Treosulfan

Treosulfan is a prodrug of a bifunctional alkylating agent with cytotoxic activity against haematopoietic precursor cells. As supplied it is pharmacologically inactive; at body pH and temperature it converts without enzymes into reactive epoxides that cross-link DNA. This depletes stem cells in the bone marrow and has antineoplastic and immunosuppressive effects, which underlie its use in conditioning before allogeneic stem cell transplantation.

Mechanism of Action

• Activation: at physiological pH (7.4) and 37 °C, treosulfan is converted spontaneously (non-enzymatically) into a mono-epoxide intermediate (S,S-EBDM) and then into L-diepoxybutane (S,S-DEB), with a half-life for this conversion of 2.2 hours.
• DNA damage: the epoxides alkylate nucleophilic centres of DNA and induce DNA cross-links, which are considered responsible for the stem cell depleting and antineoplastic effects.
• Antitumour activity: broad antineoplastic and antileukaemic activity was shown against transplanted mouse and rat lymphomas and leukaemias, sarcomas and hepatomas, and against human tumour xenografts, tumour biopsies and cell lines.
• Immunosuppression: attributed to toxicity against primitive and committed progenitor cells, T cells and NK cells, a reduction in the cellularity of primary and secondary lymphatic organs, and a preclusive effect on the ‘cytokine storm’ that precedes graft-versus-host disease and is involved in veno-occlusive disease.

Pharmacokinetics

• Absorption: given intravenously, so peak plasma levels occur at the end of the infusion. Mean maximum levels after a 2-hour infusion of 10, 12 and 14 g/m² were 306, 461 and 494 μg/mL.
• Distribution: rapid; penetration through the blood-brain barrier is limited. The volume of distribution in adults is about 20–30 L. There is no accumulation with the recommended three consecutive daily doses, and treosulfan does not bind to plasma proteins.
• Metabolism: converted spontaneously, as described above. It does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2D6 or CYP3A4 (with testosterone as substrate), but it is a reversible inhibitor of CYP2C19 and of CYP3A4 (with midazolam as substrate). It inhibits P-glycoprotein and MATE2 only at very high concentrations.
• Elimination: plasma concentrations fall exponentially (first-order elimination, two-compartment model). The terminal half-life is about 2 hours (up to 47 g/m²). About 25–40% of the dose is excreted unchanged in the urine within 24 hours, nearly 90% of that within the first 6 hours. Exposure rises linearly with dose.
• Special populations: no pharmacokinetic studies were done in severe renal or hepatic impairment, because such patients are generally excluded from alloHSCT. An influence of renal function on the renal clearance of treosulfan was not observed.

• Conditioning before allogeneic haematopoietic stem cell transplantation (alloHSCT): treosulfan in combination with fludarabine, as part of conditioning treatment before alloHSCT in adult patients and in paediatric patients older than one month with malignant and non-malignant diseases.

• Hypersensitivity to the active substance.
• Active, non-controlled infectious disease.
• Severe concomitant cardiac, lung, liver and renal impairment.
• Fanconi anaemia and other DNA breakage repair disorders.
• Pregnancy.
• Administration of a live vaccine.

Profound myelosuppression with pancytopenia is the intended effect of conditioning and occurs in all patients; blood counts usually recover after transplantation. In adults and children respectively, the most frequent reactions were nausea (38.0% and 26.4%), stomatitis (36.4% and 66.1%), vomiting (22.5% and 42.1%), diarrhoea (14.4% and 33.1%), increased bilirubin (17.1% and 6.6%), fatigue (14.4% and 1.7%), infections overall (10.1% and 11.6%) and febrile neutropenia (10.1% and 1.7%). Hepatotoxicity was far more frequent in children (26.4%) than in adults (0.3%). The frequencies below are for adults, from 613 patients in five trials of treosulfan with fludarabine (10–14 g/m² on three consecutive days).

Very common (≥1/10): myelosuppression, pancytopenia, febrile neutropenia, stomatitis or mucositis, diarrhoea, nausea, vomiting, asthenic conditions (fatigue, asthenia, lethargy), increased blood bilirubin.

Common (≥1/100 to <1/10): infections (bacterial, viral, fungal) and sepsis, hypersensitivity, decreased appetite, insomnia, headache, dizziness, cardiac arrhythmias (for example atrial fibrillation, sinus arrhythmia), hypertension, hypotension, flushing, dyspnoea, epistaxis, oral pain, gastritis, dyspepsia, constipation, dysphagia, abdominal pain, oesophageal or gastrointestinal pain, maculopapular rash, purpura, erythema, palmar-plantar erythrodysaesthesia syndrome, pruritus, alopecia, pain in the extremity, back pain, bone pain, arthralgia, acute kidney injury, haematuria, oedema, pyrexia, chills, increased transaminases (ALT/AST), increased gamma-glutamyltransferase, increased C-reactive protein, weight decreased, weight increased.

Uncommon (≥1/1,000 to <1/100): impaired glucose tolerance (including hyperglycaemia and hypoglycaemia), confusional state, intracranial haemorrhage, peripheral sensory neuropathy, vertigo, haematoma, pneumonitis, pleural effusion, pharyngeal or laryngeal inflammation, oropharyngeal pain, hiccups, mouth haemorrhage, abdominal distension, dry mouth, veno-occlusive liver disease, erythema multiforme, acneiform dermatitis, rash, dry skin, myalgia, urinary tract pain, non-cardiac chest pain, pain, increased blood alkaline phosphatase.

Not known: septic shock, treatment-related second malignancy, acidosis, encephalopathy, extrapyramidal disorder, syncope, paraesthesia, dry eye, cardiac arrest, cardiac failure, myocardial infarction, pericardial effusion, embolism, laryngeal pain, cough, dysphonia, gastric haemorrhage, neutropenic colitis, oesophagitis, anal inflammation, hepatotoxicity, hepatomegaly, skin ulcer or necrosis, dermatitis, skin hyperpigmentation (bronze), renal failure, haemorrhagic cystitis, dysuria, increased blood lactate dehydrogenase.

In children (121 patients in two trials, median age 7 years, treosulfan with fludarabine and mostly thiotepa), the pattern is similar. Very common: infections, myelosuppression, pancytopenia, stomatitis or mucositis, diarrhoea, nausea, vomiting, abdominal pain, hepatotoxicity, pruritus, alopecia, pyrexia and increased ALT. Common: headache, oropharyngeal pain, epistaxis, dysphagia, anal inflammation, oral pain, exfoliative dermatitis, maculopapular rash, rash, erythema, urticaria, skin pain, skin hyperpigmentation (bronze), chills, and increased AST, bilirubin and C-reactive protein. Febrile neutropenia, seizure, capillary leak syndrome, hypoxia, veno-occlusive liver disease, acute kidney injury, nappy rash and treatment-related second malignancy are listed with frequency not known.

Important serious reactions include infections and sepsis (overall incidence 10.1% in adults, lung infection being the most frequent type), cardiac arrhythmias (cardiac disorders in 3.4% of adults), veno-occlusive liver disease (0.8% of adults, only with the 14 g/m² daily regimen, none fatal or life-threatening) and second malignancies. The lowest rates of infection, febrile neutropenia, cardiac and gastrointestinal events in adults were seen with the 10 g/m² regimen on days −4 to −2. The median duration of neutropenia was 14 days with 10 g/m² and 17.5 days with 14 g/m² in adults, and 20–22 days in children.

No interaction of treosulfan was observed in high-dose chemotherapy. In vitro studies did not completely exclude interactions between high plasma concentrations of treosulfan and substrates of CYP3A4, CYP2C19 or P-glycoprotein.

• CYP3A4 and CYP2C19 substrates with a narrow therapeutic index: modelling predicted a weak to moderate interaction for CYP3A4, a weak one for CYP2C19 and a negligible one for P-glycoprotein. Medicines with a narrow therapeutic index that are substrates of CYP3A4 or CYP2C19 (for example tacrolimus) should therefore not be given during treatment with treosulfan.
• Timing: the interaction potential can be reduced to ‘no interaction’ if all concomitant medicines are dosed 2 hours before or 8 hours after the 2-hour treosulfan infusion.
• Fludarabine: the effect of treosulfan on the pharmacokinetics of fludarabine is not known.
• Live vaccines: contraindicated, and concomitant use of live attenuated vaccines is not recommended.

Administration should be supervised by a physician experienced in conditioning treatment followed by alloHSCT. Treosulfan is always given with fludarabine, as a two-hour intravenous infusion, and before fludarabine on each day. Day 0 is the day of the stem cell infusion.

Adults with Malignant Disease (FT10 Regimen)

• Treosulfan: 10 g/m² body surface area (BSA) per day as a two-hour infusion on three consecutive days (day −4, −3, −2); total dose 30 g/m².
• Fludarabine: 30 mg/m² BSA per day as a 0.5-hour infusion on five consecutive days (day −6, −5, −4, −3, −2); total dose 150 mg/m².

Adults with Non-Malignant Disease (FT14 Regimen)

• Treosulfan: 14 g/m² BSA per day as a two-hour infusion on three consecutive days (day −6, −5, −4); total dose 42 g/m².
• Fludarabine: 30 mg/m² BSA per day as a 0.5-hour infusion on five consecutive days (day −7, −6, −5, −4, −3); total dose 150 mg/m².
• Thiotepa (with or without, as part of the regimen): 5 mg/kg twice a day, given as two infusions over 2–4 hours on day −2.

Children Older Than One Month

• Treosulfan: 10–14 g/m² BSA per day as a two-hour infusion on three consecutive days (day −6, −5, −4); total dose 30–42 g/m². The dose per day depends on BSA: below 0.4 m², 10.0 g/m²; 0.4 m² to below 0.9 m², 12.0 g/m²; 0.9 m² or more, 14.0 g/m².
• Fludarabine: 30 mg/m² BSA per day as a 0.5-hour infusion on five consecutive days (day −7, −6, −5, −4, −3); total dose 150 mg/m².
• Thiotepa: in the intensified regimen (FT10-14TT), 5 mg/kg twice a day as two infusions over 2–4 hours on day −2. Without thiotepa the regimen is FT10-14.
• Safety and efficacy in children younger than 1 month have not been established.

Special Populations

• Elderly: no dose adjustment is necessary in any subset of the elderly population.
• Renal and hepatic impairment: no dose adjustment for mild or moderate impairment; treosulfan is contraindicated in severe impairment.

Handling and Administration

Inhalation, skin contact and contact with mucous membranes should be avoided when handling treosulfan, and pregnant personnel should be excluded from handling cytotoxics. Intravenous administration should use a safe technique to avoid extravasation. Reconstitution instructions are in section 6.6 of the SmPC.

Myelosuppression and Infections

Profound myelosuppression with pancytopenia is the desired effect of treosulfan-based conditioning and occurs in all patients, so blood cell counts should be monitored frequently until the blood-forming system recovers. During severe neutropenia (median duration 14–17.5 days in adults and 20–22 days in children) the risk of infection is increased, and prophylactic or empiric anti-infective treatment (bacterial, viral, fungal) should be considered. Growth factors (G-CSF, GM-CSF) and platelet and/or red blood cell support are given as indicated.

Secondary Malignancies

Secondary malignancies are well-established complications in long-term survivors of alloHSCT; how much treosulfan contributes to them is unknown. The possible risk of a second malignancy should be explained to the patient. On the basis of human data, treosulfan has been classified by the International Agency for Research on Cancer (IARC) as a human carcinogen.

Mucositis

Oral mucositis, including high-grade mucositis, is a very common effect. Prophylaxis (for example topical antimicrobials, barrier protectants, ice and good oral hygiene) is recommended.

Vaccines

Live attenuated vaccines are contraindicated, and their concomitant use is not recommended.

Fertility, Pregnancy and Breastfeeding

• Contraception: sexually active men and women of childbearing potential must use effective contraception during treatment and for up to 6 months afterwards.
• Pregnancy: contraindicated. There are no data from pregnant women, and animal studies are insufficient with respect to reproductive toxicity.
• Breastfeeding: it is unknown whether treosulfan passes into human milk. Breastfeeding should be discontinued during treatment.
• Fertility: treosulfan can impair fertility in men and women. Men are advised not to father a child during and up to 6 months after treatment, and to seek advice on sperm cryo-conservation beforehand because of the possibility of irreversible infertility. Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausal patients.

Use in Children

• Seizures: there have been isolated reports of seizures in infants aged 4 months or younger with primary immunodeficiencies after conditioning with treosulfan plus fludarabine or cyclophosphamide. These infants should be monitored for signs of neurological adverse reactions. Although treosulfan could not be proved to be the cause, the SmPC notes that clonazepam prophylaxis might be considered for children younger than 1 year.
• Respiratory toxicity: age was significantly associated with respiratory toxicity. Children younger than one year (mainly with non-malignant disease, especially immunodeficiencies) had more grade III/IV respiratory toxicity, possibly because of lung infections present before conditioning.
• Nappy rash: may occur in small children because treosulfan is excreted in the urine. Nappies should be changed frequently for 6–8 hours after each infusion.

Extravasation

Treosulfan is an irritant. If extravasation is suspected, general safety measures should be applied; no specific measure has been proven to be recommendable.

Effect on Driving

Treosulfan has a moderate influence on the ability to drive and use machines. Nausea, vomiting or dizziness may affect these functions.

Unopened vials need no special storage conditions. Trecondi is supplied in colourless type I glass vials with a rubber stopper and aluminium cap, containing 1 g or 5 g of treosulfan, in packs of 1 or 5 vials; not all pack sizes may be marketed. Do not store the reconstituted solution in a refrigerator (2–8 °C), as this might cause precipitation. For storage after reconstitution, see Shelf Life.

• Unopened vial: 5 years.
• Reconstituted solution: after reconstitution with sodium chloride 4.5 mg/mL (0.45%) solution, chemical and physical stability has been shown for 3 days at 25 °C. From a microbiological point of view, unless the method of reconstitution rules out the risk of microbial contamination, the product should be used immediately. If it is not, in-use storage times and conditions are the responsibility of the user.

Prescription only (Rx), under restricted medical prescription (Annex II B). Administration is supervised by a physician experienced in conditioning treatment followed by alloHSCT. Treosulfan is given as an intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it.