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Ref Type Journal Article
PMID (34978715)
Authors Abeykoon JP, Lasho TL, Dasari S, Rech KL, Ranatunga WK, Manske MK, Tischer A, Ravindran A, Young JR, Tobin WO, Flanagan EP, Nowakowski KE, Ruan GJ, Shah MV, Bennani NN, Vassallo R, Ryu JH, Koster MJ, Davidge-Pitts CJ, Patnaik MM, Wu X, Witzig TE, Goyal G, Go RS, Mayo Clinic-University of Alabama at Birmingham Histiocytosis Working Group
Title Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease.
Journal Vol Issue Date Pages Journal Short Title
American journal of hematology 97 3 2022 03 01 293-302 Am J Hematol
URL
Abstract Text Erdheim-Chester disease (ECD) is a histiocytic neoplasm that predominantly harbors mitogen-activated protein kinase (MAPK) pathway variants. MAPK inhibitors typically are effective treatments, but mutations outside the MAPK pathway, such as CSF1R variants, may cause refractory ECD. We describe a patient with a novel somatic mutation in CSF1R (CSF1RR549_E554delinsQ ) that resulted in refractory ECD affecting the central nervous system. Cell model studies, RNA sequencing analysis, and in silico protein modeling suggested that she had a gain-of-function mutation occurring in a region critical for autoinhibition. The patient was treated with pexidartinib, a CSF1R inhibitor, and has had a complete clinical and metabolic response lasting more than 1.5 years to date. To our knowledge, this is the first report to describe successful treatment of a patient with ECD by using an agent that specifically targets CSF1R. This case also highlights the critical role of individualized molecular profiling to identify novel therapeutic targets in ECD.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
CSF1R R549_E554delinsQ indel gain of function - predicted CSF1R R549_E554delinsQ results in a deletion of six amino acids in the regulatory juxtamembrane domain of the Csf1r protein from amino acids 549 to 554, combined with the insertion of a glutamine (Q) at the same site (UniProt.org). R549_E554delinsQ results in increased ligand-independent phosphorylation of Akt and Erk in culture (PMID: 34978715), and therefore, is predicted to lead to a gain of Csf1r protein function.
CSF1R Y561_I564del deletion unknown CSF1R Y561_I564del results in the deletion of four amino acids in the regulatory juxtamembrane domain of the Csf1r protein from amino acids 561 to 564 (UniProt.org). Y561_I564del has been identified in the scientific literature (PMID: 31768065, PMID: 34978715), but has not been biochemically characterized and therefore, its effect on Csf1r protein function is unknown (PubMed, Feb 2026).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CSF1R R549_E554delinsQ Erdheim-Chester disease predicted - sensitive Pexidartinib Case Reports/Case Series Actionable In a clinical case study, Turalio (pexidartinib) resulted in a complete clinical and metabolic response lasting more than 1.5 years in a patient with Erdheim-Chester disease harboring CSF1R R549_E554delinsQ (PMID: 34978715). 34978715