FDA Approves Treosulfan for alloHCT Conditioning in AML and MDS

The FDA has approved treosulfan (Grafapex) in combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHSCT) in adult and pediatric patients 1 year of age and older with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).1

The regulatory decision was supported by data from the phase 3 MC-FludT.14/L trial (NCT00822393), which compared treosulfan plus fludarabine (n = 280) vs busulfan plus fludarabine (n = 290) as a preparative regimen for alloHCT.

Findings showed that the experimental regimen led to a 33% reduction in the risk of death in the overall population compared with the control regimen (HR, 0.67; 95% CI, 0.51-0.90). Treosulfan plus fludarabine reduced the risk of death by 27% in patients with AML (HR, 0.73; 95% CI, 0.51-1.06) and 36% in patients with MDS (HR, 0.64; 95% CI, 0.40-1.02).

"This FDA approval provides a useful option for adult and pediatric patients, with the potential to enhance overall survival [OS] while minimizing [adverse] effects [AEs]," 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, stated in a news release.

MC-FludT.14/L was a multicenter, open-label, randomized, non-inferiority trial that enrolled patients 18 to 70 years of age with AML in first or consecutive complete remission with a bone marrow blast count below 5%; or MDS with a bone marrow blast count below 20%.2 Patients needed to be indicated for alloHCT and considered at increased risk for standard myeloablative conditioning, defined as being at least 50 years of age, having an HCT Comorbidity Index (HCT-CI) score above 2, or both.

Patients needed to have a Karnofsky performance status of at least 60% and availability of an HLA-identical sibling donor (matched-related donor) or HLA-identical unrelated donor (matched-unrelated donor). Receipt of a prior alloHCT excluded patients from the study.

Investigators randomly assigned patients in a 1:1 fashion to receive treosulfan at 10 g/m2 on days –4 to –2 plus fludarabine at 30 mg/m2 on days –6 to –2; or busulfan at 0.8 mg/kg on days –4 and –3 plus the same fludarabine regimen.

The 2-year event-free survival (EFS) rate after alloHCT served as the trial's primary end point. The non-inferiority margin was a HR of 1.3. Secondary end points included OS; cumulative incidence of relapse or disease progression; non-relapse mortality; and incidence of graft-vs-host disease within 2 years of alloHCT.

Data published in Lancet Haematology in 2020 showed that at a median follow-up of 15.4 months (IQR, 8.8-23.6) for the treosulfan arm and 17.4 months (IQR, 6.3-23.4) for the busulfan arm, the 2-year EFS rates were 64.0% (95% CI, 56.0%-70.9%) and 50.4% (95% CI, 42.8%-57.5%), respectively (HR, 0.65; 95% CI, 0.47-0.90; P < .0001 for non-inferiority).

The EFS benefit was consistent across prespecified subgroups, including patients at least 50 years of age, those with an HCT-CI score higher than 2, patients with unfavorable risk, and patients with matched-unrelated donors.

Two-year transplant-related mortality (HR, 0.54; 95% CI, 0.32-0.91; P = .020) and non-relapse mortality (HR, 0.60; 95% CI, 0.36-1.01; P = .053) were both improved with the treosulfan regimen.

No differences were observed between the arms regarding the incidence of disease recurrence or progression after alloHCT (P = .50)

The most common AEs reported in at least 20% of patients who received treosulfan plus fludarabine included musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting.1

Treosulfan is recommended at a dose of 10 g/m2 per day on days –4, –3, and –2 in combination with fludarabine at 30 mg/m2 per day on days –6, –5, –4, –3, and –2, followed by alloHCT on day 0.

"We are pleased to report this positive development, which marks a strategically important step forward for our business and, importantly, will now benefit eligible patients across the United States," Ken d'Entremont, chief executive officer of Medexus Pharmaceuticals, stated in a news release. "Not only will [treosulfan] make a substantial contribution to alloHCT in the United States, but it also solidifies Medexus's leadership position in this therapeutic field."

References

1. Medexus announces FDA approval of Grafapex (treosulfan) for injection and provides business update. News release. Medexus Pharmaceuticals. 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. 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