Busulfan clearance does not predict the development of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation

Abstract

Hepatic veno-occlusive disease (VOD) is a life-threatening complication following hematopoietic stem cell transplant (HSCT). Busulfan has a narrow therapeutic index and its concentration was found to correlate with VOD. Our primary objective was to assess the association between busulfan clearance and VOD in HSCT patients. In this retrospective analysis, we included patients who received their HSCT between 2003 and 2014 and followed at Sultan Qaboos University Hospital. All patients who received dose-targeted busulfan-containing conditioning were included. Target steady-state concentration (Css) was 800–900 ng/ml. VOD was assessed using modified Seattle criteria. The impact of busulfan clearance on VOD was analyzed using univariable logistic regression model. Seventy-three patients were included with a mean age of 15 years. Of those, 47% were transplanted for hematological malignancies and 53% for inherited hemoglobinopathies. Target Css was achieved in 85% of patients. The rate of VOD was 17%. There was no significant impact of busulfan clearance (p = 0.919) or area-under-the-concentration–time-curve (p = 0.275) on VOD. Targeting busulfan Css into narrow therapeutic range may have accounted for the findings. The risk of VOD might be related to other factors such as the genetic background, and more studies are required to investigate these factors.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Tran H, Petropoulos D, Worth L, Mullen CA, Madden T, Andersson B, Choroszy M, Nguyen J, Webb SK, Chan KW. Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2004;10:805–12.

    CAS  Article  Google Scholar 

  2. 2.

    Busilvex monograph in children (monograph online). Biographix. Printed in January 2006. Available at: www.onconet.org/productos/pdf/bvx_mono_pedia07.pdf. Accessed 23 Sept 2015.

  3. 3.

    AHFS Drug Information® (database on the Internet). Busulfan. Lexi-Comp Inc. 2014. Available at: https://online.lexi.com. Accessed 20 September 2014

  4. 4.

    Ciurea SO, Andersson BS. Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:523–36.

    CAS  Article  Google Scholar 

  5. 5.

    Copelan EA. Transplantation hematopoietic stem-cell. N Engl J Med. 2006;354:1813–26.

    CAS  Article  Google Scholar 

  6. 6.

    Ten Brink MH, Zwaveling J, Swen JJ, et al. Personalized busulfan and treosulfan conditioning for pediatric stem cell transplantation: the role of pharmacogenetics and pharmacokinetics. Drug Discov Today. 2004;19(10):1572–86.

    Article  Google Scholar 

  7. 7.

    Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15(12):1628–33.

    Article  Google Scholar 

  8. 8.

    dos Reis EO, Vianna-Jorge R, Suarez-Kurtz G, et al. Development of a rapid and specific assay for detection of busulfan in human plasma by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom. 2005;19:1666–744.

    Article  Google Scholar 

  9. 9.

    Jambhekar SS, Breen PJ. Basic Pharmacokinetics. 2nd ed. London: The Pharmaceutical Press; 2012.

    Google Scholar 

  10. 10.

    Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transplant. 2016;22:400–9.

    Article  Google Scholar 

  11. 11.

    Dignan FL, Wynn RF, Hadzic N, et al. BCSH/BSBMT Guideline: Diagnosis and management of veno-occlusive disease (Sinusoidal Obstruction Syndrome) following haematopoietic stem cell transplantation [Internet]. Version 1.9. Available at: https://www.bcshguidelines.com/documents/BCSHBSBMT_Guideline_VOD_version1.11_BJH_Final_copy_2_07082013.pdf. Accessed 2013 June 28

  12. 12.

    Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, Arat M, Bader P, Baron F, Bazarbachi A, Blaise D, Ciceri F, Corbacioglu S, Dalle JH, Dignan F, Fukuda T, Huynh A, Masszi T, Michallet M, Nagler A, NiChonghaile M, Okamoto S, Pagliuca A, Peters C, Petersen FB, Richardson PG, Ruutu T, Savani BN, Wallhult E, Yakoub-Agha I, Duarte RF, Carreras E. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2016;51(7):906–12.

    CAS  Article  Google Scholar 

  13. 13.

    Carreras E, Diaz Beya M, Rosinol L, Martínez C, Fernández-Avilés F, Rovira M. The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and outcome improved over the last decade. Biol Blood Marrow Transplant. 2011;17:1713–20.

    Article  Google Scholar 

  14. 14.

    Ryu SG, Lee JH, Choi SJ, Lee JH, Lee YS, Seol M, Hur EH, Lee SH, Bae KS, Noh GJ, Lee MS, Yun SC, Han SB, Lee KH. Randomized comparison of four-times-daily versus once-daily intravenous busulfan in conditioning therapy for hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007;13:1095–105.

    CAS  Article  Google Scholar 

  15. 15.

    Defibrotide for the prophylaxis or treatment of hepatic veno-occlusive disease in adults or children undergoing haematopoietic stem-cell transplantation [Internet]. London New Drugs Evaluation. Available from: https://www.medicinesresources.nhs.uk/upload/Defibrotide.pdf. Accessed September 2013

  16. 16.

    Cappelli B, Cheisa R, Evangelio C, Biffi A, Roccia T, Frugnoli I, Biral E, Noè A, Fossati M, Finizio V, Miniero R, Napolitano S, Ferrua F, Soliman C, Ciceri F, Roncarolo MG, Marktel S. Absence of VOD in paediatric thalassaemic HSCT recipients using defibrotide prophylaxis and intravenous Busulphan. Br J Haematol. 2009;147(4):554–60.

    CAS  Article  Google Scholar 

  17. 17.

    Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea EP, Soiffer RJ, Antin JH. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood. 2007;109:4586–8.

    CAS  Article  Google Scholar 

  18. 18.

    Dennison JD, Muralitharan S, Tauro M, Zadjali S, Kindi SA, Macalalad ML. Permanent alopecia in children following busulfan based conditioning is associated with glutathione M1 null genotype. Blood. 2005;106:2740.

    Article  Google Scholar 

  19. 19.

    Srivastava A, Poonkuzhali B, Shaji RV, George B, Mathews V, Chandy M, Krishnamoorthy R. Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004;104(5):1574–7.

    CAS  Article  Google Scholar 

  20. 20.

    Salman B, Al-Za'abi M, Al-Huneini M, et al. Therapeutic drug monitoring-guided dosing of busulfan differs from weight-based dosing in hematopoietic stem cell transplant patients. Hematol Oncol Stem Cell Ther. 2017;10(2):70–8.

    CAS  Article  Google Scholar 

  21. 21.

    Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014;124(3):344–53.

    CAS  Article  Google Scholar 

  22. 22.

    Michel G, Valteau-Couanet D, Gentet JC, Esperou H, Socié G, Méchinaud F, Doz F, Neven B, Bertrand Y, Galambrun C, Demeocq F, Yakouben K, Bordigoni P, Frappaz D, Nguyen L, Vassal G. Weight-based strategy of dose administration in children using intravenous busulfan: clinical and pharmacokinetic results. Pediatr Blood Cancer. 2012;58(1):90–7.

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Murtadha Al-Khabori.

Ethics declarations

Conflict of interest

We declare that there is no conflict of interest related to the subject matter discussed in this manuscript. We also clarify that we have full control of all the primary data.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Salman, B., Al-Khabori, M., Al-Huneini, M. et al. Busulfan clearance does not predict the development of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation. Int J Hematol (2020). https://doi.org/10.1007/s12185-020-02891-0

Download citation

Keywords

  • Busulfan
  • Clearance
  • Veno-occlusive disease
  • Stem cell transplant