{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:20:21Z","timestamp":1792120821693,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chimeric antigen receptor (CAR) T-cell infusion has led to improved outcomes in patients with B-lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma. The spectrum of post-CAR T-cell hematolymphoid abnormalities is expanding, although they remain under-recognized. Pathologists play a key role in characterizing hematolymphoid proliferation after CAR T-cell therapy. This review presents clinical and pathologic findings of common hematolymphoid proliferation after CAR T-cell therapy, illustrated by selected cases. A review of the literature is presented in the context of individual cases, and our current understanding of the pathomechanism is discussed. Infused CAR T-cells undergo a series of four phases: distribution, expansion, contraction, and persistence. In the expansion phase, transient peripheral blood lymphocytosis occurs, reaching a peak two weeks post-infusion. Delayed contraction of CAR T-cells may give rise to hemophagocytic lymphohistiocytosis-like syndrome. Immune effector cell-associated enterocolitis presents in the persistence phase, about 3\u20136 months after infusion. Pathologic findings include a T-cell infiltrate in the intestinal mucosa and changes resembling graft versus host disease (GVHD). This entity requires differentiation from infections and from T-cell neoplasms, including those derived from CAR T-cells. Secondary myeloid malignancies follow the same pathways as therapy-related myeloid neoplasm but present with a shorter median latency. It is essential for pathologists to recognize post-CAR T-cell hematolymphoid proliferation to support clinical decision making in a high-risk patient population.<\/jats:p>","DOI":"10.3390\/ijms26178388","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T08:01:01Z","timestamp":1756454461000},"page":"8388","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Lymphoid and Myeloid Proliferations After Chimeric Antigen Receptor (CAR) T-Cell Therapy: The Pathologist\u2019s Perspective"],"prefix":"10.3390","volume":"26","author":[{"given":"Jiehao","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"Kelemen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.2174\/0113892010257212231001082741","article-title":"FDA-approved CAR T-cell Therapy: A Decade of Progress and Challenges","volume":"25","author":"Ong","year":"2024","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1182\/blood.2022015728","article-title":"Long-term follow-up for the development of subsequent malignancies in patients treated with genetically modified IECs","volume":"140","author":"Steffin","year":"2022","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/978-1-4939-6703-2_24","article-title":"Cytogenetic Nomenclature and Reporting","volume":"1541","author":"Simons","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3859","DOI":"10.1182\/bloodadvances.2023012470","article-title":"Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma","volume":"8","author":"Pan","year":"2024","journal-title":"Blood Adv."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1182\/bloodadvances.2020004038","article-title":"Absolute lymphocyte count proliferation kinetics after CAR T-cell infusion impact response and relapse","volume":"5","author":"Faude","year":"2021","journal-title":"Blood Adv."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Santurio, D.S., Barros, L.R.C., Glauche, I., and Fassoni, A.C. (2025). Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome. PLoS Comput. Biol., 21.","DOI":"10.1371\/journal.pcbi.1012908"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.pathol.2021.02.002","article-title":"CAR-T cell therapy: Practical guide to routine laboratory monitoring","volume":"53","author":"Selim","year":"2021","journal-title":"Pathology"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Paixao, E.A., Barros, L.R.C., Fassoni, A.C., and Almeida, R.C. (2022). Modeling Patient-Specific CAR-T Cell Dynamics: Multiphasic Kinetics via Phenotypic Differentiation. Cancers, 14.","DOI":"10.20944\/preprints202209.0359.v1"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/cpt.2040","article-title":"Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells in Humans","volume":"109","author":"Liu","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wittibschlager, V., Bacher, U., Seipel, K., Porret, N., Wiedemann, G., Haslebacher, C., Hoffmann, M., Daskalakis, M., Akhoundova, D., and Pabst, T. (2023). CAR T-Cell Persistence Correlates with Improved Outcome in Patients with B-Cell Lymphoma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065688"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4577","DOI":"10.1182\/blood-2011-06-356261","article-title":"Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: Long-term results of the HLH-94 treatment protocol","volume":"118","author":"Trottestam","year":"2011","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1182\/blood.2019000936","article-title":"Pediatric hemophagocytic lymphohistiocytosis","volume":"135","author":"Canna","year":"2020","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/pbc.21039","article-title":"HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis","volume":"48","author":"Henter","year":"2007","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5344","DOI":"10.1182\/bloodadvances.2021005020","article-title":"Macrophage activation syndrome-like (MAS-L) manifestations following BCMA-directed CAR T cells in multiple myeloma","volume":"5","author":"Kennedy","year":"2021","journal-title":"Blood Adv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1182\/blood.2021011898","article-title":"Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells","volume":"138","author":"Lichtenstein","year":"2021","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1111\/bjh.17662","article-title":"Hemophagocytic lymphohistiocytosis-like toxicity (carHLH) after CD19-specific CAR T-cell therapy","volume":"194","author":"Hines","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1111\/bjh.18454","article-title":"Hyperinflammatory syndrome resembling haemophagocytic lymphohistiocytosis following axicabtagene ciloleucel and brexucabtagene autoleucel","volume":"199","author":"Porter","year":"2022","journal-title":"Br. J. Haematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1111\/bjh.16155","article-title":"Haemophagocytic lymphohistiocytosis has variable time to onset following CD19 chimeric antigen receptor T cell therapy","volume":"187","author":"Hashmi","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.bbmt.2018.12.758","article-title":"ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells","volume":"25","author":"Lee","year":"2019","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"438.e1","DOI":"10.1016\/j.jtct.2023.03.006","article-title":"Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome","volume":"29","author":"Hines","year":"2023","journal-title":"Transplant. Cell Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1182\/blood.2019003664","article-title":"Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect","volume":"136","author":"Carvelli","year":"2020","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1097\/COC.0000000000000596","article-title":"Gastrointestinal Adverse Events Observed After Chimeric Antigen Receptor T-Cell Therapy","volume":"42","author":"Tang","year":"2019","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/s41408-024-01167-8","article-title":"Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma","volume":"14","author":"Fortuna","year":"2024","journal-title":"Blood Cancer J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/ibd\/izaa320","article-title":"Colitis After CAR T-Cell Therapy for Refractory Large B-Cell Lymphoma Responds to Anti-Integrin Therapy","volume":"27","author":"Hashim","year":"2021","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zundler, S., Vitali, F., Kharboutli, S., Volkl, S., Polifka, I., Mackensen, A., Atreya, R., Neurath, M.F., and Mougiakakos, D. (2023). Case Report: IBD-like colitis following CAR T cell therapy for diffuse large B cell lymphoma. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1149450"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S234","DOI":"10.1016\/j.jtct.2025.01.357","article-title":"Risk Factors for Immune Effector Cell-Associated Enterocolitis (IEC-colitis) in Patients with Relapsed Myeloma Treated with Ciltacabtagene Autoleucel (cilta-cel)","volume":"31","author":"Lim","year":"2025","journal-title":"Transplant. Cell. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1056\/NEJMoa2401530","article-title":"Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy","volume":"390","author":"Ozdemirli","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1182\/blood.2024024166","article-title":"Second primary malignancies after commercial CAR T-cell therapy: Analysis of the FDA Adverse Events Reporting System","volume":"143","author":"Elsallab","year":"2024","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/s41591-024-03458-w","article-title":"T cell malignancies after CAR T cell therapy in the DESCAR-T registry","volume":"31","author":"Dulery","year":"2025","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4690","DOI":"10.1158\/1078-0432.CCR-24-1798","article-title":"Second Primary Malignancies after CAR T-Cell Therapy: A Systematic Review and Meta-analysis of 5517 Lymphoma and Myeloma Patients","volume":"30","author":"Tix","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1056\/NEJMoa2401361","article-title":"Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy","volume":"390","author":"Hamilton","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/s41591-024-02826-w","article-title":"T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy","volume":"30","author":"Ghilardi","year":"2024","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1182\/blood.2021010858","article-title":"Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells","volume":"138","author":"Micklethwaite","year":"2021","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1056\/NEJMoa2402730","article-title":"Aggressive Lymphoma after CD19 CAR T-Cell Therapy","volume":"391","author":"Kobbe","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41591-023-02767-w","article-title":"Unanswered questions following reports of secondary malignancies after CAR-T cell therapy","volume":"30","author":"Levine","year":"2024","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1056\/NEJMoa2309728","article-title":"CAR+ T-Cell Lymphoma after Cilta-cel Therapy for Relapsed or Refractory Myeloma","volume":"392","author":"Harrison","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S1470-2045(18)30864-7","article-title":"Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial","volume":"20","author":"Locke","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1056\/NEJMoa1804980","article-title":"Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma","volume":"380","author":"Schuster","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bbmt.2019.08.003","article-title":"Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells","volume":"26","author":"Cordeiro","year":"2020","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_40","unstructured":"Board TWCoTE (2024). Haematolymphoid Tumours Part A. Myeloid Neoplasm Post Cytotoxic Therapy, International Agency for Research on Cancer (IARC)."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"290","DOI":"10.3324\/haematol.2022.281351","article-title":"Acute myeloid leukemia development soon after anti-CD19 chimeric antigen receptor T-cell infusion in a patient with refractory diffuse large B-cell lymphoma and pre-existing clonal hematopoiesis","volume":"108","author":"Falini","year":"2023","journal-title":"Haematologica"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Accorsi Buttini, E., Farina, M., Lorenzi, L., Polverelli, N., Radici, V., Morello, E., Colnaghi, F., Almici, C., Ferrari, E., and Bianchetti, A. (2023). High risk-myelodysplastic syndrome following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma: A case report and literature review. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1036455"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41408-022-00707-4","article-title":"Therapy-related myeloid neoplasms following chimeric antigen receptor T-cell therapy for Non-Hodgkin Lymphoma","volume":"12","author":"Alkhateeb","year":"2022","journal-title":"Blood Cancer J."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Vainstein, V., Avni, B., Grisariu, S., Kfir-Erenfeld, S., Asherie, N., Nachmias, B., Auman, S., Saban, R., Zimran, E., and Assayag, M. (2023). Clonal Myeloid Dysplasia Following CAR T-Cell Therapy: Chicken or the Egg?. Cancers, 15.","DOI":"10.3390\/cancers15133471"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8388\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:34:55Z","timestamp":1760034895000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,28]]},"references-count":44,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178388"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178388","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,28]]}}}