Treosulfan Regimen Superior to Busulfan in Older Patients with AML, MDS Undergoing Transplant

A phase III study showed that treatment with treosulfan compared to a regimen of reduced-intensity conditioning (RIC) busulfan had better event-free survival (EFS) for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (HSCT).

Treosulfan demonstrated a significant improvement in EFS over RIC busulfan (P=.0005787) with a clinically meaningful benefit (hazard ratio [HR]=0.64; 95% CI, 0.49-0.84).

The multicenter, prospective, group-sequential, randomized, phase III MC-FludT.14/L study enrolled patients with AML or MDS who were ineligible for myeloablative conditioning due to patient age (50-70 years), had an HSCT-specific comorbidity index (HCT-CI) of at least three, or both.

A total of 551 patients were randomized to receive either RIC busulfan 0.8 mg/kg administered as a two-hour infusion every six hours on days −4 and −3 (total dose 6.4 mg/kg; day zero designates the day of HSCT) or treosulfan 10 g/m² administered as a two-hour infusion on days −4, −3, and −2 (total dose 30 g/m²).

All patients additionally received 30 mg/m² fludarabine on days −6 to −2 administered as a half-hour infusion (total dose 150 mg/m²). To prevent seizures, patients in the busulfan arm received either phenytoin or benzodiazepine daily between days −5 and −2.

The median follow-up was 2.5 years for all patients and nearly identical in both arms. At the last analysis, the 36-month EFS was 59.5% (95% CI, 52.2-66.1) for patients in the treosulfan arm and 49.7% (95% CI, 43.3-55.7) for the busulfan arm.

The 36-month overall survival (OS) was 66.8% (95% CI, 59.9-72.9) for patients assigned to treosulfan compared with 56.3% (95% CI, 49.6-62.6) for patients in the busulfan arm (HR=0.64; 95% CI, 0.48-0.87; P=.0037).

The impact of treosulfan on 36-month EFS was robust across categorized patient subsets (risk group of disease, underlying disease, age of patients, and HCT-CI; P>.10 for all interaction tests).

OS for patients with AML and MDS exceeded 60% at three years in the treosulfan arm. At the end of the post-surveillance period, 70% of patients assigned to treosulfan and 60.4% of patients in the busulfan arm were alive, and the median OS had not been reached in either study arm.

“The treosulfan regimen leads to superior outcomes after allogeneic HCT compared with the reference RIC busulfan regimen and thereby appears particularly suitable for older AML and MDS transplantation candidates,” the authors wrote.

Beelen DW, Stelljes M, Reményi P, et al. Treosulfan compared with reduced-intensity busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: final analysis of a prospective randomized trial. Am J Hematol. 2022. doi:10.1002/ajh.26620