Overlapping Toxicities of Pembrolizumab and Lenvatinib: A Case of Capillary Leak Syndrome with Severe Erythroblastosis

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-TKI 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.