Evaluation of Reversed Administration Order of Busulfan (BU) and Cyclophosphamide (CY) as Conditioning on Liver Toxicity in Allogenic Hematopoietic Stem Cell Transplantation (ALL-HSCT)

  • Mani Ramzi Mail Hematology and Bone Marrow Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  • Nasrin Namdari Department of Hematology and Medical Oncology, Shiraz University of Medical Sciences, Shiraz, Iran
  • Shirin Haghighat Department of Hematology, Hematology Research Center, Medical Oncology and Stem Cell Transplantation, Shiraz University of Medical Sciences, Shiraz, Iran
  • Hourvash Haghighinejad Department of Family Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
Keywords:
allogeneic transplant, conditioning, busulfan, cyclophosphamide

Abstract

Background: Busulfan (BU) in combination with cyclophosphamide (CY) is used as an effective conditioning regimen in hematopoietic SCT. Busulfan, depletes glutathione level in liver and causes elevated levels of CY metabolites. Cyclophosphamide metabolites are highly toxic for sinusoidal endothelial cells and cause VOD/ SOS with high mortality rate.

Materials and Methods: All adult patients with acute leukemia, who were candidates for myeloablative allogenic SCT admitted in Stem Cell Transplantation center of our center were enrolled in this prospective randomized clinical trial during 2 years. We tested the hypothesis that reverse administration from BU-CY (28 patients) to CY-BU group (27 patients) would reduce liver toxicity.

Results: Liver function tests were significantly higher in BU-CY group between day -1 and +4 (p<0.05), but we do not have VOD/SOS in both groups. The incidence and severity of acute GVHD was higher in BU-CY group, but not statistically significant. Engraftment and mortality rate were not different.

Conclusion: These data support the concept that CY-BU is associated with less liver toxicity, suggesting CY-BU is superior to BU-CY as conditioning.

References

1. Sadeghi B, Jansson M, Hassan Z, et al. The effect of administration order of BU and CY on engraftment and toxicity in HSCT mouse model. Bone Marrow Transplant. 2008; 41(10): 895-904
2. Dalle J, Giralt S. Hepatic Veno-Occlusive Disease after Hematopoietic Stem cell Transplantation: risk factors and Stratification, Prophylaxis, and Treatment. Biol Blood Marrow Transplant. 2016; 22(3): 400-409
3. Brodsky R, Topolsky D, Crilley P, et al. Frequency of veno-occlusive disease of the liver in bone marrow transplantation with a modified busulfan/cyclophosphamide preparative regimen. Am J Clin Oncol. 1990; 13(3): 221-5
4. Vassal G, Hartmann O, Benhamou E. Busulfan and veno-occlusive disease of the liver. Ann Intern Med. 1990; 112(11): 881.
5. Ljungman P, Hassan M, Bekasy AN, et al. High busulfan concentrations are associated with increased transplant-related mortality in allogenic bone marrow transplant patients. Bone Marrow Transplant. 1997; 20(11): 909-13.
6. Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010; 16(2): 157-168.
7. Ho VT, Revta C, Richardson PG. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Update on defibrotide and other current investigational therapies. Bone Marrow Transplant. 2008: 41(3): 229-237.
8. Cantoni N, Gerull S, Heim D, et al. Order of application and liver toxicity in patients given BU and Cy containing conditioning regimens for allogenic hematopoietic SCT. Bone Marrow Transplant. 2011; 46: 344-349.
9. Moore MJ. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 1991; 20(3): 194-208.
10. Deleve LD. Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation. Hepatology. 1996; 24(4): 830-837.
11. Deleve LD, Wang X. Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes. Pharmacology. 2000; 60 (3): 143-54.
12. Hassan Z, Hellstrom-lindberg E, Alsadi S, et al. The effect of modulation of glutathione cellular content on busulphan-induced cytotoxicity on hematopoietic cells in vitro and in vivo. Bone Marrow Transplant. 2002; 30(3): 141-7.
13. McDonald Gb, Slattery JT, bouvier ME, et al. Cyclophosphamide metabolism, liver toxicity and mortality following hematopoietic stem cell transplantation. Blood. 2003; 101(5): 2043-8.
14. Hassan M, Ljungman P, Ringden o, et al. The effect of busulfan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy related toxicity. Bone marrow Transplant. 2000; 25(9): 915-924.
15. Fleming RA. An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy. 1997; 17 (5 Pt 2): 146S-154S.
16. Dirven HA, van Ommen B, van Bladeren PJ. Involvment of human glutathione S-transferase isoenzymes in the conjugation of cyclophosphamide metabolites with glutathione. Cancer Res.1994; 54(23): 6215-20.
17. Hassan Z, Hellstrom-Lindberg E, Alsadi s, et al. The effect of modulation of Glutathione cellular content on busulfan-induced cytotoxicity on hematopoietic cells in vitro and in vivo. Bone Marrow Transplant. 2002; 30(3): 141-7.
18. Wang X, KanelGc, Deleve LD. Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat. Hepatology. 2000; 31(2): 428-34.
19. Meresse V, Hartmann O, Vassal G, et al. Risk factors for hepatic veno-occlusive disease after high-dose busulfan-cantaining regimens followed by autologous bone marrow Transplantation: a study in 136 children. Bone marrow Transplant. 1992; 10(2): 135-41.
20. Kerbauy FR, Tirapelli B, Akabane H, et al. The effect of administration order of BU and Cy on toxicity in Hematopoietic SCT in humans. Bone Marrow Transplant. 2009; 43(11): 883-5.
21. Rezvani AR, McCune JS, Storer BE. Cyclophosphamide followed by Intravenous Targeted Busulfan for Allogenic Hematopoietic Cell Transplantation: Pharmacokinetics and clinical outcomes. Biol Blood Marrow Transplant. 2013; 19(7): 1033-39.
22. Nilsson C, Forsman J, Hassan Z, et al. Effect of altering administration order of busulphan and cyclophosphamide on the myeloablative and immunosuppressive properties of the conditioning regimen in mice. Exp Hematol. 2005; 33(3): 380–7.
Published
2020-07-02
How to Cite
1.
Ramzi M, Namdari N, Haghighat S, Haghighinejad H. Evaluation of Reversed Administration Order of Busulfan (BU) and Cyclophosphamide (CY) as Conditioning on Liver Toxicity in Allogenic Hematopoietic Stem Cell Transplantation (ALL-HSCT). Int J Hematol Oncol Stem Cell Res. 14(3):171-176.
Section
Original Article(s)