High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation

J R Long-Boyle, K G Green, C G Brunstein, Q Cao, J Rogosheske, D J Weisdorf, J S Miller, J E Wagner, P B McGlave, P A Jacobson, J R Long-Boyle, K G Green, C G Brunstein, Q Cao, J Rogosheske, D J Weisdorf, J S Miller, J E Wagner, P B McGlave, P A Jacobson

Abstract

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.

Conflict of interest statement

Conflict of Interest/Funding Disclosures: We have no conflicts of interest to disclose. This work was supported by grants from the National Institutes of Health, National Cancer Institute (CA096622) (P.J.), and National Institutes of Health National Center for Research Services (M01-RR00400).

Figures

Figure 1. F-ara-A Time vs Concentration Profile…
Figure 1. F-ara-A Time vs Concentration Profile with first dose of fludarabine1
1data are mean (standard deviation), 2patients receiving standard doses of fludarabine with CrCl median (range) of 85.9ml/min (49.5-153.2), 3patients receiving dose modifications of fludarabine based on pre-existing mild to moderate renal insufficiency with CrCl median (range) of 57.1ml/min (50.5-65.1).
Figure 2. Cumulative incidence of TRM for…
Figure 2. Cumulative incidence of TRM for patients 6 months after nonmyeloablative HCT
(A) Overall TRM. (B) TRM for patient with F-ara-A AUC(0-∞) ≤6.5ug*hr/mL compared to patients with AUC(0-∞) >6.5ug*hr/mL.
Figure 3. Cumulative proportion of overall survival…
Figure 3. Cumulative proportion of overall survival for patients 6 months after nonmyeloablative HCT
(A) Overall survival. (B) Overall survival for patient with F-ara-A AUC(0-∞) ≤6.5ug*hr/mL compared to patients with AUC(0-∞) >6.5ug*hr/mL.

References

    1. Baron F, Storb R. Allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning as treatment for hematologic malignancies and inherited blood disorders. Mol Ther. 2006;13(1):26–41.
    1. Brockman RW, Cheng YC, Schabel FM, Jr, Montgomery JA. Metabolism and chemotherapeutic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine against murine leukemia L1210 and evidence for its phosphorylation by deoxycytidine kinase. Cancer Res. 1980;40(10):3610–5.
    1. Dow LW, Bell DE, Poulakos L, Fridland A. Differences in metabolism and cytotoxicity between 9-beta-D arabinofuranosyladenine and 9-beta-D-arabinofuranosyl-2-fluoroadenine in human leukemic lymphoblasts. Cancer Res. 1980;40(5):1405–10.
    1. Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D, et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood. 2003;102(6):2021–30.
    1. Brunstein CG, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR, et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007;110(8):3064–70.
    1. Anderlini P, Saliba R, Acholonu S, Giralt SA, Andersson B, Ueno NT, et al. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated M.D. Anderson Cancer Center experience. Haematologica. 2008;93(2):257–64.
    1. Plunkett W, Huang P, Gandhi V. Metabolism and action of fludarabine phosphate. Semin Oncol. 1990;17(5 Suppl 8):3–17.
    1. Danhauser L, Plunkett W, Liliemark J, Gandhi V, Iacoboni S, Keating M. 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. 1987;1(9):638–43.
    1. Danhauser L, Plunkett W, Keating M, Cabanillas F. 9-beta-D-arabinofuranosyl-2-fluoroadenine 5′-monophosphate pharmacokinetics in plasma and tumor cells of patients with relapsed leukemia and lymphoma. Cancer Chemother Pharmacol. 1986;18(2):145–52.
    1. Avramis VI, Champagne J, Sato J, Krailo M, Ettinger LJ, Poplack DG, et al. Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients. Cancer Res. 1990;50(22):7226–31.
    1. Avramis VI, Wiersma S, Krailo MD, Ramilo-Torno LV, Sharpe A, Liu-Mares W, et al. Pharmacokinetic and pharmacodynamic studies of fludarabine and cytosine arabinoside administered as loading boluses followed by continuous infusions after a phase I/II study in pediatric patients with relapsed leukemias. The Children's Cancer Group. Clin Cancer Res. 1998;4(1):45–52.
    1. Gandhi V, Plunkett W. Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet. 2002;41(2):93–103.
    1. Lichtman SM, Etcubanas E, Budman DR, Eisenberg P, Zervos G, D'Amico P, et al. The pharmacokinetics and pharmacodynamics of fludarabine phosphate in patients with renal impairment: a prospective dose adjustment study. Cancer Invest. 2002;20(7-8):904–13.
    1. Hersh MR, Kuhn JG, Phillips JL, Clark G, Ludden TM, Von Hoff DD. Pharmacokinetic study of fludarabine phosphate (NSC 312887) Cancer Chemother Pharmacol. 1986;17(3):277–80.
    1. Hutton JJ, Von Hoff DD, Kuhn J, Phillips J, Hersh M, Clark G. Phase I clinical investigation of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5′-monophosphate (NSC 312887), a new purine antimetabolite. Cancer Res. 1984;44(9):4183–6.
    1. Kuo GM, Boumpas DT, Illei GG, Yarboro C, Pucino F, Burstein AH. Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis. Pharmacotherapy. 2001;21(5):528–33.
    1. Knebel W, Davis JC, Jr, Sanders WD, Fessler B, Yarboro C, Pucino F, et al. The pharmacokinetics and pharmacodynamics of fludarabine in rheumatoid arthritis. Pharmacotherapy. 1998;18(6):1224–9.
    1. Malspeis L, Grever MR, Staubus AE, Young D. Pharmacokinetics of 2-F-ara-A (9-beta-D-arabinofuranosyl-2-fluoroadenine) in cancer patients during the phase I clinical investigation of fludarabine phosphate. Semin Oncol. 1990;17(5 Suppl 8):18–32.
    1. Bonin M, Pursche S, Bergeman T, Leopold T, Illmer T, Ehninger G, et al. F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bone Marrow Transplant. 2007;39(4):201–6.
    1. Bornhauser M, Storer B, Slattery JT, Appelbaum FR, Deeg HJ, Hansen J, et al. Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells. Blood. 2003;102(3):820–6.
    1. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.
    1. Weisdorf DJ, Snover DC, Haake R, Miller WJ, McGlave PB, Blazar B, et al. Acute upper gastrointestinal graft-versus-host disease: clinical significance and response to immunosuppressive therapy. Blood. 1990;76(3):624–9.
    1. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825–8.
    1. . (CDER) CfDEaR, (ed) 1998. Guidance for industry: Pharmacokinetics in patients with impaired renal function-study design, data analysis, and impact on dosing and labeling.
    1. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912–9.
    1. Majhail NS, Brunstein CG, McAvoy S, DeFor TE, Al-Hazzouri A, Setubal D, et al. Does the hematopoietic cell transplantation specific comorbidity index predict transplant outcomes? A validation study in a large cohort of umbilical cord blood and matched related donor transplants. Biol Blood Marrow Transplant. 2008;14(9):985–92.
    1. . Product Information: Fludara (R) (fludarabine phosphate) For Injection. Berlex Laboratories; Richmond, California: 2002.
    1. McCune JS, Batchelder A, Guthrie KA, Witherspoon R, Appelbaum FR, Phillips B, et al. Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy. Clin Pharmacol Ther. 2009;85(6):615–22.
    1. McCune JS, Salinger DH, Vicini P, Oglesby C, Blough DK, Park JR. Population pharmacokinetics of cyclophosphamide and metabolites in children with neuroblastoma: a report from the Children's Oncology Group. J Clin Pharmacol. 2009;49(1):88–102.
    1. Ding X, Herzlich AA, Bishop R, Tuo J, Chan CC. Ocular toxicity of fludarabine: a purine analog. Expert Rev Ophthalmol. 2008;3(1):97–109.
    1. Cheson BD, Vena DA, Foss FM, Sorensen JM. Neurotoxicity of purine analogs: a review. J Clin Oncol. 1994;12(10):2216–28.
    1. Narimatsu H, Miyamura K, Iida H, Hamaguchi M, Uchida T, Morishita Y. Early central nervous complications after umbilical cord blood transplantation for adults. Biol Blood Marrow Transplant. 2009;15(1):92–100.
    1. Gonzalez H, Bolgert F, Camporo P, Leblond V. Progressive multifocal leukoencephalitis (PML) in three patients treated with standard-dose fludarabine (FAMP) Hematol Cell Ther. 1999;41(4):183–6.
    1. Saumoy M, Castells G, Escoda L, Mares R, Richart C, Ugarriza A. Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine. Leuk Lymphoma. 2002;43(2):433–6.
    1. Kiewe P, Seyfert S, Korper S, Rieger K, Thiel E, Knauf W. Progressive multifocal leukoencephalopathy with detection of JC virus in a patient with chronic lymphocytic leukemia parallel to onset of fludarabine therapy. Leuk Lymphoma. 2003;44(10):1815–8.
    1. Vidarsson B, Mosher DF, Salamat MS, Isaksson HJ, Onundarson PT. Progressive multifocal leukoencephalopathy after fludarabine therapy for low-grade lymphoproliferative disease. Am J Hematol. 2002;70(1):51–4.
    1. Neff RT, Hurst FP, Falta EM, Bohen EM, Lentine KL, Dharnidharka VR, et al. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation. 2008;86(10):1474–8.
    1. Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol. 1999;246(5):339–46.
    1. Minn AY, Fisher PG, Barnes PD, Dahl GV. A syndrome of irreversible leukoencephalopathy following pediatric allogeneic bone marrow transplantation. Pediatr Blood Cancer. 2007;48(2):213–7.
    1. Mackey JR, Galmarini CM, Graham KA, Joy AA, Delmer A, Dabbagh L, et al. Quantitative analysis of nucleoside transporter and metabolism gene expression in chronic lymphocytic leukemia (CLL): identification of fludarabine-sensitive and -insensitive populations. Blood. 2005;105(2):767–74.
    1. Lamba JK, Crews K, Pounds S, Schuetz EG, Gresham J, Gandhi V, et al. Pharmacogenetics of deoxycytidine kinase: identification and characterization of novel genetic variants. J Pharmacol Exp Ther. 2007;323(3):935–45.
    1. Molina-Arcas M, Marce S, Villamor N, Huber-Ruano I, Casado FJ, Bellosillo B, et al. Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells. Leukemia. 2005;19(1):64–8.
    1. Jacobson P, Rogosheske J, Barker JN, Green K, Ng J, Weisdorf D, et al. Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation. Clin Pharmacol Ther. 2005;78(5):486–500.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅