Nelarabine is a medication used in the treatment of certain types of cancer, particularly T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). It is an antimetabolite chemotherapy drug.

Nelarabine is a prodrug, which means it is converted into an active form in the body. In this case, it is converted into ara-G, a compound that disrupts the DNA in cancer cells, preventing them from growing and dividing. This can help slow down or stop the progression of these types of cancers.

Nelarabine is a chemotherapeutic prodrug of arabinosyl-guanine nucleotide triphosphate that inhibits DNA synthesis and causes cytotoxicity.

Nelarabine Uses:

• T-cell acute lymphoblastic leukemia/lymphoma:
  • Used for treatment of relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma in patients ≥1 year of age following at least two chemotherapy regimens

Nelarabine Dose in Adults

Note:

• Make sure to drink enough water and take preventive medicine to avoid a serious condition caused by the rapid breakdown of cancer cells, called tumor lysis syndrome.

Nelarabine Dose in the treatment of T-cell acute lymphoblastic leukemia/lymphoma:

• For treating T-cell acute lymphoblastic leukemia/lymphoma, nelarabine is given through an IV (in the vein).
• The dose is 1,500 mg per square meter of body surface area.
• It's given on days 1, 3, and 5.
• This schedule is repeated every 21 days.
• This treatment continues until:
  • The patient is ready for a transplant,
  • The disease gets worse,
  • There are severe side effects, or

Nelarabine Dose in Chilldrens

• Dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol.

Nelarabine Dose in the treatment of refractory/ relapsed T-cell acute lymphoblastic leukemia (ALL) and T-cell lymphoblastic lymphoma:

For treating T-cell acute lymphoblastic leukemia (ALL) and T-cell lymphoblastic lymphoma that has come back or not responded to other treatments in babies, kids, and teenagers:

• Nelarabine is given through an IV (into the vein).
• The dose is 650 mg for every square meter of body surface area.
• It's given daily from day 1 to day 5.
• This 5-day treatment is repeated every 21 days.
• The treatment continues until:
  • The patient is ready for a transplant,
  • The disease gets worse, or
  • There are severe side effects.

Nelarabine Dosage adjustment for toxicity:

For babies, kids, and teenagers:

• If they experience neurological side effects of grade 2 or higher: Stop the nelarabine treatment.
• If they have blood-related or any other side effects (except neurological ones): Think about pausing the treatment for a while.

Nelarabine Pregnancy Risk Category: D

• Nelarabine might harm a baby if taken during pregnancy, based on how the drug works and studies on animals.
• Before starting the treatment, make sure women who can get pregnant aren't already pregnant.
• Women who can become pregnant should use reliable birth control during treatment with nelarabine.
• Male patients, even if they've had a vasectomy, should use condoms if their partners can become pregnant. This should continue during the treatment and for 3 months after the last dose of nelarabine.
• There are European guidelines about treating cancer during pregnancy. If someone is pregnant and has cancer, they should get treatment at a center that has expertise in this situation.
• The guidelines suggest a team approach with specialists like baby doctors, cancer experts, and pregnancy doctors.
• As a general rule, chemotherapy:
  • Should be avoided in the first three months of pregnancy.
  • Shouldn't be given too close to when the baby is due; ideally, there should be a 3-week gap between the last dose and the baby's birth.
  • Shouldn't be given after the 33rd week of pregnancy.
• These guidelines don't specifically talk about using nelarabine during pregnancy.

Use of Nelarabine during lactation

• We don't know if nelarabine or its active form, ara-G, are in breast milk.
• Because there's a risk of severe side effects in the baby, the manufacturer advises against breastfeeding if you're taking nelarabine.

Nelarabine Dose in Kidney Disease:

• If the kidneys filter out 50 mL or more per minute (CrCl ≥50 mL/minute): You can take the usual dose.
• If the kidneys filter less than 50 mL in a minute (CrCl <50 mL/minute): The manufacturer doesn't give a changed dose even if the drug's active form clears out slower in weaker kidneys. Since there's not enough data to suggest a different dose, it's crucial to watch the patient closely.

Nelarabine Dose in Liver disease:

• The manufacturer doesn't provide any dose changes for people with serious liver issues (where a liver function test is more than three times the upper normal limit).
• Since it hasn't been studied, it's important to watch these patients very closely if they're taking the medication.

• Pediatric adverse reactions fell within a range similar to adults except where noted.

Common Side Effects of Nelarabine:

• Cardiovascular:
  • Peripheral Edema
  • Edema
• Central Nervous System:
  • Fatigue
  • Drowsiness
  • Dizziness
  • Peripheral Neuropathy
  • Headache
  • Hypoesthesia
  • Paresthesia
  • Pain
• Endocrine & Metabolic:
  • Hypokalemia
• Gastrointestinal:
  • Nausea
  • Diarrhea
  • Vomiting
  • Constipation
• Hematologic & Oncologic:
  • Anemia
  • Neutropenia
  • Thrombocytopenia
  • Leukopenia
  • Febrile Neutropenia
  • Petechia
• Hepatic:
  • Increased Serum Transaminases
• Neuromuscular & Skeletal:
  • Weakness
  • Myalgia
• Respiratory:
  • Cough
  • Dyspnea
• Miscellaneous:
  • Fever

Less Common Side Effects Of Nelarabine:

• Cardiovascular:
  • Hypotension
  • Sinus Tachycardia
  • Chest Pain
• Central Nervous System:
  • Ataxia
  • Confusion
  • Myasthenia
  • Rigors
  • Insomnia
  • Abnormal Gait
  • Depression
  • Impaired Consciousness
  • Noncardiac Chest Pain
  • Motor Dysfunction
  • Amnesia
  • Equilibrium Disturbance
  • Sensory Disturbance
  • Disturbance In Attention
  • Dysarthria
  • Hydrocephalus
  • Hypertonia
  • Hyporeflexia
  • Lethargy
  • Mental Status Changes
  • Nerve Palsy
  • Paralysis
  • Sciatica
  • Speech Disturbance
  • Aphasia
  • Brain Disease
  • Cerebral Hemorrhage
  • Coma
  • Hemiparesis
  • Intracranial Hemorrhage
  • Leukoencephalopathy
  • Loss Of Consciousness
  • Seizure
• Endocrine & Metabolic:
  • Decreased Serum Albumin
  • Hypocalcemia
  • Dehydration
  • Hyperglycemia
  • Hypoglycemia
  • Hypomagnesemia
• Gastrointestinal:
  • Abdominal Pain
  • Anorexia
  • Stomatitis
  • Abdominal Distention
  • Dysgeusia
• Hepatic:
  • Increased Serum Bilirubin
  • Increased Serum AST
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Arthralgia
  • Back Pain
  • Limb Pain
  • Tremor
• Ophthalmic:
  • Blurred Vision
  • Nystagmus
• Renal:
  • Increased Serum Creatinine
• Respiratory:
  • Pleural Effusion
  • Epistaxis
  • Pneumonia
  • Sinusitis
  • Wheezing
  • Sinus Headache

Contraindications to Nelarabine:

• In the US: The manufacturer doesn't list any reasons someone shouldn't take nelarabine.
• In Canada: People shouldn't take nelarabine if they're allergic to it or any of its ingredients.

Warnings and precautions

Suppression of bone marrow

• Nelarabine can reduce blood cells, leading to low white blood cells, low platelets, anemia, and very low neutrophil counts (which can come with fever).
• It's important to regularly check blood levels when on this treatment.

Somnolence

• Nelarabine can make you feel drowsy during the treatment and for a few days afterward.
• This drowsiness can affect how you think and act.
• So, patients should be careful with activities that need full attention, like using machines or driving.

Neurotoxicity: [US Boxed Warn]

• Nelarabine can have serious effects on the nervous system. This can include changes in mental state, extreme drowsiness, seizures, and issues with nerves, ranging from tingling and numbness to muscle weakness and even paralysis.
• There have been reports of nerve damage that looks like Guillain-Barré syndrome, a condition where the immune system attacks the nerves.
• Some of these nerve-related side effects might not completely go away even after stopping the medicine.
• Common symptoms to look out for include feeling drowsy, headaches, tingling, sensitivity issues, dizziness, problems with coordination, shaking, and in serious cases, coma and seizures.
• These symptoms often start 5 to 8 days after the first dose but can start as early as 1 day or as late as 269 days. They typically last for 2 to 6 days but can range from 1 to 393 days.
• It's essential to watch patients closely for these side effects during the treatment and for at least a day after each dose.
• People who have had treatment directly into their spinal fluid or radiation to the brain and spine might have a higher risk of these side effects.

Patients should be made aware of these risks and monitored carefully. If they show serious symptoms (grade 2 or above), the treatment should be stopped.

Tumor lysis syndrome

• When treating leukemia, nelarabine can cause tumor lysis syndrome (TLS). This is when cancer cells break down rapidly, releasing their contents into the bloodstream.
• This rapid breakdown can lead to serious issues, like kidney failure which can be life-threatening.
• To reduce the risk, make sure the patient drinks enough water before and during the treatment. This helps flush out the substances released by the breaking down of cancer cells.
• It's also a good idea to consider preventive treatment to lower uric acid levels in the blood.
• Keep a close watch on patients for signs of TLS.

In essence, TLS is a serious side effect that needs preventive measures and close monitoring.

Hepatic impairment

• If a patient has liver problems, keep a close eye on them when they're on this treatment.
• People with severe liver issues might have a higher risk of negative side effects.

Renal impairment

• If a patient has kidney problems, it's crucial to watch them closely during the treatment.
• The body might clear out Ara-G (the active form of the drug) slower if the kidneys aren't working well. This can increase the risk of side effects, especially in patients with medium to severe kidney issues.

Nelarabine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

Before Starting Treatment:

• Check blood counts, including different types of white blood cells (CBC with differential).
• Test liver and kidney functions.
• Make sure women who can have children aren't pregnant.

Watching for Side Effects:

• Pay close attention for nervous system issues, such as:
  • Extreme drowsiness (severe somnolence).
  • Seizures.
  • Nerve problems (peripheral neuropathy).
  • Confusion.
  • Lack of coordination (ataxia).
  • Tingling feelings (paresthesia).
  • Reduced sensitivity (hypoesthesia).
  • Coma.
  • Damage to nerves in the spine and brain (craniospinal demyelination).
• Keep a close eye on these side effects, especially during treatment and for at least a day after each dose.

Tumor Lysis Syndrome:

• Watch out for symptoms of tumor lysis syndrome, a condition where cancer cells break down rapidly.

Hydration:

• Check that the patient is drinking enough water (monitor hydration status).

How to administer Nelarabine?

Preventing Tumor Lysis Syndrome:

• Make sure to give enough fluids through an IV.
• Use preventive medicine to lower uric acid levels in the blood.

How to Give the Medicine:

• Administer the medicine through an IV over 2 hours.
• Do this on days 1, 3, and 5.

Mechanism of action of Nelarabine:

• Nelarabine is a medicine that turns into ara-G in the body.
• Adenosine deaminase helps change it into ara-G, and then it becomes ara-GTP.
• Ara-GTP goes into the DNA of the leukemia cells.
• This messes up the cell's ability to make more DNA and triggers a process called apoptosis, which is like cell self-destruction.
• Ara-GTP seems to gather more in T-cells, and this seems to be linked to how well the treatment works in patients.

Nelarabine and Ara-G in the Body:

Distribution (How it spreads in the body):

• Nelarabine:
  • Kids: 213 L/m with a variation of ±358
  • Adults: 197 L/m with a variation of ±216
• Ara-G:
  • Kids: 33 L/m with a variation of ±9.3
  • Adults: 50 L/m with a variation of ±24

Protein binding (How much sticks to proteins):

• Both Nelarabine and Ara-G: Less than 25% sticks to proteins.

How it changes (Metabolism):

• It starts in the liver.
• Nelarabine becomes ara-G (the active form) with the help of adenosine deaminase.
• Ara-G can change to another substance called methylguanine.
• Both ara-G and methylguanine then turn into guanine.
• Guanine changes into xanthine and then into uric acid, and finally, it becomes allantoin.

How long it stays (Half-life):

• Nelarabine:
  • Kids: 13 minutes
  • Adults: 18 minutes
• Ara-G:
  • Kids: 2 hours
  • Adults: 3.2 hours

Peak time (When there's the most in the body):

• Ara-G in adults: Between 3 and 25 hours after the first day's dose.

How it leaves the body (Excretion):

• Through urine. Nelarabine: 5-10%. Ara-G: 20-30%.

Clearance (How quickly it leaves the body):

• Nelarabine:
  • Faster in kids (259 L/hour/m with a variation of ±409) compared to adults (197 L/hour/m with a variation of ±189).
• Ara-G:
  • Almost the same rate in both kids (11.3 L/hour/m with a variation of ±4.2) and adults (10.5 L/hour/m with a variation of ±4.5).

International Brands of Nelarabine:

• Arranon
• Atriance

Nelarabine Brand Names in Pakistan:

Not available.