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Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease.

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 (CSF1R^{R549_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.

SUBMITTER: Abeykoon JP

PROVIDER: S-EPMC9536810 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease.

Abeykoon Jithma P JP Lasho Terra L TL Dasari Surendra S Rech Karen L KL Ranatunga Wasantha K WK Manske Michelle K MK Tischer Alexander A Ravindran Aishwarya A Young Jason R JR Tobin William Oliver WO Flanagan Eoin P EP Nowakowski Kevin E KE Ruan Gordon J GJ Shah Mithun V MV Bennani Nabila Nora NN Vassallo Robert R Ryu Jay H JH Koster Matthew J MJ Davidge-Pitts Caroline J CJ Patnaik Mrinal M MM Wu Xiaosheng X Witzig Thomas E TE Goyal Gaurav G Go Ronald S RS

American journal of hematology 20220103 3

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 (CSF1R<sup>R549_E554delinsQ</sup> ) that resulted in refractory ECD affecting the central nervous system. Cell model studies, RNA sequencing analysis, and i ...[more]

PMID: 34978715

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Project description:IntroductionErdheim-Chester disease (ECD) is a rare disease that belongs to the group of Dendritic and histiocytic neoplasms. Only 2000 cases have been reported worldwide. It can present with a wide range of symptoms, making a differential diagnosis especially difficult. The primary and most important diagnostic tool is a biopsy of the affected organ/tissue. Nowadays the analysis of different mutations affecting the BRAF and MAPK pathways makes it possible to use targeted treatments, such as vemurafenib, dabrafenib, or cobimetinib.ObjectiveOur aim is to present the results of three male patients treated in our hematology department.ResultsOur BRAF mutation-positive patient presented with retroperitoneal tissue proliferation and diabetes insipidus. The initial therapy of choice was dabrafenib. After 3 months of treatment, 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scans showed regression, and after 2 years of treatment, no disease activity was detected. In our second patient, a recurrent febrile state (not explained by other reasons) and diabetes insipidus suggested the diagnosis. A femoral bone biopsy confirmed BRAF-negative ECD. The first-line therapy was interferon-alpha. After 3 months of treatment, no response was observed on 18FDG-PET/CT, and treatment with cobimetinib was started. The control 18FDG-PET/CT imaging was negative. Our third patient was evaluated for dyspnea, and a CT scan showed fibrosis with hilar lymphadenomegaly. A lung biopsy confirmed BRAF-negative ECD. We started treatment with interferon-alpha, but unfortunately, no improvement was observed. Second-line treatment with cobimetinib resulted in a partial metabolic response (PMR) according to control 18FDG-PET/CT.ConclusionsOur results demonstrate that an appropriately chosen treatment can lead to a good therapeutic response, but dose reduction may be necessary due to side effects. With advanced targeted therapeutic treatment options, survival and quality of life are significantly improved.

Dataset Information

Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease.

Publications

Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease.

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