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

Abstract

Allogeneic hematopoietic SCT is a curative treatment for a variety of hematological malignancies and genetic diseases. There is a continuous search for novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal antimalignancy effect. Treosulfan (L-threitol-1,4-bis-methanesulfonate; dihydroxybusulfan) was initially used in the treatment of certain solid tumors. Preclinical studies showed that it has a myeloablative effect on committed and non-committed stem cells. It has potent immunosuppressive characteristics, more prominent than its related chemotherapy agent BU, which makes it an attractive candidate for the use in conditioning regimens before allo-SCT. It is also associated with a favorable toxicity profile with little extramedullary toxicity. The combination of fludarabine and treosulfan was explored in several studies in patients not eligible for standard myeloablative conditioning, and data are rapidly emerging. This regimen is associated with consistent engraftment. A limited non-relapse mortality (NRM) rate in the range of 9-28% was observed. This rate is promising considering the patients selected and results from low rates of organ toxicity as well as acute and chronic GVHD. The regimen was also associated with low relapse rates of 5-30% depending on disease status at SCT. Together with low NRM rate, this resulted in favorable survival in the range of 40-80%. Promising results were seen in myelodysplastic syndrome (survival 36-70%) and leukemia in remission (60-70%). Randomized prospective studies will be needed to better define the role of treosulfan-based regimens in SCT.

Conditioning regimens in allo-SCT for thalassemia major

“…18 Structurally it is similar to BU. Unlike BU, it is water soluble and easy to reconstitute and administer intravenously.…”

Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats

“…Probably, TREO provides lower organ toxicity than busulfan, especially hepato-, pulmo-, and neurotoxicity. One hypothesis that needs experimental verification assumes that because of lower lipophilicity of TREO compared with busulfan, the former achieves lower concentrations in those key organs and, consequently, is less toxic (Główka et al, 2010;Danylesko et al, 2012;Shimoni et al, 2012). The underlying mechanism of potentially low neurotoxicity of TREO appears particularly important for infants, as maturity of their blood-brain barrier (BBB) is still unknown (Saunders et al, 2012).…”

Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies

“…Preclinical studies demonstrated that treosulfan has intense activity against several malignancies. 27 The combination of fludarabine and treosulfan (FT) has been introduced over the last few years as a relatively dose-intensive regimen with favorable toxicity, mostly in patients with myeloid malignancies (reviewed in Danyelsko et al 28 ). We have compared FT with busulfan based RIC or MAC regimens in patients with AML and myelodysplastic syndromes.…”