Regorafenib-Triggered Hemophagocytic Lymphohistiocytosis: A Report of Two Cases.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal condition, characterized by overactivation of the immune system. It can manifest as primary or secondary when triggered by infections, neoplasms, or medications. We report here two cases of regorafenib-induced HLH, one of which was life-threatening. The first patient was a 67-year-old woman with metastatic triple-negative breast cancer; the second patient was a 64-year-old woman with metastatic colon cancer. Both patients were included in the REGOMUNE clinical trial, a phase I/II trial evaluating the combination of regorafenib with avelumab. In this trial, the first administration of avelumab occurred on the 15th day of the cycle. Both patients developed a febrile rash: on the 10th day of regorafenib treatment for the first patient and on the 12th day for the second. Elevated levels of ferritin, C-reactive protein, and thrombocytopenia were observed in both cases. Bone marrow aspiration revealed hemophagocytosis, leading to the diagnosis of HLH for the two patients. The second patient had a more severe form with rapid hemodynamic deterioration, requiring transfer to the intensive care unit. The outcome was favorable in both cases after the definitive discontinuation of regorafenib and initiation of corticosteroid therapy. HLH is a rare adverse effect of regorafenib that can be life-threatening. Therefore, clinicians should promptly consider this diagnosis when encountering manifestations consistent with HLH to ensure timely and appropriate management.