Clonal hematopoiesis and cytopenias following CAR19 therapy

CD19-directed chimeric antigen receptor T-cell therapy (CAR19) improves survival in patients with relapsed/refractory large B-cell lymphoma (rrLBCL) compared to immunochemotherapy with intent for autologous hematopoietic cell transplantation (HCT). However, major toxicities of CAR19 therapy include prolonged cytopenias, infection, and secondary hematologic malignancies. To investigate the mechanisms underlying these toxicities we studied a cohort of lymphoma patients receiving CAR19. CAR19-treated patients exhibited impaired immune reconstitution and increased infection compared to propensity-matched HCT-treated controls. Bone marrow analysis revealed prolonged post-CAR cytopenias is associated with clonal cytopenias of undetermined significance (CCUS) and is characterized by interferon-mediated inflammation. Despite durable lymphoma remissions, clonal hematopoiesis (CH) commonly expanded following CAR19 infusion and was associated with impaired immune reconstitution and the development of treatment related myeloid malignancy (tMN). The molecular composition and clinical outcomes of post-CAR tMN were comparable to those of post-HCT tMN. Single-cell DNA analysis revealed that most post-CAR CH clones harbored a single independent mutation and that CAR integration into T cells with CH mutations may drive persistence. These findings broadly implicate CH mutation burden and CH expansion in the development of post-CAR cytopenias and malignancies as well as mechanistically suggest these expansions occur in a background of marrow inflammation. Together, our results provide insight into the origins of key CAR19-associated toxicities, including infection and tMN.

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Publication Details

Journal
Nature Genetics
Published
2026-11-02
DOI
https://doi.org/10.1038/s41588-026-02795-5
Citations
1
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
2.59

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article

Clonal hematopoiesis and cytopenias following CAR19 therapy

Parveen Shiraz, Maximilian Diehn, Lori S. Muffly, Jan Boegeholz et al.
1 citations
Nature Genetics
CAR-T cell therapy research
2.59
article

Clonal hematopoiesis and cytopenias following CAR19 therapy

Parveen Shiraz, Maximilian Diehn, Lori S. Muffly, Jan Boegeholz, Ash A. Alizadeh, Takeshi Sugio, Mark P. Hamilton, Judith A. Shizuru, Mohammad Shahrokh Esfahani, Surbhi Sidana, Saurabh Dahiya, Melody M. Smith, Matthew Joshua Frank, Sally Arai, Chih Long Liu, Troy Noordenbos, Zinaida Good, Ying Lü, Nick A. Phillips, Brian J. Sworder, David Matthew Kurtz, Stefan Alig, Joseph G. Schroers‐Martin, Crystal Lee Mackall, Mari Olsen, Laura Johnston, RS Negrin, Sushma Bharadwaj, Wen-Kai Weng, Everett Meyer, John Tamaresis, Zach Ehlinger, Robert Lowsky, Bita Sahaf, Moksha Desai, Andrew Rezvani
article en
1 citations

Abstract

CD19-directed chimeric antigen receptor T-cell therapy (CAR19) improves survival in patients with relapsed/refractory large B-cell lymphoma (rrLBCL) compared to immunochemotherapy with intent for autologous hematopoietic cell transplantation (HCT). However, major toxicities of CAR19 therapy include prolonged cytopenias, infection, and secondary hematologic malignancies. To investigate the mechanisms underlying these toxicities we studied a cohort of lymphoma patients receiving CAR19. CAR19-treated patients exhibited impaired immune reconstitution and increased infection compared to propensity-matched HCT-treated controls. Bone marrow analysis revealed prolonged post-CAR cytopenias is associated with clonal cytopenias of undetermined significance (CCUS) and is characterized by interferon-mediated inflammation. Despite durable lymphoma remissions, clonal hematopoiesis (CH) commonly expanded following CAR19 infusion and was associated with impaired immune reconstitution and the development of treatment related myeloid malignancy (tMN). The molecular composition and clinical outcomes of post-CAR tMN were comparable to those of post-HCT tMN. Single-cell DNA analysis revealed that most post-CAR CH clones harbored a single independent mutation and that CAR integration into T cells with CH mutations may drive persistence. These findings broadly implicate CH mutation burden and CH expansion in the development of post-CAR cytopenias and malignancies as well as mechanistically suggest these expansions occur in a background of marrow inflammation. Together, our results provide insight into the origins of key CAR19-associated toxicities, including infection and tMN.

Nature Genetics
City Of Hope National Medical Center (US), The University of Texas MD Anderson Cancer Center (US), Leiden University Medical Center (NL), City of Hope (US), Stanford Medicine (US), Stanford Cancer Institute (US), Stanford University (US)
Pfizer, AstraZeneca, Leukemia and Lymphoma Society, Gilead Sciences, Virginia and D.K. Ludwig Fund for Cancer Research, Celgene, Adaptive Biotechnologies, Swedish Orphan Biovitrum, National Institutes of Health, Genentech, Chugai Pharmaceutical, Kite Pharma, Pharmacyclics, National Heart, Lung, and Blood Institute, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 17%
CAR-T cell therapy research
2.59
DOIOpen Access PDFOpenAlex
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