FDA Approves Treosulfan With Fludarabine for alloHSCT Conditioning in AML and MDS

The FDA has approved treosulfan combined with fludarabine as a pre-transplant treatment for both children and adults.

The FDA approved treosulfan (Grafapex) with fludarabine for adult and pediatric patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) as a preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHSCT).

"This FDA approval provides a useful option for adult and pediatric patients, with the potential to enhance overall survival while minimizing side effects," said Filippo Milano, MD, PhD, a principal investigator in the clinical trials assessing treosulfan, in a press release from Medexus, the manufacturer of the alkylating agent.¹

This approval is based on findings from the phase 3, open-label trial MC-FludT.14/L Trial II (NCT00822393). These results showed that treosulfan demonstrated better rates of overall survival with fludarabine than busulfan with fludarabine. In the study, 570 patients were randomly assigned to receive intravenous treosulfan (n = 280) or busulfan (n = 290). In particular, patients with AML or MDS were aged 18 to 70 years and had a Karnofsky performance status of 60% or greater. Patients aged 50 years and older or had a hematopoietic cell transplantation comorbidity index greater than 2.

Study Findings

The major efficacy outcome of the study was overall survival. Patients receiving treosulfan had a median follow-up of 15.4 months (IQR, 8.8-23.6) and those receiving busulfan had a median follow-up of 17.4 months (IQR, 6.3-23.4).³

When stratified by donor type and risk group, the HR for overall survival in the treosulfan group compared to the busulfan group was 0.67 (95% CI; 0.51-0.90). For patients with AML, the HR was 0.73 (95% CI; 0.51-1.06), and for those with MDS, the HR was 0.64 (95% CI; 0.40-1.02).²

According to an article published in The Lancet Haematology in 2020, event-free survival, defined as survival without relapse of disease or graft failure, was 64.0% (95% CI 56·0-70·9) in the treosulfan group and 50.4% (42·8-57·5) in the busulfan group (HR = 0.65; 95% CI; 0.47-0.90; P < 0.0001 for non-inferiority, P = 0.0051 for superiority).³

Safety

Serious adverse events (AEs) occurred in 18 (8%) patients assigned treosulfan and 17 (7%) patients assigned busulfan. The most frequent AEs, occurring in at least 20% of patients, were musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting.¹

The most common AEs grade 3 or higher were abnormal blood chemistry results, for which both groups had similar results (15% of patients assigned treosulfan vs 15% of patients assigned busulfan). Gastrointestinal disorders occurred in the busulfan group at a higher rate of 16%, compared to 11% in the treosulfan group.³

Nonhematological laboratory abnormalities included increased gamma-glutamyl transferase, increased bilirubin, increased alanine aminotransferase, increased aspartate aminotransferase, and increased creatinine.¹

The recommended dose for treosulfan is 10 g/m2 once per day on days -4, -3, and -2, in combination with 30 mg/m2 of fludarabine once per day on days -6, -5, -4, -3, and -2. AlloHSCT infusion would then be performed on day 0.

References:

1. Medexus announces FDA approval of GRAFAPEX (treosulfan) for injection and provides business update. News release. Medexus Pharmaceuticals, Inc. January 22, 2025. Accessed January 24, 2025. https://www.medexus.com/en_US/news-media/press-releases/detail/176/medexus-announces-fda-approval-of-grafapex-treosulfan-for
2. Clinical phase III trial treosulfan-based conditioning versus reduced-intensity conditioning (RIC). ClinicalTrials.gov. Updated July 30, 2020. Accessed January 24, 2025. https://clinicaltrials.gov/study/NCT00822393
3. Beelen DW, Trenschel R, Stelljes M, et al. 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. 2020;7(1):e28-e39. doi:10.1016/S2352-3026(19)30157-7