Abstract 4805: Plinabulin ameliorates chemotherapy-induced neutropenia: Mechanistic insights

Abstract

Abstract Chemotherapy-induced Neutropenia (CIN) increases the risk of serious infections, sepsis, hospitalizations and mortality, in patients receiving chemotherapy. CIN is currently being treated with G-CSF, which has significant limitations; G-CSF cannot be administered in the first 24 hours after chemotherapy, and its use is associated with bone pain in the majority of patients. There is a need for new therapies with an improved profile. Plinabulin is an inhibitor of tubulin polymerization, which is currently in Phase 3 clinical trials for the treatment of non-small cell lung canacer (NSCLC) in combination with docetaxel. In a previous Phase 2 trial plinabulin significantly ameliorated CIN in patients undergoing docetaxel chemotherapy and this is currently prospectively being evaluated in a series of Phase 2/3 trials. However, the mechanisms by which plinabulin ameliorates neutropenia are unknown. We investigated the role of plinabulin in the regulation of neutrophil homeostasis under chemotherapy-induced neutropenia in mice. We tested the effect of the novel small molecule plinabulin on blood and bone marrow neutrophils and their precursors using complete differential blood counts (CBC) by electrozoning analyzer and flow cytometry of blood and bone marrow. Neutropenia was induced by single injection of the chemotherapeutic agent docetaxel (25 mg/kg, iv.), with and without plinabulin (10 or 20 mg/kg, ip, 12 mice each group) one hour later. Blood was collected on days 3, 4 and 5 post-injection from the retro-orbital plexus and analyzed for CBC. After 5 days of treatment, bone marrow was harvested and analyzed by flow cytometry for the percentage of neutrophils and their progenitors. Blood Neutrophil counts were significantly decreased in mice as a result of docetaxel treatment. Plinabulin ameliorated the docetaxel-induced neutropenia at day 5 (p<0.05) versus the docetaxel-treated mice. Bone marrow neutrophil counts were decreased by docetaxel monotherapy, but this was significantly prevented when plinabulin was given with docetaxel, (p<0.001 for plinabulin 10 mg/kg; p<0.01 for plinabulin 20 mg/kg). The docetaxel-induced accumulation of LSK cells (uncommitted hematopoietic stem cells) was significantly decreased by adding plinabulin to docetaxel-treated mice. The plinabulin effect was neutrophil-specific, because plinabulin had no effect on monocytes and monocyte precursors in the bone marrow. Collectively, these data suggest that plinabulin ameliorates chemotherapy-induced neutropenia by promoting the transition of LSK to common myeloid precursors in mice. This represents a novel mechanism for the prevention of chemotherapy-induced neutropenia. Citation Format: Amlan K. Ghosh, Yanfang P. Zhu, Jacqueline F. Miller, Catherine C. Hedrick, Ramon Mohanlal, Huang Lan, George K. Lloyd, Klaus Ley. Plinabulin ameliorates chemotherapy-induced neutropenia: Mechanistic insights [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4805.