (38%), TP53 (33%), PPM1D (24%), ASXL1 (14%), and TET2 (14%). Among 6 patients diagnosed with and requiring therapy for a myeloid malignancy, all (100%) had a canonical myeloid karyotypic aberration detected by FISH, as compared with 0 in the 14 other evaluable cases (Fig. 1A). CAR19 cells were proportionately enriched in the marrow relative to paired peripheral blood by flow cytometry (n = 12, p