{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:51:26Z","timestamp":1789480286599,"version":"build-2803163510"},"reference-count":12,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017559","name":"Recordati Rare Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017559","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia characterized by complement-mediated extravascular hemolysis. The introduction of complement inhibitors, particularly sutimlimab, has significantly improved disease control. However, a subset of patients remains refractory to treatment, particularly those with inadequate bone marrow compensatory response to hemolysis, as well as those rare cases with hypersplenism. We report the case of a woman with refractory CAD who received multiple lines of therapy, including rituximab, bendamustine, sutimlimab, and pegcetacoplan, with suboptimal or transient responses. The clinical course was complicated by progressive splenomegaly and worsening cytopenias consistent with hypersplenism. Splenectomy was eventually performed, followed by re-initiation of sutimlimab. This combined intervention led to marked hematologic improvement, with resolution of anemia and thrombocytopenia, and sustained clinical response. While current guidelines do not recommend splenectomy in CAD due to the hepatic predominance of hemolysis, this case underscores the potential role of the spleen as a modifier of treatment resistance in selected cases. We discuss emerging literature on hypersplenism-associated refractoriness and emphasizes the importance of individualized treatment strategies in the management of complex or refractory CAD phenotypes. Given the rarity of CAD complicated by hypersplenism, large prospective trials may be difficult to conduct. Collaborative multicenter registries and prospective observational studies may represent more feasible approaches to define clinical and molecular predictors of response and to guide personalized therapeutic strategies in challenging subsets.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1770676","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T05:27:07Z","timestamp":1774848427000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: Refractory cold agglutinin disease with hypersplenism: efficacy of splenectomy in a patient treated with sutimlimab"],"prefix":"10.3389","volume":"17","author":[{"given":"Antonella","family":"Sau","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Santo Spirito Hospital","place":["Pescara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Onofrillo","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Santo Spirito Hospital","place":["Pescara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Caterina","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Santo Spirito Hospital","place":["Pescara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Di Prinzio","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Santo Spirito Hospital","place":["Pescara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Quaglietta","sequence":"additional","affiliation":[{"name":"Center of Transfusion Medicine, Santo Spirito Hospital","place":["Pescara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Di Ianni","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Santo Spirito Hospital","place":["Pescara, Italy"]},{"name":"Department of Medicine and Sciences of Aging, G. D\u2019Annunzio University of Chieti and Pescara","place":["Chieti, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Fattizzo","sequence":"additional","affiliation":[{"name":"Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca\u2019 Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]},{"name":"Department of Oncology and Haemato-oncology, University of Milan","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003809","article-title":"How I treat cold agglutinin disease","volume":"137","author":"Berentsen","year":"2021","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1228142","article-title":"Severe autoimmune hemolytic anemia; epidemiology, clinical management, outcomes and knowledge gaps","volume":"14","author":"Mulder","year":"2023","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.hemonc.2020.06.005","article-title":"Cold agglutinin disease and autoimmune hemolytic anemia with pulmonary embolism as a presentation of COVID-19 infection","volume":"15","author":"Patil","year":"2022","journal-title":"Hematol Oncol Stem Cell Ther"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25084296","article-title":"Autoimmune hemolytic anemias: classifications, pathophysiology, diagnoses and management","volume":"25","author":"Loriamini","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.6004\/jadpro.2024.15.6.4","article-title":"Sutimlimab for cold agglutinin disease","volume":"15","author":"Reid","year":"2024","journal-title":"J Adv Pract Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1159\/000540475","article-title":"Autoimmune hemolytic anemias: challenges in diagnosis and therapy","volume":"51","author":"Barcellini","year":"2024","journal-title":"Transfus Med Hemother"},{"key":"B7","article-title":"Successful management of refractory autoimmune hemolytic anemia with cold agglutinin disease with splenectomy: A case report with review of literature","volume":"68","author":"Okamoto","year":"2023","journal-title":"Kobe J Med Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.htct.2021.07.009","article-title":"Cold agglutinin syndrome secondary to splenic marginal zone lymphoma: a case report","volume":"45","author":"Portich","year":"2023","journal-title":"Hematol Transfus Cell Ther"},{"key":"B9","year":"2023"},{"key":"B10","volume-title":"EBMT handbook","year":"2024"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics13182891","article-title":"The role of the spleen and the place of splenectomy in autoimmune hemolytic anemia-A review of current knowledge","volume":"13","author":"Cvetkovi\u0107","year":"2023","journal-title":"Diagnostics (Basel)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1515\/med-2016-0068","article-title":"Efficacy and safety of splenectomy in adult autoimmune hemolytic anemia","volume":"11","author":"Giudice","year":"2016","journal-title":"Open Med (Wars)"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1770676\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T05:27:09Z","timestamp":1774848429000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1770676\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":12,"alternative-id":["10.3389\/fimmu.2026.1770676"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1770676","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]},"article-number":"1770676"}}