PURPOSE: Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine's metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4(+) and CD8(+) cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients. METHODS: Participants with hematologic diseases were conditioned with fludarabine and low-dose total body irradiation (TBI) followed by allogeneic HCT and post-grafting immunosuppression. After fludarabine administration, we evaluated pharmacological biomarkers for fludarabine-F-ara-A area under the curve (AUC) and the ratio of circulating CD4(+) and CD8(+) cells (CD4(+)/CD8(+) ratio) after fludarabine administration-in 102 patients; F-ara-ATP accumulation rate in enriched CD4(+) and CD8(+) cells was evaluated in 36 and 34 patients, respectively. RESULTS: Interpatient variability in the pharmacological biomarkers was high, ranging from 3.7-fold (F-ara-A AUC) to 39-fold (F-ara-ATP in CD8(+) cells). Circulating CD8(+) cells were more sensitive to fludarabine administration. A population pharmacokinetic-based sampling schedule successfully allowed for estimation of F-ara-A AUC in this outpatient population. There was a poor correlation between the F-ara-AUC and the F-ara-ATP accumulation rate in CD4(+) (R (2) = 0.01) and CD8(+) cells (R (2) = 0.00). No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality). CONCLUSIONS: Considerable interpatient variability exists in pharmacokinetic and fludarabine-based biomarkers, but these biomarkers are not associated with clinical outcomes in fludarabine/TBI-conditioned patients.
PURPOSE:Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine's metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4(+) and CD8(+) cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients. METHODS:Participants with hematologic diseases were conditioned with fludarabine and low-dose total body irradiation (TBI) followed by allogeneic HCT and post-grafting immunosuppression. After fludarabine administration, we evaluated pharmacological biomarkers for fludarabine-F-ara-A area under the curve (AUC) and the ratio of circulating CD4(+) and CD8(+) cells (CD4(+)/CD8(+) ratio) after fludarabine administration-in 102 patients; F-ara-ATP accumulation rate in enriched CD4(+) and CD8(+) cells was evaluated in 36 and 34 patients, respectively. RESULTS: Interpatient variability in the pharmacological biomarkers was high, ranging from 3.7-fold (F-ara-A AUC) to 39-fold (F-ara-ATP in CD8(+) cells). Circulating CD8(+) cells were more sensitive to fludarabine administration. A population pharmacokinetic-based sampling schedule successfully allowed for estimation of F-ara-A AUC in this outpatient population. There was a poor correlation between the F-ara-AUC and the F-ara-ATP accumulation rate in CD4(+) (R (2) = 0.01) and CD8(+) cells (R (2) = 0.00). No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality). CONCLUSIONS: Considerable interpatient variability exists in pharmacokinetic and fludarabine-based biomarkers, but these biomarkers are not associated with clinical outcomes in fludarabine/TBI-conditioned patients.
Authors: K M Sullivan; E Agura; C Anasetti; F Appelbaum; C Badger; S Bearman; K Erickson; M Flowers; J Hansen; T Loughran Journal: Semin Hematol Date: 1991-07 Impact factor: 3.851
Authors: Marco Mielcarek; Lauri Burroughs; Wendy Leisenring; Razvan Diaconescu; Paul J Martin; Brenda M Sandmaier; David G Maloney; Michael B Maris; Thomas R Chauncey; Judith A Shizuru; Karl G Blume; Ute Hegenbart; Dietger Niederwieser; Stephen Forman; Benedetto Bruno; Ann Woolfrey; Rainer Storb Journal: Br J Haematol Date: 2005-05 Impact factor: 6.998
Authors: U Consoli; I El-Tounsi; A Sandoval; V Snell; H D Kleine; W Brown; J R Robinson; F DiRaimondo; W Plunkett; M Andreeff Journal: Blood Date: 1998-03-01 Impact factor: 22.113
Authors: Thomas F Kalhorn; Aaron G Ren; John T Slattery; Jeannine S McCune; Joanne Wang Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2005-04-21 Impact factor: 3.205
Authors: Michael Maris; Michael Boeckh; Barry Storer; Monja Dawson; Kristen White; Michael Keng; Brenda Sandmaier; David Maloney; Rainer Storb; Jan Storek Journal: Exp Hematol Date: 2003-10 Impact factor: 3.084
Authors: Michael B Maris; Brenda M Sandmaier; Barry E Storer; David G Maloney; Judith A Shizuru; Edward Agura; Constanze Kliem; Michael Pulsipher; Richard T Maziarz; Peter A McSweeney; James Wade; Amelia A Langston; Thomas R Chauncey; Benedetto Bruno; Karl G Blume; Rainer Storb Journal: Biol Blood Marrow Transplant Date: 2006-04 Impact factor: 5.742
Authors: M J Keating; S O'Brien; S Lerner; C Koller; M Beran; L E Robertson; E J Freireich; E Estey; H Kantarjian Journal: Blood Date: 1998-08-15 Impact factor: 22.113
Authors: D Przepiorka; D Weisdorf; P Martin; H G Klingemann; P Beatty; J Hows; E D Thomas Journal: Bone Marrow Transplant Date: 1995-06 Impact factor: 5.483
Authors: Elizabeth F Krakow; Boglarka Gyurkocza; Barry E Storer; Thomas R Chauncey; Jeannine S McCune; Jerald P Radich; Michelle E Bouvier; Elihu H Estey; Rainer Storb; David G Maloney; Brenda M Sandmaier Journal: Am J Hematol Date: 2019-11-08 Impact factor: 10.047
Authors: Kinjal Sanghavi; Anthony Wiseman; Mark N Kirstein; Qing Cao; Richard Brundage; Kyle Jensen; John Rogosheske; Andy Kurtzweil; Janel Long-Boyle; John Wagner; Erica D Warlick; Claudio G Brunstein; Daniel J Weisdorf; Pamala A Jacobson Journal: Transl Res Date: 2016-03-31 Impact factor: 7.012
Authors: E Mohanan; J C Panetta; K M Lakshmi; E S Edison; A Korula; N A Fouzia; A Abraham; A Viswabandya; V Mathews; B George; A Srivastava; P Balasubramanian Journal: Bone Marrow Transplant Date: 2017-05-08 Impact factor: 5.483
Authors: Jurgen B Langenhorst; Thomas P C Dorlo; Erik M van Maarseveen; Stefan Nierkens; Jürgen Kuball; Jaap Jan Boelens; Charlotte van Kesteren; Alwin D R Huitema Journal: Clin Pharmacokinet Date: 2019-05 Impact factor: 6.447