Cytarabine

Cytarabine (araC) is a synthetic isomer of the nucleoside cytidine. It differs from the physiological nucleosides cytidine and deoxycytidine only in the sugar content: instead of ribose or deoxyribose, arabinose occurs in the cytarabine molecule. Cytarabine is a pyrimidine antagonist(see also pyrimidine analogues).

Cytarabine has the molecular formula C9H13N3O5. The substance is soluble in water, but hardly soluble in ethanol and chloroform. Cytarabine has both cytostatic (antimetabolite) and virostatic effects.

As an isomer of cytidine, cytarabine is incorporated into the DNA strand by the DNA polymerase instead of cytosine triphosphate due to its great structural similarity to the nucleoside cytosine after its phosphorylation by deoxycytidine kinase and other nucleotide kinases to form cytosine abinoside triphosphate. The mechanism of action is not yet clearly understood, but cytarabine triphosphate appears to inhibit DNA polymerase by displacing the physiological substrate deoxycytidine triphosphate. By blocking all further repair and propagation mechanisms, apoptosis occurs. The metabolism takes place in the liver.

A pyrimidine nucleoside deaminase is then used to inactivate it and convert it into a non-toxic uracil derivative. In studies with mouse tumors, cytarabine has been shown to be most effective in rapidly growing tumors.

Cytarabine is orally ineffective, less than 20% is absorbed from the gastrointestinal tract. After subcutaneous or intramuscular administration of cytarabine, plasma peaks are reached in 20-60 minutes; these are significantly lower than after an i.v. injection. Relatively constant plasma levels can be achieved by continuous intravenous infusion in 8-24 hours.

Remission initiation and maintenance in combination with other cytostatic drugs in acute myeloid leukaemia (AML) in adults and children Treatment of acute lymphatic leukemia, lymphatic blast crisis of chronic myeloid leukemia and erythroleukemia. Cytarabine can be used alone or in combination with other cytostatic drugs. In children with non-Hodgkin lymphoma in combination with other cytostatic drugs. Also in acute lymphatic leukaemia (ALL) and myelodysplastic syndrome (MDS).

Induction therapy of acute myeloid leukaemia is usually performed with cytarabine in combination with other cytostatic drugs. The standard cytarabin dose is 100-200 mg/m²/day as a continuous intravenous infusion over 7 days. In high doses of 2-3 g/m², cytarabin Sandoz is administered intravenously for 1-3 hours at 12-hour intervals and for 2-6 days.

Note: The following side effects have been observed in connection with cytarabine therapy: very often ≥1/10; often ≥1/100, <1/10; occasionally ≥1/1000, <1/100; rarely ≥1/10,000, <1/1000; very rarely <1/10,000

Infections: Very frequent: sepsis, pneumonia, infections (mild, severe and sometimes fatal cases are possible) by viruses, bacteria, fungi, parasites or saprophytes.

Blood and lymphatic system: Very frequent: bone marrow insufficiency, thrombocytopenia, anemia, megaloblastic anemia, leukopenia, neutropenia, reticulocytopenia. The severity depends on the dosage and the treatment regimen. Under therapeutic doses, a decrease in leukocytes and platelets is expected within a week with a nadir by 12-14 days.

CNS: Very common: Cerebral and cerebellar dysfunction, sometimes with personality changes (with high-dose therapy), somnolence. Frequent: Dizziness, neuritis, neurotoxicity, headache (mainly with high-dose therapy), paraplegia (with intrathecal therapy). Occasionally: nystagmus, dysarthria, ataxia, thought disorders, coma, seizures. Very rarely: peripheral motor and sensory neuropathy.

Eyes: frequent: reversible corneal damage and conjunctivitis (may occur with rash; hemorrhagic conjunctivitis possible with high-dose therapy). Conjunctivitis can be prevented or alleviated by prophylactic administration of corticosteroid-containing eye drops.

Heart: rarely: pericarditis. Very rare: cardiomyopathies resulting in death at very high doses.

Vessels: Common: thrombophlebitis.

Respiratory: very common: acute respiratory distress syndrome with rapidly progressive pulmonary oedema due to increased permeability of the alveolar capillaries, and radiologically marked cardiomegaly (10-30% with high-dose therapy, occasionally after conventional doses). These pulmonary complications are usually reversible. Rare: pneumonia, dyspnoea, chest pain. Very rare: diffuse interstitial pneumonia when treated with 1 g/m² cytarabine with and without other chemotherapeutic agents (without direct relation to cytarabine).

Gastrointestinal tract: frequent: nausea and vomiting several hours after administration (especially after rapid intravenous injection), necrotizing colitis (high-dose therapy), stomatitis, oral and anal inflammation or ulceration, diarrhea, abdominal pain, esophagitis, sore throat. Rare: In high-dose therapy severe gastrointestinal necrosis or ulceration including pneumatosis cystoides intestinalis which may cause peritonitis, sepsis or liver abscesses. Isolated cases of esophageal ulcers have been reported. Individual cases of acute pancreatitis when cytarabine is administered in combination with other preparations.

Liver and bile: very frequent: liver dysfunction, liver damage with increase in cholestase-indicating enzymes and hyperbilirubinemia with high-dose therapy (25-50%); rare: icterus.

Dermatological side effects: Various dermatological side effects occur in about 53% of patients. Very common are diffuse alopecia (complete alopecia is more common with high-dose therapy than with standard therapy) and maculopapular exanthema. Cetkovská P et al. (2002) reported dermatological side effects in 172 patients with high-dose cytarabine therapy for basic hematological diseases (118 with acute myeloid leukemia, 54 with acute lymphatic leukemia, aged between 16 and 71 years) in 53% of cases. Here, dose-dependent exanthema was the most frequent with 72.7%. These occur on average 6.5 days after the start of therapy. Hemorrhagic papular and plaque-shaped exanthema with preference of the intertriginous zones, neck, ears, capillitium are described especially in high-dose therapy (Cetkovska P et al. 2002; see also cytarabine syndrome). These usually subside spontaneously. In a 2nd cycle only 1/3 of the patients relapse. Histologically an unspecific, lymphocytic, spongiotic dermatitis with erythrocyte extravasations was observed.

Frequently: are skin ulcerations. Rare: pruritus, urticaria, skin pigmentation are observed. A dermatological characteristic of cytarabine-treated patients with AML is neutropenic fever with bilateral exanthema and swelling of the auricles (AraC Ear: Berg I et al. 2013). In some cases histologically acute neutropenic dermatitis and panniculitis could be diagnosed (Barrios MP et al. 2018). Disel U et al. call this constellation in a neutropenic patient with fiber and ALM a "bilateral ear-sweet syndrome".

The frequency of palmar-plant erythrodysesthesia is unknown. Other rare skin lesions include vasculitis, eccrine squamous syringometaplasia and neutrophil eccrine hidradenitis (Ruben S et al. 2015). Individual cases of anaphylactic reactions have been published.

Kidneys and urinary tract: Rare: urinary retention, renal dysfunction.

1. Barrios MP et al. (2018) AraC ears-caused by drugs or manifestation of neutrophilic dermatosis? J Dtsch Dermatol Ges. 16: 213-215
2. Berg I et al (2013) Rash and ear swelling in a patient with febrile neutropenia. Int J Infect Dis 17: e360-e361.
3. Cetkovská P et al (2002) High-dose cytosine arabinoside-induced cutaneous reactions. J Eur Acad Dermatol Venereol16:481-485.
4. Cytarabine Sandoz ®: Technical information.
5. Disel U et al (2006) Bilateral ear Sweet's syndrome in a case with relapse acute myeloblastic leukemia. Leuk Res 30:364.
6. Ruben BS et al (2015) Generalized benign cutaneous reaction to cytarabine. J Am Acad Dermatol 73:821-828.