FDA Greenlights Treosulfan/Fludarabine Combo for AlloHSCT in AML and MDS

• The FDA has granted approval to the combination of treosulfan (Grafapex) and fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHSCT).
• This indication is for adult and pediatric patients aged 1 year and older with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
• Data from the phase 3 MC-FludT.14/L Trial II (NCT00822393) support this approval.

The FDA has approved the combination of treosulfan and fludarabine as a preparative regimen for alloHSCT in adult and pediatric patients 1 year of age and older with AML or MDS.¹

Findings from the phase 3 MC-FludT.14/L Trial II (NCT00822393) serve as the basis for this approval. The trial, which compared treosulfan plus fludarabine vs busulfan plus fludarabine as a preparative regimen for alloHCT, showed that in the experimental arm, there was a 33% reduction in the risk of death in the overall population vs those in the control arm (HR, 0.67; 95% CI, 0.51-0.90). An overall survival benefit was seen in patients with AML (HR, 0.73; 95% CI, 0.51-1.06), as well as in patients with MDS (HR, 0.64; 95% CI, 0.40-1.02).

For safety, the most common adverse events seen in at least 20% of patients who received the combination were musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting.

"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 stem cell transplant physician-scientist at Fred Hutch Cancer Center and principal investigator in clinical trials using treosulfan as part of a conditioning regimen, in a press release.

In the randomized, active-controlled study, MC-FludT.14/L Trial II, adult patients between 18 to 70 years old with AML or MDS were included if they had a Karnofsky performance status ≥60%, and age ≥50 years or hematopoietic cell transplantation comorbidity index score >2.²

A total of 570 patients were randomized to treosulfan (n = 280) or busulfan (Myleran; n = 290).

The primary end point was event-free survival and the secondary end point was the comparative evaluation of incidence of common terminology criteria grade III/IV mucositis/stomatitis between day -6 and day 28.

The recommended dose of treosulfan is 10 g/m² daily on days -4, -3, and -2 combined with fludarabine 30 mg/m² daily on days -6, -5, -4, -3, and -2, and alloHSCT infusion on day 0.¹

REFERENCES

1. Medexus announces FDA approval of GRAFAPEX (treosulfan) for injection and provides business update. News release. Medexus Pharma. January 22, 2025. Accessed January 24, 2025. https://tinyurl.com/546urmt9

2. Clinical phase III trial treosulfan-based conditioning versus reduced-intensity conditioning (RIC). National Library of Medicine. ClinicalTrials.gov. Updated July 30, 2020. Accessed January 24, 2025. https://clinicaltrials.gov/study/NCT00822393