Treosulfan (DB11678): A Comprehensive Monograph on a Modern Myeloablative Conditioning Agent

Executive Summary

Treosulfan is a bifunctional alkylating agent, classified as a pharmacologically inactive prodrug, that has emerged as a significant component of conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (alloHSCT).[1] Structurally, it is a water-soluble dihydroxy derivative of busulfan, a feature that contributes to its distinct physicochemical and pharmacokinetic profile.[3] Its primary clinical application, in combination with fludarabine, is as a myeloablative conditioning agent for adult and pediatric patients with malignant hematological diseases, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).[1] In certain jurisdictions, its use extends to non-malignant disorders requiring alloHSCT.[5]

The mechanism of action of Treosulfan is unique among alkylating agents used in this setting. It undergoes a spontaneous, non-enzymatic conversion under physiological conditions of pH and temperature to form cytotoxic epoxide metabolites.[3] These active compounds, primarily (2S,3S)-1,2:3,4-diepoxybutane (S,S-DEB), subsequently alkylate DNA, inducing intra- and inter-strand cross-links that disrupt cellular processes and lead to apoptosis, particularly in rapidly dividing hematopoietic cells.[1] This non-enzymatic activation pathway results in highly predictable pharmacokinetics, obviating the need for therapeutic drug monitoring, which is a notable advantage over traditional busulfan-based regimens.[8]