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nelarabine
Nelarabine is a pro-drug of the deoxyguanosine analogue ara-G that is demethylated by adenosine deaminase to ara-G, then phosphorylated to the active moiety ara-GTP, which is incorporated into the DNA of leukemic cells resulting in cytotoxic effects. T-cells are more sensitive than B-cells to nelarabine's cytotoxic effects.
Nelarabine is rapidly and extensively converted to ara-G.
| Peak plasma levels | Cmax 3-25 hours following 1500 mg/m2 infused over 2 hours |
Nelarabine and ara-G are extensively distributed.
| PPB | < 25% |
| Cross blood brain barrier? | yes |
| Main enzymes involved | O-demethylation by adenosine deaminase to ara-G, followed by hydrolysis to guanine. |
| Active metabolites | yes |
| Inactive metabolites | yes |
Mean clearance of nelarabine is 30% higher in pediatric compared to adult patients; clearance of ara-G is similar for both.
| Half-life | nelarabine: 30 minutes; ara-G: 2-3 hours |
| Urine | mean urinary excretion: nelarabine, 5%; ara-G: 23% of administered dose |
- T-cell acute lymphoblastic leukemia (T-ALL)
- T-cell lymphoblastic lymphoma (T-LBL)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
Extravasation Potential: None
The following adverse effects were reported mainly in adult patients receiving nelarabine monotherapy for T-cell acute lymphoblastic leukemia, lymphoblastic lymphoma, or chronic lymphocytic leukemia in phase I or II clinical trials. Other severe or life-threatening adverse effects may also be included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Hypotension (8%) | E | |||
| Tachycardia (8%) | E | ||||
| Gastrointestinal | Abdominal pain (9%) | E | |||
| Anorexia (9%) | E | ||||
| Constipation (21%) | E | ||||
| Diarrhea (22%) | E | ||||
| Mucositis (8%) | E | ||||
| Nausea, vomiting (41%) (severe - 1%) | I E | ||||
| General | Edema (15%) | E | |||
| Fatigue (50%) (12% severe) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (86%) (63% severe neutropenia, including opportunistic infections and PML) | E | |||
| Hepatobiliary | ↑ LFTs (6%) (2% severe) | E | |||
| Metabolic / Endocrine | Hyperglycemia (6%) | E | |||
| Tumor lysis syndrome (rare) | I E | ||||
| Musculoskeletal | Musculoskeletal pain (13%) | E | |||
| Rhabdomyolysis (also increased CPK; rare) | E | ||||
| Nervous System | Ataxia (9%) | E | |||
| Confusion (8%) | E | ||||
| Dizziness (21%) | E | ||||
| Hallucinations (1%) | E | ||||
| Headache (15%) | E | ||||
| Insomnia (7%) | E | ||||
| Leukoencephalopathy (rare) | E | ||||
| Myelitis (transverse - rare) | E | ||||
| Neuropathy (21%) (may be severe, including cranial - rare) | E | ||||
| Seizure (rare) | E | ||||
| Somnolence (23%) | E | ||||
| Ophthalmic | Blurred vision (4%) (also reduced vision; blindness - rare) | E | |||
| Respiratory | Cough, dyspnea (25%) | E | |||
| Pleural effusion (10%) | E | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects in adults include myelosuppression ± infection, bleeding, fatigue, nausea, vomiting, cough, dyspnea, somnolence, diarrhea, constipation, dizziness, neuropathy and edema.
The most common side effects in pediatric patients were myelosuppression +/- infection, bleeding, headache, increased transaminase and bilirubin, decreased serum potassium and albumin and vomiting. Severe neurological events, including seizures, were also reported in pediatric patients.
Patients at risk of tumour lysis syndrome (i.e. high tumour burden) should have appropriate prophylaxis and be monitored closely.
Neurotoxicity is dose-limiting and may be irreversible and fatal. The risk of severe neurotoxicity (including fatalities) is higher with intrathecal chemotherapy or craniospinal irradiation. Signs and symptoms include somnolence, confusion, altered level of consciousness, seizures, ataxia, paresthesias and hypoesthesia. Severe effects may include coma, status epilepticus, myelopathy, craniospinal demyelination or ascending neuropathy resembling Guillain-Barre syndrome.
Acute hepatic failure, including fatalities, has been reported.
Refer to protocol by which patient is being treated.
Prophylaxis for tumour lysis syndrome is recommended.
Consider antiviral and other prophylaxis for infection based on institutional guidelines.
Single Agent (T-ALL/T-LBL):
Intravenous: 1500 mg/m² Days 1, 3 and 5 every 3 weeks
In Combination with Chemotherapy (T-ALL):*
Intravenous: 650 mg/m² daily for 5 days
*NDFP funded dosing, not from Health Canada. Refer to NDFP form and Dunsmore et al for details.
Refer to the protocol by which the patient is being treated for dose modification guidelines. The following are suggested modifications.
|
Toxicity / Grade
|
Action
|
|
Platelets < 100 x 109/L and/or ANC < 1.5 x 109/L OR Febrile neutropenia
|
Hold until recovery
|
|
Grade 3 non-hematologic toxicity (NOT including neurotoxicity)
|
Hold until recovery
|
|
Grade 4 non-hematologic toxicity OR
Grade 2 or greater neurotoxicity OR rhabdomyolysis, drug-related increases in CPK
|
Discontinue
|
Nelarabine has not been studied in hepatic impairment. Patients with hepatic impairment should be monitored closely for toxicities.
Nelarabine has not been studied in renal impairment.
Nelarabine and ara-G are partially renally excreted. No dosage adjustment is recommended for CrCl ≥ 50 ml/min. No dosing data available for CrCl < 50 ml/min; monitor these patients closely as there may be an increased risk of adverse effects.
No dosage adjustment is recommended in the elderly; however, these patients may have reduced renal function (see dosage with renal impairment). Patients over age 65 had increased rates of neurologic adverse effects.
A pharmacokinetic study found that AUC was 2-3 fold greater in average adult females compared to average adult males. No safety or efficacy differences were observed in clinical trials.
The effect of race on pharmacokinetics has not been evaluated.
Refer to local protocols for details on dosing schedule.
- Should not be diluted prior to administration
- Compatible with PVC infusion bags and glass containers.
- Infuse IV over 1 hour (650 mg/m2) or 2 hours (1500 mg/m2).
- Visually inspect for particulates and discolouration prior to administration.
- Store unopened vials at 25oC with excursions permitted between 15-30oC
- Patients who have a hypersensitivity to this drug or any of its components
- Concurrent intrathecal chemotherapy or craniospinal radiation
Other Warnings/Precautions:
- Patients who have had prior craniospinal irradiation, pre-existing CNS disease, or prior intrathecal therapy may be at increased risk of severe neurologic adverse effects
- Use caution with driving or using machinery as drowsiness, dizziness, or other neurologic effects may occur with treatment
- Avoid live vaccines, since they may result in serious or fatal infections in immunocompromised patients
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Mutagenicity:
Yes
-
Genotoxicity:
Yes
-
Teratogenicity:
Yes
-
Fetotoxicity:
Yes
Nelarabine is not recommended for use in pregnancy.
- Adequate contraception should be used by patients who can become pregnant and their partners during treatment, and for at least 6 months after the last dose (general recommendation).
- Adequate contraception should be used by patients who produce sperm and their partners during treatment, and for 3 months after the last dose.
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended.
-
Fertility effects:
Unknown
No formal drug interaction studies have been performed. Nelarabine does not appear to significantly inhibit CYP-P450 isoenzymes.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| adenosine deaminase inhibitors (pentostatin) | ↓ nelarabine concentration and/or efficacy | ↓ conversion of nelarabine pro-drug to active form (in vitro) | Avoid |
| Intrathecal chemotherapy (e.g. methotrexate) | reports of fatal neurotoxicity | Additive | Avoid |
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and before each cycle |
Liver function tests |
Baseline and before each cycle |
Renal function tests |
Baseline and before each cycle |
Clinical toxicity assessment for neurotoxicity, infections and bleeding, tumour lysis syndrome, GI, musculoskeletal and respiratory effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program (NDFP Website )
- Nelarabine - Newly Diagnosed T-cell Acute Lymphoblastic Leukemia
Berg SL, Blaney SM, Devidas M, et al.; Children's Oncology Group. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol. 2005 May 20;23(15):3376-82.
CADTH reimbursement final recommendation: Nelarabine. October 2023.
DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood. 2007 Jun 15;109(12):5136-42.
Dunsmore KP, Winter SS, Devidas M, et al. Children's Oncology Group AALL0434: A phase III Randomized clinical trial testing nelarabine in newly diagnosed T-cell acute lymphoblastic leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-93.
McEvoy GK, ed in chief. AHFS: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2013: 1136-37.
Product Monograph: Atriance® (nelarabine). Sandoz Canada Inc., November 2022.
Schiff D, Wen PY, van den Bent MJ, et al. Neurological adverse effects caused by cytotoxic and targeted therapies. Nat Rev Clin Oncol 2009 Oct;6(10):596-603.
February 2024 Updated Mechanism of action, Dosing, Warnings/Precautions and Monitoring sections; added NDFP form
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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