Oral CXCR4 inhibition with mavorixafor: Emerging therapeutic applications in WHIM syndrome, chronic neutropenia, oncology, and stem cell mobilization.

The CXCR4/CXCL12 signaling axis plays a central role in regulating immune cell trafficking, hematopoietic homeostasis, and organogenesis. However, dysregulation of this axis contributes to the pathogenesis of numerous disorders, highlighting CXCR4 inhibition as a promising therapeutic strategy. Mavorixafor, the first orally available small-molecule CXCR4 antagonist, recently received FDA approval for WHIM syndrome (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) and is currently being developed for additional indications. Despite extensive research on CXCR4 biology, a comprehensive analysis of mavorixafor's pharmacologic profiles and its performance in preclinical and clinical settings is lacking. This systematic review synthesizes the pharmacology, efficacy, and safety of mavorixafor, summarizing evidence from various sources, including PubMed/MEDLINE, Web of Science, Google Scholar, conference proceedings, clinicaltrials.gov, and FDA resources. Mavorixafor demonstrates potent CXCR4 antagonism, rapid oral absorption, and a long half-life, enabling once-daily dosing. Clinically, it has been shown to increase neutrophil counts and reduce infection rates, contributing to its approval for WHIM syndrome. Early clinical studies in chronic neutropenia indicate sustained neutrophil elevation and decreased dependence on G-CSF. Additionally, emerging data suggest potential benefits in specific malignancies and its utility in mobilizing hematopoietic stem and progenitor cells, as well as in other immune-mediated disorders related to CXCR4 dysregulation. Furthermore, this review positions mavorixafor within the broader CXCR4-targeted therapeutic landscape, identifying current research gaps and suggesting directions for future studies. In conclusion, by integrating mechanistic insights with preclinical and clinical findings, this article highlights mavorixafor's promise as a targeted therapy with the potential to transform treatment paradigms for CXCR4-driven diseases.