title: Recipient pretransplant inosine monophosphate dehydrogenase activity in nonmyeloablative hematopoietic cell transplantation.
abstract: Mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH) activity. IMPDH is the rate-limiting enzyme involved in de novo synthesis of guanosine nucleotides and catalyzes the oxidation of inosine 5'-monophosphate to xanthosine 5'-monophosphate (XMP). We developed a highly sensitive liquid chromatography-mass spectrometry method to quantitate XMP concentrations in peripheral blood mononuclear cells (PMNCs) isolated from the recipient pretransplant and used this method to determine IMPDH activity in 86 nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) patients. The incubation procedure and analytical method yielded acceptable within-sample and within-individual variability. Considerable between-individual variability was observed (12.2-fold). Low recipient pretransplant IMPDH activity was associated with increased day +28 donor T cell chimerism, more acute graft-versus-host disease (GVHD), lower neutrophil nadirs, and more cytomegalovirus reactivation but not with chronic GVHD, relapse, nonrelapse mortality, or overall mortality. We conclude that quantitation of the recipient's pretransplant IMPDH activity in PMNC lysate could provide a useful biomarker to evaluate a recipient's sensitivity to MMF. Further trials should be conducted to confirm our findings and to optimize postgrafting immunosuppression in nonmyeloablative HCT recipients.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: Bemer
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Risler
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Phillips
authors.affiliation: School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wang
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Medicine, University of Washington, Seattle, Washington.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
authors.affiliation: School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Haichuan
authors.initials: H
authors.lastname: Duan
authors.affiliation: School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Brianne S
authors.initials: BS
authors.lastname: Raccor
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Medicine, University of Washington, Seattle, Washington.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boeckh
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Pharmacy, University of Washington, Seattle, Washington. Electronic address: jmccune@u.washington.edu.
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007291:Inosine Monophosphate / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012265:Ribonucleotides / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016019:Survival Analysis; D018183:Transplantation Chimera / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous; D019820:Xanthine
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D012265:Ribonucleotides; D007291:Inosine Monophosphate; D019820:Xanthine; C011141:xanthosine monophosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid
keywords: Inosine monophosphate dehydrogenase; LC-MS; Mycophenolic acid; Postgrafting immunosuppression; Predictive biomarkers