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A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients

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Abstract

Purpose

Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin®) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/Tbusulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients.

Methods

We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan, specifically busulfan concentration at steady state, and fludarabine, specifically F-ara-A area under the curve (AUC) and fludarabine triphosphate (F-ara-ATP) intracellular accumulation and concentration in separate CD4+ and CD8+ T-lymphocyte populations.

Results

Acute and chronic graft versus host disease (GvHD) occurred in 11 patients and one patient, respectively. Four patients died before day +100 of non-relapse causes, which met the protocol stopping guidelines. The cumulative incidence of relapse was 25% at 3 year post-HCT. Interpatient variability in the busulfan- and fludarabine-relevant pharmacologic biomarkers was 2.1- to 2.5-fold. F-ara-A AUC and accumulated F-ara-ATP in CD8+ cells had the highest hazard ratio for non-relapse mortality and overall survival, respectively. However, neither achieved statistical significance.

Conclusions

The low rates of GvHD, particularly in its chronic form, were encouraging, and further biomarker studies are warranted to optimize the fludarabine/Tbusulfan/rATG conditioning regimen.

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References

  1. McCune JS, Batchelder A, Deeg HJ, Gooley T, Cole S, Phillips B, Schoch HG, McDonald GB (2007) Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality. Biol Blood Marrow Transplant 13(7):853–862

    Article  PubMed  CAS  Google Scholar 

  2. Bornhauser M, Storer B, Slattery JT, Appelbaum FR, Deeg HJ, Hansen J, Martin PJ, McDonald GB, Nichols WG, Radich J, Woolfrey A, Jenke A, Schleyer E, Thiede C, Ehninger G, Anasetti C (2003) Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells. Blood 102(3):820–826

    Article  PubMed  Google Scholar 

  3. Russell JA, Turner AR, Larratt L, Chaudhry A, Morris D, Brown C, Quinlan D, Stewart D (2007) Adult recipients of matched related donor blood cell transplants given myeloablative regimens including pretransplant antithymocyte globulin have lower mortality related to graft-versus-host disease: a matched pair analysis. Biol Blood Marrow Transplant 13(3):299–306. doi:10.1016/j.bbmt.2006.10.017

    Article  PubMed  CAS  Google Scholar 

  4. Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M, Roberson S, Giralt S, Pierre B, Russell JA, Shpall EJ, Jones RB, Champlin RE (2008) Once daily i.v. busulfan and fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant 14(6):672–684

    Google Scholar 

  5. Bredeson CN, Zhang MJ, Agovi MA, Bacigalupo A, Bahlis NJ, Ballen K, Brown C, Chaudhry MA, Horowitz MM, Kurian S, Quinlan D, Muehlenbien CE, Russell JA, Savoie L, Rizzo JD, Stewart DA (2008) Outcomes following HSCT using fludarabine, busulfan, and thymoglobulin: a matched comparison to allogeneic transplants conditioned with busulfan and cyclophosphamide. Biol Blood Marrow Transplant 14(9):993–1003. doi:10.1016/j.bbmt.2008.06.009

    Article  PubMed  CAS  Google Scholar 

  6. McCune JS, Holmberg LA (2009) Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol 5(8):957–969. doi:10.1517/17425250903107764

    Article  PubMed  CAS  Google Scholar 

  7. Geddes M, Kangarloo SB, Naveed F, Quinlan D, Chaudhry MA, Stewart D, Savoie ML, Bahlis NJ, Brown C, Storek J, Andersson BS, Russell JA (2008) High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant 14 (2):220–228

    Google Scholar 

  8. Ciurea SO, Andersson BS (2009) Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 15(5):523–536. doi:10.1016/j.bbmt.2008.12.489

    Article  PubMed  CAS  Google Scholar 

  9. Danhauser L, Plunkett W, Liliemark J, Gandhi V, Iacoboni S, Keating M (1987) Comparison between the plasma and intracellular pharmacology of 1-beta-d-arabinofuranosylcytosine and 9-beta-d-arabinofuranosyl-2-fluoroadenine 5’-monophosphate in patients with relapsed leukemia. Leukemia 1(9):638–643

    PubMed  CAS  Google Scholar 

  10. Gandhi V, Plunkett W (2002) Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet 41(2):93–103

    Article  PubMed  CAS  Google Scholar 

  11. Robak T, Lech-Maranda E, Korycka A, Robak E (2006) Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Current Med Chem 13(26):3165–3189

    Article  CAS  Google Scholar 

  12. Johnson SA (2000) Clinical pharmacokinetics of nucleoside analogues: focus on haematological malignancies. Clin Pharmacokinet 39(1):5–26

    Article  PubMed  CAS  Google Scholar 

  13. Woodahl EL, Wang J, Heimfeld S, Sandmaier BM, O’Donnell PV, Phillips B, Risler L, Blough DK, McCune JS (2009) A novel phenotypic method to determine fludarabine triphosphate accumulation in T-lymphocytes from hematopoietic cell transplantation patients. Cancer Chemother Pharmacol 63(3):391–401

    Google Scholar 

  14. Petersdorf EW, Anasetti C, Martin PJ, Gooley T, Radich J, Malkki M, Woolfrey A, Smith A, Mickelson E, Hansen JA (2004) Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood 104(9):2976–2980

    Article  PubMed  CAS  Google Scholar 

  15. Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C, Stewart D, Ruether JD, Morris D, Glick S, Gyonyor E, Andersson BS (2002) Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant 8(9):468–476

    Article  PubMed  CAS  Google Scholar 

  16. Salinger DH, Vicini P, Blough DK, O’Donnell PV, Pawlikowski MA, McCune JS (2010) Development of a population pharmacokinetics-based sampling schedule to target daily intravenous busulfan for outpatient clinic administration. J Clin Pharmacol. doi:10.1177/0091270009357430

  17. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 15(6):825–828

    PubMed  CAS  Google Scholar 

  18. Lee SJ, Vogelsang G, Flowers ME (2003) Chronic graft-versus-host disease. Biol Blood Marrow Transplant 9(4):215–233. doi:10.1053/bbmt.2003.50026

    Article  PubMed  CAS  Google Scholar 

  19. Deeg HJ (2007) How I treat refractory acute GVHD. Blood 109(10):4119–4126. doi:10.1182/blood-2006-12-041889

    Article  PubMed  CAS  Google Scholar 

  20. Bonin M, Pursche S, Bergeman T, Leopold T, Illmer T, Ehninger G, Schleyer E, Bornhauser M (2007) F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bone Marrow Transplant 39(4):201–206

    Article  PubMed  CAS  Google Scholar 

  21. Segel GB, Cokelet GR, Lichtman MA (1981) The measurement of lymphocyte volume: importance of reference particle deformability and counting solution tonicity. Blood 57(5):894–899

    PubMed  CAS  Google Scholar 

  22. Slattery JT, Risler LJ (1998) Therapeutic monitoring of busulfan in hematopoietic stem cell transplantation. Ther Drug Monit 20(5):543–549

    Article  PubMed  CAS  Google Scholar 

  23. Stem Cell Trialists’ Collaborative Group (2005) Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol 23(22):5074–5087. doi:10.1200/JCO.2005.09.020

    Google Scholar 

  24. Martin PJ, McDonald GB, Sanders JE, Anasetti C, Appelbaum FR, Deeg HJ, Nash RA, Petersdorf EW, Hansen JA, Storb R (2004) Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 10(5):320–327

    Article  PubMed  Google Scholar 

  25. Hockenbery DM, Cruickshank S, Rodell TC, Gooley T, Schuening F, Rowley S, David D, Brunvand M, Berryman B, Abhyankar S, Bouvier M, McDonald GB (2007) A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisone-sparing therapy for gastrointestinal graft-versus-host disease. Blood 109(10):4557–4563

    Article  PubMed  CAS  Google Scholar 

  26. Kolb HJ, Storb R, Weiden PL, Ochs HD, Kolb H, Graham TC, Floersheim GL, Thomas ED (1974) Immunologic, toxicologic and marrow transplantation studies in dogs given dimethyl myleran. Biomedicine 20(5):341–351

    PubMed  CAS  Google Scholar 

  27. Santos GW, Tutschka PJ (1974) Marrow transplantation in the busulfan-treated rat: preclinical model of aplastic anemia. J Natl Cancer Inst 53(6):1781–1785

    PubMed  CAS  Google Scholar 

  28. Yeh RF, Pawlikowski MA, Blough DK, McDonald GB, O’Donnell PV, Rezvani A, Deeg HJ, McCune JS (2011) Accurate targeting of daily intravenous busulfan with 8-hour blood sampling in hospitalized adult hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. doi: 10.1016/j.bbmt.2011.06.013

  29. Slattery JT, Sanders JE, Buckner CD, Schaffer RL, Lambert KW, Langer FP, Anasetti C, Bensinger WI, Fisher LD, Appelbaum FR et al (1995) Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant 16(1):31–42

    PubMed  CAS  Google Scholar 

  30. McDonald GB, Slattery JT, Bouvier ME, Ren S, Batchelder AL, Kalhorn TF, Schoch HG, Anasetti C, Gooley T (2003) Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 101(5):2043–2048

    Article  PubMed  CAS  Google Scholar 

  31. McCune JS, Batchelder A, Guthrie KA, Witherspoon R, Appelbaum FR, Phillips B, Vicini P, Salinger DH, McDonald GB (2009) Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy. Clin Pharmacol Ther 85(6):615–622

    Article  PubMed  CAS  Google Scholar 

  32. Jacobson PA, Rogosheske J, Green K, Brunstein C, Barker J, Miller J, Wagner J, McGlave P, Tan Y, Weisdorf D (2005) Fludarabine Pharmacokinetics in nonmyeloablative hematopoietic cell transplantation (HCT): association with engraftment and neurotoxicity. Blood 106. Abstract #3673

  33. Salinger DH, Blough DK, Vicini P, Anasetti C, O’Donnell PV, Sandmaier BM, McCune JS (2009) A limited sampling schedule to estimate individual pharmacokinetic parameters of fludarabine in hematopoietic cell transplant patients. Clin Cancer Res 15(16):5280–5287. doi:10.1158/1078-0432.CCR-09-0427

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to the study participants, their caregivers, and the patient care staff for their support of this study. The authors acknowledge Ms. Linda Risler for her analytical expertise, Mr. Matthew Pawlikowski for his database expertise, and Ms. Meagan Bemer for her editorial expertise. This study is supported by grants from the National Institutes of Health (CA18029, CA15704, CA78902, DK56465, HL36444). ELW was supported by the Elmer M. and Joy B. Plein Fellowship for Excellence in Pharmacy Education, School of Pharmacy, Seattle, WA.

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Author notes

  1. Erica L. Woodahl

    Present address: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, USA

Authors and Affiliations

  1. School of Pharmacy, University of Washington, Box 357630, Seattle, WA, 98195-7630, USA

    Jeannine S. McCune, Erica L. Woodahl & Joanne Wang

  2. School of Medicine, University of Washington, Seattle, WA, USA

    H. Joachim Deeg & Paul V. O’Donnell

  3. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Jeannine S. McCune, Erica L. Woodahl, Terry Furlong, Barry Storer, Joanne Wang, Shelly Heimfeld, H. Joachim Deeg & Paul V. O’Donnell

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  1. Jeannine S. McCune
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Correspondence to Jeannine S. McCune.

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McCune, J.S., Woodahl, E.L., Furlong, T. et al. A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. Cancer Chemother Pharmacol 69, 263–272 (2012). https://doi.org/10.1007/s00280-011-1736-3

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