Treosulfan Plus Fludarabine Approved as alloHSCT Preparative Regimen for AML and MDS

The FDA has granted approval to treosulfan (Grafapex^TM, medac GmbH), an alkylating agent, in combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHSCT) in adult and pediatric patients one year of age and older with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Why Is the Approval of Treosulfan Important?

“Further improvement of preparative regimens before alloHSCT is an unmet medical need for the growing number of older or comorbid patients with AML or MDS,” wrote Dietrich Beelen, MD, Head of the Department of Bone Marrow Transplantation at the University Hospital Essen, and colleagues in their published results of the MC-FludT.14/L trial (NCT00822393), on which approval was based.

Investigating Treosulfan in the MC-FludT.14/L Trial

Efficacy was measured in the phase 3, active-controlled trial which enrolled 570 patients between 18 to 70 years old. Eligible patients had AML or MDS, had a Karnofsky performance status ≥60%, and were age ≥50 years or had a hematopoietic cell transplantation comorbidity index (HCTCI) score >2. Patients were randomized 1:1 to receive either treosulfan or busulfan, both with fludarabine, as a preparative regimen for allogeneic transplantation. The primary efficacy outcome measured was overall survival.

The hazard ratio for overall survival (stratified by donor type and risk group) for treosulfan versus busulfan was 0.73 for patients with AML, 0.64 for patients with MDS, and 0.67 for the overall randomized population.

Adverse Events

The most common adverse events experienced by ≥20% of patients receiving treosulfan were musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting. Selected grade 3 or 4 nonhematological laboratory abnormalities were increased gamma-glutamyl transferase (GGT), increased bilirubin, increased alanine transaminase (ALT), increased aspartate aminotransferase (AST), and increased creatinine.

Putting It Into Context

“Treosulfan was noninferior to busulfan when used in combination with fludarabine as a conditioning regimen for alloHSCT for older or comorbid patients with AML or MDS,” concluded Dr. Beelen and colleagues. “The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population.”

Dosing Instructions

The recommended dosage of treosulfan is 10 g/m² daily on Days -4, -3, and -2 in combination with fludarabine 30 mg/m² daily on Days -6, -5, -4, -3, and -2, and allogeneic hematopoietic stem cell infusion on Day 0.

Resources

Beelen DW, Trenschel R, Stelljes M, et al (2020). Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol, 7(1):e28-e39. DOI:10.1016/S2352-3026(19)30157-7

Grafapex™ (treosulfan) prescribing information (2025). medac GmbH. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/214759s001lbl.pdf

Clinicaltrials.gov (2020). Clinical phase III trial treosulfan-based conditioning versus reduced-intensity conditioning (RIC). NLM identifier: NCT00822393.

US Food and Drug Administration (2025). FDA approves treosulfan with fludarabine as a preparative regimen for alloHSCT in adult and pediatric patients with AML or MDS. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-treosulfan-fludarabine-preparative-regimen-allohsct-adult-and-pediatric-patients-aml-or