transferrin endocytosis and recycling assays showed a significantly enhanced rate of recycling suggestive of a gain-of-function effect. However, the phenotypic overlap with our patients suggests that the p.Gly425Arg variant is also pathogenic, leading to a milder phenotype within the same spectrum. Therefore, pathogenic RBSN variants, in homozygous or heterozygous state, should also be considered in cases of unexplained transient neutropenia, particularly when neurologic abnormalities and/or myelofibrosis are also present.

Purpose-Pexidartinib (PLX3397) is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor under clinical evaluation for potential CNS tumor treatment. This study aims to evaluate plasma pharmacokinetic parameters and estimate CNS penetrance of pexidartinib in a non-human primate (NHP) cerebrospinal fluid (CSF) reservoir model.Methods-Five male rhesus macaques, each with a previously implanted subcutaneous CSF ventricular reservoir and central venous lines, were used. NHPs received a single dose of 40 mg/kg pexidartinib (human equivalent dose of 800 mg/m 2 ), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0-8, 24, 48, and 72 h. Pex-idartinib concentrations were assayed by Integrated Analytical Solutions, Inc. (Berkeley, CA, USA) using HPLC/MS/MS. Pharmacokinetic (PK) analysis was performed using noncompartmental methods.Results-Samples from four NHPs were evaluable. Average (± SD) plasma PK parameters were as follows: C max = 16.50 (± 6.67) μg/mL; T max = 5.00 (± 2.58) h; AUC last = 250.25 (± 103.76) h*μg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidarti-n ib was either quantifiable (n = 2), with C max values of 16.1 and 10.1 ng/mL achieved 2-4 h after plasma T max , or undetected at all time points (n = 2, LLOQ CSF = 5 ng/mL). Conclusion-Pexidartinibwas well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pex-idartinib after single-dose oral administration to NHPs was limited.