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Acute Leukemias

Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG

Abstract

Chemomodulation of cytarabine by fludarabine has been attributed with a higher antileukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-induction chemotherapy in relapsed or refractory acute myeloid leukemia (AML). Patients (n=326, of which 281 were evaluable) were randomly assigned to SHAI (cytarabine, 1 g/m2 bid, days 1–2 and 8–9 (3 g/m2 for patients 60 years with refractory AML or 2nd relapse); idarubicin 10 mg/m2 daily, days 3–4 and 10–11) or F-SHAI (SHAI with fludarabine, 15 mg/m2, 4 h before cytarabine). Although complete remission (CR) rates (35% SHAI and 44% F-SHAI) and overall survival did not differ between both regimens, fludarabine prolonged time to treatment failure from 2.04 to 3.38 months (median, P<0.05). Twenty-seven percent of patients proceeded to allogeneic stem cell transplantation, with a significantly higher number of patients in CR or incomplete remission in the F-SHAI group (22 vs 10%, P<0.01). In conclusion, fludarabine has a beneficial, although moderate, impact on the antileukemic efficacy of high-dose cytarabine-based salvage therapy for relapsed and refractory AML.

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References

  1. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937–951.

    Article  CAS  PubMed  Google Scholar 

  2. Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.

    Article  PubMed  Google Scholar 

  3. Ellison RR, Holland JF, Weil M, Jacquillat C, Boiron M, Bernard J et al. Arabinosyl cytosine: a useful agent in the treatment of acute leukemia in adults. Blood 1968; 32: 507–523.

    CAS  PubMed  Google Scholar 

  4. Ohno R, Hirano M, Imai K, Koie K, Kamiya T, Nishiwaki H et al. Daunorubicin, cytosine arabinoside, 6-mercaptopurine riboside, and prednisolone (DCMP) combination chemotherapy for acute myelogenous leukemia in adults. Cancer 1975; 36: 1945–1949.

    Article  CAS  PubMed  Google Scholar 

  5. Lowenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009; 361: 1235–1248.

    Article  PubMed  Google Scholar 

  6. Braess J, Spiekermann K, Staib P, Gruneisen A, Wormann B, Ludwig WD et al. Dose-dense induction with sequential high-dose cytarabine and mitoxantone (S-HAM) and pegfilgrastim results in a high efficacy and a short duration of critical neutropenia in de novo acute myeloid leukemia: a pilot study of the AMLCG. Blood 2009; 113: 3903–3910.

    Article  CAS  PubMed  Google Scholar 

  7. Nazha A, Kantarjian H, Ravandi F, Huang X, Choi S, Garcia-Manero G et al. Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients 60 years with newly diagnosed acute myeloid leukemia (AML). Am J Hematol 2013; 88: 961–966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 2011; 29: 369–377.

    Article  CAS  PubMed  Google Scholar 

  9. Kufe DW, Major PP, Egan EM, Beardsley GP . Correlation of cytotoxicity with incorporation of ara-C into DNA. J Biol Chem 1980; 255: 8990–8997.

    Google Scholar 

  10. Plunkett W, Liliemark JO, Adams TM, Nowak B, Estey E, Kantarjian H et al. Saturation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate accumulation in leukemia cells during high-dose 1-beta-D-arabinofuranosylcytosine therapy. Cancer Res 1987; 47: 3005–3011.

    CAS  PubMed  Google Scholar 

  11. Gandhi V, Plunkett W . Cell cycle-specific metabolism of arabinosyl nucleosides in K562 human leukemia cells. Cancer Chemother Pharmacol 1992; 31: 11–17.

    Article  CAS  PubMed  Google Scholar 

  12. Gandhi V, Estey E, Keating MJ, Plunkett W . Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy. J Clin Oncol 1993; 11: 116–124.

    Article  CAS  PubMed  Google Scholar 

  13. Estey EH . Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia 2000; 14: 476–479.

    Article  CAS  PubMed  Google Scholar 

  14. Parker JE, Pagliuca A, Mijovic A, Cullis JO, Czepulkowski B, Rassam SM et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol 1997; 99: 939–944.

    Article  CAS  PubMed  Google Scholar 

  15. Pastore D, Specchia G, Carluccio P, Liso A, Mestice A, Rizzi R et al. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol 2003; 82: 231–235.

    CAS  PubMed  Google Scholar 

  16. Steinmetz HT, Schulz A, Staib P, Scheid C, Glasmacher A, Neufang A et al. Phase-II trial of idarubicin, fludarabine, cytosine arabinoside, and filgrastim (Ida-FLAG) for treatment of refractory, relapsed, and secondary AML. Ann Hematol 1999; 78: 418–425.

    Article  CAS  PubMed  Google Scholar 

  17. Yavuz S, Paydas S, Disel U, Sahin B . IDA-FLAG regimen for the therapy of primary refractory and relapse acute leukemia: a single-center experience. Am J Ther 2006; 13: 389–393.

    Article  PubMed  Google Scholar 

  18. Clavio M, Gatto S, Beltrami G, Quintino S, Canepa L, Pierri I et al. Fludarabine, ARA-C, idarubicin and G-CSF (FLAG-Ida), high dose ARA-C and early stem cell transplant. A feasable and effective therapeutic strategy for de novo AML patients. J Exp Clin Cancer Res 2002; 21: 481–487.

    CAS  PubMed  Google Scholar 

  19. Kim I, Koh Y, Yoon SS, Park S, Kim BK, Kim DY et al. Fludarabine, cytarabine, and attenuated-dose idarubicin (m-FLAI) combination therapy for elderly acute myeloid leukemia patients. Am J Hematol 2013; 88: 10–15.

    Article  CAS  PubMed  Google Scholar 

  20. Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol 2013; 31: 3360–3368.

    Article  CAS  PubMed  Google Scholar 

  21. Kern W, Aul C, Maschmeyer G, Schonrock-Nabulsi R, Ludwig WD, Bartholomaus A et al. Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison. Leukemia 1998; 12: 1049–1055.

    Article  CAS  PubMed  Google Scholar 

  22. Milligan DW, Wheatley K, Littlewood T, Craig JI, Burnett AK . Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood 2006; 107: 4614–4622.

    Article  CAS  PubMed  Google Scholar 

  23. Russo D, Malagola M, de Vivo A, Fiacchini M, Martinelli G, Piccaluga PP et al. Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. Br J Haematol 2005; 131: 172–179.

    Article  CAS  PubMed  Google Scholar 

  24. Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol 2012; 30: 2441–2448.

    Article  CAS  PubMed  Google Scholar 

  25. Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ . Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23: 5675–5687.

    Article  PubMed  Google Scholar 

  26. Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 2006; 108: 1092–1099.

    Article  CAS  PubMed  Google Scholar 

  27. Lowenberg B, Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med 2011; 364: 1027–1036.

    Article  PubMed  Google Scholar 

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Fiegl, M., Unterhalt, M., Kern, W. et al. Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG. Leukemia 28, 1001–1007 (2014). https://doi.org/10.1038/leu.2013.297

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