Targeted therapies for the treatment of single-system and multisystem disease

MAP2K/ERK pathway inhibitors. The finding that most patients with LCH have BRAF or other RAS pathway variants led to several reports of good responses to vemurafenib, a BRAF V600E inhibitor, in adult patients with LCH and severe cutaneous LCH.[81-85][Level of evidence C3]Of four patients with LCH who were treated with vemurafenib on the VE-BASKET (NCT01524978) trial, one patient had a complete response and three patients had partial responses.[84][Level of evidence C3] One patient with LCH who was treated with vemurafenib had improvement in ataxia.[84][Level of evidence C3] One series reported on six patients who were treated with BRAF inhibitors as initial therapy.[86] Five patients had multisystem disease, and one patient had bone-only LCH. There were two complete responses, three partial responses, and one stable disease after 4 to 27 months of treatment.A proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, was carried out in 18 adult patients with various histiocytoses, including histiocytic sarcomas. Patients were treated regardless of genomic findings. Responses were seen in patients with ARAF, BRAF, NRAS, KRAS, MAP2K1, and MAP2K2 variants. The overall response rate was 89%, with responses being durable. At 1 year, 94% of patients remained progression free.[83][Level of evidence C2]Early results of targeted inhibitor therapy are encouraging, but many questions remain, particularly the optimal duration of therapy and the reactivation rate after therapy is discontinued. A BRAF inhibitor in combination with a MEK inhibitor have been shown to be effective in patients with melanoma who have BRAF variants (with reduced toxicity). This combination may also be effective in patients with LCH, but it is generally not used for patients with histiocytic diseases.[81][Level of evidence C3] A number of clinical trials of BRAF and other RAS pathway inhibitors in adults and children with LCH are ongoing.

Other targeted therapies. A case report suggests some benefit to treating neurodegenerative CNS LCH disease with infliximab, a tumor necrosis factor (TNF)-alpha inhibitor.[87][Level of evidence C3] However, the TNF inhibitors infliximab and etanercept have limited ability to cross the blood-brain barrier. Thalidomide, which also has anti-TNF activity, has been effective in adults with skin and bone LCH.[66,88][Level of evidence C3]; [88,89]