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Hematopoietic Recovery Following Autologous Bone Marrow Transplantation in a Nonhuman Primate: Effect of Variation in Treatment Schedule with PEG-rHuMGDF

^a University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA;
^b Amgen, Inc., Thousand Oaks, California, USA

Key Words. PEG-rHuMGDF • Nonhuman primate • Platelet • Hematopoietic • Bone marrow transplant

Ann M. Farese, M.S., University of Maryland Greenebaum Cancer Center, 655 West Baltimore Street, Baltimore, Maryland 21201, USA Telephone: 410-328-5347; Fax: 410-328-5488; e-mail:
afarese{at}umaryland.edu

Mathematical modeling of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) pharmacokinetics (PK) and pharmacodynamics (PD) suggest that variations in the PEG-rHuMGDF treatment schedule could reduce the severity and duration of thrombocytopenia following myeloablation and bone marrow transplant (BMT). We tested this hypothesis in a rhesus monkey model of autologous (Au) bone marrow-derived mononuclear cell (BM-MNC) transplantation following lethal myeloablation. On day 0, animals were myeloablated by total body exposure to 920 cGy, 250 kVp x-irradiation (TBI). Four cohorts of animals were infused with 1 x 10⁸ AuBM-MNC/kg body weight within 2 hours of TBI. The AuBMT-alone cohort received no cytokine, the daily dosage cohort received PEG-rHuMGDF (2.5 µg/kg/day, s.c.) post TBI and AuBMT, and the pre/post-transplant cohort received PEG-rHuMGDF (2.5 µg/kg/day, s.c.) pre (day -9 to day -5) and post TBI and AuBMT. The post-transplant PEG-rHuMGDF administration in the above cohorts was begun on day 1 post TBI and continued until platelet counts reached 200,000 µl (range, 15-31 days). Another group received PEG-rHuMGDF (300 µg/kg/day, s.c.) on days 1 and 3 only following TBI and AuBMT. The TBI controls received neither AuBMT nor cytokine therapy. In this model of AuBMT, with regard to the PEG-rHuMGDF administration schedule, the daily dosage of the post-transplant cohort did not significantly improve platelet recovery; the pre/post-transplant schedule and an abbreviated high-dosage, post-transplant schedule (days 1 and 3) significantly improved the duration and nadir of thrombocytopenia and platelet recovery. These data confirm predictions from PK/PD modeling of PEG-rHuMGDF that thrombocytopenia is preventable following AuBMT.