Hemophagocytic lymphohistiocytosis associated with dabrafenib and trametinib combination therapy following pembrolizumab administration for advanced melanoma
Authors: K. Sasaki, J. Uehara, S. Iinuma, H. Doi, M. Honma, Y. Toki, A. Ishida-Yamamoto
Journal: Annals of Oncology (2018)

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by fever, skin rashes, cytopenia, and the presence of hemophagocytosis in bone marrow. We report a case of HLH that developed during dabrafenib and trametinib combination therapy following pembrolizumab administration for advanced melanoma. A 60-year-old Japanese woman presented with a black nodule on the right postauricular area. Radical resection and sentinel node biopsy established the diagnosis of malignant melanoma (pT3aN0M0 stage IIA). Nineteen months after the surgery, right jugular lymph node and lung metastases were detected using computed tomography. Despite administering five courses of pembrolizumab (2 mg/kg every 3 weeks), metastatic lesions enlarged. Evaluation after seven courses of pembrolizumab treatment revealed further lung metastasis and development of new liver metastasis. As the tumor harbored the BRAF V600E mutation, we initiated dabrafenib (300 mg/day) and trametinib (2 mg/day) combination therapy 1 month after the last pembrolizumab administration. Thirteen days later, the patient developed fever, hepatosplenomegaly, and erythema multiforme-like targetoid lesions all over the body (Figure 1A and B). Laboratory test results revealed pancytopenia, hyperferritinemia, increased liver enzyme levels, and coagulation abnormalities. Bone marrow smears showed increased macrophages and hemophagocytosis (Figure 1C); therefore, she was diagnosed with HLH. Dabrafenib and trametinib were discontinued and prednisolone (30 mg/day; 0.5 mg/kg/day) was initiated. Prednisolone alleviated fever, skin rashes, and the abnormal laboratory findings; thus, it was tapered to 10 mg/day within 5 weeks. Sixteen days after discontinuation, dabrafenib and trametinib were rechallenged at lower doses (100 and 1 mg/day, respectively) and gradually increased to the initial dose over 4 months without any adverse events. Partial remission was observed for 5 months after the reinitiation of dabrafenib and trametinib therapy. HLH is caused by uncontrolled activation of macrophages, NK cells, and cytotoxic lymphocytes (CTLs), leading to excessive cytokine production ('cytokine storm'). While common triggers of adult HLH include viral infections and hematologic malignancies, its association with drug exposure is less clear [1.Ramos-Casals M. Brito-Zerón P. López-Guillermo A. et al.Adult haemophagocytic syndrome.Lancet. 2014; 383: 1503-1516Abstract Full Text Full Text PDF PubMed Scopus (735) Google Scholar]. To our knowledge, this is the first report describing HLH associated with dabrafenib and trametinib combination therapy following pembrolizumab. Although the detailed mechanism via which HLH develops during dabrafenib and trametinib therapy is unclear, the pathogenesis might involve macrophage and CTL activation. The antitumor effects of BRAF inhibitors are mediated by inhibiting MAPK signaling and increasing the antigenicity of melanoma cells [2.Boni A. Cogdill A.P. Dang P. et al.Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.Cancer Res. 2010; 70: 5213-5219Crossref PubMed Scopus (601) Google Scholar]. Indeed, CTL infiltration in tumor samples and serum levels of IFN-γ, CCL4, and tumour necrosis factor-α were increased in BRAF inhibitor-treated patients [3.Wilmott J.S. Haydu L.E. Menzies A.M. et al.Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment.J Immunol. 2014; 192: 2505-2513Crossref PubMed Scopus (56) Google Scholar]. Furthermore, pretreatment using anti-programmed cell death 1 (PD-1) agents might enhance the immunostimulatory effects of BRAF inhibitors and contribute to HLH development. Elevated serum cytokine levels, which suggest macrophage activation, were reported with dabrafenib and trametinib therapy following anti-PD-1 therapy [4.Umemura H. Yamasaki O. Morizane S. Iwatsuki K. Possible macrophage activation in melanoma patients receiving combined kinase inhibitor therapy following anti-PD-1 therapy: a cytokine profiling study of two cases.Ann Oncol. 2017; 28: 2624-2625Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. Adult HLH generally responds to systemic corticosteroids, as observed in our case. Furthermore, dabrafenib and trametinib can be reinitiated without the recurrence of HLH under systemic corticosteroids. Intermittent dosing of dabrafenib and trametinib should also be considered when reinitiating the treatment [5.Atkinson V. Long G.V. Menzies A.M. et al.Optimizing combination dabrafenib and trametinib therapy in BRAF mutation-positive advanced melanoma patients: guidelines from Australian melanoma medical oncologists.Asia-Pac J Clin Oncol. 2016; 12: 5-12Crossref PubMed Scopus (20) Google Scholar]. Because delayed initiation of HLH treatment can lead to increased mortality, clinicians should be aware of potential adverse events during BRAF/MEK inhibitor therapy after anti-PD-1 therapy. None declared.