Hemophagocytic lymphohistiocytosis in advanced melanoma treated with dabrafenib and trametinib combination: two cases

Abstract

Hemophagocytic lymphohistiocytosis (HLH) has been only rarely reported in patients with BRAF-mutated advanced melanoma treated with targeted therapies and never with first-line dabrafenib/trametinib combination thus far. Two patients treated with first-line dabrafenib and trametinib combination therapy for metastatic melanoma presented with sudden occurrence of fever, cytopenia, rhabdomyolysis, hepatic cytolysis, hypertriglyceridemia and very high ferritin levels after few weeks of treatment, associated with concomitant epstein-barr virus (EBV) reactivation in one patient. In both cases, drug-induced HLH was primarily considered owing to a high H-score and the absence of other etiology. Patients rapidly improved after treatment discontinuation associated with oral steroids in one patient and did not relapse after subsequent treatment resumption with a concurrent anti-BRAF/anti-MEK combination. In metastatic melanoma HLH may occur either spontaneously in the absence of any treatment as a paraneoplastic condition, related to an intercurrent infection or drug-induced mainly with various immunotherapy or with dabrafenib and trametinib following immunotherapy. However, such observations are scarce and these are the first cases of HLH occurring during first-line treatment with dabrafenib and trametinib in advanced melanoma to our knowledge. Pathomechanisms remain to be elucidated since triggering factors may encompass the treatment itself but also other significant actors including viral reactivation along with the underlying disease. The liability of treatment should be considered in cases of HLH occurring in patients with advanced melanoma successfully treated with a combined targeted therapy. A rechallenge with a concurrent anti-BRAF/anti-MEK can be proposed in this setting.

Macrophage activation syndrome associated with BRAF and MEK inhibitors during adjuvant treatment of melanoma

“…4 In literature, few cases have described MAS during progressive tumour with dabrafenib and trametinib used for metastatic melanoma. 5,6 In one of those case reports, 6 patient also developed MAS 5 months after the initiation of dabrafenib trametinib (8 months in our case) which was disappeared after discontinuation of treatment. In our case, MAS appeared during adjuvant therapy without signs of progressive tumour.…”

Recurrent hemophagocytic lymphohistiocytosis in advanced melanoma treated with two different BRAF/MEK-inhibitor regimens

“…In some cases, the authors suggested that a change in targeted therapies was sufficient to control the evolution of HLH [4]. In our situation, the patient relapsed a second time, which motivated us to start corticosteroid therapy at 0.5 mg/kg/day while maintaining actual DTT to achieve a therapeutic response, as reported in two cases [5].…”

“…Less than 40 cases of HLH during dabrafenib/trametinib therapy have been reported in the literature [3,4] and international pharmacovigilance database (VigiLyze), and only four cases have been reported during vemurafenib/cobimetinib therapy, which is mostly prescribed for first-line melanoma treatment. The median time lag between the initiation of DDT and the development of HLH was 33 days (6 days–6 months) when data were available.…”

Effective Treatment of a Melanoma Patient with Hemophagocytic Lymphohistiocytosis after Nivolumab and Ipilimumab Combined Immunotherapy

“…In the literature there are available case reports in which treatment interruption or corticosteroids alone were used with sufficient response (Sadaat and Jang, 2018;Mizuta et al, 2020;Gambichler et al, 2021). In melanoma patients HLH can be also attributed to a solid tumour as a first presentation of the disease (Stabler et al, 2017), Epstein-Barr virus (EBV) infection (Davis et al, 2019) and can be associated with BRAF/MEK inhibitors (Samaran et al, 2020;Dudda et al, 2021). These cases represented rather moderate HLH where treatment discontinuation, basic supportive care (intravenous rehydration and paracetamol), and low dose steroids (or even without steroids prescription) (Samaran et al, 2020) were sufficient methods of treatment.…”

“…In melanoma patients HLH can be also attributed to a solid tumour as a first presentation of the disease (Stabler et al, 2017), Epstein-Barr virus (EBV) infection (Davis et al, 2019) and can be associated with BRAF/MEK inhibitors (Samaran et al, 2020;Dudda et al, 2021). These cases represented rather moderate HLH where treatment discontinuation, basic supportive care (intravenous rehydration and paracetamol), and low dose steroids (or even without steroids prescription) (Samaran et al, 2020) were sufficient methods of treatment. In 19% of cases in VigiBase, concomitant Epstein-Barr virus infection was reported, suggesting a potentially augmented immune response in case of chronic underlying infection (Davis et al, 2019).…”