International Journal of Hematology

, Volume 87, Issue 2, pp 118–125

The value of oral cytarabine ocfosfate and etoposide in the treatment of refractory and elderly AML patients

  • Akira Horikoshi
  • Kazuhiro Takei
  • Yoshifumi Hosokawa
  • Shigemasa Sawada
Original Article

Abstract

Twenty-one acute myeloid leukemia (AML) patients were enrolled and received oral induction therapy with cytarabine ocfosfate (SPAC) and etoposide (EP). The median age was 69 years (range: 33–86). There were 11 patients with de novo AML and 10 AML cases that had evolved from myelodysplastic syndromes. Seventeen patients had abnormal karyotypes including eight complex abnormalities, various complications, and 7 of 21 had a poor performance status (PS) with Eastern Cooperative Oncology Group (ECOG) scores of 3–4. All patients completed induction therapy without severe adverse events. Seven achieved complete remission (CR), and two achieved partial remission (PR). Uni- and multivariate analyses demonstrated a positive and significant correlation between the results of therapy (CR ± PR) and overall survival. The plasma concentrations of cytosine arabinoside (ara-C) in some cases were higher than those previously reported, indicating the accumulation of ara-C with increasing numbers of days of SPAC administration. We conclude that this therapy is well tolerated and useful for refractory and elderly AML patients.

Keywords

Cytarabine ocfosfate Ara-C Etoposide Refractory acute myeloid leukemia Induction therapy 

References

  1. 1.
    Champlin R, Gale RP. Acute myelogenous leukemia: recent advances in therapy. Blood. 1987;69:1551–62.PubMedGoogle Scholar
  2. 2.
    Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia. 2000;14:476–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Liu Yin JA. Acute myeloid leukaemia in the elderly: biology and treatment. Br J Haematol. 1993;83:1–6.PubMedGoogle Scholar
  4. 4.
    Mayer RJ, Davis RB, Schiffer CA et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994;331:896–903.PubMedCrossRefGoogle Scholar
  5. 5.
    Löwenberg B, Suciu S, Archimbaud E et al. Use of recombinant granulocyte-macrophage colony-stimulating factor during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia (AML): final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organization for the Research and Treatment of Cancer (EORTC-LCG) and the Dutch Belgian Hemato-Oncology Cooperative Group (HOVON). Blood. 1997;90:2952–61.PubMedGoogle Scholar
  6. 6.
    Bauer KS, Karp JE, Garimella TS, Wu S, Tan M, Ross DD. A phase I and pharmacologic study of idarubicine, cytarabine, etoposide, and the multidrug resistance protein (MDR1/Pgp) inhibitor PSC-833 in patients with refractory leukemia. Leuk Res. 2005;29:263–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Baccarani M, Zaccaria A, Bandini G, Cavazzini G, Fanin R, Tura S. Low dose arabinosyl cytosine for treatment of myelodysplastic syndromes and subacute myeloid leukemia. Leuk Res. 1983;7:539–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Hartmann F, Jacobs G, Gotto H, Schwamborn J, Pfreundschuh M. Cytosine arabinoside, idarubicin and divided dose etoposide for the treatment of acute myeloid leukemia in elderly patients. Leuk Lymphoma. 2001;42:347–55.PubMedCrossRefGoogle Scholar
  9. 9.
    Kodama K, Morozumi M, Saitoh K, Kuninaka A, Yoshino H, Saneyoshi M. Antitumor activity and pharmacology of I-β-d-arabinofuranosylcytosine-5’-stearylphosphate: an orally active derivative of 1-β-d-Arabinofuranosylcytosine. Jpn J Cancer Res. 1989;80:679–85.PubMedGoogle Scholar
  10. 10.
    Ueda T, Kamiya K, Urasaki Y et al. Clinical pharmacology of 1-β-d-arabinofuranosylcytosine-5’-stearylphosphate, an orally administered long-acting derivative of low-dose β-d-arabinofuranosylcytosine. Cancer Res. 1994;54:109–13.PubMedGoogle Scholar
  11. 11.
    Bennet JM, Catovsky D, Daniel MT et al. Proposed revised criteria for the classification of acute myeloid leukemia. Ann Intern Med. 1985;103:620–9.Google Scholar
  12. 12.
    Sato T, Morozumi M, Kodama K, Kuninaka A, Yoshino H. Sensitive radioimmunoassay for cytarabine and uracil arabinoside in plasma. Cancer Trea Rep. 1984;68:1357–66.Google Scholar
  13. 13.
    Kawashiro T, Yamashita K, Zhao XJ et al. A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J Pharmacol Exp Ther. 1998;286:1294–300.PubMedGoogle Scholar
  14. 14.
    Ota K, Ogawa N. Randomized controlled study of chemoimmunotherapy with bestatin of acute nonlymphocytic leukemia in adults. Biomed Pharmacother. 1990;44:93–102.PubMedCrossRefGoogle Scholar
  15. 15.
    Ossenkoppele GJ, Graveland WJ, Sonneveld P et al. The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients. Blood. 2004;103:2908–13.PubMedCrossRefGoogle Scholar
  16. 16.
    van der Holt B, Lowenberg B, Burnett AK et al. The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis. Blood. 2005;106:2646–54.PubMedCrossRefGoogle Scholar
  17. 17.
    Fukuoka M, Miyazaki T, Yoshida Y et al. Phase 1 study of YNK 01 (1-β-d-arabinofuranosylcytosine-5’-stearylphosphate) (in Japanese, with English abstract). Jpn J Cancer Chemother. 1990;17:2213–9.Google Scholar
  18. 18.
    Kreis W, Chaudhri F, Chan K et al. Pharmacokinetics of low-dose 1-β-d-arabinofuranosylcytosine given by continuous intravenous infusion over twenty-one days. Cancer Res. 1985;45:6498–501.PubMedGoogle Scholar
  19. 19.
    Tatsumi N, Yamada K, Ohshima T et al. Phase II study of YNK01 (1-β-d-arabinofuranosylcytosine-5’-stearylphosphate) on hematological malignancy(in Japanese, with English abstract). Jpn J Cancer Chemother. 1990;17:2387–95.Google Scholar
  20. 20.
    Ohno R, Tatsumi N, Hirano M et al. Treatment of Myelodysplastic syndromes with orally administrated-D-arabinofuranosylcytosine-5’-Stearylphosphate. Oncology. 1991;48:451–5.PubMedGoogle Scholar
  21. 21.
    Okumura H, Yoshida T, Takamatsu H et al. Treatment of acute myeloid leukemia and myelodysplastic syndrome with orally administered cytarabine ocfosfate and granulocyte colony-stimulating factor. Int J Hematology. 1997;65:263–8.CrossRefGoogle Scholar
  22. 22.
    Nakaya K, Chou S, Kaneko M, Nakamura Y. Topoisomerase inhibitors have potent differentiation-inducing activity for human and mouse myeloid leukemia cells. Jpn J Cancer Res. 1991;82:184–91.PubMedGoogle Scholar
  23. 23.
    Edick MJ, Gajjar A, Mahmoud HH et al. Pharmacokinetics and pharmacodynamics of oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia. J Clin Oncol. 2003;21:1340–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Ogata K, Yamada T, Ito T et al. Low-dose etoposide: a potential therapy for myelodysplastic syndromes. Brit J Haematol. 1992;82:354–7.Google Scholar
  25. 25.
    Kuriya S, Murai K, Miyairi Y et al. A combination chemotherapy with low doses of cytarabine and etoposide for high risk myelodysplastic syndromes and their leukemic stage. Cancer. 1996;78:422–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Lazzarino M, Morra E, Alessandrino EP et al. Etoposide-cytarabine therapy for acute leukemia following myelodysplastic syndromes or secondary to treatment for malignant diseases. Hematologica. 1987;72:341–5.Google Scholar
  27. 27.
    Rivera G, Avery T, Roberts D. Response of L1210 to combinations of cytosine arabinoside and VM-26 or VP16–213. Eur J Cancer. 1975;11:639–47.PubMedGoogle Scholar
  28. 28.
    Ohkubo T, Higashigawa M, Kawasaki H et al. Sequence-dependent antitumor effect of VP-16 and 1-β-d-arabinofuranosylcytosine in L1210 ascites tumor. Eur J Cancer Clin Oncol. 1988;24:1823–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Ooi K, Ohkubo T, Kuwabata H et al. Enhanced incorporation of 1-β-d-arabinofuranosylcytosine by pretreatment with etoposide. Cancer Investigation. 1993;11:388–92.PubMedCrossRefGoogle Scholar
  30. 30.
    Housset M, Daniel MT, Degos L. Small doses of ARA-C in the treatment of acute myeloid leukaemia: differentiation of myeloid leukaemia cells? Br J Haematol. 1982;51:125–9.PubMedGoogle Scholar
  31. 31.
    Löwenberg B, Suciu S, Archimbaud E et al. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy-the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report of the Leukemia Cooperative Group of the European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon group randomized phase III study AML-9. J Clin Oncol. 1998;16:872–81.PubMedGoogle Scholar
  32. 32.
    Haferlach T, Kern W, Schoch C et al. A new prognostic score for patients with acute myeloid leukemia based on cytogenetics and early blast clearance in trials of the German AML Cooperative Group. Haematologica. 2004;89:408–18.PubMedGoogle Scholar
  33. 33.
    Schlenk RF, Frohling S, Hartmann F et al. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004;18:1798–803.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2008

Authors and Affiliations

  • Akira Horikoshi
    • 1
  • Kazuhiro Takei
    • 1
  • Yoshifumi Hosokawa
    • 1
  • Shigemasa Sawada
    • 1
  1. 1.Department of Internal MedicineNihon University, Nerima-Hikarigaoka HospitalNerima-ku, TokyoJapan

Personalised recommendations