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FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience

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Abstract

We evaluated the efficacy and toxicity profiles of the combination of fludarabine, high-dose cytosine arabinoside (AraC), idarubicin, and granulocyte colony-stimulating factor (G-CSF) in refractory/relapsed acute myeloblastic leukemia (AML) patients. Between October 1998 and February 2002, 46 AML patients were treated with FLAG-IDA (fludarabine 30 mg/m2, AraC 2 g/m2 for 5 days, idarubicin 10 mg/m2 for 3 days, and G-CSF 5 µg/kg from day +6 until neutrophil recovery). Thirty patients were in relapse after conventional chemotherapy including cytarabine, etoposide, and daunorubicin or mitoxantrone according to the GIMEMA protocols. Four were in relapse after autologous peripheral stem cell transplantation and two after allogeneic bone marrow transplantation. Ten patients had refractory disease (after 10 days of standard doses of cytarabine, 3 days of mitoxantrone or daunorubicin, and 5 days of etoposide). Recovery of neutrophils and platelets required a median of 19 and 22 days from the start of therapy. Complete remission (CR) was obtained in 24 of 46 patients (52.1%) and 3 of 46 (6.6%) died during reinduction therapy: 2 due to cerebral hemorrhage and 1 due to fungemia (Candida tropicalis). Fever >38.5°C was observed in 40 of 46 patients (86.9%), 27 had fever of unknown origin (FUO) and 13 documented infections; 31 of 46 (67.3%) developed mucositis and 14 of 46 (30.4%) had grade 2 WHO transient liver toxicity. After achieving CR, 11 patients received allogeneic stem cell transplantation, 4 patients received autologous stem cell transplantation, 4 were judged unable to receive any further therapy, and 5 refused other therapy. Ten patients are at present in continuous CR after a median follow-up of 13 months (range: 4–24). In our experience, FLAG-IDA is a well-tolerated and effective regimen in relapsed/refractory AML. The toxicity is acceptable, enabling most patients to receive further treatment, including transplantation procedures.

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References

  1. Angelov L, Brandwein J, Baker M (1991) Results of therapy for acute myeloid leukemia in first relapse. Leuk Lymphoma 6:15–24

    Google Scholar 

  2. Bassan R, Lerede T, Buelli M, Boleri G, Bellavita P, Rambaldi A, Barbui T (1998) A new combination of carboplatin, high-dose cytarabine and cross-over mitoxantrone or idarubicin for refractory and relapsed acute myeloid leukemia. Hematologica 83:422–427

    CAS  Google Scholar 

  3. Bennet JM, Catowsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103:620–625

    CAS  PubMed  Google Scholar 

  4. Berman E, Heller G, Santorsa J, McKenzie S, Gee T, Kempin S, Gulati S, Andreeff M, Kolitz J, Gabrilove J (1991) Results of randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myeloid leukemia. Blood 77:1666–1671

    CAS  PubMed  Google Scholar 

  5. Carella AM, Carlier P, Pungolino E, Resegotti L, Liso V, Stasi R, Montillo M, Iacopino P, Mirto S, Pagano L (1993) Idarubicin in combination with intermediate dose of cytarabine and VP-16 in the treatment of refractory or rapidly relapsed patients with acute myeloid leukemia. The GIMEMA Cooperative Group. Leukemia 7:196

    CAS  PubMed  Google Scholar 

  6. Clavio M, Carrara P, Miglino M, Pierri I, Canepa L, Balleari E, Gatti A, Cerri R, Celesti L, Vallebella E, Sessarego M, Patrone F, Ghio R, Damasco E, Gobbi M (1996) High efficacy of fludarabine-containing therapy (FLAG-FLANG) in poor risk acute myeloid leukemia. Haematologica 81:513–520

    CAS  PubMed  Google Scholar 

  7. Davis C, Rohatiner A, Amess J, Lim J, Lister TA (1993) The management of recurrent acute myelogenous leukemia at a single center over a fifteen year period. Br J Haematol 83:404–411

    CAS  PubMed  Google Scholar 

  8. De la Rubia J, Regadera A, Martin G, Cervera J, Sanz G, Martinez J, Garcia I, Andreu R, Moscardo F, Jimenez C, Molla S, Benlloch L, Sanz M (2002) FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. Leuk Res 26:725–730

    Article  PubMed  Google Scholar 

  9. Estey E, Plunkett W, Gandhi V, Rios M, Kantarjian H, Keating MJ (1993) Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. Leuk Lymphoma 9:343–350

    CAS  PubMed  Google Scholar 

  10. Ferra' C, Berlanga J, Gallardo D, Ancin I, Marin D, Gonzales J, Peris J, Munoz J, Sarra J, Granena A (2000) Mitoxantrone, etoposide, carboplatinum and ARA-C combination therapy (MECA) in refractory and relapsed acute leukemia. Leuk Lymphoma 39:583–590

    CAS  PubMed  Google Scholar 

  11. Ferrara F, Melillo L, Montillo M, Leoni F, Pinto A, Mele G, Mirto S (1999) Fludarabine, cytarabine, and G-CSF(FLAG) for the treatment of acute myeloid leukemia relapsing after autologous stem cell transplantation. Ann Hematol 78:380–384

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A (1998) The importance of diagnostic cytogenetic on outcome in AML: analysis of 1612 patients entered into the MRC AML 14 trial. The Medical Research Council Adult and Children's Leukemia Working Parties. Blood 92:2322–2333

    CAS  PubMed  Google Scholar 

  14. Ho AD, Lipp T, Ehninger G, Illiger HJ, Meyer P, Freund M, Hunstein W (1988) Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia: an active and well tolerated regimen. J Clin Oncol 6:213

    CAS  PubMed  Google Scholar 

  15. Huhmann IM, Watzke HH, Geisller K, Gisslinger H, Jager U, Knobl P, Pabinger I, Korninger L, Mannhalter C, Mitterbauer G, Schwarzinger I, Kahls P, Haas OA, Lechner K (1996) FLAG (fludarabine, cytosine arabinoside, G-CSF) for refractory and relapsed acute myeloid leukemia. Ann Hematol 73:265–271

    Article  CAS  PubMed  Google Scholar 

  16. Keating MJ, Kantarjian H, Smith TL, Estey E, Walters R, Andersson B, Beran M, McCredie KB, Freireich EJ (1989) Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 7:1071–1080

    CAS  PubMed  Google Scholar 

  17. Kern W, Aul C, Maschmeyer G, Schonrock-Nabulsi R, Ludwig WD, Bartholomaus A, Bettelheim P, Wormann B, Buchner T, Hiddemann W (1998) Superiority of high dose over intermediate dose cytarabine arabinoside in the treatment of patients with high-risk acute myeloid leukemia. Leukemia 12:1049–1055

    Article  CAS  PubMed  Google Scholar 

  18. Kern W, Schleyer E, Braess J, Wittmer E, Ohnesorge J, Unterhalt M, Wormann B, Buchner T, Hiddemann W (2001) Efficacy of fludarabine, intermittent sequential high-dose cytosine arabinoside, and mitoxantrone (FIS-HAM) salvage therapy in highly resistant acute leukemias. Ann Hematol 80:334–339

    Article  CAS  PubMed  Google Scholar 

  19. Liso V, Albano F, Pastore D, Carluccio P, Mele G, Lamacchia M, Mestice A, Specchia G (2000) Bone marrow aspirate on the 14th day of induction treatment as a prognostic tool in de novo adult myeloid leukemia. Haematologica 85:1285–1290

    CAS  PubMed  Google Scholar 

  20. Liso V, Iacopino P, Avvisati G, Petti MC, Broccia G, Carotenuto M, Falda M, Fazzi P, Lazzarino M, Leoni P, Mirto S, Pucci G, Nobile F, Nosari AM, Specchia G, Stasi R, Tabilio A, Mandelli F (1996) Outcome of patients with acute myeloid leukemia who failed to respond to a single course of first-line induction therapy: a GIMEMA study of 218 unselected consecutive patients. Leukemia 110:1443–1452

    Google Scholar 

  21. Michelutti A, Michieli M, Damiani D, Melli C, Ermacora A, Grimaz S, Candoni A, Russo D, Fanin R, Baccarani M, et al. (1997) Effect of fludarabine and arabinosylcytosine on multidrug-resistant cells. Haematologica 82:143–147

    CAS  PubMed  Google Scholar 

  22. Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S, Pinto A, Zagonel V, Mele G, Tedeschi A, Ferrara F (1998) Fludarabine, cytarabine and G-CSF for the treatment of poor risk acute myeloid leukemia. Am J Hematol 58:105–109

    CAS  PubMed  Google Scholar 

  23. Nokes TJ, Johnson S, Harvey D, Goldstone AH (1997) FLAG is a useful regimen for poor prognosis adult myeloid leukemia and myelodysplastic syndromes. Leuk Lymphoma 27:93–101

    CAS  PubMed  Google Scholar 

  24. Ossenkoppele G, Graveland W, Sonneveld P, Daenen S, Biesma D, Verdonk L, Schaafsma M, Westveer P, Peters G, Noordhuis P, Maas P, Sellesla D, van der Holt B, Delforge M, Lowenberg B, Verhoef G (2002) Final analysis of a randomized study on the value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high risk myelodysplastic syndromes and elderly AML (abstract 3130). Blood 100:792a

    Google Scholar 

  25. Parker JE, Pagliuca A, Mijovic A, Cullis JO, Czepulkowski B, Rassam SM, Samaratunga IR, Grace R, Gover PA, Mufti GJ (1997) Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for treatment of poor-risk myelodysplastic syndromes and acute leukemia. Br J Haematol 99:939–944

    CAS  PubMed  Google Scholar 

  26. Thalhammer F, Geissler K, Jager U, Kyrle PA, Pabinger I, Mitterbauer M, Gisslinger H, Knobl P, Laczika K, Schneider B, Ilaas OA, Lechmer K (1996) Duration of second complete remission in patients with acute myeloid leukemia treated with chemotherapy: a retrospective single-center study. Ann Hematol 72:216–222

    Article  CAS  PubMed  Google Scholar 

  27. Vignetti M, Orsini E, Petti MC, Moleti MR, Andrizzi C, Pinto RM, Amdori S, Meloni G (1996) Probability of long term disease free survival for acute myeloid leukemia patients after first relapse: a single center experience. Ann Oncol 7:933-938

    CAS  PubMed  Google Scholar 

  28. Visani G, Tosi P, Zinzani PL, Manfroi S, Ottaviani E, Testoni N, Clavio M, Cenacchi A, Gamberi B, Carrara B, Gobbi M, Tura S(1994) FLAG (fludarabine+high dose cytarabine +G-CSF): an effective and tolerable protocol for the treatment of "poor risk" acute myeloid leukemia. Leukemia 8:1842–1846

    CAS  PubMed  Google Scholar 

  29. Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kimgsbury 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 untreated acute myeloid leukemia : a southwest oncology group study. Blood 88:2841–2851

    CAS  PubMed  Google Scholar 

  30. Wiernick PH, Banks PL, Case DC, Arlin ZA, Periman PO, Todd MB, Ritch PS, Ence RE, Weitberg AB (1992) Cytarabine plus idarubucin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 79:313–320

    CAS  PubMed  Google Scholar 

  31. World Health Organization (1979) A handbook for reporting results of cancer treatment. WHO publication, Geneva

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Acknowledgement

This work was supported by MIUR (Ministero Istruzione Università e Ricerca) and AIL Bari (Associazione Italiana contro le Leucemie).

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Authors and Affiliations

  1. Hematology Section, Department DIMIMP, University of Bari, Piazza Giulio Cesare n. 11, 70124, Bari, Italy

    D. Pastore, G. Specchia, P. Carluccio, A. Liso, A. Mestice, R. Rizzi, G. Greco, C. Buquicchio & V. Liso

  2. Hematology Section, Department of Medicine, University of Foggia, Foggia, Italy

    G. Specchia

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  1. D. Pastore
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Correspondence to G. Specchia.

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Pastore, D., Specchia, G., Carluccio, P. et al. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol 82, 231–235 (2003). https://doi.org/10.1007/s00277-003-0624-2

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  • DOI: https://doi.org/10.1007/s00277-003-0624-2

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