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Cited by 74

The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.

Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma

Saini, Neeraj Y., Swoboda, David M., Greenbaum, Uri, Ma, Junsheng, Patel, Romil D., Devashish, Kartik, Das, Kaberi, Tanner, Mark R., Strati, Paolo, Nair, Ranjit, Fayad, Luis, Ahmed, Sairah, Lee, Hun Ju, Iyer, Swaminathan P., Steiner, Raphael, Jain, Nitin, Nastoupil, Loretta, Loghavi, Sanam, Tang, Guilin, Bassett, Roland L., Jain, Preetesh, Wang, Michael, Westin, Jason R., Green, Michael R., Sallman, David A., Padron, Eric, Davila, Marco L., Locke, Frederick L., Champlin, Richard E., Garcia-Manero, Guillermo, Shpall, Elizabeth J., Kebriaei, Partow, Flowers, Christopher R., Jain, Michael D., Wang, Feng, Futreal, Andrew P., Gillis, Nancy, Neelapu, Sattva S., Takahashi, Koichi·2022·Blood Cancer Discovery
DOI 10.1158/2643-3230.bcd-21-0177

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Abstract

To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5–38.7) vs. 4.2% (95% CI, 0.3–18.4), P = 0.028]. Significance: Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369

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Authors
Saini, N. Y., Swoboda, D. M., Greenbaum, U., Ma, J., Patel, R. D., Devashish, K., Das, K., Tanner, M. R., Strati, P., Nair, R., Fayad, L., Ahmed, S., Lee, H. J., Iyer, S. P., Steiner, R., Jain, N., Nastoupil, L., Loghavi, S., Tang, G., Bassett, R. L., Jain, P., Wang, M., Westin, J. R., Green, M. R., Sallman, D. A., Padron, E., Davila, M. L., Locke, F. L., Champlin, R. E., Garcia-Manero, G., Shpall, E. J., Kebriaei, P., Flowers, C. R., Jain, M. D., Wang, F., Futreal, A. P., Gillis, N., Neelapu, S. S., & Takahashi, K.
Affiliations
  • 1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 3Department of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida.
  • 4Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 6Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 7Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida.
  • 8Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
ORCID
Venue
Blood Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2022-05-06
Volume
3
Issue
5
Pages
385-393
ISSN
  • 2643-3230
  • 2643-3249
DOI
10.1158/2643-3230.bcd-21-0177
Cited by
74
References
36
Language
en
Update notices
correction (2023-05-01)
Funders
  • NIH NCI (R01 CA237291)
  • University of Texas MD Anderson Cancer Center (P30 CA016672)
  • H. Lee Moffitt Cancer Center and Research Institute (P30-CA076292)

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