title: A phase 1 trial of eltrombopag in patients undergoing stem cell transplantation after total body irradiation.
abstract: Stem cell transplantation can be associated with significant periods of thrombocytopenia, necessitating platelet transfusions and contributing to the risk of bleeding. Thrombopoietin receptor agonists have been shown to enhance platelet counts in other clinical settings, and so a phase 1 clinical trial was conducted to assess the safety, pharmacokinetics, and maximum tolerated dose of once-daily eltrombopag in patients undergoing stem cell transplantation with conditioning regimens containing total body irradiation ≥400 cGy. Eltrombopag was examined at dosage levels of 75, 150, 225, and 300 mg given orally once daily for 27 days, starting at 24 to 48 hours post-transplantation. Pharmacokinetic sampling was performed over a 24-hour period after the first dose of eltrombopag, as well as during the second week of treatment (steady-state). Nineteen patients were enrolled, 15 of whom completed protocol treatments. Three patients completed each dose level up to 225 mg, and 6 completed treatment at the highest dose of 300 mg. Four patients were replaced because drug compliance was <75% of planned doses. No dose-limiting toxicities were observed in this heterogeneous post-transplantation patient population. Common adverse events were related to standard stem cell transplantation. One episode of pulmonary embolus occurred 9 days after discontinuation of eltrombopag, and the only other thromboembolic episode was a grade 2 catheter-related clot. We conclude that up to 27 days of once-daily dosing of eltrombopag after stem cell transplantation is well tolerated.
authors.affiliation: Department of Medicine, Hematology/Oncology Division, University of Rochester Medical Center, Rochester, New York.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Liesveld
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Phillips
authors.forename: Michael
authors.initials: M
authors.lastname: Becker
authors.forename: Louis S
authors.initials: LS
authors.lastname: Constine
authors.forename: Jonathan
authors.initials: J
authors.lastname: Friedberg
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Andolina
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Milner
authors.forename: Jessica
authors.initials: J
authors.lastname: DeBolt
authors.forename: Therese
authors.initials: T
authors.lastname: Smudzin
authors.forename: Ollivier
authors.initials: O
authors.lastname: Hyrien
authors.forename: Connie L
authors.initials: CL
authors.lastname: Erickson-Miller
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Johnson
authors.forename: Katie-Louise
authors.initials: KL
authors.lastname: Dawson
authors.forename: Yuhchyau
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D001565:Benzoates / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000601:surgery / Q000628:therapy; D006801:Humans; D006834:Hydrazines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D013921:Thrombocytopenia / Q000188:drug therapy / Q000209:etiology; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014182:Transplantation, Autologous; D014916:Whole-Body Irradiation / Q000009:adverse effects / Q000379:methods*; D055815:Young Adult
chemical_list: D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; C520809:eltrombopag
keywords: Bone marrow engraftment; Pharmacokinetics; Platelet; Radiation; Thrombocytopenia; Thrombopoietin mimetic