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

  • Mazor, Roei D1
  • Weissman, Ran1, 2, 3
  • Luckman, Judith4
  • Domachevsky, Liran4, 5
  • Diamond, Eli L6
  • Abdel-Wahab, Omar7
  • Shapira, Shirley8, 9
  • Hershkovitz-Rokah, Oshrat1, 2, 3
  • Groshar, David4, 5
  • Shpilberg, Ofer1, 3, 10
  • 1 Clinic of Histiocytic Neoplasms, Institute of Hematology, Assuta Medical Center, Israel , (Israel)
  • 2 Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Israel , (Israel)
  • 3 Translational Research Lab, Assuta Medical Centers, Israel , (Israel)
  • 4 Department of Imaging, Assuta Medical Center, Israel , (Israel)
  • 5 Department of Nuclear Medicine, Assuta Medical Center, Israel , (Israel)
  • 6 Department of Neurology, Memorial Sloan Kettering Cancer Center
  • 7 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center
  • 8 Institute of Hematology, Meir Hospital, Israel , (Israel)
  • 9 Maccabi Health Services, Israel , (Israel)
  • 10 Pre-Medicine Department, School of Health Sciences, Ariel University, Israel , (Israel)
Published Article
Neuro-oncology Advances
Oxford University Press
Publication Date
Mar 03, 2020
DOI: 10.1093/noajnl/vdaa024
PMID: 32642685
PMCID: PMC7212923
PubMed Central


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.

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