Cytarabine

Article Author:
Arjumand Faruqi
Article Editor:
Prasanna Tadi
Updated:
7/8/2020 8:44:39 AM
PubMed Link:
Cytarabine

Indications

In the early 1950s, researchers discovered cytarabine as a nucleoside (containing arabinose sugar) in Cryptotethia crypta, a species of sponges. Cytarabine is an antimetabolite and an antineoplastic agent that belongs to the category of drugs known as anthracyclines. 

Indications for cytarabine fall into labeled and off-labeled indications. Labeled indications of cytarabine include- for the treatment of acute lymphoblastic leukemia, for remission induction therapy in acute myeloid leukemia in adult and pediatric patients, for the treatment of chronic myeloid leukemia (blast phase), and prophylaxis and treatment of meningeal leukemia.  Amongst many, some off-labeled indications of cytarabine in adults are- refractory chronic lymphocytic leukemia and refractory or relapsed Hodgkin’s disease. It is also an option for non-Hodgkin’s lymphoma and primary central nervous system (CNS) lymphoma.

Mechanism of Action

Cytarabine is a pyrimidine analog and is also known as arabinosylcytosine (ARA-C). It is converted into the triphosphate form within the cell and competes with cytidine to incorporate itself in the DNA. The sugar moiety of cytarabine hinders the rotation of the molecule within the DNA. The DNA replication ceases, specifically during the S phase of the cell cycle, which makes it a specific drug for rapidly dividing cells, such as those seen in cancer. DNA replication and repair also halts due to the inhibition of DNA polymerase by cytarabine. This drug must act for a time that is equivalent to one cell cycle to inhibit the replication of tumor cells effectively. Hence the bolus dose of cytarabine is given every 8 to 12 hours to maintain optimum intracellular levels.

Pharmacokinetics

The absorption of cytarabine is not effective when taken orally due to high first-pass metabolism. When administered subcutaneously, intrathecally, or intravenously, it has a high bioavailability. It has a low plasma protein binding capacity and thus a high volume of distribution. It can cross the blood-brain barrier and hence has an off-label use in primary CNS lymphomas. Cytarabine metabolism primarily occurs in the liver. It has an active metabolite- azacytidine triphosphate; and an inactive metabolite- uracil arabinoside, which is cleared by the kidney.

Administration

Dosage Forms:

Solution, Injection: 10mg/ml, 20 mg/mL (25 mL), 100 mg/ml

Intrathecal injection, liposomal: 50mg/5ml

Administration- Rapid intravenous infusion, infuse over 1-3 hours intravenously or subcutaneously or intrathecally. 

Storage- Store at room temperature. 

Dosing: Adult

1. Acute lymphoblastic leukemia (off-label dosing):

Induction regimen, relapsed or refractory- Administer 3,000 mg/sq.meter of cytarabine over 3 hours by intravenous infusion daily for five days in combination with idarubicin for three days.[1]

Dose-intensive regimen- 3,000 mg/sq.meter of cytarabine over 2 hours by intravenous infusion. This dose is to be given every 12 hourly on days 2 and 3 (4 doses/cycle) of even-numbered cycles in combination with methotrexate.[2]

 2. Acute myeloid leukemia (remission induction chemotherapy):

Administer standard dose 100 mg/sq.meter/day of cytarabine by continuous intravenous infusion for 7 days or give 200 mg/sq.meter/day by continuous intravenous infusion for 7 days(as 100 mg/m2 over 12 hours every 12 hours).[3]

3. Acute myeloid leukemia consolidation therapy (off-label use):

5+2 regimen: Administer 100 mg/sq.meter/day of cytarabine for five days by intravenous infusion in combination with daunorubicin or idarubicin or mitoxantrone.[3][4]

4. Acute myeloid leukemia salvage treatment (off-label use):

CLAG-M regimen: Administer 2,000 mg/sq.meter/day of cytarabine by intravenous infusion over 4 hours for five days in combination with cladribine, G-CSF, and mitoxantrone.[5]

5. Acute promyelocytic leukemia consolidation therapy (off-label use):

First consolidation course: Administer 200 mg/sq.meter/day of cytarabine by intravenous infusion for seven days in combination with daunorubicin.[6]

Second consolidation course:

  • If age is ≤60 years and low risk (WBC <10,000/cubic mm), then administer 1,000 mg/sq.meter of cytarabine every 12 hours for four days (8 doses) by intravenous infusion.
  • If age is <50 years and high risk (WBC ≥10,000/cubic mm), then administer 2,000 mg/sq.meter of cytarabine every 12 hours for five days (10 doses) by intravenous infusion.
  • If age is 50 to 60 years and high risk (WBC ≥10,000/cubic mm), then administer 1500 mg/sq.meter of cytarabine every 12 hours for five days (10 doses) by intravenous infusion.
  • If age is >60 years and high risk (WBC ≥10,000/cubic mm) then administer 1,000 mg/sq.meter every 12 hours for four days (8 doses) by intravenous infusion.

6. Acute promyelocytic leukemia induction (off-label dosing):

Administer 200 mg/sq.meter/day of cytarabine by continuous intravenous infusion for seven days beginning on the third day of treatment in combination with tretinoin and daunorubicin.[6][7]

Adverse Effects

Myelosuppression is the most dreaded adverse effect of cytarabine and can present as acute and severe pancytopenia with striking megaloblastic changes.[8] Other, less life-threatening symptoms include irritation at the site of administration, gastrointestinal disturbances, stomatitis, conjunctivitis, reversible hepatic enzyme elevation, and dermatitis. Severe hypersensitivity, such as anaphylaxis, occurs on rare occasions but is a strong indication for discontinuation of cytarabine therapy. Cerebral and cerebellar toxicity may follow an intrathecal administration of cytarabine. Manifestations of cerebellar toxicity include ataxia and slurred speech, while that of cerebral toxicity are seizures and dementia.[9][10] Cytarabine might affect the cardiovascular system also, causing angina pectoris and even pericarditis. Cytarabine syndrome is a rare illness produced shortly after administration of cytarabine, characterized by non-specific symptoms like fever, malaise, rash, joint pain, and muscle pain and is manageable with corticosteroids. Severe symptoms tend to occur more commonly in patients with renal impairment as the renal clearance of the drug decreases.

Contraindications

Cytarabine is contraindicated in patients who have had a hypersensitivity reaction to it or any of the fundamental ingredients used in the preparation of the drug. With active meningeal infections, liposomal cytarabine is also contraindicated.

Monitoring

As cytarabine affects various organs, a panel of tests is necessary to monitor the patients. These are :

  • Liver function tests
  • Complete blood count
  • Differential WBC count
  • Platelet count
  • Serum creatinine
  •  Blood urea nitrogen (BUN)
  • Serum uric acid

Toxicity

Toxicity caused by cytarabine can classify into either low dose or high dose toxicity. The only noteworthy low dose toxicity is myelosuppression, while corneal toxicity is a frequent occurrence with high doses of cytarabine. Continuous infusion may prove more toxic than the typical intermittent dosage. Considerable cardiac toxicity has been observed only in the standard induction schedules.[11]

Enhancing Healthcare Team Outcomes

Patient safety and cytarabine: 

It is an observation that in delivering therapeutic drugs, incorrect doses of drugs are sometimes administered.[12] Lack of proper care during intrathecal administration of cytarabine in pediatric patients can lead to overdose. Previously cerebrospinal fluid exchange was recommended if such an incident occurred. Contrary to this belief, there have been recent reports that if there is prompt identification of such an error, then management via a cerebrospinal fluid exchange is not necessary.[13][14] In the above case reports, hydrocortisone was administered, and the patient received adequate supportive care. All patients were neurologically stable at the time of overdose. They did not show any signs of cytarabine toxicity or complications and quickly recovered.


References

[1] Weiss MA,Aliff TB,Tallman MS,Frankel SR,Kalaycio ME,Maslak PG,Jurcic JG,Scheinberg DA,Roma TE, A single, high dose of idarubicin combined with cytarabine as induction therapy for adult patients with recurrent or refractory acute lymphoblastic leukemia. Cancer. 2002 Aug 1;     [PubMed PMID: 12209751]
[2] Kantarjian HM,O'Brien S,Smith TL,Cortes J,Giles FJ,Beran M,Pierce S,Huh Y,Andreeff M,Koller C,Ha CS,Keating MJ,Murphy S,Freireich EJ, Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2000 Feb;     [PubMed PMID: 10653870]
[3] Wiernik PH,Banks PL,Case DC Jr,Arlin ZA,Periman PO,Todd MB,Ritch PS,Enck RE,Weitberg AB, Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992 Jan 15;     [PubMed PMID: 1730080]
[4] Arlin Z,Case DC Jr,Moore J,Wiernik P,Feldman E,Saletan S,Desai P,Sia L,Cartwright K, Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Lederle Cooperative Group. Leukemia. 1990 Mar;     [PubMed PMID: 2179638]
[5] Wierzbowska A,Robak T,Pluta A,Wawrzyniak E,Cebula B,Hołowiecki J,Kyrcz-Krzemień S,Grosicki S,Giebel S,Skotnicki AB,Piatkowska-Jakubas B,Kuliczkowski K,Kiełbiński M,Zawilska K,Kłoczko J,Wrzesień-Kuś A, Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. European journal of haematology. 2008 Feb;     [PubMed PMID: 18076637]
[6] Adès L,Sanz MA,Chevret S,Montesinos P,Chevallier P,Raffoux E,Vellenga E,Guerci A,Pigneux A,Huguet F,Rayon C,Stoppa AM,de la Serna J,Cahn JY,Meyer-Monard S,Pabst T,Thomas X,de Botton S,Parody R,Bergua J,Lamy T,Vekhoff A,Negri S,Ifrah N,Dombret H,Ferrant A,Bron D,Degos L,Fenaux P, Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008 Feb 1;     [PubMed PMID: 17975017]
[7] Powell BL,Moser B,Stock W,Gallagher RE,Willman CL,Stone RM,Rowe JM,Coutre S,Feusner JH,Gregory J,Couban S,Appelbaum FR,Tallman MS,Larson RA, Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;     [PubMed PMID: 20705755]
[8] McCarthy PW,Lawson SN, Cell type and conduction velocity of rat primary sensory neurons with calcitonin gene-related peptide-like immunoreactivity. Neuroscience. 1990;     [PubMed PMID: 2352644]
[9] Baker WJ,Royer GL Jr,Weiss RB, Cytarabine and neurologic toxicity. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1991 Apr;     [PubMed PMID: 1648599]
[10] Sainz de la Maza Cantero S,Jiménez Martín A,de Felipe Mimbrera A,Corral Corral Í, Cerebellar toxicity due to cytarabine: A series of 4 cases. Neurologia (Barcelona, Spain). 2016 Sep;     [PubMed PMID: 25728956]
[11] Stentoft J, The toxicity of cytarabine. Drug safety. 1990 Jan-Feb;     [PubMed PMID: 2178634]
[12] van der Veen W,van den Bemt PMLA,Wouters H,Bates DW,Twisk JWR,de Gier JJ,Taxis K,Duyvendak M,Luttikhuis KO,Ros JJW,Vasbinder EC,Atrafi M,Brasse B,Mangelaars I, Association between workarounds and medication administration errors in bar-code-assisted medication administration in hospitals. Journal of the American Medical Informatics Association : JAMIA. 2018 Apr 1;     [PubMed PMID: 29025037]
[13] Al Omar S,Amayiri N,Madanat F, Safety of inadvertent administration of overdose of intrathecal Cytarabine in a pediatric patient. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2015 Oct;     [PubMed PMID: 24781453]
[14] Thienprayoon R,Heym KM,Pelfrey L,Bowers DC, Accidental overdose of intrathecal cytarabine in children. The Annals of pharmacotherapy. 2013 May;     [PubMed PMID: 23606548]