Nelarabine

Nelarabine is a prodrug of the deoxyguanosine analogue ara-G. It acts as an antimetabolite in leukaemic cells: once activated inside the cell, its triphosphate is incorporated into DNA and stops DNA synthesis.

Mechanism of Action

• Activation: nelarabine is rapidly demethylated by adenosine deaminase (ADA) to ara-G. Inside cells, deoxyguanosine kinase and deoxycytidine kinase phosphorylate ara-G to its 5’-monophosphate, which is then converted to the active 5’-triphosphate, ara-GTP.
• DNA effect: ara-GTP accumulates in leukaemic blasts and is preferentially incorporated into DNA, which inhibits DNA synthesis and leads to cell death. Other mechanisms may contribute to its cytotoxic effect.
• T-cell selectivity: in vitro, T cells are more sensitive than B cells to nelarabine. T lymphoblasts express more deoxycytidine kinase, so ara-G accumulates preferentially in them.

Pharmacokinetics

• Absorption: given intravenously. Plasma ara-G peaks at the end of the infusion at higher levels than nelarabine, showing rapid and extensive conversion. After 1,500 mg/m² over 2 hours in adults, mean plasma nelarabine Cmax was 13.9 µM (AUC 13.5 µM·h) and ara-G Cmax 115 µM (AUC 571 µM·h). Intracellular ara-GTP peaked 3 to 25 hours after the day 1 dose (mean Cmax 95.6 µM).
• Distribution: nelarabine and ara-G are widely distributed. The volume of distribution of nelarabine is 115 L/m² in adults and 89.4 L/m² in children; for ara-G (Vss/F) it is 44.8 and 32.1 L/m². Binding to plasma proteins is below 25% in vitro. Neither compound accumulates in plasma on a daily or a day 1, 3, 5 schedule, but ara-GTP builds up inside cells: on day 3 its Cmax and AUC were about 50% and 30% higher than on day 1.
• Metabolism: the main route is O-demethylation by adenosine deaminase to ara-G, which is hydrolysed to guanine. Some nelarabine is hydrolysed to methylguanine, then O-demethylated to guanine. Guanine is deaminated to xanthine and oxidised to uric acid.
• Elimination: half-lives are about 30 minutes for nelarabine and 3 hours for ara-G. Nelarabine clearance on day 1 is about 138 L/h/m² in adults and 125 L/h/m² in children. The kidneys remove a part: in 28 adults, urinary excretion over 24 hours was 5.3% (nelarabine) and 23.2% (ara-G) of the dose. The half-life of ara-GTP inside cells could not be estimated because it lasts so long.
• Special populations: age has no effect on nelarabine or ara-G pharmacokinetics, although reduced renal function in the elderly may lower ara-G clearance. Sex does not affect plasma levels, but intracellular ara-GTP was on average 2 to 3 times higher in adult women than in men. Race had no apparent effect. Data are limited below 4 years of age. Renal impairment has not been studied specifically; ara-G apparent clearance was about 7% lower in mild impairment.

• T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL): treatment of patients whose disease has not responded to, or has relapsed following, treatment with at least two chemotherapy regimens.
• Because these patient populations are small, the information supporting the indications is based on limited data.

• Hypersensitivity to nelarabine or to any of the excipients (SmPC section 6.1).

The safety profile comes from pivotal studies at the recommended doses in 103 adults (1,500 mg/m²) and 84 paediatric patients (650 mg/m²). The most frequent events were fatigue, gastrointestinal disorders, haematological disorders, respiratory disorders, nervous system disorders (somnolence, peripheral sensory and motor neurological disorders, dizziness, hypoaesthesia, paraesthesia, headache) and pyrexia. Neurotoxicity is the dose-limiting toxicity. Frequencies differ between adults and children, as shown below.

Very common (≥1/10): in adults and children, infection (including sepsis, bacteraemia, pneumonia and fungal infection), neutropenia, thrombocytopenia, anaemia, peripheral neurological disorders (sensory and motor) and headache. In adults, also febrile neutropenia, somnolence, hypoaesthesia, paraesthesia, dizziness, cough, dyspnoea, nausea, vomiting, diarrhoea, constipation, myalgia, oedema, peripheral oedema, pain, pyrexia, fatigue and asthenia. In children, also leucopenia, hypokalaemia and raised transaminases.

Common (≥1/100 to <1/10): in adults and children, hypocalcaemia, hypomagnesaemia, confusion, seizures (including convulsions, grand mal convulsions and status epilepticus), ataxia, tremor, stomatitis, hyperbilirubinaemia, arthralgia, pain in extremity and increased serum creatinine. In adults, also tumour lysis syndrome, leucopenia, hypokalaemia, anorexia, amnesia, balance disorder, dysgeusia, blurred vision, hypotension, pleural effusion, wheezing, abdominal pain, increased aspartate aminotransferase, muscle weakness, back pain and abnormal gait. In children, also febrile neutropenia, hypoglycaemia, and the reactions listed above as very common in adults that are only common in children (somnolence, hypoaesthesia, paraesthesia, nausea, vomiting, diarrhoea, constipation, pyrexia, fatigue and asthenia).

Rare (≥1/10,000 to <1/1,000): rhabdomyolysis and increased creatine phosphokinase (from post-marketing data).

The most important serious reactions are severe neurological reactions (see Special Instructions), myelosuppression (leukopenia, thrombocytopenia, anaemia and neutropenia, including febrile neutropenia), serious infections and tumour lysis syndrome.

• Adenosine deaminase inhibitors such as pentostatin: the combination is not recommended; it may reduce the efficacy of nelarabine and/or change the adverse event profile of either medicine.
• Intrathecal chemotherapy and craniospinal irradiation: previous or concurrent intrathecal chemotherapy, or previous craniospinal irradiation, may raise the risk of neurological adverse events; concomitant use is not recommended.
• Live vaccines: not recommended (see Special Instructions).
• Cytochrome P450: in vitro, nelarabine and ara-G did not significantly inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4.

Nelarabine must be given only under the supervision of a physician experienced in the use of cytotoxic agents. Complete blood counts, including platelets, must be monitored regularly. It is for intravenous use only and must not be diluted before administration. The dose is transferred into polyvinylchloride (PVC) or ethyl vinyl acetate (EVA) infusion bags or glass containers and infused over 2 hours in adults and over 1 hour in paediatric patients.

Recommended Dose

• Adults and adolescents aged 16 years and older: 1,500 mg/m² intravenously over 2 hours on days 1, 3 and 5, repeated every 21 days.
• Children and adolescents aged 21 years and younger: 650 mg/m² intravenously over 1 hour daily for 5 consecutive days, repeated every 21 days.
• Patients aged 16 to 21 years: both regimens were used in clinical studies with similar efficacy and safety, and the prescribing physician should decide which is appropriate.
• Clinical pharmacology data are limited below the age of 4 years.

Dose Modification

Nelarabine must be discontinued at the first sign of a neurological event of NCI CTCAE grade 2 or greater. For other toxicities, including haematological toxicity, delaying the next dose is an option.

Special Populations

• Elderly: too few patients aged 65 and older were treated to say whether they respond differently. In an exploratory analysis, increasing age, especially 65 and older, seemed linked to more neurological adverse events.
• Renal impairment: not studied. Nelarabine and ara-G are partly excreted by the kidneys, and the data do not support a dose recommendation for creatinine clearance below 50 mL/min. Patients with renal impairment must be closely monitored for toxicity.
• Hepatic impairment: not studied; treat with caution.

Neurological Adverse Reactions

Severe neurological reactions have been reported with nelarabine. They have included altered mental states (including severe somnolence, confusion and coma), central nervous system effects (including convulsions, ataxia and status epilepticus), and peripheral neuropathy (including hypoaesthesia ranging from numbness and paraesthesia to motor weakness and paralysis). Reactions associated with demyelination, and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome, have also been reported. Neurotoxicity is the dose-limiting toxicity of nelarabine. Full recovery has not always followed stopping the medicine. Close monitoring for neurological reactions is therefore strongly recommended, and nelarabine must be discontinued at the first sign of neurological reactions of NCI CTCAE grade 2 or greater.

Intrathecal Therapy and Craniospinal Irradiation

Patients treated before or at the same time with intrathecal chemotherapy, or before with craniospinal irradiation, may be at higher risk of neurological adverse events. Concomitant intrathecal therapy and/or craniospinal irradiation is therefore not recommended.

Live Vaccines

Immunisation with a live organism vaccine can cause infection in immunocompromised patients, so live vaccines are not recommended.

Blood Counts and Tumour Lysis

Leukopenia, thrombocytopenia, anaemia and neutropenia (including febrile neutropenia) have been associated with nelarabine, and blood counts including platelets must be monitored regularly. Intravenous hydration according to standard medical practice is recommended for the management of hyperuricaemia in patients at risk of tumour lysis syndrome, and allopurinol should be considered in patients at risk of hyperuricaemia.

Carcinogenicity and Mutagenicity

Carcinogenicity testing has not been done. Nelarabine is known to be genotoxic to mammalian cells.

Sodium

A 50 mL vial contains 88.51 mg (3.85 mmol) of sodium, equivalent to 4.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Pregnancy, Breastfeeding and Fertility

• Contraception: sexually active men and women should use effective contraception during treatment. Men with partners who are pregnant or could become pregnant should use condoms during treatment and for at least three months afterwards.
• Pregnancy: there are no or few data. Animal studies showed reproductive toxicity, and exposure during pregnancy will likely lead to foetal anomalies and malformations. Nelarabine should not be used in pregnancy unless clearly necessary, and a patient who becomes pregnant should be told of the possible risk to the foetus.
• Breastfeeding: it is unknown whether nelarabine or its metabolites pass into human milk; a risk to the infant cannot be excluded, so breast-feeding should be stopped during treatment.
• Fertility: the effect in humans is unknown, but undesirable effects on fertility are possible given its pharmacological action. Family planning should be discussed as appropriate.

Effect on Driving

Atriance has a major influence on the ability to drive and use machines. Patients may be somnolent during treatment and for several days afterwards, and must be warned that this can affect skilled tasks such as driving.

The SmPC sets no special storage conditions for the unopened vial. Once a vial has been opened, Atriance is stable for up to 8 hours at up to 30 °C. It comes in clear glass (Type I) vials of 50 mL with a bromobutyl rubber stopper and an aluminium seal with a red snap-off cap, in packs of 1 or 6 vials.

3 years. After the vial has been opened, the solution is stable for up to 8 hours at up to 30 °C.

Prescription only (Rx); a medicinal product subject to restricted medical prescription (Annex II B), used under the supervision of a physician experienced in the use of cytotoxic agents. Atriance is given as an intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it.