title: Effect of c-mpl ligands after total body irradiation (TBI) with and without allogeneic hematopoietic stem cell transplantation: low-dose TBI does not prevent sensitization.
abstract: This study investigates the potential role of the recombinant c-mpl ligands (recombinant human thrombopoietin [rhTPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rhMGDF]) on the recovery of platelet counts after TBI with and without allogeneic hematopoietic stem cell transplantation (HSCT) in an established canine model. Initially, 3 cohorts, each with 2 nonirradiated dogs, received increasing doses of rhTPO (5 microg/kg per day; 10 microg/kg per day; 20 microg/kg per day) for 7 days to determine the optimal dose. The dose of 10 microg/kg per day of rhTPO was selected for subsequent studies. Ten dogs then received either rhTPO or placebo for 28 days after 200 cGy TBI without HSCT. The rhTPO group had fewer days with platelet counts <20,000/microL (9.8 days versus 17.8 days, P < .05) and significantly increased granulocyte counts (n = 5) compared to the controls (n = 5). RhTPO-specific antibodies developed in 2 dogs, which caused a significant but transient decrease of the platelet counts. Retreatment of these sensitized dogs with rhTPO resulted in profound transient decreases in platelet counts. In the next study, 20 dogs received either PEG-rhMGDF or placebo for 21 days after 920 cGy TBI and allogeneic HSCT. The median time to platelet recovery (>20,000/microL) for the PEG-rhMGDF group (n = 10) was 14.0 days compared to 15.5 days for the control group (n = 10; log rank, P = .35). There were no significant differences in the total time to platelet counts <20,000/microL or in the time to recover neutrophil counts >500/microL. The effects of rhTPO on recovery of platelet and granulocyte counts after sublethal TBI were modest, and no effects of PEG-rhMGDF were observed on hematopoietic recovery after high-dose TBI and allogeneic HSCT. The significant effect that rhTPO-specific antibodies had on the platelet counts may limit the clinical role of recombinant c-mpl ligands unless sensitization can be prevented.
authors.affiliation: rnash@fhcrc.org
authors.forename: Richard A
authors.initials: RA
authors.lastname: Nash
authors.forename: Alessandra
authors.initials: A
authors.lastname: Takatu
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.forename: Sherrill
authors.initials: S
authors.lastname: Slichter
authors.forename: Kraig
authors.initials: K
authors.lastname: Abrams
authors.forename: German
authors.initials: G
authors.lastname: Espino
authors.forename: M John
authors.initials: MJ
authors.lastname: Gass
authors.forename: George E
authors.initials: GE
authors.lastname: Georges
authors.forename: Peter A
authors.initials: PA
authors.lastname: McSweeney
authors.forename: Howard M
authors.initials: HM
authors.lastname: Shulman
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000528:radiation effects; D016026:Bone Marrow Transplantation / Q000379:methods; D003131:Combined Modality Therapy; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007518:Isoantibodies / Q000097:blood; D010976:Platelet Count; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D013921:Thrombocytopenia / Q000209:etiology / Q000517:prevention & control; D013926:Thrombopoietin / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D014184:Transplantation, Homologous / Q000379:methods; D014916:Whole-Body Irradiation / Q000009:adverse effects*
chemical_list: D007518:Isoantibodies; D011994:Recombinant Proteins; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin