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Cytarabine
Cytarabine See also Cytotoxic and immunosuppressant drugs
GENERAL INFORMATION Cytarabine is a pyrimidine nucleoside that is used to treat acute myelogenous leukemia and lymphocytic leukemias. It is activated intracellularly by deoxycytidine kinase to phosphorylated nucleotides that interfere with DNA synthesis in the S phase of the cell, and is rapidly deaminated intracellularly to the inactive metabolite uracil arabinoside.
ORGANS AND SYSTEMS Respiratory Two cases of respiratory failure occurred during induction chemotherapy for acute myelomonocytic leukemia with cytarabine and all-trans-retinoic acid [1]. The authors attributed this to a manifestation of the retinoic acid syndrome. Both patients developed acute respiratory failure with widespread pulmonary infiltrates about 60 hours after starting chemotherapy. Both were managed successfully using high-dose dexamethasone and ventilation.
Nervous system Central nervous system disturbances, especially impaired cerebellar function, limit doses of cytarabine, and age is an important predictive factor. Of 418 patients who received 36–48 g/m2 only 35 (8%) had severe cerebellar toxicity, which was irreversible or fatal in 4 (1%) [2]. Patients over 50 years of age were significantly more likely to develop cerebellar problems than younger patients (26/137, 19%, compared with 9/281, 3%); a second course did not increase the incidence, implying that it is the individual rather than the cumulative dose that is important. The cerebellar syndrome is the most common complication of high-dose cytarabine therapy. In a study of the cerebellar syndrome caused by cytarabine [3], in which it was found in seven of 30 patients treated, symptoms of toxicity appeared between the third and seventh days of chemotherapy, manifesting first as lethargy and confusion [3]. Within the next 24 hours there were signs of cerebellar dysfunction, including dysarthria, ataxia, tremor, nystagmus, and dysmetria. In most patients in whom neurotoxicity developed, liver function worsened during chemotherapy. Abnormal liver function at the start of therapy and the development of neurotoxicity appear to be linked. The symptoms of neurotoxicity resolved within 4–49 days. Aseptic meningitis can also occur in patients given cytarabine [4,5], and signs of cerebellar dysfunction after the administration of cytarabine 24 g/m2 have been reported in association with aseptic meningitis [6].
ã 2016 Elsevier B.V. All rights reserved.
Sensory systems Keratoconjunctivitis is a complication of cytarabine therapy, with a reported incidence of 30–100% and commonly associated with high doses (3 g/m2). Corneal and conjunctival toxicity have been described after therapy for 4 days with 235 mg (100 mg/m2) daily [7].
Gastrointestinal The addition of cytarabine 10 mg/m2/day subcutaneously for 10 days to interferon monotherapy more than doubled the incidence of gastrointestinal toxicity in the treatment of chronic myeloid leukemia in 139 patients [8].
Skin Acute, painful, swollen, and self-limiting erythema of the hands and soles has been reported after induction therapy for acute myeloid leukemia and attributed to cytarabine [9].
Immunologic A hypersensitivity reaction has been ascribed to cytarabine [10].
DRUG ADMINISTRATION Drug administration route The safe intrathecal administration of a long-acting formulation of cytarabine has been reported [11].
DRUG-DRUG INTERACTIONS Daunorubicin Hepatotoxicity, with either hyperbilirubinemia or increased alkaline phosphatase activity, occurred in five of 14 patients in a trial of cytarabine 200 mg/m2/day for 9 days by continuous infusion and daunorubicin 70 mg/m2/ day for 3 days [12].
REFERENCES [1] Lester WA, Hull DR, Fegan CD, Morris TC. Respiratory failure during induction chemotherapy for acute myelomonocytic leukaemia (FAB M4Eo) with ara-C and all-trans retinoic acid. Br J Haematol 2000; 109(4): 847–50. [2] Herzig RH, Hines JD, Herzig GP, Wolff SN, Cassileth PA, Lazarus HM, Adelstein DJ, Brown RA, Coccia PF, Strandjord S, Mazza JJ, Fay J, Phillips GL. Cerebellar toxicity with high-dose cytosine arabinoside. J Clin Oncol 1987; 5(6): 927–32.
Cytarabine [3] Nand S, Messmore HL Jr, Patel R, Fisher SG, Fisher RI. Neurotoxicity associated with systemic high-dose cytosine arabinoside. J Clin Oncol 1986; 4(4): 571–5. [4] Pease CL, Horton TM, McClain KL, Kaplan SL. Aseptic meningitis in a child after systemic treatment with high dose cytarabine. Pediatr Infect Dis J 2001; 20(1): 87–9. [5] van den Berg H, van der Flier M, van de Wetering MD. Cytarabine-induced aseptic meningitis. Leukemia 2001; 15(4): 697–9. [6] Thordarson H, Talstad I. Acute meningitis and cerebellar dysfunction complicating high-dose cytosine arabinoside therapy. Acta Med Scand 1986; 220(5): 493–5. [7] Thaler J, Hilbe W. Comparative analysis of two consecutive phase II studies with IFN-alpha and IFN-alphaþ ara-C in untreated chronic-phase CML patients. Austrian CML Study Group Bone Marrow Transplant 1996; 17(Suppl. 3): S25–8. [8] Shall L, Lucas GS, Whittaker JA, Holt PJ. Painful red hands: a side-effect of leukaemia therapy. Br J Dermatol 1988; 119(2): 249–53.
ã 2016 Elsevier B.V. All rights reserved.
799
[9] Barletta JP, Fanous MM, Margo CE. Corneal and conjunctival toxicity with low-dose cytosine arabinoside. Am J Ophthalmol 1992; 113(5): 587–8. [10] Williams SF, Larson RA. Hypersensitivity reaction to highdose cytarabine. Br J Haematol 1989; 73(2): 274–5. [11] Jaeckle KA, Phuphanich S, Bent MJ, Aiken R, Batchelor T, Campbell T, Fulton D, Gilbert M, Heros D, Rogers L, O’Day SJ, Akerley W, Allen J, Baidas S, Gertler SZ, Greenberg HS, LaFollette S, Lesser G, Mason W, Recht L, Wong E, Chamberlain MC, Cohn A, Glantz MJ, Gutheil JC, Maria B, Moots P, New P, Russell C, Shapiro W, Swinnen L, Howell SB. Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 2001; 84(2): 157–63. [12] Kouides PA, Rowe JM. A dose intensive regimen of cytosine arabinoside and daunorubicin for chronic myelogenous leukemia in blast crisis. Leuk Res 1995; 19(10): 763–70.
GENERAL INFORMATION Cytarabine is a pyrimidine nucleoside that is used to treat acute myelogenous leukemia and lymphocytic leukemias. It is activated intracellularly by deoxycytidine kinase to phosphorylated nucleotides that interfere with DNA synthesis in the S phase of the cell, and is rapidly deaminated intracellularly to the inactive metabolite uracil arabinoside.
ORGANS AND SYSTEMS Respiratory Two cases of respiratory failure occurred during induction chemotherapy for acute myelomonocytic leukemia with cytarabine and all-trans-retinoic acid [1]. The authors attributed this to a manifestation of the retinoic acid syndrome. Both patients developed acute respiratory failure with widespread pulmonary infiltrates about 60 hours after starting chemotherapy. Both were managed successfully using high-dose dexamethasone and ventilation.
Nervous system Central nervous system disturbances, especially impaired cerebellar function, limit doses of cytarabine, and age is an important predictive factor. Of 418 patients who received 36–48 g/m2 only 35 (8%) had severe cerebellar toxicity, which was irreversible or fatal in 4 (1%) [2]. Patients over 50 years of age were significantly more likely to develop cerebellar problems than younger patients (26/137, 19%, compared with 9/281, 3%); a second course did not increase the incidence, implying that it is the individual rather than the cumulative dose that is important. The cerebellar syndrome is the most common complication of high-dose cytarabine therapy. In a study of the cerebellar syndrome caused by cytarabine [3], in which it was found in seven of 30 patients treated, symptoms of toxicity appeared between the third and seventh days of chemotherapy, manifesting first as lethargy and confusion [3]. Within the next 24 hours there were signs of cerebellar dysfunction, including dysarthria, ataxia, tremor, nystagmus, and dysmetria. In most patients in whom neurotoxicity developed, liver function worsened during chemotherapy. Abnormal liver function at the start of therapy and the development of neurotoxicity appear to be linked. The symptoms of neurotoxicity resolved within 4–49 days. Aseptic meningitis can also occur in patients given cytarabine [4,5], and signs of cerebellar dysfunction after the administration of cytarabine 24 g/m2 have been reported in association with aseptic meningitis [6].
ã 2016 Elsevier B.V. All rights reserved.
Sensory systems Keratoconjunctivitis is a complication of cytarabine therapy, with a reported incidence of 30–100% and commonly associated with high doses (3 g/m2). Corneal and conjunctival toxicity have been described after therapy for 4 days with 235 mg (100 mg/m2) daily [7].
Gastrointestinal The addition of cytarabine 10 mg/m2/day subcutaneously for 10 days to interferon monotherapy more than doubled the incidence of gastrointestinal toxicity in the treatment of chronic myeloid leukemia in 139 patients [8].
Skin Acute, painful, swollen, and self-limiting erythema of the hands and soles has been reported after induction therapy for acute myeloid leukemia and attributed to cytarabine [9].
Immunologic A hypersensitivity reaction has been ascribed to cytarabine [10].
DRUG ADMINISTRATION Drug administration route The safe intrathecal administration of a long-acting formulation of cytarabine has been reported [11].
DRUG-DRUG INTERACTIONS Daunorubicin Hepatotoxicity, with either hyperbilirubinemia or increased alkaline phosphatase activity, occurred in five of 14 patients in a trial of cytarabine 200 mg/m2/day for 9 days by continuous infusion and daunorubicin 70 mg/m2/ day for 3 days [12].
REFERENCES [1] Lester WA, Hull DR, Fegan CD, Morris TC. Respiratory failure during induction chemotherapy for acute myelomonocytic leukaemia (FAB M4Eo) with ara-C and all-trans retinoic acid. Br J Haematol 2000; 109(4): 847–50. [2] Herzig RH, Hines JD, Herzig GP, Wolff SN, Cassileth PA, Lazarus HM, Adelstein DJ, Brown RA, Coccia PF, Strandjord S, Mazza JJ, Fay J, Phillips GL. Cerebellar toxicity with high-dose cytosine arabinoside. J Clin Oncol 1987; 5(6): 927–32.
Cytarabine [3] Nand S, Messmore HL Jr, Patel R, Fisher SG, Fisher RI. Neurotoxicity associated with systemic high-dose cytosine arabinoside. J Clin Oncol 1986; 4(4): 571–5. [4] Pease CL, Horton TM, McClain KL, Kaplan SL. Aseptic meningitis in a child after systemic treatment with high dose cytarabine. Pediatr Infect Dis J 2001; 20(1): 87–9. [5] van den Berg H, van der Flier M, van de Wetering MD. Cytarabine-induced aseptic meningitis. Leukemia 2001; 15(4): 697–9. [6] Thordarson H, Talstad I. Acute meningitis and cerebellar dysfunction complicating high-dose cytosine arabinoside therapy. Acta Med Scand 1986; 220(5): 493–5. [7] Thaler J, Hilbe W. Comparative analysis of two consecutive phase II studies with IFN-alpha and IFN-alphaþ ara-C in untreated chronic-phase CML patients. Austrian CML Study Group Bone Marrow Transplant 1996; 17(Suppl. 3): S25–8. [8] Shall L, Lucas GS, Whittaker JA, Holt PJ. Painful red hands: a side-effect of leukaemia therapy. Br J Dermatol 1988; 119(2): 249–53.
ã 2016 Elsevier B.V. All rights reserved.
799
[9] Barletta JP, Fanous MM, Margo CE. Corneal and conjunctival toxicity with low-dose cytosine arabinoside. Am J Ophthalmol 1992; 113(5): 587–8. [10] Williams SF, Larson RA. Hypersensitivity reaction to highdose cytarabine. Br J Haematol 1989; 73(2): 274–5. [11] Jaeckle KA, Phuphanich S, Bent MJ, Aiken R, Batchelor T, Campbell T, Fulton D, Gilbert M, Heros D, Rogers L, O’Day SJ, Akerley W, Allen J, Baidas S, Gertler SZ, Greenberg HS, LaFollette S, Lesser G, Mason W, Recht L, Wong E, Chamberlain MC, Cohn A, Glantz MJ, Gutheil JC, Maria B, Moots P, New P, Russell C, Shapiro W, Swinnen L, Howell SB. Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 2001; 84(2): 157–63. [12] Kouides PA, Rowe JM. A dose intensive regimen of cytosine arabinoside and daunorubicin for chronic myelogenous leukemia in blast crisis. Leuk Res 1995; 19(10): 763–70.