Treosulfan

Detailed in vitro studies did not completely exclude potential interactions between high plasma concentrations of treosulfan and CYP3A4, CYP2C19, or P-gp substrates. Therefore, medicinal products with a narrow therapeutic index (e.g. digoxin) that are substrates for CYP3A4, CYP2C19 or P-gp should not be given during treatment with treosulfan.

Treosulfan might impair fertility in men and women. Men should seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility.

As known for other alkylating conditioning agents treosulfan can cause ovarian suppression and amenorrhoea with menopausal symptoms in pre-menopausal women.

Oral mucositis (including high-grade severity) is a very common undesirable effect of treosulfan-based conditioning followed by alloHSCT. Use of mucositis prophylaxis (e.g. topical antimicrobials, barrier protectants, ice and adequate oral hygiene) is recommended.

There was a significant association between age and respiratory toxicity in paediatric patients treated with treosulfan-based conditioning. Children younger than one year (mainly non-malignant diseases, especially immunodeficiencies) experienced more respiratory grade III/IV toxicity, possibly due to pulmonary infections already existing before the start of conditioning treatment.

There have been isolated reports of seizures in infants (≤4 months of age) with primary immunodeficiencies after conditioning treatment with treosulfan in combination with fludarabine or cyclophosphamide. Therefore, infants ≤4 months of age should be monitored for signs of neurological adverse reactions. Although it cannot be proved that treosulfan was the cause, the use of clonazepam prophylaxis for children younger than 1 year might be considered.

Dermatitis diaper may occur in small children because of excretion of treosulfan in the urine. Therefore, nappies should be changed frequently up to 6–8 hours after each infusion of treosulfan.

There are no data from the use of treosulfan in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Treosulfan is contraindicated during pregnancy.

It is unknown whether treosulfan is excreted in human milk. Breast-feeding should be discontinued during treatment with treosulfan.

Women of childbearing potential/Contraception in males and females

Both sexually active men and women of childbearing potential have to use effective contraception during and up to 6 months after treatment.

Fertility

Treosulfan might impair fertility in men and women. Men should seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility.

As known for other alkylating conditioning agents treosulfan can cause ovarian suppression and amenorrhoea with menopausal symptoms in pre-menopausal women.

Treosulfan has moderate influence on the ability to drive and use machines. It is likely that certain adverse reactions of treosulfan like nausea, vomiting or dizziness could affect these functions.

Summary of the safety profile

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 commonly observed adverse reactions (adults/paediatric patients) after treosulfan-based conditioning followed by alloHSCT include infections (13.1% /11.4%), gastrointestinal disorders (nausea [39.5%/30.7%], stomatitis [36.0%/69.3%], vomiting [22.5%/43.2%], diarrhoea [15.6%/33.0%], abdominal pain [10.4%/17%]), fatigue (15.1%/2.3%), febrile neutropenia (11.3%/1.1%), oedema (7.8%/0%), rash (7.2%/12.5%), and increases of alanine transaminase (ALT [5.1%/9.1%]), aspartate transaminase (AST [4.4%/8.0%]), gamma-glutamyl transferase (γGT [3.7%/2.3%]), and bilirubin (18.8%/5.7%).

Adults

List of adverse reactions

The frequencies of adverse reactions reported in the list below are derived from 5 clinical trials (including a total of 564 patients) where treosulfan combined with fludarabine was investigated as conditioning treatment prior to alloHSCT in adult patients. Treosulfan was administered in a dose range of 10-14 g/m² BSA on 3 consecutive days.

Adverse reactions are listed below, by system organ class and by frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency group, undesirable effects are presented in order of decreasing seriousness.

All Adverse Reactions:

Infections and infestations

Very common: Infections (bacterial, viral, fungal)

Common: Sepsis^a

Not known: Septic shock^c

Neoplasms benign, malignant and unspecified (including cysts and polyps)*

Not known: Treatment-related second malignancy

Blood and lymphatic system disorders*

Very common: Myelosuppression, pancytopenia, febrile neutropenia

Immune system disorders*

Common: Hypersensitivity

Metabolism and nutrition disorders

Common: Decreased appetite

Uncommon: Hyperglycaemia

Not known: Acidosis^b, glucose tolerance impaired, electrolyte imbalance

Psychiatric disorders

Common: Insomnia

Uncommon: Confusional state

Not known: Agitation

Nervous system disorders

Common: Headache, dizziness

Uncommon: Peripheral sensory neuropathy

Not known: Encephalopathy, intracranial haemorrhage, extrapyramidal disorder, syncope, paraesthesia

Eye disorders

Not known: Dry eye

Cardiac disorders*

Common: Cardiac arrhythmias (e.g. atrial fibrillation, sinus arrhythmia)

Not known: Cardiac arrest, cardiac failure, myocardial infarction, pericardial effusion

Vascular disorders

Common: Hypertension, flushing

Uncommon: Haematoma, hypotension

Not known: Embolism, haemorrhage

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, epistaxis

Uncommon: Pneumonitis, pleural effusion, pharyngeal or laryngeal inflammation, cough, laryngeal pain, hiccups

Not known: Oropharyngeal pain, hypoxia, dysphonia

Gastrointestinal disorders*

Very common: Stomatitis/mucositis, diarrhoea, nausea, vomiting, abdominal pain

Common: Oral pain, gastritis, dyspepsia, constipation, dysphagia

Uncommon: Mouth haemorrhage, abdominal distension, oesophageal or gastrointestinal pain, dry mouth

Not known: Gastrointestinal haemorrhage, neutropenic colitis, oesophagitis, anal inflammation, mouth ulceration

Hepatobiliary disorders*

Uncommon: Veno-occlusive liver disease, hepatotoxicity

Not known: Hepatic failure, hepatomegaly, hepatic pain

Skin and subcutaneous tissue disorders

Common: Maculo-papular rash, purpura, erythema, palmar-plantar erythrodysaesthesia syndrome, pruritus, alopecia

Uncommon: Erythema multiforme, dermatitis acneiform, rash, hyperhidrosis

Not known: Generalised erythema, dermatitis, skin necrosis or ulcer, skin hyperpigmentation^d, dry skin

Musculoskeletal and connective tissue disorders

Common: Pain in extremities, back pain, bone pain, arthralgia, myalgia

Not known: Muscular weakness

Renal and urinary disorders

Common: Acute kidney injury, haematuria

Not known: Renal failure, cystitis^c, dysuria

General disorders and administration site conditions

Very common: Asthenic conditions (fatigue, asthenia, lethargy)

Common: Oedema, pyrexia^e, chills

Uncommon: Non-cardiac chest pain, pain

Not known: Injection site reaction, feeling cold

Investigations

Very common: Bilirubin increased

Common: Transaminases (ALT/AST) increased, γGT increased, blood alkaline phosphatase increased, C-reactive protein increased, weight decreased, weight increased

Not known: Blood creatinine increased, blood lactate dehydrogenase (LDH) increased

Grade 3-4 Adverse Reactions:

Infections and infestations

Common: Infections (bacterial, viral, fungal), sepsis^a

Not known: Septic shock^c

Neoplasms benign, malignant and unspecified (including cysts and polyps)*

Not known: Treatment-related second malignancy

Blood and lymphatic system disorders*

Very common: Myelosuppression, pancytopenia, febrile neutropenia

Metabolism and nutrition disorders

Common: Decreased appetite

Uncommon: Hyperglycaemia

Not known: Acidosis^b , glucose tolerance impaired, electrolyte imbalance

Psychiatric disorders

Rare: Confusional state

Nervous system disorders

Rare: Headache, peripheral sensory neuropathy

Not known: Encephalopathy, intracranial haemorrhage, syncope

Cardiac disorders*

Common: Cardiac arrhythmias (e.g. atrial fibrillation, sinus arrhythmia)

Not known: Cardiac arrest, myocardial infarction

Vascular disorders

Uncommon: Hypertension

Not known: Embolism, haemorrhage

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea, pleural effusion, pharyngeal or laryngeal inflammation

Rare: Epistaxis, pneumonitis

Not known: Hypoxia

Gastrointestinal disorders*

Common: Stomatitis/mucositis, diarrhoea, nausea, abdominal pain

Uncommon: Vomiting, oral pain, dysphagia, mouth haemorrhage, oesophageal or gastrointestinal pain

Not known: Gastrointestinal haemorrhage, neutropenic colitis

Hepatobiliary disorders*

Rare: Veno-occlusive liver disease, hepatotoxicity

Not known: Hepatic failure

Skin and subcutaneous tissue disorders

Uncommon: Maculo-papular rash, purpura, erythema

Not known: Skin necrosis

Musculoskeletal and connective tissue disorders

Rare: Pain in extremities, bone pain

Renal and urinary disorders

Uncommon: Acute kidney injury, haematuria

General disorders and administration site conditions

Common: Fatigue

Rare: Non-cardiac chest pain, oedema pyrexia^e

Investigations

Common: Bilirubin increased, transaminases (ALT/AST) increased, γGT increased

Uncommon: Blood alkaline phosphatase increased, C-reactive protein increased

Not known: Blood LDH increased

* See detailed sections below.
^a Clinically or microbiologically documented infection with grade 3 or 4 neutropenia (absolute neutrophil count [ANC] <1.0 × 10⁹/L) and sepsis.
^b Acidosis might be a consequence of the release of methanesulfonic acid through treosulfan activation/cleavage in the plasma.
^c Case reports (>2) after treosulfan-based conditioning obtained from other sources.
^d Bronze pigmentation.
^e Fever in the absence of neutropenia where neutropenia is defined as ANC <1.0 × 10⁹/L.

Description of selected adverse reactions

Infections

The overall incidence of infections was 13.1% (74/564). The most frequent type was lung infection (12/74 [16.2%]). Pathogens included bacteria (e.g. Staphylococcus, Enterococcus, Corynebacterium), viruses (e.g. cytomegalovirus [CMV], Epstein-Barr virus [EBV], herpes) as well as fungi (e.g. candida). The infection rate was lowest in patients treated with the dose regimen of 10 g/m² of treosulfan per day, from day -4 to -2 (7.7%).

Neoplasms benign, malignant and unspecified (including cysts and polyps)

One of 564 adult patients (0.2%) developed a second malignancy (breast cancer). A few further cases of second malignancies after treosulfan-based conditioning have been reported by other investigators. After long-term therapy with conventional doses of oral treosulfan in patients with solid tumours acute myeloid leukaemia was observed in 1.4% of 553 patients.

Blood and lymphatic system disorders

Blood disorders were observed in 67 of 564 adult patients (11.9%). The most frequent adverse reaction was febrile neutropenia (11.3%). The lowest incidence was noted with the dose regimen of 10 g/m²/day, day -4 to -2 (4.1%).

The median (25%/75% percentiles) duration of neutropenia was 14 (12, 20) days with the 10 g/m² treosulfan dose and 17.5 (14, 21) days with the 14 g/m² treosulfan dose.

Cardiac disorders

Cardiac disorders were observed in 25 patients (4.4%). The most frequent adverse reactions were cardiac arrhythmias, e.g. atrial fibrillation (1.2%), sinus tachycardia (0.9%), supraventricular tachycardia (0.4%), and ventricular extrasystole (0.4%). Isolated cases of cardiac arrest, cardiac failure, and myocardial infarction occurred. The lowest frequency of cardiac disorders was seen with the dose regimen of 10 g/m²/day, day -4 to -2 (2.7%).

Gastrointestinal disorders

Gastrointestinal disorders were observed in 357 patients (63.3%). The most frequent adverse reactions reported were nausea (39.5%), stomatitis (36%), vomiting (22.5%), diarrhoea (15.6%), and abdominal pain (10.4%). The lowest frequencies of these adverse reactions were seen with the dose regimen of 10 g/m² per day, day -4 to -2 (20.4%, 30.3%, 13.1%, 5.0%, and 5.5% respectively).

Hepatobiliary disorders

The overall incidence of veno-occlusive liver disease (VOD) was 0.9% (5/564). VOD occurred only with the dose regimen of 14 g/m²/day treosulfan. None of these cases were fatal or life-threatening.

Paediatric population

Tabulated list of adverse reactions

The adverse reactions reported in the list below are derived from two clinical trials (including a total of 88 patients; median age 8 years [range 0–17 years]) where treosulfan combined with fludarabine (and mostly with additional thiotepa) was administered as conditioning treatment prior to alloHSCT in paediatric patients with malignant or non-malignant diseases. Treosulfan was administered in a dose range of 10-14 g/m² BSA on three consecutive days.

Adverse reactions are listed below, by system organ class and by frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency group, undesirable effects are presented in order of decreasing seriousness.

All Adverse Reactions:

Infections and infestations*

Very common: Infections (bacterial, viral, fungal)

Neoplasms benign, malignant and unspecified (including cysts and polyps)*

Not known: Treatment-related second malignancy^a

Blood and lymphatic system disorders*

Very common: Myelosuppression, pancytopenia

Not known: Febrile neutropenia

Metabolism and nutrition disorders

Not known: Alkalosis, electrolyte imbalance, hypomagnesaemia

Nervous system disorders*

Not known: Headache, paraesthesia, seizure

Eye disorders

Not known: Conjunctival haemorrhage, dry eye

Vascular disorders

Not known: Capillary leak syndrome, hypertension, hypotension

Respiratory, thoracic and mediastinal disorders

Common: Oropharyngeal pain, epistaxis

Not known: Hypoxia

Gastrointestinal disorders*

Very common: Stomatitis/mucositis, diarrhoea, nausea, vomiting, abdominal pain

Common: Dysphagia, oral pain

Not known: Neutropenic colitis, anal inflammation, dyspepsia, proctitis, gastrointestinal pain, constipation

Hepatobiliary disorders

Not known: Veno-occlusive liver disease, hepatomegaly, hepatotoxicity

Skin and subcutaneous tissue disorders

Very common: Pruritus

Common: Dermatitis exfoliative, maculo-papular rash, rash, erythema, pain of skin, skin hyperpigmentation^b, alopecia

Not known: Skin ulcer, erythema multiforme, urticaria, dermatitis bullous, dermatitis acneiform, palmar-plantar erythrodysaesthesia syndrome, dermatitis diaper^a

Musculoskeletal and connective tissue disorders

Not known: Pain in extremities

Renal and urinary disorders

Not known: Acute kidney injury, renal failure, noninfective cystitis

Reproductive system and breast disorders

Not known: Scrotal erythema

General disorders and administration site conditions

Very common: Pyrexia^c

Not known: Chills, fatigue, pain

Investigations

Common: Transaminases (ALT/AST) increased, bilirubin increased

Not known: γGT increased

Grade 3-4 Adverse Reactions:

Infections and infestations*

Common: Infections (bacterial, viral, fungal)

Neoplasms benign, malignant and unspecified (including cysts and polyps)*

Not known: Treatment-related second malignancy^a

Blood and lymphatic system disorders*

Very common: Myelosuppression, pancytopenia

Not known: Febrile neutropenia

Metabolism and nutrition disorders

Not known: Alkalosis

Nervous system disorders*

Not known: Paraesthesia

Vascular disorders

Not known: Capillary leak syndrome, hypertension, hypotension

Respiratory, thoracic and mediastinal disorders

Not known: Hypoxia

Gastrointestinal disorders*

Very common: Stomatitis/mucositis, nausea

Common: Dysphagia, diarrhoea, vomiting, abdominal pain

Not known: Neutropenic colitis

Hepatobiliary disorders

Not known: Veno-occlusive liver disease

Skin and subcutaneous tissue disorders

Common: Dermatitis exfoliative, maculo-papular rash, erythema

Renal and urinary disorders

Not known: Acute kidney injury, renal failure

Investigations

Common: Bilirubin increased

Uncommon: Transaminases (ALT/AST) increase

Not known: γGT increased

* See detailed sections below.
^a Case reports (>1) after treosulfan-based conditioning obtained from other sources.
^b Bronze pigmentation.
^c Fever in the absence of neutropenia where neutropenia is defined as ANC <1.0 × 10⁹/L.

Description of selected adverse reactions

Infections

The overall incidence of infections in 88 paediatric patients was 11.4% (10/88) and thus comparable to that seen in adults. The frequency was higher in the paediatric age group 12–17 years (6/35 [17.1%]) compared to younger children (4/53 [7.5%]).

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Five cases of a second malignancy (myelodysplastic syndrome, acute lymphoblastic leukaemia, Ewing’s sarcoma) were reported by other investigators after treosulfan-based conditioning. All five paediatric patients received alloHSCT for primary immunodeficiencies, i.e. diseases with an increased risk for neoplasias per se.

Blood and lymphatic system disorders

The median (25%/75% percentiles) duration of neutropenia was 21 (16, 26) days in paediatric patients with malignant diseases and 24 (17, 26) days in patients with non-malignant disorders.

Nervous system disorders

Seizure in the context of an encephalitis infection was reported in one of 88 paediatric patients. A report from an investigator-initiated trial performed in children with primary immunodeficiencies lists four cases of seizures occurring after other treosulfan-based conditioning regimens.