Treosulfan, in combination with fludarabine, is used as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (alloHSCT).
It is indicated for:

• Adult patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who are at increased risk with standard conditioning therapies.
• Pediatric patients older than 1 year with AML or MDS.

The administration of Treosulfan should be carried out under the supervision of a physician experienced in conditioning therapy followed by alloHSCT.

Treosulfan is a prodrug that converts into an active bifunctional alkylating agent with cytotoxic effects on hematopoietic stem cells. It undergoes spontaneous, pH-dependent transformation into reactive epoxide compounds (mono-epoxide and diepoxybutane). These compounds bind to DNA and other biological molecules, causing cross-linking and disruption of essential cellular functions. This leads to stem cell depletion, immune suppression, and antitumor activity.

Treosulfan is given in combination with fludarabine.

The recommended dose and schedule of administration is:

• Treosulfan 10 g/m² body surface area (BSA) per day as a two-hour intravenous infusion, given on three consecutive days (day -4, -3, -2) before stem cell infusion (day 0). The total treosulfan dose is 30 g/m².
• Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on five consecutive days (day -6, -5, -4, -3, -2) before stem cell infusion (day 0). The total fludarabine dose is 150 mg/m².
• Treosulfan should be administered before fludarabine on days -4, -3, -2 (FT-10 regimen).

Health Canada has not authorized the use of Treosulfan in children less than 1 year of age.

No dose adjustment is necessary for mild or moderate liver or renal impairment, but treosulfan is contraindicated in patients with severe impairment.

Pediatrics (>1 year to 18 years): The use of Treosulfan has not been fully investigated in the pediatric population.

Geriatrics: Eighty-one (13.2%) of the 613 adult patients treated within the clinical trial program for Treosulfan were above the age of 65 years.

Hepatic Insufficiency: No pharmacokinetic studies with treosulfan were conducted in patients with severe hepatic impairment, because such patients are generally excluded from alloHSCT.

Renal Insufficiency: No pharmacokinetic studies with treosulfan were conducted in patients with severe renal impairment.

Drug interaction studies of treosulfan in humans are limited. In vitro data suggest possible interactions with CYP3A4, CYP2C19, and P-glycoprotein (P-gp) substrates at high plasma levels. Pharmacokinetic modeling indicates weak interactions with CYP3A4 and CYP2C19 substrates, and minimal interaction with P-gp substrates. Therefore, medicines with a narrow therapeutic index that are metabolized by CYP3A4 or CYP2C19 should be avoided during treosulfan treatment.

Treosulfan should not be used in patients with hypersensitivity to the drug or any of its components. It is also contraindicated in patients with:

• Active uncontrolled infections
• Severe heart, lung, liver, or kidney impairment
• Fanconi anemia or other DNA repair disorders
• Pregnancy
• Concurrent administration of live vaccines

Profound myelosuppression/pancytopenia is the desired therapeutic effect of conditioning therapy and occurs in all patients. Blood cell counts usually recover after HSCT.

The most common (>10%) adverse reactions observed in 5 clinical studies in 613 adults with treosulfan-based conditioning followed by alloHSCT include gastrointestinal disorders (nausea 38.5%, stomatitis 36.4%, vomiting 22.5%, diarrhea 15.2%), increases of bilirubin 17.9%, fatigue 14.8%, infections 12.9%, and febrile neutropenia 10.9%.

The most common (>10%) adverse reactions observed in two clinical studies in 115 pediatric patients with treosulfan-based conditioning followed by alloHSCT include gastrointestinal disorders (stomatitis 67.0%, vomiting 41.7%, diarrhea 34.8%, nausea 27.8%, abdominal pain 17.4%), hepatotoxicity 26.1%, pyrexia 13.0%, infections 12.2%, increased alanine aminotransferase 11.3%, alopecia 10.4%, and pruritus 10.4%.

Treosulfan is contraindicated during pregnancy, as there is no sufficient safety data and potential risk to the fetus exists. It is unknown whether the drug passes into breast milk; therefore, breastfeeding should be discontinued during treatment.

Tresofuran is considered an irritant. Intravenous application should be performed using a safe technique. If extravasation is suspected, general safety measures should be implemented. No specific measure has been proven to be recommendable. During a phase 3 clinical trial (MC-FludT.14/L Trial II), treatment emergent adverse events (TEAEs) were reported by 92.6% of patients in the tresofuran treatment group. TEAEs were most commonly reported in the SOCs "Gastrointestinal disorders", "General disorders and administration site conditions", and "Musculoskeletal and connective tissue disorders" (TEAEs reported by 68.1%, 56.3%, and 37.8% of patients, respectively). TEAEs of at least CTCAE Grade III were reported by 54.8% of patients in the tresofuran treatment group. Severe Adverse Events (SAEs) were reported by 8.5% of patients in the tresofuran treatment group.

Cytotoxic chemotherapy

Store unopened vials at 15°C–30°C. After dilution in suitable solutions (e.g., sodium chloride, glucose, or water for injection), the solution remains stable for up to 3 days at room temperature. Do not refrigerate, as this may cause precipitation. Do not use if precipitation occurs.