{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T01:57:25Z","timestamp":1789178245071,"version":"build-2803163510"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Med Case Reports"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hemophagocytic lymphohistiocytosis is rare and does not have any distinct clinical features or laboratory abnormalities, whereby a high index of suspicion is required for diagnosis. Hemophagocytic lymphohistiocytosis can be divided into primary\/genetic or secondary causes that can be immunotherapy-induced. With the increasing use of immune checkpoint inhibitors for treatment of multiple solid tumor malignancies, the incidence of rare complications such as hemophagocytic lymphohistiocytosis can be expected to rise.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>We describe a fatal case of immunosuppression-refractory pembrolizumab-induced hemophagocytic lymphohistiocytosis complicated by secondary disseminated fungal infection. A 75-year-old white Australian man with resected stage IIC melanoma who received four cycles of adjuvant pembrolizumab presented 11\u00a0weeks after commencement with febrile neutropenia, elevated C-reactive protein, and nonspecific symptoms. He developed progressive transaminitis, acute kidney injury, pancytopenia, hyperferritinemia, and hypofibrinogenemia. In addition, a bone marrow aspiration and trephine biopsy demonstrated hemophagocytosis. Treatment was commenced with high-dose corticosteroids and mycophenolate mofetil initially for suspected immune-related side effects, followed by tocilizumab and anakinra once a diagnosis of hemophagocytic lymphohistiocytosis was made. Unfortunately, his disease was refractory to treatment with development of multiorgan failure secondary to hemophagocytic lymphohistiocytosis, complicated by disseminated candidemia from prolonged immunosuppression, leading to death 26\u00a0days after admission.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This case underscores the diagnostic complexities of hemophagocytic lymphohistiocytosis, the importance of a multidisciplinary approach to management, and the fatal side effects of extended immunosuppression. This also highlights the importance of the discussion of risks versus benefits of treatment, particularly in the adjuvant setting, emphasizing the rare but real risk of fatal toxicities. Prolonged immunosuppression can lead to severe complications, and judicious use of corticosteroids with intensive prophylaxis is crucial. Further research into the mechanism of checkpoint inhibitor-induced toxicities is critical in the era of immunotherapy to allow personalized immunosuppressive and steroid-sparing strategies in complex cases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13256-025-05302-2","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T11:05:05Z","timestamp":1761217505000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Treatment-refractory immune checkpoint inhibitor-induced hemophagocytic lymphohistiocytosis in the setting of adjuvant pembrolizumab for resected stage IIC melanoma: a case report"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8726-4428","authenticated-orcid":false,"given":"Kar Ven Cavan","family":"Chow","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley","family":"Mui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stewart","family":"Hunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun Loo","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"issue":"1","key":"5302_CR1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1146\/annurev-pathol-020117-043625","volume":"13","author":"H Al-Samkari","year":"2018","unstructured":"Al-Samkari H, Berliner N. Hemophagocytic lymphohistiocytosis. Annu Rev Pathol. 2018;13(1):27\u201349.","journal-title":"Annu Rev Pathol"},{"key":"5302_CR2","volume-title":"Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis","year":"2014","unstructured":"Parikh SA, Kapoor P, Letendre L, Kumar S, Wolanskyj AP, editors. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Amsterdam: Elsevier; 2014."},{"issue":"1","key":"5302_CR3","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1532\/IJH97.07012","volume":"86","author":"E Ishii","year":"2007","unstructured":"Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, et\u00a0al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol. 2007;86(1):58\u201365.","journal-title":"Int J Hematol"},{"key":"5302_CR4","doi-asserted-by":"publisher","DOI":"10.1097\/COC.0000000000000239","author":"EI Buchbinder","year":"2016","unstructured":"Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016. https:\/\/doi.org\/10.1097\/COC.0000000000000239.","journal-title":"Am J Clin Oncol"},{"issue":"9","key":"5302_CR5","doi-asserted-by":"publisher","first-page":"2406","DOI":"10.1111\/1759-7714.13541","volume":"11","author":"P Song","year":"2020","unstructured":"Song P, Zhang D, Cui X, Zhang L. Meta-analysis of immune-related adverse events of immune checkpoint inhibitor therapy in cancer patients. Thoracic Cancer. 2020;11(9):2406\u201330.","journal-title":"Thoracic Cancer"},{"issue":"2","key":"5302_CR6","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1056\/NEJMra1703481","volume":"378","author":"MA Postow","year":"2018","unstructured":"Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158\u201368.","journal-title":"N Engl J Med"},{"issue":"24","key":"5302_CR7","doi-asserted-by":"publisher","first-page":"2719","DOI":"10.1200\/JCO.19.02362","volume":"38","author":"SN Lo","year":"2020","unstructured":"Lo SN, Ma J, Scolyer RA, Haydu LE, Stretch JR, Saw RPM, et\u00a0al. Improved risk prediction calculator for sentinel node positivity in patients with melanoma: the Melanoma Institute Australia nomogram. J Clin Oncol. 2020;38(24):2719\u201327.","journal-title":"J Clin Oncol"},{"issue":"2","key":"5302_CR8","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1111\/bjd.19895","volume":"185","author":"MA El Sharouni","year":"2021","unstructured":"El Sharouni MA, Varey AHR, Witkamp AJ, Ahmed T, Sigurdsson V, van Diest PJ, et\u00a0al. Predicting sentinel node positivity in patients with melanoma: external validation of a risk-prediction calculator (the Melanoma Institute Australia nomogram) using a large European population-based patient cohort*. Br J Dermatol. 2021;185(2):412\u20138.","journal-title":"Br J Dermatol"},{"issue":"5","key":"5302_CR9","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1111\/bjh.16630","volume":"189","author":"A Dupr\u00e9","year":"2020","unstructured":"Dupr\u00e9 A, Michot J-M, Schoeffler A, Frumholtz L, Baroudjian B, Delyon J, et\u00a0al. Haemophagocytic lymphohistiocytosis associated with immune checkpoint inhibitors: a descriptive case study and literature review. Br J Haematol. 2020;189(5):985\u201392.","journal-title":"Br J Haematol"},{"issue":"23","key":"5302_CR10","doi-asserted-by":"publisher","first-page":"2465","DOI":"10.1182\/blood.2018894618","volume":"133","author":"P La Ros\u00e9e","year":"2019","unstructured":"La Ros\u00e9e P, Horne A, Hines M, von Bahr GT, Machowicz R, Berliner N, et\u00a0al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465\u201377.","journal-title":"Blood"},{"issue":"17","key":"5302_CR11","doi-asserted-by":"publisher","first-page":"3229","DOI":"10.1002\/cncr.30826","volume":"123","author":"N Daver","year":"2017","unstructured":"Daver N, McClain K, Allen CE, Parikh SA, Otrock Z, Rojas-Hernandez C, et\u00a0al. A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer. 2017;123(17):3229\u201340.","journal-title":"Cancer"},{"issue":"12","key":"5302_CR12","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1016\/j.annonc.2020.08.2101","volume":"31","author":"BC \u00d6zdemir","year":"2020","unstructured":"\u00d6zdemir BC, Latifyan S, Perreau M, Fenwick C, Alberio L, Waeber G, et\u00a0al. Cytokine-directed therapy with tocilizumab for\u00a0immune checkpoint inhibitor-related hemophagocytic lymphohistiocytosis. Ann Oncol. 2020;31(12):1775\u20138.","journal-title":"Ann Oncol"},{"issue":"7655","key":"5302_CR13","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nature22396","volume":"545","author":"SR Gordon","year":"2017","unstructured":"Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, et\u00a0al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545(7655):495\u20139.","journal-title":"Nature"},{"issue":"2","key":"5302_CR14","doi-asserted-by":"publisher","first-page":"49","DOI":"10.14740\/wjon1464","volume":"13","author":"P Rajapakse","year":"2022","unstructured":"Rajapakse P, Andanamala H. Hemophagocytic lymphohistiocytosis secondary to immune checkpoint inhibitor therapy. World J Oncol. 2022;13(2):49.","journal-title":"World J Oncol"},{"issue":"1","key":"5302_CR15","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s40425-019-0598-9","volume":"7","author":"R Noseda","year":"2019","unstructured":"Noseda R, Bertoli R, M\u00fcller L, Ceschi A. Haemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: analysis of WHO global database of individual case safety reports. J Immunother Cancer. 2019;7(1):117.","journal-title":"J Immunother Cancer"},{"issue":"1","key":"5302_CR16","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s40425-018-0365-3","volume":"6","author":"M Sadaat","year":"2018","unstructured":"Sadaat M, Jang S. Hemophagocytic lymphohistiocytosis with immunotherapy: brief review and case report. J Immunother Cancer. 2018;6(1):49.","journal-title":"J Immunother Cancer"},{"issue":"4","key":"5302_CR17","doi-asserted-by":"publisher","first-page":"142","DOI":"10.14740\/jh1033","volume":"11","author":"R Marar","year":"2022","unstructured":"Marar R, Prathivadhi-Bhayankaram S, Krishnan M. Immune checkpoint inhibitor-induced hemophagocytic lymphohistiocytosis in a patient with squamous cell carcinoma. J Hematol. 2022;11(4):142.","journal-title":"J Hematol"},{"issue":"1","key":"5302_CR18","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1136\/jmedgenet-2018-105485","volume":"56","author":"A-S Hanny","year":"2019","unstructured":"Hanny A-S, Gregory DS, Sarah N, Sara MT, Rachel AF, Julie-Aurore L. Haemophagocytic lymphohistiocytosis complicating pembrolizumab treatment for metastatic breast cancer in a patient with the <em>PRF1A91V<\/em> gene polymorphism. J Med Genet. 2019;56(1):39.","journal-title":"J Med Genet"},{"issue":"2","key":"5302_CR19","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/pbc.21039","volume":"48","author":"J-I Henter","year":"2007","unstructured":"Henter J-I, Horne A, Aric\u00f3 M, Egeler RM, Filipovich AH, Imashuku S, et\u00a0al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124\u201331.","journal-title":"Pediatr Blood Cancer"},{"issue":"9","key":"5302_CR20","doi-asserted-by":"publisher","first-page":"2613","DOI":"10.1002\/art.38690","volume":"66","author":"L Fardet","year":"2014","unstructured":"Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et\u00a0al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthr Rheumatol. 2014;66(9):2613\u201320.","journal-title":"Arthr Rheumatol"},{"issue":"36","key":"5302_CR21","doi-asserted-by":"publisher","first-page":"4073","DOI":"10.1200\/JCO.21.01440","volume":"39","author":"BJ Schneider","year":"2021","unstructured":"Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et\u00a0al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073\u2013126.","journal-title":"J Clin Oncol"},{"issue":"12","key":"5302_CR22","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.annonc.2022.10.001","volume":"33","author":"J Haanen","year":"2022","unstructured":"Haanen J, Obeid M, Spain L, Carbonnel F, Wang Y, Robert C, et\u00a0al. Management of toxicities from immunotherapy: ESMO clinical practice guideline for diagnosis, treatment and follow-up<sup>\u2606<\/sup>. Ann Oncol. 2022;33(12):1217\u201338.","journal-title":"Ann Oncol"},{"issue":"1","key":"5302_CR23","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nrclinonc.2017.148","volume":"15","author":"SS Neelapu","year":"2018","unstructured":"Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et\u00a0al. Chimeric antigen receptor T-cell therapy\u2014Assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47\u201362.","journal-title":"Nat Rev Clin Oncol"},{"issue":"9","key":"5302_CR24","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1177\/0885066617711386","volume":"34","author":"P Wohlfarth","year":"2019","unstructured":"Wohlfarth P, Agis H, Gualdoni GA, Weber J, Staudinger T, Schellongowski P, Robak O. Interleukin 1 receptor antagonist anakinra, intravenous immunoglobulin, and corticosteroids in the management of critically ill adult patients with hemophagocytic lymphohistiocytosis. J Intensive Care Med. 2019;34(9):723\u201331.","journal-title":"J Intensive Care Med"},{"issue":"2","key":"5302_CR25","doi-asserted-by":"publisher","first-page":"284","DOI":"10.3109\/s10165-011-0491-y","volume":"22","author":"H Watanabe","year":"2012","unstructured":"Watanabe H, Hirase N, Goda H, Nishikawa H, Ikuyama S. Oral low-dose tacrolimus therapy for refractory hemophagocytic syndrome associated with systemic lupus erythematosus. Mod Rheumatol. 2012;22(2):284\u20139.","journal-title":"Mod Rheumatol"},{"key":"5302_CR26","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/4159727","author":"T Nawata","year":"2017","unstructured":"Nawata T, Kubo M, Shiragami K, Nakamura Y, Yano M. Successful treatment of hemophagocytic lymphohistiocytosis associated with lupus nephritis by using mycophenolate mofetil. Case Rep Rheumatol. 2017. https:\/\/doi.org\/10.1155\/2017\/4159727.","journal-title":"Case Rep Rheumatol"},{"issue":"2","key":"5302_CR27","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.jiac.2023.09.026","volume":"30","author":"S Higuchi","year":"2024","unstructured":"Higuchi S, Lee S, Fujita K, Hara T, Tsurumi H. Filgrastim-induced hemophagocytic lymphohistiocytosis in a patient with mantle cell lymphoma: a case report. J Infect Chemother. 2024;30(2):150\u20133.","journal-title":"J Infect Chemother"}],"container-title":["Journal of Medical Case Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13256-025-05302-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13256-025-05302-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13256-025-05302-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T11:05:06Z","timestamp":1761217506000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmedicalcasereports.biomedcentral.com\/articles\/10.1186\/s13256-025-05302-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,23]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["5302"],"URL":"https:\/\/doi.org\/10.1186\/s13256-025-05302-2","relation":{},"ISSN":["1752-1947"],"issn-type":[{"value":"1752-1947","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,23]]},"assertion":[{"value":"30 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent was obtained from the patient\u2019s next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"535"}}