Toward a myeloablative regimen with clinical potential: II. Treosulfan induces specific skin graft tolerance across haploidentical MHC barriers

Abstract

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-celldepleted 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.

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.…”

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

“…One could surmise that researchers in the field have a pre-determined bias (full tolerance is the preferred outcome clinically), as evidenced by the numerous studies that chose to use clinically irrelevant MHC-congenic donors (minor antigen-matched) that are likely to give a false impression of full tolerance (skin acceptance) [16,[38][39][40][41][42][43][44], including in protocols very similar to our own [45]. No explanation is given in such studies for the unusual choice of donor/recipient combination.…”

Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial

“…2,[4][5][6][7][8] Treosulfan is a bifunctional alkylating prodrug with proven myelotoxic and immunosuppressive properties and demonstrated strong activity against hematopoietic stem cells. [9][10][11] Treosulfan-based conditioning regimens have recently been shown to have a favorable safety profile and to enable fast and sustained engraftment. [12][13][14][15][16] Low transplantation-related morbidity and sustained engraftment have also been reported in children, even in those with non-malignant diseases and at high risk of both regimen-related toxicity and graft failure.…”