{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:37:59Z","timestamp":1781649479608,"version":"3.54.5"},"reference-count":33,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Combined immune checkpoint inhibition (ICI) and multitargeted tyrosine kinase inhibition (TKI) improve outcomes in advanced melanoma, especially in heavily pretreated patients, but introduce complex, overlapping toxicities. Although immune-related adverse events and TKI-specific toxicities are well characterized individually, their concurrent presentation is uncommon and can obscure diagnosis. Capillary leak syndrome (CLS), a rare but potentially life-threatening complication of ICIs, further complicates recognition due to nonspecific features and variable onset. A 43-year-old woman with metastatic BRAF wild-type melanoma, in complete metabolic response on lenvatinib and pembrolizumab, presented with generalized edema, hypotension, thrombocytopenia, and marked erythroblastosis. Extensive evaluation, including bone marrow analysis, excluded malignancy, infection, and autoimmune disease, but revealed multilineage dysplasia with pronounced erythroid stress. Imaging confirmed sustained remission with pleural effusions and ascites. Dual toxicity was suspected: lenvatinib-related hematologic toxicity and pembrolizumab-associated CLS. Both agents were discontinued, and corticosteroids followed by IVIG for steroid-refractory edema led to gradual recovery. This case underscores the diagnostic challenge of overlapping ICI\u2013TKI toxicities. Mechanistically, VEGF pathway inhibition may disrupt marrow endothelial integrity and hematopoietic homeostasis, promoting cytopenias and erythroid precursor release, while immune activation drives cytokine-mediated endothelial dysfunction and vascular hyperpermeability. Early recognition and prompt immunomodulatory management are critical to improving outcomes.<\/jats:p>","DOI":"10.3390\/curroncol33050268","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:03:37Z","timestamp":1778144617000},"page":"268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Overlapping Toxicities of Pembrolizumab and Lenvatinib: A Case of Capillary Leak Syndrome with Severe Erythroblastosis"],"prefix":"10.3390","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5644-8208","authenticated-orcid":false,"given":"Aikaterini","family":"Gkoufa","sequence":"first","affiliation":[{"name":"First Department of Internal Medicine, Laiko General Hospital, National & Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iraklis","family":"Patsialos","sequence":"additional","affiliation":[{"name":"Hematology Unit, First Department of Internal Medicine, Laiko General Hospital, National & Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Stafylidis","sequence":"additional","affiliation":[{"name":"Hematology Unit, First Department of Internal Medicine, Laiko General Hospital, National & Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalia","family":"Anastasopoulou","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, Laiko General Hospital, National & Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitra","family":"Adamou","sequence":"additional","affiliation":[{"name":"Hematology Laboratory, Laiko General Hospital, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Gogas","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, Laiko General Hospital, National & Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis T.","family":"Diamantopoulos","sequence":"additional","affiliation":[{"name":"Hematology Unit, First Department of Internal Medicine, Laiko General Hospital, National & Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lyrarakis, G., Liontos, M., Anastasopoulou, A., Bouros, S., Gkoufa, A., Diamantopoulos, P., Gogas, H., and Ziogas, D.C. (2024). Immunotherapy after progression to double immunotherapy: Pembrolizumab and lenvatinib versus conventional chemotherapy for patients with metastatic melanoma after failure of PD-1\/CTLA-4 inhibition. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1420879"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Wang, S.J., Sun, L., Shih, Y.H., Lu, T.F., Chen, Y.F., Hsu, S.T., Liu, C.K., Hwang, S.F., Chen, J.K., and Chen, H.H. (2025). Lenvatinib plus pembrolizumab compared to carboplatin plus paclitaxel for carboplatin and paclitaxel pretreated, recurrent, or advanced endometrial cancer. BMC Med., 23.","DOI":"10.1186\/s12916-025-03989-0"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"44545","DOI":"10.18632\/oncotarget.10019","article-title":"Safety and efficacy profile of lenvatinib in cancer therapy: A systematic review and meta-analysis","volume":"7","author":"Zhu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ygyno.2023.09.010","article-title":"Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer","volume":"178","author":"Zammarrelli","year":"2023","journal-title":"Gynecol. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e002896","DOI":"10.1136\/jitc-2021-002896","article-title":"Immune-related adverse events associated with immune checkpoint inhibitors: A call to action for collecting and sharing clinical trial and real-world data","volume":"9","author":"Reynolds","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"507","DOI":"10.7326\/0003-4819-77-4-507","article-title":"Pleural effusions: The diagnostic separation of transudates and exudates","volume":"77","author":"Light","year":"1972","journal-title":"Ann. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3847","DOI":"10.2147\/CMAR.S188316","article-title":"Lenvatinib, a molecule with versatile application: From preclinical evidence to future development in anti-cancer treatment","volume":"11","author":"Capozzi","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1182\/blood.2020005699","article-title":"VEGF-C protects the integrity of the bone marrow perivascular niche in mice","volume":"136","author":"Fang","year":"2020","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.stem.2009.01.006","article-title":"Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells","volume":"4","author":"Hooper","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1056\/NEJMoa1406470","article-title":"Lenvatinib versus placebo in radioiodine-refractory thyroid cancer","volume":"372","author":"Schlumberger","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial","volume":"391","author":"Kudo","year":"2018","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40425-017-0210-0","article-title":"Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy","volume":"5","author":"Shiuan","year":"2017","journal-title":"J. Immunother. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.kint.2016.11.029","article-title":"Capillary leak syndrome: Etiologies, pathophysiology, and management","volume":"92","author":"Siddall","year":"2017","journal-title":"Kidney Int."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Enokida, T., and Tahara, M. (2021). Management of VEGFR-Targeted TKI for Thyroid Cancer. Cancers, 13.","DOI":"10.3390\/cancers13215536"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1006\/meth.1998.0735","article-title":"Regulation of megakaryocytopoiesis and platelet production by tyrosine kinases and tyrosine phosphatases","volume":"17","author":"Avraham","year":"1999","journal-title":"Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.revmed.2021.05.012","article-title":"Capillary leak syndrome: State of the art in 2021","volume":"42","author":"Bichon","year":"2021","journal-title":"Rev. Med. Interne"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9815","DOI":"10.1073\/pnas.96.17.9815","article-title":"Vascular endothelial\u2013cadherin is an important determinant of microvascular integrity in vivo","volume":"96","author":"Corada","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1083\/jcb.201108120","article-title":"Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling","volume":"196","author":"Huveneers","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00018-025-05753-2","article-title":"Distinct VE-cadherin serine and tyrosine phosphorylation sites and their role for inflammation-induced vascular permeability in vivo","volume":"82","author":"Holtermann","year":"2025","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/joim.13641","article-title":"Immune checkpoint inhibitor-associated capillary leak syndrome: A systematic review and a worldwide pharmacovigilance study","volume":"294","author":"Bouibede","year":"2023","journal-title":"J. Intern. Med."},{"key":"ref_21","first-page":"e55719","article-title":"Checkpoint Inhibitor-Related Capillary Leak Syndrome (CLS)","volume":"16","author":"Raja","year":"2024","journal-title":"Cureus"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"189536","DOI":"10.1016\/j.bbcan.2026.189536","article-title":"Precision cytokine modulation to overcome tumor microenvironment-driven resistance to immune checkpoint blockade","volume":"1881","author":"Wang","year":"2026","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Neuville, C., Aubin, F., Puzenat, E., Popescu, D., Crepin, T., and Nardin, C. (2022). Nivolumab-induced capillary leak syndrome associated with chylothorax in a melanoma patient: A case report and review of the literature. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1032844"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"807","DOI":"10.2217\/imt-2020-0335","article-title":"Nivolumab-induced systemic capillary leak syndrome as an ultra rare life-threatening phenomenon of late toxicity and intravenous immunoglobulin efficacy","volume":"13","author":"Polishchuk","year":"2021","journal-title":"Immunotherapy"},{"key":"ref_25","first-page":"e95038","article-title":"Pembrolizumab-Induced Capillary Leak Syndrome: A Rare but Life-Threatening Immune-Related Adverse Event","volume":"17","author":"Branford","year":"2025","journal-title":"Cureus"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Anastasopoulou, A., Gkoufa, A., Kouzis, P., Kyriakakis, G., Belivanis, M., Sypsa, G., Bouros, S., Gogas, H., and Diamantopoulos, P.T. (2025). Rhinosinusitis as an Immune-Related Adverse Event: Clinical Characteristics, Management, and Prognostic Implications in Metastatic Melanoma Patients. Cancers, 17.","DOI":"10.3390\/cancers17142297"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e70679","DOI":"10.1002\/cam4.70679","article-title":"Exploring the Dynamics of Immune Checkpoint Inhibitor-Induced Eosinophilia in Advanced\/Metastatic Melanoma: A Comprehensive Retrospective Analysis","volume":"14","author":"Diamantopoulos","year":"2025","journal-title":"Cancer Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1611330","DOI":"10.3389\/pore.2023.1611330","article-title":"Case report: Clinical experience of treating pembrolizumab-induced systemic capillary leak syndrome (SCLS) in one patient with metastatic gastroesophageal junction squamous cell carcinoma","volume":"29","author":"Ni","year":"2023","journal-title":"Pathol. Oncol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Roberge-Maltais, E., L\u00e9vesque, E., Castonguay, V., Marcoux, N., Grenier, L.P., and Veilleux, M. (2025). Pembrolizumab-Induced Simultaneous and Refractory Systemic Capillary Leak and Cytokine Release Syndromes: A Case Report. Curr. Oncol., 32.","DOI":"10.3390\/curroncol32080469"},{"key":"ref_30","unstructured":"(2026, March 02). Available online: https:\/\/dctd.cancer.gov\/research\/ctep-trials\/for-sites\/adverse-events\/ctcae-v5-5x7.pdf."},{"key":"ref_31","unstructured":"(2026, March 02). Available online: https:\/\/www.nccn.org\/guidelines\/guidelines-detail?category=3&id=1486."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.mayocpiqo.2021.01.004","article-title":"Successful Treatment of Pembrolizumab-Induced Severe Capillary Leak Syndrome and Lymphatic Capillary Dysfunction","volume":"5","author":"Qin","year":"2021","journal-title":"Mayo Clin. Proc. Innov. Qual. Outcomes"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.1016\/j.jtho.2019.02.003","article-title":"Systemic capillary leak syndrome (Clarkson\u2019s disease) as a complication of anti-programmed death 1 immunotherapy","volume":"14","author":"Lescure","year":"2019","journal-title":"J. Thorac. Oncol."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/5\/268\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T04:12:37Z","timestamp":1778818357000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/5\/268"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,6]]},"references-count":33,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["curroncol33050268"],"URL":"https:\/\/doi.org\/10.3390\/curroncol33050268","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,6]]}}}