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:

• Adequate hydration and prophylactic anti-hyperuricemic therapy are recommended to prevent tumor lysis syndrome.

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

• 1,500 mg/m²/dose intravenous on days 1, 3, and 5
• Repeat every 21 days until a transplant candidate, disease progression, unacceptable toxicity, or until no longer benefiting from therapy.

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:

• 650 mg/m²/dose IV on days 1 through 5
• Repeat cycle every 21 days until transplant, disease progression, or unacceptable toxicity

Nelarabine Dosage adjustment for toxicity:

• Neurologic toxicity ≥grade 2:
  • Discontinue treatment

• Hematologic or other (non-neurologic) toxicity:

  • Consider treatment delay

Nelarabine Pregnancy Risk Category: D

• Nelarabine's mechanism of action and animal reproduction research findings suggest that it could cause harm to fetal health if given during pregnancy.
• Before initiating therapy, verify the status of a female's pregnancy.
• Effective contraception should be used during nelarabine treatment for females with reproductive potential.
• Condoms should be used by male patients, even those who have had vasectomies, with female partners with reproductive potential.
• They should also be used for the three months following the last dose of nelarabine.
• Guidelines for treatment and follow-up for cancer in pregnancy have been published by the European Society for Medical Oncology.
• These guidelines recommend that you refer to a cancer center during pregnancy.
• They also encourage the use of a multidisciplinary team (obstetrician/neonatalian, oncology team).
• If chemotherapy is indicated, it should not be given during the first trimester.
• There should be a three-week period between the last dose of chemotherapy and the delivery date. Additionally, chemotherapy should not exceed week 33 of gestation.
• Peccatori 2013, however, does not discuss the specific use of nelarabine.

Use of Nelarabine during lactation

• It is unknown if nelarabine and ara-G are secreted into breast milk.
• The manufacturer does not recommend breastfeeding due to the risk of serious adverse reactions in breastfed babies.

Nelarabine Dose in Kidney Disease:

CrCl ≥50 mL/minute:

• No dosage adjustment necessary.

CrCl <50 mL/minute:

• There are no dosage adjustments provided in the manufacturer's labeling, (although ARA-G clearance is decreased as renal function declines, data is insufficient for a dosing recommendation)
• Monitor closely.

Nelarabine Dose in Liver disease:

• No dosage adjustments provided in the manufacturer's labeling (has not been studied)
• Closely monitor with severe impairment (total bilirubin >3 times ULN).

• 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:

• Hypersensitivity to nelarabine and any component of the formula

Warnings and precautions

• Suppression of bone marrow

  • Nelarabine treatment is associated with anemia, leukopenia and thrombocytopenia.
  • Regular monitoring of blood counts is recommended.

• Somnolence

  • Nelarabine can cause somnolence for several days following treatment. This may lead to impairment of mental or physical abilities.
  • It is important to warn patients about tasks that require mental alertness, such as driving or operating machinery.

• Neurotoxicity: [US Boxed Warn]

  • There have been reports of severe neurotoxicities including mental state changes, severe somnolence and seizures as well as peripheral neuropathy (ranging in severity from paralysis and motor weakness to numbness, paresthesias, and motor weakness).
  • Monitor regularly during treatment for signs or symptoms of neurotoxicity. Stop if you are >= grade 2.
  • There have been adverse reactions to demyelination, ascending peripheral neuropathies and other conditions similar to Guillain Barre syndrome.
  • After treatment is stopped, neurologic toxicities might not return fully to baseline.
  • Neurotoxicity can manifest as somnolence and headaches, paresthesia, dysesthesia and dizziness.
  • The median time for symptoms to appear after the first infusion is between 5 and 8 days (range 1 to 269 day), with a median duration from 2 to 6 days (range 1 to 393 day).
  • Monitor closely for any signs of neurologic toxicity throughout and for at least 24 hours following each treatment.
  • Patients who have received prior intrathecal chemotherapy, or craniospinal radiation may be at greater risk of developing neurotoxicity.

• Tumor lysis syndrome

  • As a result of treatment for leukemia, tumor lysis syndrome (TLS), may develop.
  • Could lead to serious acute renal failure.
  • To prevent hyperuricemia or TLS, ensure adequate water intake before and during treatment.
  • Consider prophylactic antihyperuricemic therapy.
  • Pay attention.

• Hepatic impairment

  • Toxicities should be monitored closely
  • Severe hepatic dysfunction may increase the risk of adverse reactions.

• Renal impairment

  • Toxicities should be monitored closely
  • Patients with severe or moderate impairment may have a lower clearance of ara-G.

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:

• CBC with differential
• Liver and kidney functions
• Verify pregnancy status prior to therapy initiation in females of reproductive potential
• Monitor closely for neurologic toxicity (severe somnolence, seizure, peripheral neuropathy, confusion, ataxia, paresthesia, hypoesthesia, coma, or craniospinal demyelination), especially during and for at least 24 hours after each treatment
• Monitor for signs and symptoms of tumor lysis syndrome
• Monitor hydration status

How to administer Nelarabine?

• Adequate IV hydration and prophylactic anti-hyperuricemic therapy are recommended to prevent tumor lysis syndrome.
• Infuse over 2 hours on days 1, 3, and 5.

Mechanism of action of Nelarabine:

• Nelarabine is a prodrug from ara–G that is demethylated using adenosine to ara–G. It then becomes ara–GTP.
• Ara-GTP is in the DNA of leukemic blasts. This causes inhibition of DNA synthesis, and induces apoptosis.
• Ara-GTP seems to accumulate in higher amounts in T-cells. This correlates with clinical response.

Protein binding:

• Nelarabine and Ara-G: <25%

Metabolism: Hepatic

• Demethylated by adenosine deaminase to form ara-G (active)
• Also hydrolyzed to form methylguanine.
• Both ara-G and methylguanine metabolized to guanine.
• Guanine is deaminated into xanthine, which is further oxidized to form uric acid, which is then oxidized to form allantoin.

Half-life elimination: Pediatric patients:

• Nelarabine: 13 minutes
• Ara-G: 2 hours

Adults:

• Nelarabine: 18 minutes
• Ara-G: 3.2 hours

Time to peak: Ara-G:

• Adults: 3 to 25 hours (of day 1)

Excretion:

• Urine (nelarabine 5% to 10%, Ara-G 20% to 30%)

Clearance:

• Nelarabine clearance is ~30% higher in pediatric patients (259 ± 409 L/hour/m ) than in adults (197 ± 189 L/hour/m )
• Ara-G clearance in pediatric patients (11.3 ± 4.2 L/hour/m ) is similar to adults (10.5 ± 4.5 L/hour/m )

International Brands of Nelarabine:

• Arranon
• Atriance

Nelarabine Brand Names in Pakistan:

No Brands Available in Pakistan.