Treosulfan (Monograph)

Brand name: Grafapex
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on May 10, 2025. Written by ASHP.

Introduction

Treosulfan, an alkylating drug, is an antineoplastic agent.¹

Uses for Treosulfan

Treosulfan has the following uses:

Treosulfan is used in combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in adult and pediatric patients 1 year of age and older with acute myeloid leukemia (AML).¹

Treosulfan is also used in combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation in adult and pediatric patients 1 year of age and older with myelodysplastic syndrome (MDS).¹

Treosulfan Dosage and Administration

General

Treosulfan is available in the following dosage form(s) and strength(s):

For injection: Single-dose vials containing 1 g or 5 g of treosulfan as a lyophilized powder for reconstitution. ¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults and Pediatric Patients

Recommended dosage of treosulfan in adults and pediatric patients ≥1 year of age with AML or MDS is 10 g/m² body surface area (BSA) per day as a 2 hour IV infusion, given on 3 consecutive days beginning on day -4 prior to transplantation in combination with fludarabine before hematopoietic stem cell infusion (day 0) as outlined in Table 1.¹

Premedicate patients with antiemetics.¹

Reconstitute treosulfan prior to IV infusion.¹

Treosulfan is a hazardous drug.¹ Follow applicable special handling and disposal procedures.¹

See Full Prescribing Information for instructions on preparation and administration.¹

Cautions for Treosulfan

Contraindications

• Hypersensitivity to any component of the drug product.¹

Warnings/Precautions

Myelosuppression

Profound myelosuppression with pancytopenia is the desired therapeutic effect of treosulfan-based preparative regimens, occurring in all patients.¹ Time to neutrophil counts > 0.5 Gi/L occurred at a median of 18 days (range 7-42 days) after allogeneic hematopoietic stem cell transplantation in adult patients treated with treosulfan in combination with fludarabine as the preparative regimen.¹

Do not begin the preparative regimen if the stem cell donor is not available.¹ Monitor blood cell counts daily until hematopoetic recovery.¹ Provide standard supportive care for infections, anemia, and thrombocytopenia until there is adequate hematopoietic recovery.¹

Seizures

There have been reports of seizures in patients following treatment with treosulfan.¹ Monitor patients for signs of neurological adverse reactions.¹ Clonazepam prophylaxis may be considered for patients at higher risk for seizures, including infants.¹

Skin Disorders

An increase of skin disorders (e.g., rash, dermatitis) was observed when patients received sodium bicarbonate-containing hydration in the course of treosulfan infusion, potentially because of acceleration of the pH-dependent formation of alkylating epoxides.¹ Keep skin clean and dry on days of treosulfan infusion.¹ Diaper dermatitis may occur because of excretion of treosulfan in the urine.¹ Change diapers frequently during the 12 hours after each infusion of treosulfan.¹ Dermatitis may occur under occlusive dressings; change occlusive dressings after each infusion of treosulfan. ¹

Injection Site Reactions and Tissue Necrosis

Treosulfan may cause local tissue necrosis and injection site reactions, including erythema, pain, and swelling, in case of extravasation.¹ Assure venous access patency prior to starting treosulfan infusion, and monitor the IV infusion site for redness, swelling, pain, infection, and necrosis during and after administration of treosulfan.¹ If extravasation occurs, stop the infusion immediately and manage medically as required.¹ Do not administer by the intramuscular or subcutaneous routes.¹

Secondary Malignancies

There is an increased risk of a secondary malignancy with use of treosulfan.¹ Treosulfan is carcinogenic and genotoxic. ¹

The risk of secondary malignancy is increased in patients with Fanconi anemia and other DNA breakage disorders.¹ The safety and efficacy of treosulfan have not been established for patients with these disorders.¹

Increased Early Morbidity and Mortality at Dosages Higher than Recommended

In MC-FludT.14/L Trial I (NCT00822393), 330 adult patients were randomized to treosulfan at 14 g/m²/day (1.4 times the recommended dose) for three consecutive days or busulfan at 3.2 mg/kg/day for two days, in combination with fludarabine as a preparative regimen for allogeneic transplantation.¹ This trial was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in patients receiving treosulfan.¹ Avoid exceeding the recommended treosulfan dosage of 10 g/m² daily for three consecutive days. ¹

Embryo-fetal Toxicity

Based on its mechanism of action, treosulfan can cause fetal harm when administered to a pregnant woman because it is genotoxic and affects dividing cells.¹ Advise pregnant women of the potential risk to the fetus.¹ Advise females of reproductive potential to use effective contraception during treatment with treosulfan and for 6 months following the last dose of the drug.¹ Advise males with female partners of reproductive potential to use effective contraception during treatment with treosulfan and for 3 months after the last dose. ¹

Specific Populations

Pregnancy

Based on its mechanism of action, treosulfan can cause fetal harm when administered to a pregnant woman because it is genotoxic and affects dividing cells.¹ There are no available human clinical data on the use of treosulfan in pregnant women to support an estimation of a drug-associated risk.¹ Specific embryo-fetal developmental toxicity studies with treosulfan in animals were not conducted.¹ Advise pregnant women of the potential risk to a fetus ¹

In the U.S. general population, the estimated background risk of major birth defects is 2% – 4% and of miscarriage is 15% – 20% of clinically recognized pregnancies.¹

Lactation

There is no data on the presence of treosulfan or its metabolites in human milk, the effects on the breastfed child, or on milk production.¹ Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with treosulfan and for 1 week after the last dose.¹

Females and Males of Reproductive Potential

Based on its mechanism of action, treosulfan can cause fetal harm when administered to a pregnant woman. ¹

Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with treosulfan.¹

Advise females of reproductive potential to use effective contraception during and up to 6 months after treatment with treosulfan.¹

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with treosulfan and for 3 months after the last dose. ¹

Based on findings in animal studies, treosulfan can impair fertility in females and males, and may cause temporary or permanent infertility. ¹

Pediatric Use

The safety and efficacy of treosulfan as part of a preparative regimen prior to allogeneic hematopoietic stem cell transplant in pediatric patients 1 year of age and older with AML or MDS have been established based on evidence from an adequate and well-controlled study in adults, with additional pharmacokinetic and safety data in 111 pediatric patients, including 22 infants (1 month to < 2 years), 54 children (2 to < 12 years), and 35 adolescents (12 to < 17 years).¹ The incidence of hepatic and GI adverse reactions was higher in pediatric patients than in adults. ¹

Safety and effectiveness of treosulfan as part of a preparative regimen prior to allogeneic hematopoietic stem cell transplant in pediatric patients with AML or MDS younger than 1 year of age have not been established.¹

Treatment of juvenile rats from postnatal day (PND) 10 to 35 with daily doses of 10, 50 or 100 mg/kg treosulfan (approximately 0.006, 0.03, 0.06-fold the human dose based on body surface area, BSA) generally resulted in findings comparable to those seen in adult animals.¹ A delayed physical development indicated by decreased body weight, reduced relative organs weights, and delayed time point of vaginal opening were noted in the high-dosed rats.¹ In a separate study, single IV doses of 500 mg/kg treosulfan (0.3-fold the human dose based on BSA) were administered to juvenile (PND 10) and young adult (PND 34 – 35) rats; treosulfan concentrations in brain tissue were low compared to plasma concentrations, but were approximately 2- to 3-fold higher in juvenile rats (4-6%) in comparison to young adults (2-3%).¹

Geriatric Use

Of the total number of treosulfan-treated patients with AML or MDS in Study MC-FludT.14/L Trial II (n=270), 73 (27%) were 65 to 74 years of age, and none were 75 years of age and older.¹ No significant differences in safety or effectiveness were observed between these subjects and younger subjects. ¹

Common Adverse Effects

The most common adverse reactions (≥20%) are musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting.¹ Selected Grade 3 or 4 nonhematological laboratory abnormalities are increased GGT, increased bilirubin, increased ALT, increased AST, and increased creatinine. ¹

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Certain CYP2C19 and CYP3A4 Substrates: Monitor for adverse reactions of these substrates where minimal concentration changes may lead to serious or life-threatening toxicities. ¹

Actions

Mechanism of Action

Treosulfan is an alkylating agent.¹ DNA alkylation is thought to be responsible for the cytotoxic activities of treosulfan.¹ Treosulfan showed hematopoietic stem cell depleting activity as well as immunosuppressive and antitumor activity in mouse models of leukemia.¹

Advice to Patients

• Inform patients of the increased risk of infections after treatment with treosulfan that may require antibiotic, antiviral, or antifungal treatment and hospitalization.¹

• Advise patients to contact their healthcare provider immediately in case of any new or worsening signs of infection (e.g., cough, headache, diarrhea, fever). ¹

• Inform patients that seizures may occur. ¹

• Advise patients to clean “sweaty” skin parts (armpit, groin, genital area, inframammary line) with a disposable washcloth and clear water.¹

• Advise patients not to apply any cream to the skin on the days of chemotherapy, and clothing should not be too tight, in order to let the skin “breathe”. ¹

• Inform patients of the possible risk of a second malignancy. ¹

• Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. ¹

• Advise females of reproductive potential to use effective contraception during treatment with treosulfan and for 6 months following the last dose of treosulfan. ¹

• Advise males with female partners of reproductive potential to use effective contraception during treatment with treosulfan and for 3 months after the last dose. ¹

• Advise women not to breastfeed during treatment with treosulfan and for 1 week after the last dose. ¹

• Advise patients that treosulfan can impair fertility in females and males, and may cause temporary or permanent infertility. ¹

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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