Annals of Hematology

, Volume 87, Issue 5, pp 361–367 | Cite as

Daunorubicin, cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety, tolerance and early outcome—Polish Adult Leukemia Group (PALG) pilot study

  • Jerzy Hołowiecki
  • Sebastian GrosickiEmail author
  • Sławomira Kyrcz-Krzemien
  • Aleksander B. Skotnicki
  • Beata Piatkowska-Jakubas
  • Krzysztof Warzocha
  • Ilona Seferynska
  • Barbara Zdziarska
Original Article


In 1992–1993, synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (Ara-C) increasing Ara-CTP concentration in myeloblasts was proved. Based on these findings and encouraging results of the addition of cladribine to standard daunorubicin+Ara-C induction regimen (DAC) in acute myeloid leukemia (AML), the Polish Adult Leukemia Group (PALG) conducted a pilot study on the administration of cytarabine, daunorubicin, and fludarabine (DAF) as a reinduction treatment of AML to assess tolerance, toxicity, and early outcome. The DAF regimen consisted of daunorubicine 60 mg m−2 day−1 iv on days 1–3 and fludarabine 25 mg m−2 day−1 iv on days 1–5 given before cytarabine 200 mg m−2 day−1 in ci on days 1–7. Thirty-four AML patients with median age 39, 24% relapsed and 76% refractory, were included into the study between September 2003 and August 2004. Achieved response rate in the whole study population was 56%; n = 16 patients with complete remission (CR), and n = 3 patients with partial remission (PR). Fifteen of 16 patients achieved CR after the first course of therapy. Only 9% of total population died before the assessment of remission. All patients developed severe neutropenia. Serious infections were observed in 47% of the cases. Severe thrombocytopenia was observed in 72% of the patients. All patients required substitution of platelet concentrates (median 4), and PRBC (median 5). Severe alopecia, mucositis, vomiting were of low frequency. Liver, kidney, or circulatory failure, diarrhea, or polyneuropathy were not observed. The probability of overall survival (OS) for 1 year for the whole study population (34 patients) and the group of 16 patients in CR was: 44% (95% confidence interval [CI] 36–52%) and 69% (95% CI 55–83%), respectively. The probability of leukemia-free survival (LFS) for 1 year was 38% (95% CI 22–54%). Summarizing, DAF regimen used as the induction therapy in relapsed/refractory AML was well tolerated with acceptable toxicity and early efficacy.


Acute myeloid leukemia AML Induction Fludarabine 


  1. 1.
    Gandhi V (1993) Fludarabine for treatment of adult acute myelogenous leukemia. Leuk Lymphoma 11:7–13PubMedCrossRefGoogle Scholar
  2. 2.
    Santana VM, Hurvitz CA, Blakley RL, Crom WR, Luo X, Roberts WM, Ribeiro R, Mahmoud H, Krance RA (1994) Complete hematologic remissions induced by 2-chlorodeioxyadenosine in children with newly diagnosed acute myeloid leukemia. Blood 84:1237–1242PubMedGoogle Scholar
  3. 3.
    Gandhi V, Plunkett W (1992) Cell cycle-specific metabolism of arabinosyl nucleosides in K 562 human leukemia cells. Cancer Chemother Pharmacol 31:11–17PubMedCrossRefGoogle Scholar
  4. 4.
    Gandhi V, Estey E, Keating MJ, Chucrallah A, Plunkett W (1996) Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: pharmacokinetic, pharmacodynamic, and molecular interactions. Blood 87:256–264PubMedGoogle Scholar
  5. 5.
    Kornblau SM, Gandhi V, Andreeff HM, Beran M, Kantarjian HM, Koller CA, O’Brien S, Plunkett W, Estey E (1996) Clinical and laboratory srudies of 2-chlorodeoxyadenosine ± cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults. Leukemia 24:1563–1569Google Scholar
  6. 6.
    Gandhi V, Estey E, Keating MJ, Plunkett W (1993) Fludarabine potentiates metabolism of cytarabine in patients with myelogenous leukemia during therapy. J Clin Oncol 11:116–124PubMedGoogle Scholar
  7. 7.
    Ahlmann M, Lanvers C, Lumkemann K, Rossig C, Freund A, Baumann M, Boos J (2001) Modulation of ara-CTP levels by fludarabine and hydroxyurea in leukemic cells. Leukemia 15:69–73PubMedCrossRefGoogle Scholar
  8. 8.
    Clavio M, Venturino C, Pierri I, Garrone A, Miglino M, Canepa L, Balleari E, Balocco M, Michelis GL, Ballerini F, Gobbi M (2004) Combination of liposomal daunorubicin (DaunoXome), fludarabine, and cytarabine (FLAD) in patients with poor-risk acute leukemia. Ann Hematol 83:696–703PubMedCrossRefGoogle Scholar
  9. 9.
    Russo D, Pricolo G, Michieli M, Michelutti A, Raspadori D, Bertone A, Marin L, Pierri I, Bucalossi A, Zuffa E, De Vivo A, Mazza P, Gobbi M, Lauria F, Zaccaria A, Baccarani M (2001) Fludarabine, arabinosyl cytosine and idarubicin (FLAI) for remission induction in poor-risk acute myeloid leukemia. Leuk Lymphoma 40:335–443PubMedCrossRefGoogle Scholar
  10. 10.
    Clavio M, Carrara P, Miglino M, Pierri I, Canepa L, Balleari E, Gatti AM, Cerri R, Celesti L, Vallebella E, Sessarego M, Patrone F, Ghio R, Damasio E, Gobbi M (1996) High efficacy of fludarabine-containing therapy (FLAG-FLANG) in poor risk acute myeloid leukemia. Haematologica 81:513–520PubMedGoogle Scholar
  11. 11.
    Visani G, Tosi P, Zinzani PL, Manfroi S, Ottaviani E, Testoni N, Clavio M, Cenacchi A, Gamberi B, Carrara P et al (1994) FLAG (fludarabine + high-dose cytarabine + G-CSF): an effective and tolerable protocol for the treatment of ‘poor risk’ acute myeloid leukemias. Leukemia 8:1842–1846PubMedGoogle Scholar
  12. 12.
    Wrzesien-Kus A, Robak T, Lech-Maranda E, Wierzbowska A, Dmoszynska A, Kowal M, Holowiecki J, Kyrcz-Krzemien S, Grosicki S, Maj S, Hellmann A, Skotnicki A, Jedrzejczak W, Kuliczkowski K; Polish Adult Leukemia Group (2003) A multicenter, open, non-comparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine, and G-CSF as induction therapy in refractory acute myeloid leukemia—a report of the Polish Adult Leukemia Group (PALG). Eur J Haematol 71:155–162PubMedCrossRefGoogle Scholar
  13. 13.
    Robak T, Wrzesien-Kus A, Lech-Maranda E, Kowal M, Dmoszynska A (2000) Combination regimen of cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 39:121–129PubMedGoogle Scholar
  14. 14.
    Wrzesien-Kus A, Robak T, Wierzbowska A, Lech-Maranda E, Pluta A, Wawrzyniak E, Krawczynska A, Kuliczkowski K, Mazur G, Kiebinski M, Dmoszynska A, Wach M, Hellmann A, Baran W, Holowiecki J, Kyrcz-Krzemien S, Grosicki S; Polish Adult Leukemia Group (2005) A multicenter, open, noncomparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine, granulocyte colony-stimulating factor and mitoxantrone as induction therapy in refractory acute myeloid leukemia: a report of the Polish Adult Leukemia Group. Ann Hematol 84:557–564PubMedCrossRefGoogle Scholar
  15. 15.
    Holowiecki J, Robak T, Kyrcz-Krzemien S, Grosicki S, Hellmann A, Skotnicki A, Jedrzejczak W, Konopka L, Giebel S, Kuliczkowski K, Zdziarska B, Dmoszynska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J (2002) Daunorubicin, cytarabine, and 2-CdA (DAC-7) for remission induction in “de novo” adult acute myeloid leukaemia patients. Acta Haematol Pol 33:839–847Google Scholar
  16. 16.
    Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszynska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K (2004) Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 18:989–997PubMedCrossRefGoogle Scholar
  17. 17.
    Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD, LoCocco F; International Working Group for Diagnosis, Standardization of Response Criteria (2003) Treatment outcomes, and reporting standards for therapeutic trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642–4649PubMedCrossRefGoogle Scholar
  18. 18.
    Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR (2000) Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/ Eastern Cooperative Oncology Group study. Blood 96:4075–4083PubMedGoogle Scholar
  19. 19.
    Adkins JC, Peters DH, Markham A (1997) Fludarabine. An update of its pharmacology and use in the treatment of haematological malignancies. Drugs 53:1005–1037PubMedGoogle Scholar
  20. 20.
    Kantarjian HM, Alexanian R, Koller CA, Kurzrock R, Keating MJ (1990) Fludarabine therapy in macroglobulinemic lymphoma. Blood 75:1928–1931PubMedGoogle Scholar
  21. 21.
    Warrell RP Jr, Berman E (1986) Phase I and II study of fludarabine phosphate in leukemia: therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol 4:74–79PubMedGoogle Scholar
  22. 22.
    Michelutti A, Michieli M, Damiani D, Melli C, Ermacora A, Grimaz S, Candoni A, Russo D, Fanin R, Baccarani M (1997) Effect of fludarabine and arabinosylcytosine on multidrug resistant cells. Haematologica 82:143–147PubMedGoogle Scholar
  23. 23.
    Estey E, Plunkett W, Gandhi V, Rios MB, Kantarjian H, Keating MJ (1993) Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. Leuk Lymphoma 9:343–350PubMedCrossRefGoogle Scholar
  24. 24.
    te Boekhorst PA, Lowenberg B, Sonneveld P (1994) Hematopoietic growth factor stimulation and cytarabine cytotoxicity in vitro: effects in untreated and relapsed or primary refractory acute myeloid leukemia cells. Leukemia 8:1480–1486Google Scholar
  25. 25.
    Estey E, Thall P, Andreeff M, Beran M, Kantarjian H, O’Brien S, Escudier S, Robertson LE, Koller C, Kornblau S et al (1994) Use of granulocyte colony-stimulating factor before, during, and after fludarabine plus cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndromes: comparison with fludarabine plus cytarabine without granulocyte colony-stimulating factor. J Clin Oncol 12:671–678PubMedGoogle Scholar
  26. 26.
    Dillman RO, Davis RB, Green M, Weiss RB, Gottlieb AJ, Caplan S, Kopel S, Preisler H, McIntyre OR, Schiffer C (1991) A comparative study of two different doses of cytarabin for acute myeloid leukaemia: a phase III trial of Cancer and Leukemia Group B. Blood 78:2520–2526PubMedGoogle Scholar
  27. 27.
    Weick JK, Kopecky TJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M (1996) A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previosly untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88:2841–2951PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Jerzy Hołowiecki
    • 1
  • Sebastian Grosicki
    • 1
    Email author
  • Sławomira Kyrcz-Krzemien
    • 1
  • Aleksander B. Skotnicki
    • 2
  • Beata Piatkowska-Jakubas
    • 2
  • Krzysztof Warzocha
    • 3
  • Ilona Seferynska
    • 3
  • Barbara Zdziarska
    • 4
  1. 1.Department of Haematology and BMTSilesian Medical UniversityKatowicePoland
  2. 2.Department of HaematologyCollegium Medicum, Jagiellonian UniversityCracowPoland
  3. 3.Department of HaematologyInstitute of Haematology and Transfusion MedicineWarsawPoland
  4. 4.Department of HaematologyPomeranian Medical UniversitySzczecinPoland

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