Usage
- Treosulfan is prescribed as part of a conditioning regimen, in combination with fludarabine, prior to allogeneic hematopoietic stem cell transplantation (alloHSCT). It is used in adult and pediatric patients (1 year and older) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
- Pharmacological Classification: Alkylating agent, antineoplastic.
- Mechanism of Action: Treosulfan is a prodrug that is converted to its active epoxide form in the body. These epoxides crosslink DNA, leading to cell cycle arrest and apoptosis, particularly in rapidly dividing cells like those in the bone marrow. This myeloablation makes room for the engraftment of the donor’s stem cells.
Alternate Names
- International Nonproprietary Name (INN): Treosulfan
- Brand Name: Grafapex
How It Works
- Pharmacodynamics: Treosulfan causes profound myelosuppression with pancytopenia. It targets rapidly dividing cells, primarily hematopoietic stem cells in the bone marrow, disrupting DNA replication and causing cell death. This creates space for the engraftment of donor stem cells.
- Pharmacokinetics:
- Absorption: Peak plasma levels are reached at the end of the two-hour intravenous infusion.
- Metabolism: Treosulfan is spontaneously converted to its active epoxide metabolites in the body. No specific enzyme system is primarily involved.
- Elimination: Primarily via renal excretion (25-40% unchanged drug within 24 hours); minor elimination occurs via fecal and other routes. The terminal half-life is approximately 2 hours.
- Mode of Action: The active epoxide metabolites alkylate DNA, forming crosslinks which interfere with DNA replication and cell division. This leads to apoptosis (programmed cell death).
- Receptor Binding/Enzyme Inhibition: No specific receptor binding or enzyme inhibition is identified as the primary mode of action. Non-enzymatic hydrolysis in plasma leads to the formation of the active epoxides.
- Elimination Pathways: Primarily renal excretion of unchanged drug and metabolites.
Dosage
Standard Dosage
Adults:
- 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). This is given concurrently with fludarabine.
Children (1 year and older):
- 10 g/m² BSA per day as a two-hour intravenous infusion for three consecutive days (day -4, -3, -2) before stem cell infusion (day 0). This is given concurrently with fludarabine.
- Pediatric Safety Considerations: Children may experience higher rates of hepatic and gastrointestinal toxicities compared to adults. Close monitoring is necessary.
Special Cases:
- Elderly Patients: No specific dose adjustment is routinely recommended, though caution is warranted due to potential age-related decline in organ function. Closely monitor patients for adverse events.
- Patients with Renal Impairment: No dose adjustment is necessary for mild renal impairment. Moderate to severe impairment may require cautious dose adjustments.
- Patients with Hepatic Dysfunction: No dose adjustment is necessary for mild to moderate hepatic impairment. For severe hepatic impairment, caution is needed.
- Patients with Comorbid Conditions: Carefully consider the potential for increased toxicity in patients with cardiac, lung, or other significant comorbidities.
Clinical Use Cases
Treosulfan is not indicated for the clinical use cases listed (Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, Emergency Situations). Its sole indication is as a conditioning regimen prior to alloHSCT in AML or MDS.
Dosage Adjustments
Dose adjustments may be necessary in cases of moderate to severe renal or hepatic impairment. It is contraindicated in severe hepatic impairment.
Side Effects
Common Side Effects
Musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, vomiting, rash, diarrhea, headache, abdominal pain, hypertension, hemorrhage, fatigue, constipation, elevated liver enzymes (ALT, AST, GGT), hyperbilirubinemia, and elevated creatinine.
Rare but Serious Side Effects
Seizures, severe skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis), veno-occlusive disease, capillary leak syndrome, acute kidney injury, and secondary malignancies.
Long-Term Effects
Infertility, secondary malignancies.
Adverse Drug Reactions (ADR)
Severe myelosuppression requiring transfusions and supportive care, severe hepatic or renal dysfunction, anaphylaxis, and severe skin reactions.
Contraindications
Hypersensitivity to treosulfan, pregnancy, active uncontrolled infections, severe cardiac or pulmonary dysfunction, Fanconi anemia or other DNA breakage repair disorders.
Drug Interactions
Drugs metabolized by CYP3A4 or CYP2C19 (especially those with a narrow therapeutic index). Monitor closely and consider adjusting dosing of concomitant medications. Live vaccines are contraindicated during treosulfan treatment.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Treosulfan is contraindicated in pregnancy (may cause fetal harm). Effective contraception is required during and for 6 months after treatment.
- Breastfeeding: Treosulfan is contraindicated during breastfeeding. It is unknown whether it is excreted in breast milk. Discontinue breastfeeding during treatment.
Drug Profile Summary
- Mechanism of Action: Alkylates DNA leading to cell death.
- Side Effects: Myelosuppression, mucositis, nausea, vomiting, rash, fever, infection, hepatic dysfunction.
- Contraindications: Hypersensitivity, pregnancy, active infection, severe organ dysfunction, Fanconi anemia.
- Drug Interactions: CYP3A4 and CYP2C19 substrates.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 10g/m² IV infusion for 3 days before HSCT.
- Monitoring Parameters: Blood counts (CBC with differential), liver function tests (LFTs), renal function tests.
Popular Combinations
Fludarabine (required for use), thiotepa (in some regimens).
Precautions
- General Precautions: Monitor blood counts, liver function, and renal function before and during treatment. Implement infection prophylaxis.
- Specific Populations: Pregnant and breastfeeding women (contraindicated), elderly and children (close monitoring).
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Treosulfan?
A: 10 g/m² BSA given as a 2-hour IV infusion daily for 3 consecutive days (day -4, -3, -2) before alloHSCT (day 0), in combination with fludarabine.
Q2: What is the main toxicity of Treosulfan?
A: Profound myelosuppression, which is the intended therapeutic effect to prepare for transplantation. Supportive care with transfusions and growth factors is often necessary.
Q3: What are the contraindications for using Treosulfan?
A: Hypersensitivity, pregnancy, breastfeeding, active severe infection, severe organ dysfunction, and DNA breakage repair disorders (like Fanconi anemia).
Q4: What are the clinically significant drug interactions with Treosulfan?
A: Drugs metabolized by CYP3A4 or CYP2C19, particularly those with a narrow therapeutic index. Live vaccines are also contraindicated.
Q5: What is the role of Treosulfan in alloHSCT?
A: It is used as part of a conditioning regimen to ablate the patient’s bone marrow, making space for engraftment of donor stem cells.
Q6: What are the common side effects patients experience during Treosulfan treatment?
A: Mucositis, nausea, vomiting, fever, rash, infections, and fatigue.
Q7: How should Treosulfan be administered?
A: As a two-hour intravenous infusion.
Q8: What monitoring is essential during Treosulfan therapy?
A: Daily complete blood counts, regular liver and kidney function tests, and monitoring for signs of infection.
Q9: Can Treosulfan be used in patients with renal impairment?
A: It can be used with caution in patients with mild to moderate renal impairment. Dosage adjustments may be required. It’s contraindicated in severe renal impairment.
Q10: What premedication should be considered before administering Treosulfan?
A: Premedication with antiemetics is recommended to prevent nausea and vomiting.
