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The Toxicity of Cytarabine

  • Review Article
  • Drug Experience
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Summary

The principal toxicity of standard induction regimens for acute non-lymphocytic leukaemia (ANLL) [including cytarabine (ARA-C) 100 mg/m2 for 7 days plus an anthracycline] is myelotoxicity, leading to death in at least 25% of cases during induction in non-selected patients. The complete remission rate is less than 35% in patients over 65 years of age, due in part to an age-related increase of myelotoxicity. The other important adverse effect of standard-dose cytarabine is gastrointestinal toxicity, especially oral mucositis, diarrhoea, intestinal ulceration, ileus and subsequent Gram-negative septicaemia. Idiosyncratic reactions like exanthema, fever and elevation of hepatic enzymes are relatively frequent, but do not represent therapeutic problems.

Intermittent high-dose cytarabine (3 g/m2 in 8 to 12 doses) is extremely myelosuppressive. Similarly, the gastrointestinal toxicity is formidable and dose-limiting. Severe, and sometimes irreversible, cerebellar/cerebral toxicity in 5 to 15% of courses of treatment limits the peak dose of cytarabine. The pathogenesis, prophylactic and therapeutic measures are unknown. These major toxicities are age-related and prohibitive to the use of high-dose cytarabine therapy in patients older than 55 to 60 years. Subacute noncardiogenic pulmonary oedema occurs in some patients, with an incidence of about 20%, and seems to have an intriguing coincidence with precedent streptococcal septicaemia; high-dose systemic steroids may be beneficial. Corneal toxicity is very frequent in high-dose cytarabine therapy but is always reversible. It is largely preventable with prophylactic steroid or 2-deoxycytidine eyedrops. Fever, exanthema and hepatic toxicity have an incidence similar to that in standard dosage. The maximum tolerable cumulated dose of cytarabine is significantly lower when the agent is administered as a continuous infusion, due to myelosuppression and gastrointestinal toxicity. Conversely, continuous infusion may be less neurotoxic. The antileukaemic effect of continuous infusion high-dose cytarabine is less well established.

The only significant toxicity of low-dose cytarabine is myelosuppression. Given the generally poor condition of leukaemia patients, low-dose cytarabine therapy is well tolerated, although occasional cases of diarrhoea, reversible cerebellar symptoms, peritoneal and pericardial reactions, and ocular toxicity have been reported. Continuous infusion may be more toxic than the usual intermittent dosage.

It is concluded that the toxicity of the standard induction regimen for ANLL is acceptable in patients younger than 60 to 65 years with no concurrent disease. Low dose cytarabine is tolerable for virtually all ANLL patients, but the overall therapeutic efficacy still needs to be defined and compared to standard therapy in the relevant age groups.

High-dose cytarabine is valuable, even though it is extremely toxic, in relapsed and refractory acute leukaemia in patients younger than 55 to 60 years. It is not recommended as induction therapy, due to its toxicity. The regimen seems to be slightly more tolerable as consolidation therapy but cases of severe toxicity with lethal outcome cannot be avoided; doses of 0.5 to 1.0 g/m2 may have comparably favourable pharmacological properties with less toxicity, but need more clinical documentation.

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References

  • Adelstein DJ, Lazarus HM, Hines JD, Herzig RH. High-dose cytosine arabinoside in previously treated patients with poor prognosis non-Hodgkin’s lymphoma. Cancer 56: 1493–1496, 1985.

    PubMed  CAS  Google Scholar 

  • Altman AJ, Dinndorf P, Quinn JJ. Acute pancreatitis in association with cytosine arabinoside therapy. Cancer 49: 1384–1386, 1982.

    PubMed  CAS  Google Scholar 

  • Andersson BS, Cogan BM, Keating MJ, Estey EH, McCredie KB, et al. Subacute pulmonary failure complicating therapy with high-dose Ara-C in acute leukemia. Cancer 56: 2181–2184, 1985.

    PubMed  CAS  Google Scholar 

  • Arlin ZA, Gaddipati J, Ahmed T, Mittelman A, Friedland M, et al. Treatment of acute leukemia with amsacrine and high-dose cytarabine. Cancer Treatment Reports 69: 1001–1002, 1985.

    PubMed  CAS  Google Scholar 

  • Baer MR, King LE, Wolff SN. Palmar-plantar erythrodysesthesia and cytarabine. Annals of Internal Medicine 102: 556, 1985.

    PubMed  CAS  Google Scholar 

  • Band PR, Holland JF, Bernard J, Weil M, Walker M, et al. Treatment of central nervous system leukemia with intrathecal cytosine arabinoside. Cancer 32: 744–748, 1973.

    PubMed  CAS  Google Scholar 

  • Barnett MJ, Ganesan TS, Waxman JH, Richards MA, Smith BF, et al. Neurotoxicity of high-dose cytosine arabinoside. Progress in Experimental Tumor Research 29: 177–182, 1985.

    PubMed  CAS  Google Scholar 

  • Barrios NJ, Tebbi CK, Freeman AI, Brecher ML. Toxicity of high-dose ARA-C in children and adolescents. Cancer 60: 165–169, 1987.

    PubMed  CAS  Google Scholar 

  • Beguin Y, Bury J, Fillet G, Lennes G. Treatment of acute nonlymphocytic leukemia in young and elderly patients. Cancer 56: 2587–2592, 1985.

    PubMed  CAS  Google Scholar 

  • Benger A, Preisler HD, Goldberg J. Clinical evidence of a cumulative effect of high-dose cytarabine on the cerebellum in patients with acute leukemia: a leukaemia intergroup report. Cancer Treatment Reports 69: 240–241, 1985.

    PubMed  CAS  Google Scholar 

  • Berkowitz FE, Wehde S, Ngwenya ET, Greef M, Wadee AA, et al. Anaphylactic shock due to cytarabine in a leukemic child. American Journal of Diseases in Children 141: 1000–1001, 1987.

    CAS  Google Scholar 

  • Boesen P, Fallingborg J, Spaun E. Severe persistent cerebellar dysfunction complicating cytosine arabinoside therapy. Acta Medica Scandinavica 224: 189–191, 1988.

    PubMed  CAS  Google Scholar 

  • Borgeat A, Muralt B, Stalder M. Peripheral neuropathy associated with high-dose Ara-C therapy. Cancer 58: 852–854, 1986.

    PubMed  CAS  Google Scholar 

  • Botti RE, Lazarus HM, Imperia PS, Lass JH. Cytotoxicity of antineoplastic agents on rabbit corneal epithelium in vitro. Journal of Toxicology — Cutaneous and Ocular Toxicology 6: 79–87, 1987.

    Google Scholar 

  • Breithaupt H, Pralle H, Echkhardt T, von Hattingberg M, Schick J, et al. Clinical results and pharmacokinetics of high-dose cytosine arabinoside (HD ARA-C). Cancer 50: 1248–1257, 1982.

    PubMed  CAS  Google Scholar 

  • Breuer AC, Pitman SW, Dawson DM, Schoene WC. Paraparesis following intrathecal cytosine arabinoside. Cancer 40: 2817–2822, 1977.

    PubMed  CAS  Google Scholar 

  • Brincker H. Estimation of overall treatment results in acute nonlymphocytic leukemia based on age-specific rates of incidence and of complete remission. Cancer Treatment Reports 69: 5–11, 1985.

    PubMed  CAS  Google Scholar 

  • Burgdorf WHC, Gilmore WA, Ganick RG. Peculiar acral erythema secondary to high-dose chemotherapy for acute myelogenous leukemia. Annals of Internal Medicine 97: 61–62, 1982.

    PubMed  CAS  Google Scholar 

  • Cantin G, Brennan JK. High-dose cytosine arabinoside for acute nonlymphocytic leukemia. American Journal of Hematology 16: 59–66, 1984.

    PubMed  CAS  Google Scholar 

  • Capizzi RL, Poole M, Cooper MR, Richards F, Stuart JJ, et al. Treatment of poor risk acute leukemia with sequential high-dose ARA-C and asparaginase. Blood 63: 694–700, 1984.

    PubMed  CAS  Google Scholar 

  • Cassileth PA, Begg CB, Silber R, Spiers A, Burkart PT, et al. Prolonged unmaintained remission after intensive consolidation therapy in adult acute nonlymphocytic leukemia. Cancer Treatment Reports 71: 137–140, 1987.

    PubMed  CAS  Google Scholar 

  • Castleberry RP, Grist WM, Holbrook T, Malluk A, Gaddy D. The cytosine arabinoside (ARA-C) syndrome. Medical and Pediatric Oncology 9: 257–264, 1981.

    PubMed  CAS  Google Scholar 

  • Cersosimo RJ, Carter RT, Matthews SJ, Coderre M, Karp DD. Acute cerebellar syndrome, conjunctivitis, and hearing loss associated with low-dose cytarabine administration. Drug Intelligence and Clinical Pharmacy 21: 798–803, 1987.

    PubMed  CAS  Google Scholar 

  • Champlin R, Ho W, Winston D, Decker R, Greenberg P, et al. Treatment of adults with acute myelogenous leukemia: prospective evaluation of high-dose cytarabine in consolidation chemotherapy and with bone marrow transplantation. Seminars in Oncology 14 (Suppl. 1): 1–6, 1987.

    PubMed  CAS  Google Scholar 

  • Clark AW, Cohen SR, Nissenblatt J, Wilson SK. Paraplegia following intrathecal chemotherapy. Cancer 50: 42–47, 1982.

    PubMed  CAS  Google Scholar 

  • Craig JB, Powell BL, White DR, Capizzi RL. Antiemetic therapy in patients treated with high-dose cytosine arabinoside. Oncology 44: 90–92, 1987.

    PubMed  CAS  Google Scholar 

  • Damon LC, Mass R, Linker CA. The association between high-dose cytarabine neurotoxicity and renal insufficiency. Journal of Clinical Oncology 7: 1563–1568, 1989.

    PubMed  CAS  Google Scholar 

  • Degos L, Castaigne S, Tilly H, Siganx F, Daniel MT. Treatment of leukemia with low-dose ARA-C: a study of 160 cases. Seminars in Oncology 12 (Suppl. 3): 196–199, 1985.

    PubMed  CAS  Google Scholar 

  • Donehower RC, Karp JE, Burke PJ. Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion. Cancer Treatment Reports 70: 1059–1065, 1986.

    PubMed  CAS  Google Scholar 

  • Dudley JM, Duncombe AS, Slater NGP, Sturgess I. C-reactive protein and cytosine arabinoside. British Journal of Haematology 66: 280–281, 1987.

    PubMed  CAS  Google Scholar 

  • Dunton SF, Nitschke R, Spruce WE, Bodensteiner J, Krous HF. Progressive ascending paralysis following administration of intrathecal and intravenous cytosine arabinoside. Cancer 57: 1083–1088, 1986.

    PubMed  CAS  Google Scholar 

  • Dworkin LA, Goldman RD, Zivin LS, Fuchs PC. Cerebellar toxicity following high-dose cytosine arabinoside. Journal of Clinical Oncology 3: 613–616, 1985.

    PubMed  CAS  Google Scholar 

  • Dybedal I, Lamvik J. Respiratory insufficiency in acute leukemia following treatment with cytosine arabinoside and septicemia with streptococcus viridans. European Journal of Haematology 42: 405–406, 1989.

    PubMed  CAS  Google Scholar 

  • Early AP, Preisler HD, Slocum H, Rustum YM. A pilot study of high-dose l-β-D-arabinofuranosylcytosine for acute leukemia and refractory lymphoma: clinical response and pharmacology. Cancer Research 42: 1587–1594, 1982.

    PubMed  CAS  Google Scholar 

  • Elliot GA, Schut AL. Studies with cytarabine HC1 (CA). American Journal of Ophthalmology 60: 1074–1082, 1965.

    Google Scholar 

  • Estey EH, Keating MJ, McCredie KB, Bodey GP, Freireich EJ. Causes of initial remission induction failure in acute myelogenous leukemia. Blood 60: 309–315, 1982.

    PubMed  CAS  Google Scholar 

  • Fière D, Campos L, Van HV, Guyotat D, Archimband E, et al. Intensive timed chemotherapy protocol for 37 resistant or relapsing acute myeloid leukemias. Cancer Treatment Reports 70: 285–286, 1986.

    PubMed  Google Scholar 

  • Foon KA, Zighelboim J, Yale C, Gale RP. Intensive chemotherapy is the treatment of choice for elderly patients with acute myelogenous leukemia. Blood 58: 467–470, 1981.

    PubMed  CAS  Google Scholar 

  • Frick J, Ritch PS, Hansen RM, Anderson T. Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside. Journal of Clinical Oncology 2: 365–368, 1984.

    PubMed  CAS  Google Scholar 

  • Gale RP, Foon KA, Cline MJ, Zighelboim J, UCLA Acute Leukemia Study Group. Intensive chemotherapy for acute myelogenous leukemia. Annals of Internal Medicine 94: 753–757, 1981.

    PubMed  CAS  Google Scholar 

  • George CB, Mansour RP, Redmond J, Gandara DR. Hepatic dysfunction and jaundice following high-dose cytosine arabinoside. Cancer 54: 2360–2362, 1984.

    PubMed  CAS  Google Scholar 

  • Glucksberg H, Cheever MA, Farewell VT, Fefer A, Sale GE, et al. High dose combination chemotherapy for acute nonlymphoblastic leukemia in adults. Cancer 48: 1073–1081, 1981.

    PubMed  CAS  Google Scholar 

  • Goodell B, Leventhal B, Henderson E. Cytosine arabinoside in acute granulocytic leukemia. Clinical Pharmacology and Therapeutics 12: 599–606, 1971.

    PubMed  CAS  Google Scholar 

  • Gore M, Powles R, Lakhani A, Milan S, Maitland J, et al. Treatment of relapsed and refractory acute leukaemia with high-dose cytosine arabinoside and etoposide. Cancer Chemotherapy and Pharmacology 23: 373–376, 1989.

    PubMed  CAS  Google Scholar 

  • Gottlieb D, Bradstock K, Koutts J, Robertson T, Lee C, et al. The neurotoxicity of high-dose cytosine arabinoside is age-related. Cancer 60: 1439–1441, 1987.

    PubMed  CAS  Google Scholar 

  • Graham FL, Withmore GF. Studies in the mouse L-cells on the incorporation of 1 β-D-arabinofuranosylcytosine into DNA and on inhibition of DNA polymerase by 1-β-D arabinofuranosylcytosine 5′-triphosphate. Cancer Research 30: 2636–2644, 1970.

    PubMed  CAS  Google Scholar 

  • Graves T, Hooks MA. Drug-induced toxicities associated with high-dose cytosine arabinoside infusions. Pharmacotherapy 9: 23–28, 1989.

    PubMed  CAS  Google Scholar 

  • Grosman L, Baker MA, Sutton DMC, Deck JHN. Central nervous system toxicity of high-dose cytosine arabinoside. Medical and Pediatric Oncology 11: 246–250, 1983.

    Google Scholar 

  • Grümayer ER, Schmidmeier W, Panzer S, Gadner H. Toxicity of sequential high-dose ARA-C asparaginase treatment in childhood poor risk leukemia. Blut 53: 309–314, 1986.

    PubMed  Google Scholar 

  • Haupt HM, Hutchins GM, Moore GW. ARA-C lung: noncardiogenic cytosine arabinoside therapy of leukemia. American Journal of Medicine 70: 256–261, 1981.

    PubMed  CAS  Google Scholar 

  • Hayhoe FGJ. Survival in acute myeloid leukaemia. Lancet 2: 1200–1201, 1975.

    PubMed  CAS  Google Scholar 

  • Herzig RH, Herzig GP, Wolff SN, Hines JD, Fay JW, et al. Central nervous system effects of high-dose cytosine arabinoside. Seminars in Oncology 14 (Suppl. 1): 21–24, 1987a.

    PubMed  CAS  Google Scholar 

  • Herzig RH, Hines JD, Herzig GP, Wolff SN, Cassileth PA, et al. Cerebellar toxicity with high-dose cytosine arabinoside. Journal of Clinical Oncology 5: 927–932, 1987b.

    PubMed  CAS  Google Scholar 

  • Herzig RH, Lazarus HM, Wolff SN, Phillips GL, Herzig GP. High-dose cytosine arabinoside with and without anthracycline antibiotics for remission induction of acute nonlymphoblastic leukemia. Journal of Clinical Oncology 3: 992–997, 1985a.

    PubMed  CAS  Google Scholar 

  • Herzig RH, Phillips GL, Lazarus HM, Wolff SN, Herzig GP. High-dose cytarabine for the treatment of blastic phase chronic myelogenous leukemia. Cancer Treatment Reports 69: 881–883, 1985b.

    PubMed  CAS  Google Scholar 

  • Herzig RH, Wolff SN, Lazarus HM, Phillips GL, Karanes C, et al. High-dose cytosine arabinoside therapy for refractory leukemia. Blood 62: 361–369, 1983.

    PubMed  CAS  Google Scholar 

  • Hiddemann W, Aul C, Maschmeyer, Lathan B, Köppler H, et al. Age related randomized comparison of sequentially applied high-dose versus intermediate dose cytosine arabinoside in combination with mitoxanthrone (S-HAM) in the treatment of relapsed and refractory acute myeloid leukemia: study design and preliminary results. Onkologie 12: 4–6, 1989.

    PubMed  CAS  Google Scholar 

  • Hines JD, Oken MM, Mazza JJ, Keller AM, Streeter RR, et al. High-dose cytosine arabinoside and m-AMSA is effective therapy in relapsed acute nonlymphocytic leukemia. Journal of Clinical Oncology 2: 545–549, 1984.

    PubMed  CAS  Google Scholar 

  • Ho DHW, Frei III E. Clinical pharmacology of 1-β-D-arabinofuranosylcytosine. Clinical Pharmacology and Therapeutics 12: 944–954, 1971.

    PubMed  CAS  Google Scholar 

  • Hopen G, Mondino BJ, Johnson BL, Chervenick PA. Corneal toxicity with systemic cytarabine. American Journal of Ophthalmology 91: 500–504, 1981.

    PubMed  CAS  Google Scholar 

  • Hwang T, Yung WKA, Lee Y, Borit A, Fields WS. High dose Ara-C related leukoencephalopathy. Journal of Neuro-Oncology 3: 335–339, 1986.

    PubMed  CAS  Google Scholar 

  • Jehn U, Göldel N, Rienmüller R, Wilmanns W. Non-cardiogenic pulmonary edema complicating intermediate and high-dose ARA C treatment for relapsed acute leukemia. Medical Oncology and Tumor Pharmacotherapy 5: 41–47, 1988.

    PubMed  CAS  Google Scholar 

  • Johnson H, Smith TJ, Desforges J. Cytosine-arabinoside-induced colitis and peritonitis: nonoperative management. Journal of Clinical Oncology 3: 607–612, 1985.

    PubMed  CAS  Google Scholar 

  • Kampmann KK, Graves T, Rogers SD. Acral erythema secondary to high-dose cytosine arabinoside with pain worsened by cyclosporine infusions. Cancer 63: 2482–2485, 1989.

    PubMed  CAS  Google Scholar 

  • Kantarjian H, Barlogie B, Plunkett W, Velasquez W, McLaughlin P, et al. High-dose cytosine arabinoside in non-Hodgkin’s lymphoma. Journal of Clinical Oncology 1: 689–694, 1983.

    PubMed  CAS  Google Scholar 

  • Kantarjian HM, Estey EH, Plunkett W, Keating MJ, Walters RS, et al. Phase I–II clinical and pharmacologic studies of high-dose cytosine arabinoside in refractory leukemia. American Journal of Medicine 81: 387–394, 1986.

    PubMed  CAS  Google Scholar 

  • Katz ME, Cassileth PA. Hyperbilirubinemia during induction therapy of acute granulocytic leukemia. Cancer 40: 1390–1392, 1977.

    Google Scholar 

  • Keating MJ, Smith TL, McCredie KB, Bodey GP, Hersh EM, et al. A four-year experience with anthracycline, cytosine arabinoside, vincristine and prednisone combination chemotherapy in 325 adults with acute leukemia. Cancer 47: 2779–2788, 1981.

    PubMed  CAS  Google Scholar 

  • Kern W, Kurrle E, Vanek E. High risk of streptococcal septicemia after high dose cytosine arabinoside treatment for acute myelogenous leukemia. Klinische Wochenschrift 65: 773–780, 1987.

    PubMed  CAS  Google Scholar 

  • Kessel D, Hall TC, Wodinsky I. Transport and phosphorylation as factors in the antitumour action of cytosine arabinoside. Science 156: 1240–1241, 1967.

    PubMed  CAS  Google Scholar 

  • Krogh Jensen M, Ahlbom G. Low-dose cytosine arabinoside in the treatment of acute non-lymphocytic leukemia. Scandinavian Journal of Haematology 34: 261–263, 1985.

    Google Scholar 

  • Krogh Jensen M, Stentoft J. Low-dose cytosine arabinoside in the treatment of relapsed and refractory acute non-lymphocytic leukaemia. Acta Haematologica (Basel) 76: 127–129, 1986.

    CAS  Google Scholar 

  • Kumar L, Dua H, Agarwal S, Singh S, Kochupillai V. Ocular toxicity of low dose cytosar. New Zealand Medical Journal 100: 361, 1987.

    PubMed  CAS  Google Scholar 

  • Lakhani A, Gore M, Powles R. Management of an acute abdomen following high-dose cytosine arabinoside. Postgraduate Medical Journal 63: 413–414, 1987.

    PubMed  CAS  Google Scholar 

  • Lass JH, Lazarus HM, Reed MD, Herzig RH. Topical corticosteroid therapy for corneal toxicity from systematically administered cytarabine. American Journal of Ophthalmology 94: 617–621, 1982.

    PubMed  CAS  Google Scholar 

  • Lazarus HM, Hartnett ME, Reed MD, Murphy BF, Lass JH. Comparison of the prophylactic effects of 2-deoxycytidine and prednisolone for high-dose intravenous cytarabine-induced keratitis. American Journal of Ophthalmology 104: 476–480, 1987.

    PubMed  CAS  Google Scholar 

  • Lazarus HM, Herzig RH, Herzig GP, Phillips GL, Roessmann U, et al. Central nervous sytem toxicity of high-dose systemic cytosine arabinoside. Cancer 48: 2577–2582, 1981.

    PubMed  CAS  Google Scholar 

  • Lazarus HM, Vogler WR, Burns CP, Winton EF. High-dose cytosine arabinoside and daunorubicin as primary therapy in elderly patients with acute myelogenous leukemia. A Phase I–II study of the Southeastern Cancer Study Group. Cancer 63: 1055–1059, 1989.

    PubMed  CAS  Google Scholar 

  • Levey AS, Perrone RD, Madias NE. Serum creatinine and renal function. Annual Reviews of Medicine 39: 465–490, 1988.

    CAS  Google Scholar 

  • Lokich JJ, Moore C. Chemotherapy-associated palmar-plantar erythrodysesthesia syndrome. Annals of Internal Medicine 101: 798–800, 1984.

    PubMed  CAS  Google Scholar 

  • Lopez JA, Agarwal RP. Acute cerebellar toxicity after high-dose cytarabine associated with CNS accumulation of its metabolite, uracil arabinoside. Cancer Treatment Reports 68: 1309–1310, 1984.

    PubMed  CAS  Google Scholar 

  • Lopez JA, Beardsley GP, Krikorian JG, Mortara RW, Agarwal RP. Cerebrospinal fluid and plasma pharmacokinetics of high doses of 1-β-D-arabinofuranosylcytosine in nonhuman primates. Cancer Research 43: 5190–5193, 1983.

    PubMed  CAS  Google Scholar 

  • Margolis D, Ross E, Miller KB. Rhabdomyolysis associated with high-dose cytarabine. Cancer Treatment Reports 71: 1325–1326, 1987.

    PubMed  CAS  Google Scholar 

  • Martell RW, Jacobs P. Surgery for the acute abdomen in adults with leukemia. Postgraduate Medical Journal 62: 915–918, 1986.

    PubMed  CAS  Google Scholar 

  • Mayer RJ, Schiffer CA, Peterson BA, Budman DR, Silver RT, et al. Intensive post-remission therapy in adults with acute nonlymphocytic leukemia using various dose schedules of ara-C: progress report from the CALGB. Seminars in Oncology 14 (Suppl. 1): 25–31, 1987.

    PubMed  CAS  Google Scholar 

  • Nand S, Messmore HL, Patel R, Fisher SG, Fisher RI. Neurotoxicity associated with systemic high-dose cytosine arabinoside. Journal of Clinical Oncology 4: 571–575, 1986.

    PubMed  CAS  Google Scholar 

  • Ochs J, Sinkule JA, Danks MK, Look AT, Bowman P, et al. Continuous infusion high-dose cytosine arabinoside in refractory childhood leukemia. Journal of Clinical Oncology 2: 1092–1097, 1984.

    PubMed  CAS  Google Scholar 

  • Ognibene FP, Martin SE, Parker MM, Schlesinger T, Roach P, et al. Adult respiratory distress syndrome in patients with severe neutropenia. New England Journal of Medicine 315: 547–551, 1986.

    PubMed  CAS  Google Scholar 

  • Omura GA, Vogler WR, Lefante J, Silberman H, Knospe W, et al. Treatment of acute myelogenous leukemia. Influence of three induction regimens and maintenance with chemotherapy or BCG immunotherapy. Cancer 49: 1530–1536, 1982.

    PubMed  CAS  Google Scholar 

  • Onundarson PT, Rowe JM. Lowe dose cytosine arabinoside as remission induction therapy in refractory adult acute lymphocytic leukemia. American Journal of Medicine 86: 493–494, 1989.

    PubMed  CAS  Google Scholar 

  • Paterson ARP, Oliver UM. Nucleoside transport II. Inhibition by p-nitrobenzyl thioguanoside and related compounds. Canadian Journal of Biochemistry 49: 271–274, 1971.

    PubMed  CAS  Google Scholar 

  • Peters WG, Colby LP, Willemze R. High-dose cytosine arabinoside: pharmacological and clinical aspects. Blut 56: 1–11, 1988.

    PubMed  CAS  Google Scholar 

  • Peters WG, Willemze R. Palmar-plantar changes and cytarabine. Annals of Internal Medicine 103: 805, 1985.

    PubMed  CAS  Google Scholar 

  • Peters WG, Willemze R, Colly LP, Guiot HFL. Side effects of intermediate- and high-dose cytosine arabinoside in the treatment of refractory or relapsed acute leukaemia and non-Hodgkin’s lymphoma. Netherlands Journal of Medicine 30: 64–74, 1987.

    PubMed  CAS  Google Scholar 

  • Petti MC, Mandelli F, Arrisati G, Covelli A, Amadori S, et al. High-dose ARA-C (HiDAC) plus asparaginase in elderly patients with acute non-lymphocytic leukemia. A pilot multicentric study by the Italian cooperative group GINEMA. European Journal of Haematology 42: 24–31, 1989.

    PubMed  CAS  Google Scholar 

  • Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. American Journal of Medicine 72: 101–110, 1982.

    PubMed  CAS  Google Scholar 

  • Pizzuto J, Avilés A, Ramos E, Cervera J, Aguirre J. Cytosine arabinoside induced liver damage: histopathological demonstration. Medical and Pediatric Oncology 11: 287–290, 1983.

    PubMed  CAS  Google Scholar 

  • Powell BL, Capizzi RL, Lyerly ES, Cooper MR. Peripheral neuropathy after high-dose cytosine arabinoside, daunorubicin, and asparaginase consolidation for acute nonlymphocytic leukemia. Journal of Clinical Oncology 4: 95–97, 1986a.

    PubMed  CAS  Google Scholar 

  • Powell BL, Capizzi RL, Muss HB, Bearden JD, Lyerly ES, et al. Low-dose Ara-C therapy for acute myelogenous leukemia in elderly patients. Leukemia 3: 23–28, 1989.

    PubMed  CAS  Google Scholar 

  • Powell BL, Zekan PJ, Muss HB, Richards F, Lyerly ES, et al. ARA-C syndrome during low-dose continuous infusion therapy. Medical and Pediatric Oncology 14: 310–312, 1986b.

    PubMed  CAS  Google Scholar 

  • Preisler HD, Raza A, Barcos M, Azarnia N, Larson R, et al. Highdose cytosine arabinoside as the initial treatment of poor-risk patients with acute non-lymphocytic leukemia. A leukemia intergroup study. Journal of Clinical Oncology 5: 75–82, 1987.

    PubMed  CAS  Google Scholar 

  • Preisler HD, Rustum Y, Henderson ES, Bjornsson S, Creaven PJ, et al. Treatment of acute nonlymphocytic leukemia: use of anthracycline-cytosine arabinoside induction therapy and comparison of two maintenance regimens. Blood 53: 455–464, 1979.

    PubMed  CAS  Google Scholar 

  • Przuntek H, Breithaupt H. Cytarabine: distribution in cerebrospinal fluid after lumbar injection. Journal of Neurology 226: 73–76, 1981.

    PubMed  CAS  Google Scholar 

  • Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, et al. Treatment of acute myelocytic leukemia. A study by Cancer and Leukemia Group B. Blood 58: 1203–1212, 1981.

    PubMed  CAS  Google Scholar 

  • Rassiga AL, Schwartz HJ, Forman WB, Crum ED. Cytarabineinduced anaphylaxis. Demonstration of antibody and successful desensitization. Archives of Internal Medicine 140: 425–426, 1980.

    PubMed  CAS  Google Scholar 

  • Roda PI. Clostridium difficile colitis induced by cytarabine. American Journal of Oncology 10: 451–452, 1987.

    CAS  Google Scholar 

  • Rubinstein LJ, Herman MM, Long TF, Wilbur JR. Disseminated necrotizing leukencephalopathy: a complication of treated central nervous system leukemia and lymphoma. Cancer 35: 291–305, 1975.

    PubMed  CAS  Google Scholar 

  • Rudnick SA, Cadman EC, Capizzi RL, Skeel RT, Bertino JR, et al. High dose cytosine arabinoside (HDARAC) in refractory acute leukemia. Cancer 44: 1189–1193, 1979.

    PubMed  CAS  Google Scholar 

  • Russell JA, Powles RL. Neuropathy due to cytosine arabinoside. British Medical Journal 4: 652–653, 1974.

    PubMed  CAS  Google Scholar 

  • Sachs L. The differentiation of myeloid leukaemia cells. British Journal of Haematology 40: 509–517, 1978.

    PubMed  CAS  Google Scholar 

  • Saleh MN, Christian ES, Diamond BR. Intrathecal cytosine arabinoside induced acute, rapidly reversible paralysis. American Journal of Medicine 86: 729–730, 1989.

    PubMed  CAS  Google Scholar 

  • Salinsky MC, Levine RL, Aubuchon JP, Schutta HS. Acute cerebellar dysfunction with high-dose ARA-C therapy. Cancer 51: 426–429, 1983.

    PubMed  CAS  Google Scholar 

  • Scherokman B, Filling-Katz MR, Tell D. Brachial plexus neuropathy following high-dose cytarabine in acute monoblastic leukemia. Cancer Treatment Reports 69: 1005–1006, 1985.

    PubMed  CAS  Google Scholar 

  • Shah SS, Rybak ME, Griffin TW. The cytarabine syndrome in an adult. Cancer Treatment Reports 67: 405–406, 1983.

    PubMed  CAS  Google Scholar 

  • Shipp MA, Takvorian RC, Canellos GP. High-dose cytosine arabinoside. Active agent in treatment of non-Hodgkin’s lymphona. American Journal of Medicine 77: 845–850, 1984.

    PubMed  CAS  Google Scholar 

  • Siemers RF, Friedenberg WR, Norfleet RG. High-dose cytosine arabinoside-associated pancreatitis. Cancer 56: 1940–1942, 1985.

    PubMed  CAS  Google Scholar 

  • Slavin RE, Dias MA, Saral R. Cytosine arabinoside induced gastrointestinal toxic alterations in sequential chemotherapeutic protocols. Cancer 43: 1747–1759, 1978.

    Google Scholar 

  • Spriggs DR, Robbins G, Arthur K, Mayer RJ, Kufe D. Prolonged high dose ARA-C infusions in acute leukemia. Leukemia 2: 304–306, 1988.

    PubMed  CAS  Google Scholar 

  • Sylvester RK, Fisher AJ, Lobell M. Cytarabine-induced cerebellar syndrome: case report and literature review. Drug Intelligence and Clinical Pharmacy 21: 177–180, 1987.

    PubMed  CAS  Google Scholar 

  • Thordarson H, Talstad I. Acute meningitis and cerebellar dysfunction complicating high-dose cytosine arabinoside therapy. Acta Medica Scandinavica 220: 493–495, 1986.

    PubMed  CAS  Google Scholar 

  • Vaickus L, Letendre L. Pericarditis induced by high-dose cytarabine therapy. Archives of Internal Medicine 144: 1868–1869, 1984.

    PubMed  CAS  Google Scholar 

  • van Prooijen HC, Dekker AW, Punt K. The use of intermediate dose cytosine arabinoside (ID ARA-C) in the treatment of acute non-lymphocytic leukaemia in relapse. British Journal of Haematology 57: 291–299, 1984.

    PubMed  Google Scholar 

  • Ventura GJ, Keating MJ, Castellanos AM, Glass JP. Reversible bilateral rectus muscle palsy associated with high-dose cytosine arabinoside and mitoxantrone therapy. Cancer 58: 1633–1635, 1986.

    PubMed  CAS  Google Scholar 

  • Vilpo JA, Veronaa T, Eerola E. Effect of cytosine arabinoside on the human immunosystem: toxicity against quiescent human peripheral blood mononuclear cells in vitro. International Journal of Immunopharmacology 9: 379–383, 1987.

    PubMed  CAS  Google Scholar 

  • Vogler WR, Preisler HD, Winton EF, Gottlieb AJ, Goldberg J, et al. Randomized trial of high-dose cytarabine versus amsacrine in acute myelogenous leukemia in relapse: a leukemia intergroup study. Cancer Treatment Reports 70: 455–459, 1986.

    PubMed  CAS  Google Scholar 

  • Watson PR, Brubaker LH, Yaghmai F. Severe central nervous system toxicity from high-dose cytarabine: expressive aphasia occurring after the second day of treatment. Cancer Treatment Reports 69: 313–314, 1985.

    PubMed  CAS  Google Scholar 

  • Wells RJ, Feusner J, Devney R, Woods WG, Provisor AJ, et al. Sequential high-dose cytosine arabinoside-asparaginase treatment in advanced childhood leukemia. Journal of Clinical Oncology 3: 998–1004, 1985.

    PubMed  CAS  Google Scholar 

  • Weiser B, Lange M, Fialk MA, Single C, Szatrowski TH, et al. Prophylactic trimethoprim-sulfamethoxazole during consolidation chemotherapy for acute leukemia: a controlled trial. Annals of Internal Medicine 95: 436–438, 1981.

    PubMed  CAS  Google Scholar 

  • Weiss HD, Walker MD, Wiernik PH. Neurotoxicity of commonly used antineoplastic agents. New England Journal of Medicine 291: 75–81, 1974.

    PubMed  CAS  Google Scholar 

  • Wiley JS, Jones SP, Sawyer WH, Paterson ARP. Cytosine arabinoside influx and nucleoside transport sites in acute leukemia. Journal of Clinical Investigation 69: 479–489, 1982.

    PubMed  CAS  Google Scholar 

  • Willemze R, Jager U, Jehn U, Stryckmans P, Bury J, et al. Intermediate and high dose ARA-C and m-AMSA for remission induction and consolidation treatment of patients with acute myeloid leukemia: an EORTC leukemia cooperative group phase II study. European Journal of Cancer and Clinical Oncology 24: 1721–1725, 1988.

    CAS  Google Scholar 

  • Willemze R, Peters WG, Van Hennik MB, Fibbe WE, Kootte AMM, et al. Intermediate and high dose ARA-C and m-AMSA (or daunorubicin) as remission and consolidation treatment for patients with relapsed acute leukaemia and lymphoblastic non-Hodgkin lymphoma. Scandinavian Journal of Haematology 34: 83–87, 1985.

    PubMed  CAS  Google Scholar 

  • Willemze R, Zwaan FE, Colpin G, Keuning JJ. High dose cytosine arabinoside in the management of refractory acute leukaemia. Scandinavian Journal of Haematology 29: 141–146, 1982.

    PubMed  CAS  Google Scholar 

  • Winkelman MD, Hines JD. Cerebellar degeneration caused by high-dose cytosine arabinoside: a clinicopathological study. Annals of Neurology 14: 520–527, 1983.

    PubMed  CAS  Google Scholar 

  • Wolff L, Zighelboim J, Gale RP. Paraplegia following intrathecal cytosine arabinoside. Cancer 43: 83–85, 1979.

    PubMed  CAS  Google Scholar 

  • Wolf SN, Herzig RH, Phillips GL, Lazarus HM, Greer JP, et al. High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: an update. Seminars in Oncology 14 (Suppl. 1): 12–17, 1987.

    Google Scholar 

  • Wolff SN, Marion J, Stein RS, Flexner JM, Lazarus HM, et al. High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: a pilot study. Blood 65: 1407–1411, 1985.

    PubMed  CAS  Google Scholar 

  • Woodruff RK, Wiley J. High dose cytosine arabinoside: advances in clinical pharmacology and therapeutic results. Australian and New Zealand Journal of Medicine 13: 561–563, 1983.

    PubMed  CAS  Google Scholar 

  • Yates J, Glidewell O, Wiernik P, Cooper MR, Steinberg D, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 60: 454–462, 1982.

    PubMed  CAS  Google Scholar 

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    Jesper Stentoft

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Stentoft, J. The Toxicity of Cytarabine. Drug-Safety 5, 7–27 (1990). https://doi.org/10.2165/00002018-199005010-00003

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