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Efficacy of the MEK inhibitor cobimetinib for wild‐type BRAF Erdheim‐Chester disease

2016; Wiley; Volume: 180; Issue: 1 Linguagem: Inglês

10.1111/bjh.14284

1365-2141

F. Cohen Aubart, Jean‐François Emile, Philippe Maksud, Damien Galanaud, Philippe Cluzel, Neïla Benameur, O. Aumaître, Zahir Amoura, Julien Haroche,

Eosinophilic Disorders and Syndromes

Approximately 60% of patients with Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytic disorder, harbour the BRAFV600E mutation, leading to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway (Haroche et al, 2012). The BRAF inhibitor vemurafenib has shown a dramatic efficacy in histiocytoses harbouring the BRAFV600E mutation (Haroche et al, 2013, 2015; Hyman et al, 2015). Whole-exome sequencing studies led to the discovery of several other somatic mutations in histiocytic disorders, in particular ECD, supporting the hypothesis that the extracellular signal-regulated kinases (ERKs) activation is the universal end point arising from pathological activation of upstream signalling proteins (Chakraborty et al, 2014; Diamond et al, 2016). The MEK inhibitor cobimetinib has been evaluated in association with vemurafenib in metastatic melanoma (Larkin et al, 2014; Ribas et al, 2014). The efficacy of MEK inhibitors has been previously reported in two ECD patients with MAP2K1 mutations who were treated with trametinib and cobimetinib (Diamond et al, 2016). Here we report the efficacy of the MEK inhibitor cobimetinib used alone in three wild-type (WT) BRAF ECD patients refractory to conventional therapy [including the follow-up of a previously reported case (Diamond et al, 2016)]. We report the retrospective results of cobimetinib treatment in three patients with definite ECD (Diamond et al, 2014) seen in a single centre. Cobimetinib was given as sole therapy at the dose of 40 mg/day (20 mg twice a day), for 21 days of a 28-day cycle. All patients gave written informed consent. Cobimetinib efficacy was assessed with the use of an 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) scanner, as described elsewhere (Haroche et al, 2015). Additionnally, serum C-reactive protein levels and histiocytic infiltration evaluated by magnetic resonance imaging (MRI) were recorded. The clinical characteristics of the three patients are reported in Table 1. All patients had histologically-proven ECD with perirenal infiltration and a 'coated aorta'. The following additional manifestations were observed: long bone infiltrations (n = 2), sinus hypermetabolism (n = 2), pericardial effusion (n = 1) and dural compressive lesions (n = 1). The absence of BRAFV600 mutation was confirmed by high sensitivity picodroplet digital polymerase chain reaction (Emile et al, 2014). The metabolic response was evaluated with 18F-FDG PET scan (Haroche et al, 2015). Two patients were previously treated with vemurafenib before their BRAF status was determined. They experienced worsening of the target lesions, as assessed by 18F-FDG PET, while under treatment. The introduction of cobimetinib was justified for these three patients given the progression of renal failure and refractory arterial hypertension in Patient one, the medullar compression by a spinal dural lesion in Patient two and circumferential pericardial effusion in Patient three. At 1 month, all the patients were in metabolic partial remission as evidenced by 18F-FDG PET results (Fig 1A,B). The creatinine level of Patient one decreased significantly (from 337 to 187 μmol/l). The pericardial effusion of the Patient three disappeared completely (Fig 1C). Patients one and two were further evaluated at 8 and 7 months, respectively, after the initiation of cobimetinib therapy. The 18F-FDG PET scans showed improvment (Fig 1A,B), displaying metabolic partial remission for the three patients (Haroche et al, 2015). C-reactive protein levels also improved in the three patients (Table 1). Spinal MRI displayed a decrease in dural histiocytic infiltrations in Patient three (Fig 1C). These three patients, who are still on treatment, experienced minimal side effects. Patient one experienced vomiting and cycline-responsive acneiform rash. Patients two and three had benign acneiform rash. There were no cardiac or ocular treatment complications. Perirenal infiltration (JJ stents, renal failure) Sinus hypermetabolism Retro-orbital masses Coated aorta Perirenal infiltration Long bones hypermetabolism Sinus hypermetabolism Coated aorta Spinal dural compressive lesions Hypopituitarism Perirenal infiltration (JJ stents) Long bones infiltration (MRI) Coated aorta (non hypermetabolic) Pericardial thickening and effusion Pegylated interferon-α: stopped because of progression) Infliximab: (1 perfusion followed by septic shock) Vemurafenib: stopped due to disease progression Corticosteroids and anakinra: stopped due to progression) Cladribine: stopped after 3 cycles due to acute renal failure and septic shock Wild type BRAF MAP2K1 Wild type BRAF MAP2K1 Erdheim-Chester disease is an inflammatory myeloid neoplasm characterized by infiltration with foamy histiocytes that can lead to long bone, perirenal and periaortic involvement. Recurrent BRAFV600E somatic mutations have been described in ECD leading to constitutively active tyrosine kinase that activates the downstream MAPK signalling and consequently the ERKs (Haroche et al, 2012; Diamond et al, 2016). Somatic mutations in MAP2K1 have also been reported in histiocytic disorders and mutant MAP2K1 products were shown to activate ERK (Chakraborty et al, 2014). Cobimetinib, an orally bioavailable potent selective MEK inhibitor, has been used in combination with vemurafenib in BRAF-mutated melanoma (Larkin et al, 2014). Here we report the efficacy of cobimetinib used in monotherapy for ECD patients without the BRAFV600E mutation. This strong efficacy was assessed with 18F-FDG PET as well as measurements of histiocytic infiltrations. The three patients had a sustained metabolic response, and response was confirmed by decrease of creatinine and C-reactive protein levels and/or MRI. The safety profile of this drug was good and no patient experienced either cardiac or ocular toxic effects. Interestingly, previous treatment with vemurafenib in two patients before their BRAF status was determined was associated with worsening disease in both cases, suggesting that this drug may have a paradoxical effect in WT BRAF patients. In conclusion, cobimetinib may be a valuable therapeutic option for WT BRAF patients presenting with serious organ involvement. The use of the combined therapy (BRAF and MEK inhibitors) in BRAFV600E patients should be further evaluated. FC-A, JH and ZA designed the study. J-FE provided information about BRAF status. FC-A, PM, DG and JH contributed to acquisition of the data. FC-A designed Table 1 and Fig 1. All authors critically reviewed the manuscript and approved the final version. None of the authors have a conflict of interest regarding this study.