Abstract
Introduction: Leucopenia following myelosuppressive chemotherapy is associated with substantial mortality and costs. Whereas there is a lack of therapeutic options for lymphopenia, in chemotherapy-induced neutropenia, Granulocyte Colony-Stimulating Factor (G-CSF) has proven to be effective in secondary prophylaxis. Despite currently available therapies, mortality due to chemotherapy-induced neutropenia remains high, and safety, tolerability and costs limit the use of available treatment options.
Imidazolyl Ethanamide Pentandioic Acid (IEPA, Myelo001) is a novel small molecule for the treatment of chemotherapy-induced leucopenia. Preclinical and clinical studies have shown that in its oral form IEPA is effective in reducing neutropenia and has antiviral properties without noticeable toxicity.
Objective: To evaluate the effect of IEPA after multiple oral administration in different posologies and at a low (1.0mg/kg) and high dose (100mg/kg) on peripheral components of hematopoiesis in a mouse model of acute cytostatic myelosuppression in comparison to vehicle and Filgrastim (Neupogen¨).
Methods: Twenty-five female CD-1 mice, 6 weeks of age, were randomly assigned to 5 treatment groups: Cyclophosphamide (CPH) (200mg/kg), CPH+Filgrastim (subcutaneous) (0.3mg/kg) (quaque die (q.d.) day (d) 1 to 5), CPH+IEPA (100mg/kg) (q.d., d -1 to 5), CPH+IEPA (100mg/kg) (q.d., d -5 to 5), CPH+IEPA (1.0mg/kg) (q.d., d -5 to 5). The experimental phase started with the determination of baseline white blood cell, red blood cell and platelet counts one day before (pre-) treatment start with IEPA (d -6) and was continued on days 1, 3, 5, 8, 23, 32. A single intraperitoneal (i.p.) injection of Cyclophosphamide (200mg/kg) was administered in all 5 groups on day 0 to induce leuco- and thrombocytopenia. The longitudinal data were analyzed by response profile analysis.1
Results: The three groups of IEPA had lower baseline leucocyte counts compared to the CPH+Filgrastim and CPH groups. CPH application caused leucopenia across all 5 groups with the nadir on day 3 to 5. Comparing change from baseline, IEPA significantly reduced leucopenia on days 3, 5, 8 relative to the control group (CPH). No clear dose- or posology-effect relationship was discernible between doses of 1.0 (for 11d), 100 (7d) or 100mg/kg (11d). Compared to Filgrastim, IEPA led to an earlier recovery of leucocytes, followed by a delayed and less pronounced increase in leucocytes above baseline, with the peak of Filgrastim (change of baseline relative to CPH) on day 5 (10.2∙109/L, 95%CI: 7.1 to 13.2∙109/L, p < 0.001) versus day 8 for IEPA (change of baseline relative to CPH) (4.7∙109/L, 95%CI: 1.5 to 8.0∙109/L, p = 0.004 at a dose of 100mg/kg (11d))
Figure 1: Figure 1:. Leucocyte count (109/L) absolute change from baseline in 5 parallel treatment groups
Figure 2: Figure 2:. Treatment effect on Leucocyte counts (109/L) of IEPA and Filgrastim relative to the CPH group. Treatment effects are significant if the 95CI% error bar excludes the no-effect value 0 corresponding to no difference in change from baseline versus CPH control
Lymphocyte counts change from baseline in all three IEPA groups was numerically higher than in the Filgrastim and CPH arm on day 3, 5 and 8, and day 3 and 8, respectively (not statistically significant). Filgrastim led to a substantial granulocytosis on day 5 (change of baseline relative to CPH) (7.2∙109/L, 95%CI: 5.6 to 8.9∙109/L p < 0.001), whereas a minor increase was observed in the three IEPA groups on day 8. Thrombocytes numbers were slightly increased throughout days 3 to 23 in the IEPA groups, contrasting with a pronounced thrombocytopenia under Filgrastim on day 5. Red blood cell counts decreased after CPH injection (nadir on day 3 to 8), but did not differ among groups.
Conclusion: IEPA demonstrated in 2 doses and posologies a consistent reduction of chemotherapy-induced leucopenia and thrombocytopenia in CD1 mice. Its effect on leucopoiesis and thrombocytopoiesis differs from Filgrastim in a less pronounced early nadir and subsequent lower amplitude of leuco- and granulocytosis. IEPA may offer a new therapeutic option for myelosuppression due to chemotherapy, but requires further preclinical and clinical investigation.
1Fitzmaurice GM, Laird NM, Ware JH. Applied longitudinal analysis, Wiley. Hoboken, NJ: Interscience; 2004 p103-140.
Disclosures
Pleimes: Myelo Therapeutics: Employment, Equity Ownership, Managing Director Other; Bayer Pharma AG/ Bayer Healthcare Pharmaceuticals: Consultancy. Flechsig:EPO Berlin-Buch GmbH: Contract Research on behalf and in account of Myelo Therapeutics GmbH Other, Employment. Meyer:Myelo Therapeutics GmbH: Consultancy.
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