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Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon α-2b for the treatment of chronic myelogenous leukemia patients in chronic phase

Abstract

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon α-2b (IFN-α2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-α-2b (3 MU/m2/day 1st week and then 5 MU/m2/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54–73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9–24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2–38 months). At 3 years the overall survival was 79% (95% CI, 70–88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.

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References

  1. Kantarjian HM, Talpaz M, Smith TL, Cortes J, Giles FJ, Rios MB, Mallard S, Gajewski J, Murgo A, Cheson B, O'Brien S . Homoharrringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia J Clin Oncol 2000 18: 3513–3521

    Article  CAS  Google Scholar 

  2. Chronic Myeloid Leukemia Trialists’ Collaborative Group. Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials J Natl Cancer Inst 1997 89: 1616–1620

  3. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med 2001 344: 1031–1037

    Article  CAS  Google Scholar 

  4. Ozer H, George SL, Schiffer CA, Rao K, Rao PN, Wurster-Hill DH, Arthur DD, Powell B, Gottlieb A, Peterson BA . Prolonged subcutaneous administration of recombinant alpha-2b interferon in patients with previously untreated Philadelphia chromosome positive chronic-phase chronic myelogenous leukemia: effect on remission durantion and survival: Cancer and Leukemia Group B Study 8583 Blood 1993 82: 2975–2984

    CAS  PubMed  Google Scholar 

  5. Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK, Queiber W, Löffler H, Hochhaus A, Heinze B, Georgii A, Bartram CR, Griebhammer M, Bergmann L, Essers U, Falge C, Queiber U, Meyer P, Schmitz N, Eimermacher H, Walther F, Fett W, Kleeberg UR, Käbisch A, Nerl C, Zimmermann R, Meuret G, Tichelli A, Kanz L, Tiggges FJ, Schmid L, Brockhaus W, Tobler A, Reiter M, Perker M, Emmerich B, Verpoort K, Zankovich R, Wussow PV, Prümmer O, Thiele J, Buhr T, Carbonell F, Ansari H the German CML Study Group. Randomized comparison of interferon-α with busulfan and hydroxyurea in chronic myelogenous leukemia Blood 1994 84: 4064–4077

    CAS  Google Scholar 

  6. Allan N, Richard S, Shepherd P . UK Medical Research Council randomised, multicentre trial of interferon-α n1 for chronic myeloid leukemia: improved survival irrespective of cytogenetic response Lancet 1995 345: 1392–1397

    Article  CAS  Google Scholar 

  7. Ohnishi K, Ohno R, Tomonaga M, Kamada N, Onozawa K, Kuramoto A, Dohy H, Mizoguchi H, Miyawaki S, Tsubaki K, Miura Y, Omine M, Kobayashi T, Naoe T, Ohshima T, Hirashima K, Ohtake S, Takahashi, Morishima Y, Naito K, Asou N, Tanimoto M, Sakuma A, Yamada K the Kouseisho Leukemia Study Group. A randomized trial comparing interferon-α with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase Blood 1995 86: 906–916

    CAS  PubMed  Google Scholar 

  8. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Long term follow-up of the Italian trial of interferon-α versus conventional chemotherapy in chronic myeloid leukemia Blood 1998 92: 1541–1548

  9. Talpaz M, Kantarjian H, Kurzrock R, Trujillo JM, Gutterman JU . Interferon alpha produces sustained cytogenetic responses in chronic myelogenous leukemia Ann Intern Med 1991 114: 532–538

    Article  CAS  Google Scholar 

  10. Sokal JE, Leong SS, Gomez GA . Preferential inhibition by cytarabine of CFU-GM from patients with chronic granulocytic leukemia Cancer 1987 59: 197–202

    Article  CAS  Google Scholar 

  11. Sokal JE, Gockerman JP, Bigner SH . Evidence for a selective antileukemic effect of cytosine arabinoside in chronic granulocytic leukemia Leukemia Res 1988 12: 453–458

    Article  CAS  Google Scholar 

  12. Robertson MJ, Tantravahi R, Griffin JD, Canellos GP, Cannistra SA . Hematologic remission and cytogenetic improvement after treatment of stable-phase chronic myelogenous leukemia with continuous infusion of low dose cytarabine Am J Hematol 1993 43: 95–102

    Article  CAS  Google Scholar 

  13. Bezwoda WR, Mansoor N, Seymour L . Combined cytosine arabinoside plus interfron alpha: I. Interferon α potentiates the effect of cytosine arabinoside in HL 60 cells by stimulation of apoptosis. II. Clinical studies in leukemia and lymphoma Int J Oncol 1993 2: 463–467

    CAS  PubMed  Google Scholar 

  14. Guilhot F, Dreyfus B, Brizard A, Huret JL, Tanzer J . Cytogenetic remissions in chronic myelogenous leukemia using interferon alpha-2a and hydroxyurea with or without low dose cytosine-arabinoside Leuk Lymphoma 1991 4: 49–55

    Article  CAS  Google Scholar 

  15. Kantarjian HM, Keating MJ, Esthey EH, O'Brien S, Pierce S, Beran M, Koller C, Feldman E, Talpaz M . Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-α and the low dose cytarabine J Clin Oncol 1992 10: 772–778

    Article  CAS  Google Scholar 

  16. Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J . Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia N Engl J Med 1997 337: 223–229

    Article  CAS  Google Scholar 

  17. Guilhot F, Guerci A, Maloisel F, Harousseau JL, Brière J, Ifrah N, Abgrall JF, Guyotat D, Christian B, Bauduer F, Jaubert D, Martin C, Guilhot J, Chastang C . Follow-up of 1047 patients with chronic myelogenous leukemia treated with interferon or interferon with cytarabine Blood 1997 90 (Suppl. 1): 2299a (Abstr.)

    Google Scholar 

  18. Rosti G, Bonifazi F, De Vivo A, Martinelli G, Russo D, Trabacchi E, Tura S . Cytarabine increases karyotypic response and survival in IFNα treated chronic myelogenous leukemia patients: results of a national prospective randomized trial of the Italian Cooperative Study Group in CML Blood 1999 94 (Suppl. 1): 2669a (Abstr.)

    Google Scholar 

  19. Braess J, Freund M, Hanauske A, Heil G, Kaufmann C, Kern W, Schüssler M, Hiddemann W, Schleyer E . Oral cytarabine ocfosfate in acute myeloid leukemia and non-Hodgkin's lymphoma phase I/II studies and pharmacokinetics Leukemia 1998 12: 1618–1626

    Article  CAS  Google Scholar 

  20. Guilhot F, Harousseau JC, Fiere D, Rapp MJ, Michallet M, David M, Schuessler M . Phase I/II trial of Ara-c prodrug YNKO1 in chronic myelogenous leukemia patients: hematologic and cytogenetic responses Proc Am Soc Clin Oncol 1996 15: 1402a (Abstr.)

    Google Scholar 

  21. Guilhot F, Maloisel F, Guyotat D, Vilque JP, Michallet M, Harousseau JL, Bordessoule D, Bouabdallah R, Tertian G, Blanc M, Ifrah N, Audhuy B, Christian B, Bauduer F, Eisenmann JC, Traulle C, Rossanino S, Wetterwald C, Casassus P, Maisonneuve H, Guilhot J, Chastang C . Significant survival improvement with a combination of interferon alpha 2b (IFN) and cytarabine (Ara-C) in chronic myeloid leukemia (CML). Update of randomized trial Proc Am Soc Clin Oncol 1999 18: 23a (Abstr.)

    Google Scholar 

  22. Kühr T, Eisterer W, Apfelbeck U, Linkesch W, Bechter O, Zabernigg A, Geissler K, Barbieri G, Duba C, Gastl G, Thaler J . Treatment of patients with advanced chronic myelogenous leukemia with interferon-alpha-2b and continuous oral cytarabine ocfosfate (YNKO1): a pilot study Leukemia Res 2000 24: 583–587

    Article  Google Scholar 

  23. Mollee P, Taylor K, Arthur C, Januszewciz H, Grigg A, Hughes T, Bradstock K, Wolf M, Gibson J, Schwarer T, Spencer A, Browett P, Hawkins T, Seldon M, Herrmann R, Martin N, Shina S, Low C, Nagalingam V, Wright S, Rodwell R, Coulston J, Morton J, Taylor D . A phase II study of interferon alpha (IFN) and intermittent oral cytarabine (YNKO) in the treatment of newly diagnosed chronic myeloid leukemia (CML) Blood 2000 96 (Suppl. 1): 545a (Abstr.)

    Google Scholar 

  24. Kantarjian HM, O'Brien S, Smith TL, Rios MB, Cortes J, Beran M, Koller C, Giles FJ, Andreef M, Kornblau S, Giralt S, Keating MJ, Talpaz M . Treatment of Philadelphia chromosome-positive early chronic-phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine J Clin Oncol 1999 17: 284–292

    Article  CAS  Google Scholar 

  25. Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, Furukawa Y . In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents Blood 2000 97: 1999–2007

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Schering-Plough, USA, the Programme Hospitalier de Recherche Clinique and Ligue Nationale contre le Cancer, France. We are indebted to Doctor Stephen O'Brien for reviewing this manuscript and to Cécile Vignaud-Demer for technical assistance.

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Maloisel, F., Guerci, A., Guyotat, D. et al. Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon α-2b for the treatment of chronic myelogenous leukemia patients in chronic phase. Leukemia 16, 573–580 (2002). https://doi.org/10.1038/sj.leu.2402433

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