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

Abstract

Summary:To investigate whether we could create a radiation-free conditioning regimen to induce permanent mixed and multilineage chimerism and donor-specific tolerance, we treated recipient mice with anti-T-cell antibodies, varying and fractionated doses of Treosulfan and fully MHC disparate bone marrow cells. Treosulfan is mainly used in the treatment of ovarian cancer. It is a structural analog of busulfan, but it does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has limited organ toxicity. We report here the successful induction of permanent mixed multilineage chimerism and donor-specific tolerance as was proven by skin transplantation and IFN-c ELISPOT. In conclusion, because of its lower nonhematological toxicity, compared with other myeloablative regimens (eg irradiation or busulfan administration), Treosulfan could be a better candidate for conditioning to induce donor-specific allograft tolerance.

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

“…2,17 The repeated dose regimen was selected for this study on the basis of preclinical studies which assessed dose-and regimen-dependent haematopoietic stem cell toxicity of treosulphan in mice. 4,6,7,9 The C max and AUC values after each treosulphan dose were predictable and showed a low interpatient and interday variability. We detected no evidence for accumulation of treosulphan plasma levels or an increased drug elimination.…”

“…4 In a murine transplantation model, repeated doseregimens of treosulphan proved to be at least as effective as busulphan or total body irradiation (TBI), and further allowed the development of stable donor chimerism in recipient animals. [5][6][7][8][9] Beside its potent haematopoietic stem cell toxicity, treosulphan also demonstrated in vitro activity against a variety of haematological malignancies including acute leukaemias, chronic myelogenous leukaemia, and multiple myeloma. [10][11][12] The antileukaemic efficacy of treosulphan in human acute lymphoblastic leukaemia (ALL) xenograft models was superior compared to equitoxic doses of cyclophosphamide (Cy) or busulphan.…”

Substitution of cyclophosphamide and busulfan by fludarabine, treosulfan and melphalan in a preparative regimen for children and adolescents with Shwachman–Diamond syndrome

“…27 In vitro data have confirmed the pronounced effect of treosulfan against hematopoietic stem cells, and repeated dosing of treosulfan has been shown to be as effective as busulfan or TBI in inducing reliable donor-cell engraftment in preclinical models. 28 Additionally, antileukemic activity superior to equitoxic doses of cyclophosphamide or busulfan has been demonstrated in human acute lymphoblastic leukemia models. 29 As a result of its limited nonhematologic toxicity and robust myeloablative properties, we decided to substitute busulfan by treosulfan.…”

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

“…Treosulfan induced an immediate, strong and persisting myeloablative effect, comparable to that of BU. Moreover, when administered in combination with T-cell-depleted donor BM cells, 31,32 it provided permanent donor-specific tolerance and stable mixed multilineage chimerism across fully disparate and haploidentical MHC barriers.…”