Targeted therapy using BRAF/MEK inhibitor therapy is a mainstay of melanoma management in patients with early and late-stage disease. The toxicity profile is well defined with pyrexia being a commonly observed side effect. The underlying aetiology is unclear; elevated levels of proinflammatory cytokines in the serum of treated patients, however, suggest activation of the monocyte/ macrophage system.
Hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder that is mediated by aberrantly activated macrophages and characterized by cytopenia and excessive cytokine production. Next to a primary genetic form, HLH can by triggered by various causes, including infections, cancer, and drugs.
We report on a 42-year-old patient with resected stage IIID BRAF V600E-mutant melanoma who developed HLH shortly after commencing adjuvant treatment with Dabrafenib and Trametinib.
The patient presented to our emergency department with fever, headache and skin rash; Dabrafenib and Trametinib were ceased on arrival and laboratory tests demonstrated thrombocytopenia and lymphopenia. Septic workup and imaging were uninformative. Shortly after admission, the patient’s condition deteriorated rapidly with the patient developing multiorgan failure requiring inotropic support and intubation in the intensive care.
A diagnosis of HLH was made based on fever > 38.5oC, bicytopenias, splenomegaly, markedly elevated ferritin levels >100,000 ng/ml and hypofibrinogenemia. A bone marrow aspirate demonstrated an increased number of histocytes. Other acquired causes of HLH as viral infections and autoimmune disorders were excluded, and treatment with methylprednisolone and tocilizumab was initiated, leading to a rapid clinical response.
This case is the third reported patient developing HLH under BRAF/MEK inhibitor therapy. HLH should be recognised as a rare side effect of this treatment modality and may represent an extreme manifestation of commonly recognized pyrexia with these agents. Ongoing translational research aims to further elicit the mechanisms of pyrexia and HLH associated with BRAF/MEK inhibitor therapy.