Summary:
Treosulfan is a water-soluble structural analog of busulfan, acting as a prodrug of alkylating epoxide species. It does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has a limited organ toxicity. It is mainly indicated for the treatment of patients with ovarian cancer. In the present study, we report that permanent donor-specific tolerance and stable mixed multilineage chimerism can successfully be achieved across haploidentical MHC barriers when Treosulfan is administered in combination with anti-T-cell mAb and T-cell-depleted donor bone marrow cells. Furthermore, we show that less T-cell suppression is required when Treosulfan is included in the conditioning regimen. In conclusion, Treosulfan is a well-tolerated myeloablative agent with a low toxicity, and is a promising candidate drug for conditioning prior to bone marrow transplantation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Glover MT, Deeks JJ, Raftery MJ et al. Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients. Lancet 1997; 349: 398.
Penn I . Occurrence of cancers in immunosuppressed organ transplant recipients. In: Cecka GM, Terasaki PI (eds.) Clinical Transplants, Tissue Typing Laboratory: Los Angeles, California, USA, 1998; 147–158.
Falkenhain ME, Cosio FG, Sedmak DD . Progressive histologic injury in kidneys from heart and liver transplant recipients receiving cyclosporine. Transplantation 1996; 62: 364–370.
Sharabi Y, Sachs DH . Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen. J Exp Med 1989; 169: 493–502.
Wekerle T, Sykes M . Mixed chimerism as an approach for the induction of transplantation tolerance. Transplantation 1999; 68: 459–467.
de Vries-van der Zwan A, Besseling AC, Kievits F et al. Anti-CD3 treatment facilitates engraftment of full H-2-disparate donor bone marrow cells and subsequent skin allograft tolerance. Transplantation 1994; 58: 610–617.
de Vries-van der Zwan A, Besseling AC, van der Pol MA et al. Specific tolerance induction and organ transplantation. Leuk Lymphoma 1998; 31: 131–142.
de Vries-van der Zwan A, Besseling AC, de Waal LP et al. Specific tolerance induction and transplantation: a single-day protocol. Blood 1997; 89: 2596–2601.
van Pel M, Hilbrands L, Smits D et al. Permanent acceptance of both cardiac and skin allografts using a mild conditioning regimen for the induction of stable mixed chimerism in mice. Transplant Immunol 2003; 11: 57–63.
Scheulen ME, Hilger RA, Oberhoff C et al. Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies. Clin Cancer Res 2000; 6: 4209–4216.
Breitbach GP, Meden H, Schmid H et al. Treosulfan in the treatment of advanced ovarian cancer: a randomised co-operative multicentre phase III-study. Anticancer Res 2002; 22: 2923–2932.
Merkle E, Ackermann S, Beck EP et al. High-dose versus low-dose Cisplatin chemotherapy plus Treosulfan in epithelial ovarian carcinoma FIGO II-IV: results of a prospective randomized trial. Onkologie 2000; 23: 232–238.
Gropp M, Meier W, Hepp H . Treosulfan as an effective second-line therapy in ovarian cancer. Gynecol Oncol 1998; 71: 94–98.
Harstrick A, Wilke H, Eberhardt W et al. A phase I dose escalation trial of intravenous Treosulfan in refractory cancer. Onkologie 1996; 19: 153–156.
van Pel M, van Breugel DWJG, Vos W et al. Towards a myeloablative regimen with clinical potential: I Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers. Bone Marrow Transplant 2003; 32: 15–22.
Hiruma K, Hirsch R, Patchen M et al. Effects of anti-CD3 monoclonal antibody on engraftment of T-cell- depleted bone marrow allografts in mice: host T-cell suppression, growth factors, and space. Blood 1992; 79: 3050–3058.
Ferran C, Sheehan K, Dy M et al. Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T cell activation. Eur J Immunol 1990; 20: 509–515.
Leo O, Foo M, Sachs DH et al. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci USA 1987; 84: 1374–1378.
Zeiger E, Pagano DA . Mutagenicity of the human carcinogen treosulphan in Salmonella. Environ Mol Mutagen 1989; 13: 343–346.
Beelen DW, Trenschel R, Casper J et al. Evaluation of safety, efficacy and pharmacokinetics of dose-escalated Treosulfan (TREO)/cyclophosphamdie (CY) conditioning prior to allogeneic transplantation of high-risk leukemia patients. 44th Annual Meeting of the American Society of Hematology, 2002, Philadelphia, USA. Blood 100: 415a (Abstr. 1608).
Casper J, Knauf W, Kiefer T et al. Treosulfan and Fludarabine: a new toxicity-reduced conditioning regimen for allogeneic blood stem cell transplantation. Blood 2003, in press.
Westerhof GR, Ploemacher RE, Boudewijn A et al. Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients. Cancer Res 2000; 60: 5470–5478.
Westerhof GR, Blokland I, Down JD et al. In vivo and in vitro sensitivity of murine bone marrow hematopoietic progenitors for Treosulfan. Blood 1998; 92: 197b.
Ploemacher RE, Westerhof GR, Blokland I et al. Treosulfan as an alternative conditioning agent in bone marrow transplantation. Bone Marrow Transplant 2000; 25 (Abstr. P421).
Fichtner I, Becker M, Baumgart J . Antileukaemic activity of Treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). Eur J Cancer 2003; 39: 801–807.
Griskevicius L, Gaughan U, Nilsson C et al. The myeloablative and immunosuppressive properties of Treosulfan in mice. 28th Annual Meeting of the European Group of Blood and Marrow Transplantation, 2002, Montreux, Switzerland. Bone Marrow Transplant 29: S2–S153, (Abstr. P603).
Hirsch R, Eckhaus M, Auchincloss Jr H et al. Effects of in vivo administration of anti-T3 monoclonal antibody on T cell function in mice. I. Immunosuppression of transplantation responses. J Immunol 1988; 140: 3766–3772.
van Pel M, Vingerhoed J, de Vries-van der Zwan et al. Mechanisms of donor-specific tolerance in a skin transplantation model. Transplant Proc 2001; 33: 152–153.
Andersson G, Illigens BMW, Johnson KW et al. Non-myeloablative conditioning is sufficient to allow engraftment of EGFP-expressing bone marrow and subsequent acceptance of EGFP-transgenic skin grafts in mice. Blood (2003), in press.
Acknowledgements
We thank Sacco Luypen and Mathijs van Eck for assistance in the animal experiments and animal care, Joost Uittenboogaard and Wilma Witkamp for technical assistance and Wietse Kuis and Joachim Baumgart (medac) for critically reading the manuscript. This study was financially supported by the Dutch Kidney Foundation (Grant C97.1669)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
van Pel, M., van Breugel, D., Vos, W. et al. Toward a myeloablative regimen with clinical potential: II. Treosulfan induces specific skin graft tolerance across haploidentical MHC barriers. Bone Marrow Transplant 33, 153–159 (2004). https://doi.org/10.1038/sj.bmt.1704333
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bmt.1704333
Keywords
This article is cited by
-
Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike
Bone Marrow Transplantation (2012)
-
Second hematopoietic SCT in patients with thalassemia recurrence following rejection of the first graft
Bone Marrow Transplantation (2008)
-
Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic haematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications
Bone Marrow Transplantation (2005)