FDA Approves Treosulfan with Fludarabine for AlloHSCT in AML/MDS Patients

On January 21, 2025, the U.S. Food and Drug Administration (FDA) granted approval to a drug called treosulfan, marketed as Grafapex by medac GmbH. This approval allows the use of treosulfan, in combination with fludarabine, as a preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHSCT). This treatment is intended for both adult and pediatric patients aged one year and older who are diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Treosulfan is classified as an alkylating agent, which works by interfering with the DNA of cancer cells, thereby inhibiting their growth and proliferation. The approval was based on findings from the MC-FludT.14/L Trial II, a randomized, controlled study that compared the efficacy of treosulfan with busulfan, another chemotherapy agent, both used alongside fludarabine for alloHSCT.

The clinical trial enrolled a total of 570 patients, all between the ages of 18 and 70, who had either AML or MDS. Participants in the study also needed to have a Karnofsky performance status of at least 60% and be either 50 years or older or have a hematopoietic cell transplantation comorbidity index (HCTCI) score greater than 2. In the study, 280 patients received the treosulfan regimen, while 290 were administered the busulfan regimen.

The primary measure of efficacy in the trial was overall survival (OS), defined as the duration from the point of randomization in the study to death from any cause. The results demonstrated a favorable hazard ratio for overall survival of 0.67 (95% Confidence Interval: 0.51 to 0.90) in the overall population treated with treosulfan compared to those treated with busulfan. Specifically, for patients with AML, the hazard ratio was 0.73 (95% CI: 0.51 to 1.06), and for those with MDS, it was 0.64 (95% CI: 0.40 to 1.02).

Common adverse reactions observed in the study, occurring in 20% or more of patients, included musculoskeletal pain, mouth sores (stomatitis), fever, nausea, swelling, infections, and vomiting. Additionally, some patients experienced significant laboratory abnormalities, such as elevated levels of GGT, bilirubin, ALT, AST, and creatinine.

The recommended dosing regimen for treosulfan is 10 g/m² per day, administered on three consecutive days (-4, -3, and -2) prior to the stem cell infusion. This is used in combination with fludarabine at a dose of 30 mg/m² per day, given over five days (-6, -5, -4, -3, and -2). The infusion of the allogeneic hematopoietic stem cells is conducted on day 0.

Healthcare providers are encouraged to report any serious adverse events associated with this treatment to the FDA's MedWatch Reporting System. This approval provides a new option for patients undergoing alloHSCT for AML or MDS, potentially improving outcomes in these challenging cases. 

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