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Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease
Jithma P Abeykoon1, Terra L Lasho1, Surendra Dasari2
1Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
Abstract:
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.
Insights
Erdheim-Chester disease (ECD) can be refractory to standard treatments due to rare mutations. A novel CSF1R mutation causing refractory ECD was successfully treated with the targeted inhibitor pexidartinib.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm often driven by MAPK pathway mutations.
- Refractory ECD cases may involve mutations outside the MAPK pathway, such as in CSF1R.
Observation:
- A patient presented with refractory ECD affecting the central nervous system.
- This patient harbored a novel somatic mutation in CSF1R (CSF1RR549_E554delinsQ).
Findings:
- In vitro studies indicated the mutation resulted in a gain-of-function in a critical autoinhibition region of CSF1R.
- The patient achieved a complete clinical and metabolic response to pexidartinib, a CSF1R inhibitor, for over 1.5 years.
Implications:
- This is the first report of successful treatment for ECD using a CSF1R-targeted agent.
- Highlights the importance of molecular profiling for identifying novel therapeutic targets in refractory ECD.
