Plasma Proteomic Profile of Chemotherapy‐Induced Severe Neutropenia: A Pilot Discovery Phase Study

Transient severe neutropenia and thrombocytopenia are frequent during treatment of hematological malignancies and contribute to early mortality through sepsis and bleeding. While neutrophils and platelets are essential for host defense and tissue repair, little is known about immune adaptations during their depletion. In this pilot, discovery phase study, we evaluated the plasma proteome of 10 patients with chemotherapy-induced severe neutropenia and thrombocytopenia, prior to any clinical complication. At sampling, mean neutrophil and platelet counts were 0.15 ± 0.18 × 10⁹/L and 34.6 ± 17.4 × 10⁹/L, respectively. A total of 762 proteins were identified, of which 71 were downregulated and 21 were upregulated in patients compared with healthy controls. Over-representation analyses revealed that most downregulated proteins were related to immune responses, hemostasis, and protein metabolism. Notably, six upregulated proteins (USP8, IGFBP2, RCN1, B2M, LRG1, and C9) also mapped to these pathways, supporting the hypothesis that they may contribute to early systemic responses to chemotherapy-induced myelotoxicity and tissue damage. This exploratory study leveraged a unique clinical window to examine how the human immune system responds to the marked reduction of neutrophils and platelets in the context of tissue and barrier disruption. The downregulation profile suggests impairment of the host's immunothrombotic defense, whereas the upregulated proteins may represent early compensatory mechanisms aimed at preserving homeostasis. Together, these findings provide insights into systemic responses during profound cytopenias and highlight candidate proteins that may mediate early adaptations to hematopoietic and tissue injury in patients undergoing intensive chemotherapy.