Nelarabine is indicated for the treatment of patients with acute T-cell lymphoblastic leukemia (LAL-T) or non-responding or T-cell lymphoblastic lymphoma after at least two lines of chemotherapy. >

Due to the low patient population in these diseases, the information supporting these indications is based on limited data.


Dosage

It is recommended that patients treated with nelarabine should be given intravenous hydration according to the usual medical practices for the management of hyperuricaemia in patients who may develop tumor lysis syndrome. For patients who may develop hyperuricemia, the use of allopurinol should be considered (see Warnings and Precautions for Use).
The blood count, including the platelet count, should be regularly monitored (see sections 4.4 and 4.4).
Adults and adolescents (aged 16 years or older)

In adults, the recommended dosage of nelarabine is 1 500 mg / m 2 administered intravenously for 2 hours per day on the 1 st, 3 rd and 5 th day and every 21; Days.

Population, pediatric

Children and adolescents (aged 21 or under)

In children and adolescents, the recommended dose of nelarabine is 650 mg / m 2 administered intravenously for 1 hour daily for 5 consecutive days every 21 days. >

In clinical studies, doses of 650 mg / m 2 and 1500 mg / m 2 were studied in patients aged 16-21 years, and efficacy and tolerability were similar for the 2 Regimens. The physician should consider the most appropriate dosage when treating a patient in this age group.
Changing the dosage

Treatment with nelarabine should be discontinued as soon as the first signs of adverse reactions occur, or a grade 2 or greater neurological disorder defined according to the NCI-CTCAE (National Cancer Institute Common Terminology Criteria Adverse Event). In the event of other toxicities, including haematological, the postponement of the following treatment may be considered.

Subjects, aged

The number of patients aged 65 or older treated with nelarabine is not sufficient to determine whether their treatment response differs from that of younger patients (see sections 4.4 and 4.4). Properties, pharmacokinetics).

Renal insufficiency

Nelarabine has not been studied in subjects with renal insufficiency. Nelarabine and 3-D-arabinofuranosyl guanine (ara-G) are partially excreted by the kidneys (see section 4.8 Pharmacokinetic properties). The data are insufficient to establish a dose adjustment recommendation in patients whose creatinine clearance is less than 50 ml / min. Patients with renal impairment should be closely monitored for potential toxicities under treatment with nelarabine

Hepatic Insufficiency

Nelarabine has not been studied in patients with hepatic impairment. These patients should be the subject of special attention.

Mode of administration

Nelarabine should not be diluted before administration. The required dose of nelarabine should be transferred to plastic infusion pockets (PVC or EVA) or glass vials, and administered intravenously to a two-hour infusion in adults, and Time at the child

Clear and colorless solution.

Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, purine analogues, ATC code: L01B B, 07

Nelarabine is a prodrug of the deoxy-guanosine analogue: ara-G. Nelarabine is rapidly demethylated by adenosine deaminase (ADA) to ara-G and then intracellularly phosphorylated by deoxyguanosine kinase and deoxycytidine kinase to its 5'-monophosphate metabolite. The metabolite, monophosphate is then converted to its active conjugate, 5'-triphosphate, ara-GTP. The accumulation of ara-GTP in leukemic blasts allows for the preferential incorporation of ara-GTP into deoxyribonucleic acid (DNA) leading to inhibition of DNA synthesis and resulting in one; Cell death. Other mechanisms may contribute to the cytotoxic effects of nelarabine. In vitro, T cells are more sensitive than B cells to the cytotoxic effects of nelarabine

Clinical studies

Studies at the adult

In an open-label study conducted by Cancer and Leukaemia Group B and the Southwest Oncology Group, the safety and efficacy of nelarabine were evaluated in 39 adults with acute T-cell lymphoblastic leukemia (LAL-T) or T-cell lymphoblastic lymphoma. Twenty-eight out of a total of 39 patients were relapsed or refractory, at least two previous induction therapies and aged 16-65 years (mean age A dose of 1,500 mg / m 2 / day of nelarabine was administered intravenously for two hours on days 1, 3 and 5 of a 21-day cycle Five of 28 (18%) [IC 95%: 6% - 37%] treated with nelarabine obtained complete response (number of blasts in bone marrow, ≤ 5% without further manifestation, disease and full recovery Of the total number of peripheral blood cells.) A total of 6 patients (21%) [95% CI: 8% - 41%] achieved complete response, with or without hematologic recovery. Response, the time required to obtain a complete response was 2.9 to 11.7 weeks. Response durations (in both response categories, n '= 5) ranged from 15 weeks to over 195 weeks. The median overall survival was 20.6 weeks [95% CI: 10.4 - 36.4]. The one-year survival rate was 29% [95% CI: 12% - 45%].
Pediatric studies

In an open-label multicentre study conducted by the Children Oncology Group, nelarabine was administered intravenously for 1 hour for 5 consecutive days to 151 patients aged 21 years or less, of whom 149 had leukemia; Acute T-cell lymphoblastic or lymphoma T-cell lymphoblastic, relapsed or refractory Eighty-four (84) patients, of whom 39 had previously received at least two previous induction therapies and 31 had only one treatment Were treated with 650 mg / m 2 / day of nelarabine, administered intravenously for 1 hour per day, for 5 consecutive days, every 21 days. >

Of the 39 patients who received at least two previous induction treatments, 5 (13%) [95% CI: 4% - 27%] achieved complete response (number of blasts in the marrow, bone ≤; 5%, no further evidence of disease and complete recovery of peripheral blood cells) and 9 (23%) [95% CI: 11% - 39%] achieved complete response with or without haematological recovery; . In both response categories, response times ranged from 4.7 to 36.4 weeks and the median overall survival was 13.1 weeks [95% CI: 8.7 -17.4], Survival at one year was 14% [95% CI: 3% - 26%].
In total, thirteen (42%) of the 31 patients who received previous induction therapy achieved a complete response: Nine of these 31 patients had no response to previous induction therapy (patients; Refractory). Four (44%) of the nine refractory patients achieved complete response to treatment with nelarabine

Discontinuation of treatment with nelarabine did not always result in complete recovery following the occurrence of these adverse effects. Therefore, it is strongly recommended to carefully monitor any adverse neurological effects, and treatment with nelarabine should be discontinued, as soon as the first signs of the adverse effect, neurological adverse reaction grade 2 or more according to the NCI classification - CTCAE.

Neurotoxicity is the dose-limiting toxicity of nelarabine. Careful monitoring of nelarabine-treated patients is recommended to detect any signs and symptoms suggestive of neurological toxicity

Signs and symptoms commonly associated with nelarabine-related neurotoxicity include somnolence, mental confusion, convulsions, ataxia, paraesthesia, and hypoesthesia. Signs of severe neurological toxicity include: coma, disease state, epilepsy, demyelination or neuropathy, similar in appearance to Guillain-Barré syndrome (see side effects). >

Patients previously or simultaneously treated with intrathecal chemotherapy or having previously been treated with cranio-spinal irradiation are potentially at greater risk of developing adverse reactions, neurological (see Dosage and Mode of Administration, Dosage), therefore concomitant treatment with intrathecal and / or cranio-spinal irradiation is not recommended.

Immunization by a live vaccine may potentially be the cause of infection in immunocompromised individuals. That is why live vaccines are not recommended.

Leukopenia, thrombocytopenia, anemia and neutropenia (including febrile neutropenia) have been associated with treatment with nelarabine. The blood count including platelet count should be regularly monitored (see sections Posology and method of administration and Effects undesirable)

It is recommended that patients treated with nelarabine receive intravenous hydration in accordance with the usual medical practices for the management of hyperuricaemia in patients at risk of developing tumor lysis syndrome. For patients who may develop hyperuricemia, the use of allopurinol should be considered.
Elderly subjects

Clinical studies with nelarabine did not permit the inclusion of a sufficient number of patients aged 65 years or older to determine whether their response differs from that of younger patients. An exploratory analysis has shown that age, more especially at age 65, appears to be associated with an increase in the frequency of adverse reactions, neurological. >

Carcinogenicity and Mutagenicity

No carcinogenicity assays were performed with nelarabine. However, nelarabine is known to be genotoxic at the mammalian cell level (see section Preclinical safety data).


This drug contains 1.725 mg / ml (75 micromoles) of sodium. Patients following a low-salt diet will need to take this information into account.

In vitro, nelarabine and ara-G do not significantly inhibit the activity of the main hepatic cytochrome P450 (CYP), CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.

Concomitant administration of nelarabine and inhibitors of adenosine deaminase, such as pentostatin, is not recommended. Concomitant administration may reduce the efficacy of nelarabine and / or alter the profile of the adverse reactions of each of these active substances

Not applicable.

No cases of overdose have been reported.

In clinical studies, nelarabine was administered at a dosage of up to 75 mg / kg (approximately 2250 mg / m 2) per day for 5 days in a child at a dose up to 60 mg / kg (approximately 2400 mg / m 2) per day for 5 days in 5 adult patients and at a dosage of up to 2900 mg / m 2 on days 1, 3 and 5 in two Other adult patients.

Signs and symptoms

Overdosage with nelarabine is likely to result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression and possibly fatal. At the dose of 2200 mg / m 2 administered on days 1, 3, and 5 of each 21-day period, 2 patients developed grade 3 ascending sensitive neuropathy. A process of demyelination of the cervical marrow

Processing

There is no known antidote for nelarabine overdose. Appropriate care shall be provided in accordance with good clinical practice.
Contraception in men and women

Men and women of childbearing age should use effective contraceptive methods throughout treatment and for at least three months after cessation.
>
Pregnancy

There are no relevant data concerning the use of nelarabine in pregnant women.

Nelarabine should not be used during pregnancy unless absolutely necessary. If pregnancy occurs during treatment with nelarabine, the patient should be informed of the potential risks to the fetus.


No data on the passage of nelarabine or its metabolites into human breast milk is available. The passage of nelarabine into milk has not been studied in animals. However, because of the risk, serious adverse reactions in the infant, breastfeeding, breastfeeding should be interrupted.

Fertility

In man, the effect of nelarabine on fertility is not known. Because of the pharmacological action of the product, adverse effects on fertility are possible. If the conception of a child is envisaged, its planning should be discussed with patients.

Summary of the security profile

The safety profile determined in the pivotal clinical studies at nelarabine doses recommended in adults (1500 mg / m 2) and in children (650 mg / m 2) is based on the data obtained Respectively in 103 adults and 84 children. The most frequently observed adverse effects were fatigue, disorders, gastrointestinal disorders, haematological disorders, disorders, respiratory disorders, nervous system disorders and pyrexia. Neurotoxicity is the dose-limiting toxicity of nelarabine (see Warnings and Precautions for Use).


The following convention was used for their classification, very frequent (≥ 1/10), frequent (≥ 1/100 and