Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma
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 cell...
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| Veröffentlicht in: | Blood cancer discovery 2022-09, Vol.3 (5), p.385-393 |
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| creator | 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 |
| description | 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].
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. |
| doi_str_mv | 10.1158/2643-3230.BCD-21-0177 |
| format | Article |
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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.</description><identifier>ISSN: 2643-3230</identifier><identifier>ISSN: 2643-3249</identifier><identifier>EISSN: 2643-3249</identifier><identifier>DOI: 10.1158/2643-3230.BCD-21-0177</identifier><identifier>PMID: 35533245</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Antigens, CD19 - adverse effects ; Biological Products ; Clonal Hematopoiesis ; Humans ; Immunotherapy, Adoptive - adverse effects ; Lymphoma, Large B-Cell, Diffuse - genetics ; Neurotoxicity Syndromes - epidemiology ; Receptors, Antigen, T-Cell - genetics ; Research Brief</subject><ispartof>Blood cancer discovery, 2022-09, Vol.3 (5), p.385-393</ispartof><rights>2022 American Association for Cancer Research.</rights><rights>2022 American Association for Cancer Research 2022 American Association for Cancer Research</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-75425d853f6a58a0fc161e86a1dc9f37f56d1d2d1ca5f9cce6938282affb6a713</citedby><cites>FETCH-LOGICAL-c411t-75425d853f6a58a0fc161e86a1dc9f37f56d1d2d1ca5f9cce6938282affb6a713</cites><orcidid>0000-0003-2735-168X ; 0000-0001-9063-6691 ; 0000-0002-8582-4572 ; 0000-0001-8980-3202 ; 0000-0002-7744-8490 ; 0000-0003-1045-4914 ; 0000-0002-1646-813X ; 0000-0002-8027-9659 ; 0000-0001-9748-5486 ; 0000-0003-3717-3629 ; 0000-0002-6270-3065 ; 0000-0002-7789-1257 ; 0000-0001-7302-8299 ; 0000-0003-4702-0386 ; 0000-0002-1824-2337 ; 0000-0001-6309-9472 ; 0000-0001-7435-0933</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9445749/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9445749/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35533245$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Saini, Neeraj Y</creatorcontrib><creatorcontrib>Swoboda, David M</creatorcontrib><creatorcontrib>Greenbaum, Uri</creatorcontrib><creatorcontrib>Ma, Junsheng</creatorcontrib><creatorcontrib>Patel, Romil D</creatorcontrib><creatorcontrib>Devashish, Kartik</creatorcontrib><creatorcontrib>Das, Kaberi</creatorcontrib><creatorcontrib>Tanner, Mark R</creatorcontrib><creatorcontrib>Strati, Paolo</creatorcontrib><creatorcontrib>Nair, Ranjit</creatorcontrib><creatorcontrib>Fayad, Luis</creatorcontrib><creatorcontrib>Ahmed, Sairah</creatorcontrib><creatorcontrib>Lee, Hun Ju</creatorcontrib><creatorcontrib>Iyer, Swaminathan P</creatorcontrib><creatorcontrib>Steiner, Raphael</creatorcontrib><creatorcontrib>Jain, Nitin</creatorcontrib><creatorcontrib>Nastoupil, Loretta</creatorcontrib><creatorcontrib>Loghavi, Sanam</creatorcontrib><creatorcontrib>Tang, Guilin</creatorcontrib><creatorcontrib>Bassett, Roland L</creatorcontrib><creatorcontrib>Jain, Preetesh</creatorcontrib><creatorcontrib>Wang, Michael</creatorcontrib><creatorcontrib>Westin, Jason R</creatorcontrib><creatorcontrib>Green, Michael R</creatorcontrib><creatorcontrib>Sallman, David A</creatorcontrib><creatorcontrib>Padron, Eric</creatorcontrib><creatorcontrib>Davila, Marco L</creatorcontrib><creatorcontrib>Locke, Frederick L</creatorcontrib><creatorcontrib>Champlin, Richard E</creatorcontrib><creatorcontrib>Garcia-Manero, Guillermo</creatorcontrib><creatorcontrib>Shpall, Elizabeth J</creatorcontrib><creatorcontrib>Kebriaei, Partow</creatorcontrib><creatorcontrib>Flowers, Christopher R</creatorcontrib><creatorcontrib>Jain, Michael D</creatorcontrib><creatorcontrib>Wang, Feng</creatorcontrib><creatorcontrib>Futreal, Andrew P</creatorcontrib><creatorcontrib>Gillis, Nancy</creatorcontrib><creatorcontrib>Neelapu, Sattva S</creatorcontrib><creatorcontrib>Takahashi, Koichi</creatorcontrib><title>Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma</title><title>Blood cancer discovery</title><addtitle>Blood Cancer Discov</addtitle><description>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].
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.</description><subject>Antigens, CD19 - adverse effects</subject><subject>Biological Products</subject><subject>Clonal Hematopoiesis</subject><subject>Humans</subject><subject>Immunotherapy, Adoptive - adverse effects</subject><subject>Lymphoma, Large B-Cell, Diffuse - genetics</subject><subject>Neurotoxicity Syndromes - epidemiology</subject><subject>Receptors, Antigen, T-Cell - genetics</subject><subject>Research 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titles)</collection><jtitle>Blood cancer discovery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Saini, Neeraj Y</au><au>Swoboda, David M</au><au>Greenbaum, Uri</au><au>Ma, Junsheng</au><au>Patel, Romil D</au><au>Devashish, Kartik</au><au>Das, Kaberi</au><au>Tanner, Mark R</au><au>Strati, Paolo</au><au>Nair, Ranjit</au><au>Fayad, Luis</au><au>Ahmed, Sairah</au><au>Lee, Hun Ju</au><au>Iyer, Swaminathan P</au><au>Steiner, Raphael</au><au>Jain, Nitin</au><au>Nastoupil, Loretta</au><au>Loghavi, Sanam</au><au>Tang, Guilin</au><au>Bassett, Roland L</au><au>Jain, Preetesh</au><au>Wang, Michael</au><au>Westin, Jason R</au><au>Green, Michael R</au><au>Sallman, David A</au><au>Padron, Eric</au><au>Davila, Marco L</au><au>Locke, Frederick L</au><au>Champlin, Richard E</au><au>Garcia-Manero, Guillermo</au><au>Shpall, Elizabeth J</au><au>Kebriaei, Partow</au><au>Flowers, Christopher R</au><au>Jain, Michael D</au><au>Wang, Feng</au><au>Futreal, Andrew P</au><au>Gillis, Nancy</au><au>Neelapu, Sattva S</au><au>Takahashi, Koichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma</atitle><jtitle>Blood cancer discovery</jtitle><addtitle>Blood Cancer Discov</addtitle><date>2022-09-06</date><risdate>2022</risdate><volume>3</volume><issue>5</issue><spage>385</spage><epage>393</epage><pages>385-393</pages><issn>2643-3230</issn><issn>2643-3249</issn><eissn>2643-3249</eissn><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].
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.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>35533245</pmid><doi>10.1158/2643-3230.BCD-21-0177</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-2735-168X</orcidid><orcidid>https://orcid.org/0000-0001-9063-6691</orcidid><orcidid>https://orcid.org/0000-0002-8582-4572</orcidid><orcidid>https://orcid.org/0000-0001-8980-3202</orcidid><orcidid>https://orcid.org/0000-0002-7744-8490</orcidid><orcidid>https://orcid.org/0000-0003-1045-4914</orcidid><orcidid>https://orcid.org/0000-0002-1646-813X</orcidid><orcidid>https://orcid.org/0000-0002-8027-9659</orcidid><orcidid>https://orcid.org/0000-0001-9748-5486</orcidid><orcidid>https://orcid.org/0000-0003-3717-3629</orcidid><orcidid>https://orcid.org/0000-0002-6270-3065</orcidid><orcidid>https://orcid.org/0000-0002-7789-1257</orcidid><orcidid>https://orcid.org/0000-0001-7302-8299</orcidid><orcidid>https://orcid.org/0000-0003-4702-0386</orcidid><orcidid>https://orcid.org/0000-0002-1824-2337</orcidid><orcidid>https://orcid.org/0000-0001-6309-9472</orcidid><orcidid>https://orcid.org/0000-0001-7435-0933</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2643-3230 |
| ispartof | Blood cancer discovery, 2022-09, Vol.3 (5), p.385-393 |
| issn | 2643-3230 2643-3249 2643-3249 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9445749 |
| source | MEDLINE; PubMed Central |
| subjects | Antigens, CD19 - adverse effects Biological Products Clonal Hematopoiesis Humans Immunotherapy, Adoptive - adverse effects Lymphoma, Large B-Cell, Diffuse - genetics Neurotoxicity Syndromes - epidemiology Receptors, Antigen, T-Cell - genetics Research Brief |
| title | Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T02%3A33%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Clonal%20Hematopoiesis%20Is%20Associated%20with%20Increased%20Risk%20of%20Severe%20Neurotoxicity%20in%20Axicabtagene%20Ciloleucel%20Therapy%20of%20Large%20B-Cell%20Lymphoma&rft.jtitle=Blood%20cancer%20discovery&rft.au=Saini,%20Neeraj%20Y&rft.date=2022-09-06&rft.volume=3&rft.issue=5&rft.spage=385&rft.epage=393&rft.pages=385-393&rft.issn=2643-3230&rft.eissn=2643-3249&rft_id=info:doi/10.1158/2643-3230.BCD-21-0177&rft_dat=%3Cproquest_pubme%3E2661956178%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2661956178&rft_id=info:pmid/35533245&rfr_iscdi=true |