Dual BRAF/MEK blockade restores CNS responses in BRAF-mutant Erdheim–Chester disease patients following BRAF inhibitor monotherapy

Abstract

Background Erdheim–Chester disease (ECD), a rare inflammatory myeloid neoplasm, is known to be fundamentally reliant on the constitutive activation of the MAPK signaling pathway in the majority of patients. Consequently, inhibition of the V600E-mutant BRAF kinase has proven to be a safe and efficacious long-term therapeutic strategy for BRAF-mutant ECD patients. Nevertheless, in a subset of patients with CNS disease, the efficacy of long-term treatment may diminish, facilitating suboptimal responses or disease progression. Methods We retrospectively describe 3 BRAF-mutant ECD patients whose treatment with Vemurafenib was upgraded to Vemurafenib/Cobimetinib due to either disease progression, insufficient response, or unacceptable toxicity. CNS response to therapy was evaluated using magnetic resonance imaging (MRI) and extra-cranial disease was monitored using 18F-fludeoxyglucose positron emission tomography/computed tomography (PET/CT). Results Three patients with a mean age of 52.6 years were treated with Vemurafenib for a mean duration of 26.6 months (range: 6–52). Monotherapies were upgraded to Vemurafenib/Cobimetinib dual therapy. The combination therapy was administered for a mean duration of 21 months (range: 19–23). All patients exhibited clinical and neurological improvement. Regression of lesions on MRI was noted in 2 patients. Both patients characterized by a PET-avid disease responded to the biological treatment regimen with complete metabolic remissions. Conclusion Dual inhibition of BRAF and downstream MEK may be a safe and effective therapeutic strategy for BRAF-mutant ECD patients for whom BRAF inhibitor therapy proved insufficient and as such appropriate for the long-term management of CNS disease in ECD.

Histiocytosis and the nervous system: from diagnosis to targeted therapies

“…There are limited reports of unfavorable CNS responses to BRAF inhibitor monotherapy in BRAF V600E -mutated ECD that are salvaged with combined BRAF/MEK inhibitor therapy. 96 Our collective clinical experience reflects a related phenomenon of differential systemic vs neurologic responses to targeted therapies, with neurologic sites of disease responding to a lesser degree than systemic sites. In some cases, suboptimal response can be augmented by higher dosing or combined treatment, but a price is paid with toxicity and tolerability.…”

MicroRNA-15a-5p acts as a tumor suppressor in histiocytosis by mediating CXCL10-ERK-LIN28a-let-7 axis

“…Recurrent activating kinase mutations and fusions involving the ERK cascade and PI3K/AKT pathways and specifically, mutations in BRAF V600E and its downstream gene, MAP2K1 [ 2 , 3 ] have been discovered in a large proportion of ECD patients [ 1 ]. Treatments that block the pro-inflammatory pathway of IL-1 or the RAS/RAF/ MEK/ERK tumorigenic mutational network have shown efficacy in refractory ECD [ 4 – 6 ]; however, some of these treatments (e.g., the BRAF inhibitors, vemurafenib, and dabrafenib) demonstrated only partial efficacy and caused severe adverse effects [ 7 , 8 ].…”

Intra-arterial Melphalan for Neurologic Non-Langerhans Cell Histiocytosis

“…However, there are non-LCH patients who do not benefit from targeted therapies, particularly those with histiocytic infiltration of the nervous system, which is associated with mortality in one non-LCH disorder. BRAF and MEK inhibitors have limited penetration into the nervous system, and worsening neurologic disease despite targeted therapy has been observed 2 . Additionally, these treatments can be limited or contraindicated by disease-related organ dysfunction or comorbidities.…”

“…BRAF and MEK inhibitors have limited penetration into the nervous system and worsening neurologic disease despite targeted therapy has been observed. 2 These treatments can be limited or contraindicated by disease-related organ dysfunction or comorbidities. The subset of patients without MAPK alterations may not benefit from targeted therapies.…”