Treosulfan in combination with fludarabine as part of conditioning treatment prior to allogeneic hematopoietic stem cell transplantation.

The combination of treosulfan with fludarabine (Treo-Flu) is one of the new megatherapies prior to hematopoietic stem cell transplantation. Preclinical studies have documented the myeloablative and myelosuppressive effects of treosulfan, in addition to its immunosuppressive and antimalignant activities. Treosulfan pharmacokinetics involves nonenzymatic activation and generation of epoxides as active compounds. In the clinical studies, the most common adverse effects of Treo-Flu were grade 4 hematologic toxicities with leukopenia, neutropenia and thrombocytopenia. Among the most common nonhematologic toxicities, grade 2 or lower mucositis was usually reported. One of the advantages of treosulfan-based conditioning regimens is their good safety profile, especially the low risk of hepatic venoocclusive disease. Additional drugs reported in combination with the Treo-Flu backbone are thiotepa and melphalan. Treo-Flu alone and in multiple drug combinations can be successfully and safely combined with posttransplant cyclophosphamide immunosuppression for unma¬nipulated haploidentical transplantations. On the basis of chimerism studies, the Treo-Flu megatherapy lacks full myeloablative potential, but the profound myelosuppression with donor cell-mediated alloreactivity can result in full donor chimerism in the majority of transplant recipients. The clinical studies of allogeneic hematopoietic stem cell transplantation show high heterogeneity, but the safety and feasibility of the Treo-Flu regimen are evident and support its place among reduced-intensity protocols.