Abstract 4109: Romiplostim promotes platelet recovery in a mouse model of multicycle chemotherapy-induced thrombocytopenia.
Authors: McElroy Patricia L. , Buck Keri , Eschenberg Michael , Sasu Barbra J. , Molineux Graham 
Published: August 2014

Chemotherapy-induced thrombocytopenia (CIT) is a serious complication of some cancer therapies and can necessitate treatment delay or chemotherapy dose reduction. Romiplostim is a thrombopoietin (TPO) receptor agonist approved for the treatment of immune thrombocytopenia (ITP). The ability of romiplostim to promote platelet recovery in a mouse model of multicycle chemotherapy/radiation therapy (CRT)-induced thrombocytopenia was examined. A secondary aim was to determine the optimum dose and timing of romiplostim treatment. In humans, an inverse relationship between platelet numbers and endogenous (e) TPO concentrations has been reported. Studies confirmed a similar relationship in both naïve mice and mice with CIT. Platelet numbers and eTPO concentration were measured during three 28-day cycles of CRT in mice. eTPO did not increase during the first five days after each CRT (the ‘eTPO gap’ time period, eTPO concentration of 2.8 ± 0.88 ng/mL), then increased to a peak 10 days after each CRT treatment (6.1 ± 1.5 ng/mL), as platelet numbers decreased. The window of time before eTPO concentration increased was used to design dosing paradigms that would supplement eTPO activity while concentrations were low. Since it was anticipated that patients would be unlikely to receive primary prophylaxis for first cycle CIT, a model was established in which romiplostim treatment was administered during the second or third cycle of CRT. In an attempt to ‘bridge’ the eTPO gap, mice were treated with 10 to 1000 μg/kg of romiplostim given on day 0, 1 or 2 after CRT in either cycle 2, cycle 3 or in both cycles, and platelet numbers were measured throughout that cycle. In some mice the total dose of romiplostim was divided over three days (i.e. one third on each of days 0, 1 and 2). Platelet recovery occurred faster in animals that received romiplostim in most conditions tested, with platelet counts significantly higher for groups that received CRT plus romiplostim compared to CRT alone (as determined by ANOVA with Dunnett's post-hoc test). Romiplostim also provided benefit in terms of decreasing the severity of the platelet nadir. Doses of &gt;100 μg/kg given on day 0 significantly lessened the platelet nadir in both cycle 2 and cycle 3. Fractionating the dose and administering it over 3 days was effective but not superior to a single administration on day 0. In summary, an inverse relationship between platelet numbers and eTPO concentrations was observed during multiple cycles of CRT in mice. This decrease in eTPO created a ‘eTPO gap’ in each CRT cycle, which was effectively bridged by romiplostim treatment. These data may provide a rationale for clinical studies of romiplostim in patients undergoing myelosuppressive chemotherapy.

Citation Format: Patricia L. McElroy, Keri Buck, Michael Eschenberg, Barbra J. Sasu, Graham Molineux. Romiplostim promotes platelet recovery in a mouse model of multicycle chemotherapy-induced thrombocytopenia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4109. doi:10.1158/1538-7445.AM2013-4109