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

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

doi:10.1158/2643-3230.BCD-21-0177

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

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

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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.

Original language	English
Pages (from-to)	385-393
Number of pages	9
Journal	Blood cancer discovery
Volume	3
Issue number	5
DOIs	https://doi.org/10.1158/2643-3230.BCD-21-0177
State	Published - 1 Sep 2022
Externally published	Yes

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General Medicine

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10.1158/2643-3230.BCD-21-0177

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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., ... Takahashi, K. (2022). Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma. Blood cancer discovery, 3(5), 385-393. https://doi.org/10.1158/2643-3230.BCD-21-0177

@article{48bea9ec3fb64b9e888df031e78ff040,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",

year = "2022",

month = sep,

day = "1",

doi = "10.1158/2643-3230.BCD-21-0177",

language = "English",

volume = "3",

pages = "385--393",

journal = "Blood cancer discovery",

issn = "2643-3230",

publisher = "NLM (Medline)",

number = "5",

}

Saini, NY, Swoboda, DM, Greenbaum, U, Ma, J, Patel, RD, Devashish, K, Das, K, Tanner, MR, Strati, P, Nair, R, Fayad, L, Ahmed, S, Lee, HJ, Iyer, SP, Steiner, R, Jain, N, Nastoupil, L, Loghavi, S, Tang, G, Bassett, RL, Jain, P, Wang, M, Westin, JR, Green, MR, Sallman, DA, Padron, E, Davila, ML, Locke, FL, Champlin, RE, Garcia-Manero, G, Shpall, EJ, Kebriaei, P, Flowers, CR, Jain, MD, Wang, F, Futreal, AP, Gillis, N, Neelapu, SS & Takahashi, K 2022, 'Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma', Blood cancer discovery, vol. 3, no. 5, pp. 385-393. https://doi.org/10.1158/2643-3230.BCD-21-0177

TY - JOUR

T1 - Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma

AU - Saini, Neeraj Y.

AU - Swoboda, David M.

AU - Greenbaum, Uri

AU - Ma, Junsheng

AU - Patel, Romil D.

AU - Devashish, Kartik

AU - Das, Kaberi

AU - Tanner, Mark R.

AU - Strati, Paolo

AU - Nair, Ranjit

AU - Fayad, Luis

AU - Ahmed, Sairah

AU - Lee, Hun Ju

AU - Iyer, Swaminathan P.

AU - Steiner, Raphael

AU - Jain, Nitin

AU - Nastoupil, Loretta

AU - Loghavi, Sanam

AU - Tang, Guilin

AU - Bassett, Roland L.

AU - Jain, Preetesh

AU - Wang, Michael

AU - Westin, Jason R.

AU - Green, Michael R.

AU - Sallman, David A.

AU - Padron, Eric

AU - Davila, Marco L.

AU - Locke, Frederick L.

AU - Champlin, Richard E.

AU - Garcia-Manero, Guillermo

AU - Shpall, Elizabeth J.

AU - Kebriaei, Partow

AU - Flowers, Christopher R.

AU - Jain, Michael D.

AU - Wang, Feng

AU - Futreal, Andrew P.

AU - Gillis, Nancy

AU - Neelapu, Sattva S.

AU - Takahashi, Koichi

PY - 2022/9/1

Y1 - 2022/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85133230942&partnerID=8YFLogxK

U2 - 10.1158/2643-3230.BCD-21-0177

DO - 10.1158/2643-3230.BCD-21-0177

M3 - Article

C2 - 35533245

AN - SCOPUS:85133230942

SN - 2643-3230

VL - 3

SP - 385

EP - 393

JO - Blood cancer discovery

JF - Blood cancer discovery

IS - 5

ER -

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

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