{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:52:37Z","timestamp":1781650357101,"version":"3.54.5"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006544","name":"Ministry of Health, State of Israel","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006544","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Ann Hematol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Bone marrow toxicity, or immune effector cell-associated hematotoxicity (ICAHT), is a notable complication of CAR T-cell therapy, characterized by persistent cytopenia\u2019s and typically classified into three phenotypes: transient, intermittent and aplastic. This study aimed to characterize the bone marrow immune landscape associated with ICAHT phenotype( aplastic and intermittent) by analyzing patients with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene ciloleucel (axi-cel) who developed ICAHT, in comparison to healthy controls and between the two ICAHT subtypes. Bone marrow samples were profiled using mass cytometry (CyTOF) with a 41-antibody panel. Compared to healthy individuals, ICAHT patients showed increased frequencies of activated\/effector T cells and reduced levels of B cells and CD34\n                    <jats:sup>+<\/jats:sup>\n                    early hematopoietic cells. Within the ICAHT cohort, patients with the aplastic phenotype exhibited significantly higher levels of CAR T cells, activated T cells, regulatory T cells (Tregs), Th1, and Th17 cells, along with a higher proportion of CD34\n                    <jats:sup>+<\/jats:sup>\n                    early hematopoietic cells. In contrast, the intermittent phenotype was characterized by a greater abundance of na\u00efve T cells, Th2 cells, and myeloid lineage markers such as CD33, CD11b, and CD11c. In this small, exploratory analysis, distinct immunological patterns were observed between intermittent and aplastic ICAHT phenotypes, suggesting potentially different mechanisms of hematopoietic disruption after CAR T-cell therapy that require confirmation in larger studies.\n                  <\/jats:p>","DOI":"10.1007\/s00277-026-06993-3","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T07:50:53Z","timestamp":1776153053000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct cellular signatures in aplastic and intermittent phenotypes of immune effector cell-associated hematotoxicity"],"prefix":"10.1007","volume":"105","author":[{"given":"Ben","family":"Varon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Grau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noga Setter","family":"Marco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwar","family":"Khatib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsofia","family":"Levi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riva","family":"Fineman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Tzoran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nivin","family":"Mustafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsila","family":"Zuckerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Netanel A.","family":"Horowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noa","family":"Lavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rostislav","family":"Novak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofrat","family":"Beyar-Katz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"6993_CR1","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1182\/blood.2023020578","volume":"142","author":"K Rejeski","year":"2023","unstructured":"Rejeski K, Subklewe M, Aljurf M, Bachy E, Balduzzi A, Barba P et al (2023) Immune effector cell-associated hematotoxicity: EHA\/EBMT consensus grading and best practice recommendations. Blood 142:865\u2013877","journal-title":"Blood"},{"key":"6993_CR2","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.1182\/bloodadvances.2023011767","volume":"8","author":"K Rejeski","year":"2024","unstructured":"Rejeski K, Wang Y, Hansen DK, Iacoboni G, Bachy E, Bansal R et al (2024) Applying the EHA\/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality. Blood Adv 8:1857\u20131868","journal-title":"Blood Adv"},{"key":"6993_CR3","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg3919","volume":"9","author":"K Rejeski","year":"2023","unstructured":"Rejeski K, Perez A, Iacoboni G, Blumenberg V, B\u00fccklein VL, V\u00f6lkl S et al (2023) Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion. Sci Adv 9:eadg3919","journal-title":"Sci Adv"},{"key":"6993_CR4","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1182\/blood.2022017015","volume":"140","author":"K Rejeski","year":"2022","unstructured":"Rejeski K, Wu Z, Blumenberg V, Kunz WG, M\u00fcller S, Kajigaya S et al (2022) Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL. Blood 140:2175\u20132179","journal-title":"Blood"},{"key":"6993_CR5","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1182\/bloodadvances.2024012992","volume":"9","author":"A Looka","year":"2025","unstructured":"Looka A, Qualls DA, Matthews D, Redd RA, Sakellis C, Duffy C et al (2025) A real-world comparison of commercial-use axicabtagene ciloleucel and lisocabtagene maraleucel in large B-cell lymphoma. Blood Adv 9:455\u2013462","journal-title":"Blood Adv"},{"key":"6993_CR6","doi-asserted-by":"publisher","first-page":"110","DOI":"10.3324\/haematol.2022.280805","volume":"108","author":"M Kwon","year":"2023","unstructured":"Kwon M, Iacoboni G, Reguera JL, Corral LL, Morales RH, Ortiz-Maldonado V et al (2023) Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma. Haematologica 108:110\u2013121","journal-title":"Haematologica"},{"key":"6993_CR7","doi-asserted-by":"publisher","first-page":"77.e1","DOI":"10.1016\/j.jtct.2023.10.017","volume":"30","author":"CA Jacobson","year":"2024","unstructured":"Jacobson CA, Munoz J, Sun F, Kanters S, Limbrick-Oldfield EH, Spooner C et al (2024) Real-world outcomes with chimeric antigen receptor T cell therapies in large B cell lymphoma: a systematic review and meta-analysis. Transplantation and Cellular Therapy 30:77.e1-77.e15","journal-title":"Transplantation and Cellular Therapy"},{"key":"6993_CR8","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1038\/s41591-022-01969-y","volume":"28","author":"E Bachy","year":"2022","unstructured":"Bachy E, Le Gouill S, Di Blasi R, Sesques P, Manson G, Cartron G et al (2022) A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma. Nat Med 28:2145\u20132154","journal-title":"Nat Med"},{"key":"6993_CR9","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.bbmt.2018.12.758","volume":"25","author":"DW Lee","year":"2019","unstructured":"Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN et al (2019) ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 25:625\u2013638","journal-title":"Biol Blood Marrow Transplant"},{"key":"6993_CR10","doi-asserted-by":"publisher","DOI":"10.3390\/v14071493","author":"FHN Howard","year":"2022","unstructured":"Howard FHN, Kwan A, Winder N, Mughal A, Collado-Rojas C, Muthana M (2022) Understanding immune responses to viruses-do underlying Th1\/Th2 cell biases predict outcome? Viruses. https:\/\/doi.org\/10.3390\/v14071493","journal-title":"Viruses"},{"key":"6993_CR11","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1046\/j.1440-1711.2002.01055.x","volume":"80","author":"FJ Salgado","year":"2002","unstructured":"Salgado FJ, Lojo J, Fern\u00e1ndez-Alonso CM, Vi\u00f1uela J, Cordero OJ, Nogueira M (2002) Interleukin-dependent modulation of HLA-DR expression on CD4and CD8 activated T cells. Immunol Cell Biol 80:138\u2013147","journal-title":"Immunol Cell Biol"},{"key":"6993_CR12","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1189\/jlb.0404262","volume":"77","author":"C Sandoval-Montes","year":"2005","unstructured":"Sandoval-Montes C, Santos-Argumedo L (2005) CD38 is expressed selectively during the activation of a subset of mature T cells with reduced proliferation but improved potential to produce cytokines. J Leukoc Biol 77:513\u2013521","journal-title":"J Leukoc Biol"},{"key":"6993_CR13","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","volume":"15","author":"EJ Wherry","year":"2015","unstructured":"Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 15:486\u2013499","journal-title":"Nat Rev Immunol"},{"key":"6993_CR14","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.3892\/mmr.2014.2344","volume":"10","author":"L Xing","year":"2014","unstructured":"Xing L, Liu C, Fu R, Wang H, Wang J, Liu X et al (2014) CD8+HLA-DR+ T cells are increased in patients with severe aplastic anemia. Mol Med Rep 10:1252\u20131258","journal-title":"Mol Med Rep"},{"key":"6993_CR15","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.jaci.2023.07.008","volume":"153","author":"TH Nguyen","year":"2024","unstructured":"Nguyen TH, Kumar D, Prince C, Martini D, Grunwell JR, Lawrence T et al (2024) Frequency of HLA-DR+CD38hi T cells identifies and quantifies T-cell activation in hemophagocytic lymphohistiocytosis, hyperinflammation, and immune regulatory disorders. J Allergy Clin Immunol 153:309\u2013319","journal-title":"J Allergy Clin Immunol"},{"key":"6993_CR16","doi-asserted-by":"publisher","first-page":"735125","DOI":"10.3389\/fimmu.2021.735125","volume":"12","author":"J Du","year":"2021","unstructured":"Du J, Wei L, Li G, Hua M, Sun Y, Wang D et al (2021) Persistent high percentage of HLA-DR+CD38high CD8+ T cells associated with immune disorder and disease severity of COVID-19. Front Immunol 12:735125","journal-title":"Front Immunol"},{"key":"6993_CR17","doi-asserted-by":"publisher","first-page":"954","DOI":"10.4161\/onci.20307","volume":"1","author":"RC Wu","year":"2012","unstructured":"Wu RC, Hwu P, Radvanyi LG (2012) New insights on the role of CD8(+)CD57(+) T-cells in cancer. Oncoimmunology 1:954\u2013956","journal-title":"Oncoimmunology"},{"key":"6993_CR18","doi-asserted-by":"publisher","first-page":"2711","DOI":"10.1182\/blood-2002-07-2103","volume":"101","author":"JM Brenchley","year":"2003","unstructured":"Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE et al (2003) Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101:2711\u20132720","journal-title":"Blood"},{"key":"6993_CR19","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1111\/j.1365-2567.2011.03470.x","volume":"134","author":"M Strioga","year":"2011","unstructured":"Strioga M, Pasukoniene V, Characiejus D (2011) CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease. Immunology 134:17\u201332","journal-title":"Immunology"},{"key":"6993_CR20","first-page":"107","volume":"29","author":"L Shiqi","year":"2023","unstructured":"Shiqi L, Jiasi Z, Lvzhe C, Huailong X, Liping H, Lin L et al (2023) Durable remission related to CAR-T persistence in R\/R B-ALL and long-term persistence potential of prime CAR-T. Mol Ther 29:107\u2013117","journal-title":"Mol Ther"},{"key":"6993_CR21","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.coi.2007.04.005","volume":"19","author":"B Stockinger","year":"2007","unstructured":"Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19:281\u2013286","journal-title":"Curr Opin Immunol"},{"key":"6993_CR22","doi-asserted-by":"publisher","first-page":"4733","DOI":"10.4049\/jimmunol.181.7.4733","volume":"181","author":"I Kryczek","year":"2008","unstructured":"Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L et al (2008) Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J Immunol 181:4733\u20134741","journal-title":"J Immunol"},{"key":"6993_CR23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00630","volume":"5","author":"J Geginat","year":"2014","unstructured":"Geginat J, Paroni M, Maglie S, Alfen JS, Kastirr I, Gruarin P et al (2014) Plasticity of human CD4 T cell subsets. Front Immunol 5:630","journal-title":"Front Immunol"},{"key":"6993_CR24","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1146\/annurev-immunol-051116-052350","volume":"35","author":"T Nakayama","year":"2017","unstructured":"Nakayama T, Hirahara K, Onodera A, Endo Y, Hosokawa H, Shinoda K et al (2017) Th2 cells in health and disease. Annu Rev Immunol 35:53\u201384","journal-title":"Annu Rev Immunol"},{"key":"6993_CR25","doi-asserted-by":"publisher","first-page":"7740","DOI":"10.1111\/febs.16192","volume":"289","author":"I Skulimowska","year":"2022","unstructured":"Skulimowska I, Sosniak J, Gonka M, Szade A, Jozkowicz A, Szade K (2022) The biology of hematopoietic stem cells and its clinical implications. FEBS J 289:7740\u20137759","journal-title":"FEBS J"},{"key":"6993_CR26","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023012522","author":"ML Palacios-Berraquero","year":"2024","unstructured":"Palacios-Berraquero ML, Rodriguez-Marquez P, Calleja-Cervantes ME, Berastegui N, Zabaleta A, Burgos L et al (2024) Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in multiple myeloma. Blood Adv. https:\/\/doi.org\/10.1182\/bloodadvances.2023012522","journal-title":"Blood Adv"}],"container-title":["Annals of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-06993-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00277-026-06993-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-06993-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T21:59:31Z","timestamp":1781647171000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00277-026-06993-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["6993"],"URL":"https:\/\/doi.org\/10.1007\/s00277-026-06993-3","relation":{},"ISSN":["1432-0584"],"issn-type":[{"value":"1432-0584","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]},"assertion":[{"value":"15 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Rambam Health Care Campus Institutional Review Board (IRB) (Helsinki Committee; approval number 0491\u201322-RMB) and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"IRB approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"243"}}