Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

IG Budaeva, EG Ovsyannikova, EN Goryunova, OV Kulemina, DV Zaitsev, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, KV Bogdanov, OS Pisotskaya, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskey, LL Girshova

VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Irina Garmaevna Budaeva, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(931)351-07-06; e-mail:

For citation: Budaeva IG, Ovsyannikova EG, Goryunova EN, et al. Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia. Clinical oncohematology. 2019;12(3):289-96 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-289-296


Aim. To assess the efficacy of FLAG/FLAG-Ida regimen and to identify factors that influence remission, duration of disease-free survival (DFS) and overall survival (OS) of patients with relapsed/refractory acute myeloid leukemia (AML).

Materials & Methods. The trial included 54 patients (28 men and 26 women), median age was 37 years (range 18–70 years). 27 (50 %) out of 54 patients had refractory AML and 27 (50 %) patients had relapsed AML. FLAG and FLAG-Ida regimens were administered as induction therapy. 37 (68.5 %) patients received bone marrow transplantation. Molecular genetic and cytogenetic examinations were performed prior to therapy and on the 28th day after the start of treatment. WT1 gene expression was evaluated on the 14th–16th day of treatment.

Results. Complete remission (CR) was achieved in 42 (77.8 %) out of 54 patients. Refractoriness to therapy was observed in 9 (16.7 %) out of 54 patients, mortality was 5.5 % (3/54). Remission rate was higher in patients with relapsed AML compared with refractory AML: 85.2 % (23/27) and 70.4 % (19/27), respectively. On the 14th–16th day of treatment patients with blast cell count ≥ 10 % in bone marrow (BM) showed significantly lower CR rate (60 %) compared with the group of patients with < 10 % blast cells in BM (89.6 %; = 0.024) and shorter DFS (median 7.6 vs. 17.6 months, respectively; = 0.03). Median DFS in patients with WT1 expression reduction to < 1 log on the 14th–16th day was 5 vs. 18 months in patients without WT1 expression reduction (= 0.01). DFS varied in groups of patients with blast cell count < 10 % in BM on the 14th–16th day of treatment based on the level of WT1 expression reduction (= 0.04). MRD-negative patients (57.1 %) showed significantly longer DFS and OS compared with MRD-positive patients (median DFS was 17.6 vs. 5.2 months, respectively, = 0.02; median OS was 19 vs. 6.9 months, = 0.0002). Median DFS and OS were different only in ELN low- and high-risk groups (median not reached vs. 5.2 months, respectively, = 0.039; median not reached vs. 10.2 months, = 0.039).

Conclusion. FLAG and FLAG-Ida are effective and safe regimens in the treatment of relapsed/refractory AML. Achieving remission depends on neither the risk group nor the time of relapse occurrence. The blast cell count in BM on the 14th–16th day of FLAG/FLAG-Ida treatment is a prognostic factor determining achievement and duration of remission. WT1 expression level in the early post-induction period is a sensitive DFS marker. MRD status and molecular genetic risk (ELN) group affiliation are essential prognostic factors determining DFS and OS.

Keywords: acute myeloid leukemia, relapse, refractoriness, FLAG and FLAG-Ida regimens.

Received: November 2, 2018

Accepted: May 28, 2019

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  1. Papaemmanuil E, Gerstung M, Bullinger L. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21. doi: 10.1056/NEJMoa1516192.

  2. Cheson BD, Bennett JM, Kopecky KJ, et al. 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. 2003;21(24):4642–9. doi: 10.1200/JCO.2003.04.036.

  3. Dohner H, Elihu H, Estey EH, 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(3):453–74. doi: 10.1182/blood-2009-07-235358.

  4. Othus M, Appelbaum FR, Petersdorf SH, et al. Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy. Biol Blood Marrow Transplant. 2015;21(3):559–64. doi: 10.1016/j.bbmt.2014.10.025

  5. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47. doi: 10.1182/blood-2016-08-733196.

  6. Elihu H, Estey E. Acute myeloid leukemia: 2016 Update on risk-stratification and management. Am J Hematol. 2016;91(8):824–46. doi: 10.1002/ajh.24439.

  7. Biggs JC, Horowitz MM, Gale RP, et al. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood. 1992;80(4):1090–3.

  8. Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010;28(23):3730–8. doi: 10.1200/JCO.2010.28.8852.

  9. Sureda A. Indications for allo- and auto-SCT for hematological diseases, solid tumours and immune disorders: current practice in Europe. Bone Marrow Transplant. 2015;50(8):1037–56. doi: 10.1038/bmt.2015.6.

  10. Araki D, Othus M, Walter RB, et al. Effect of allogeneic hematopoietic cell transplantation in first complete remission on post-relapse complete remission rate and survival in acute myeloid leukemia. Haematologica. 2015;100(7):254–6. doi: 10.3324/haematol.2014.

  11. Delia M, Pastore D, Carluccio P, et al. FLAG-Ida regimen as bridge therapy to allotransplant in refractory/relapsed AML patients. Clin Lymph Myel Leuk. 2017;17(11):767–773. doi: 10.1016/j.clml.2017.06.002.

  12. Estey E, Kornblau S, Pierce S, et al. A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. Blood. 1996;88(2):756.

  13. Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia. 2000;14(3):476–9. doi: 10.1038/sj.leu.2401568.

  14. Estey E, Plunkett W, Gandhi V, et al. Fludarabine and arabinosylcytosine therapy for refractory and relapsed acute myelogenous leukemia. Leuk Lymphoma. 1993;9(4–5):343–50. doi: 10.3109/10428199309148532.

  15. Estey E, Thall P, Andreeff M, et al. 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. 1994;12(4):671–8. doi: 10.1200/JCO.1994.12.4.671.

  16. Gandhi V, Plunkett W. Modulation of arabinosylnucleoside metabolism by arabinosylnucleotides in human leukemia cells. Cancer Res. 1988;48(2):329–34.

  17. Gandhi V, Estey E, Keating MJ, et al. Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy. J Clin Oncol. 1993;11(1):116–24. doi: 10.1200/JCO.1993.11.1.116.

  18. Anderlini P. Idarubicin cardiotoxicity: A retrospective study in acute myeloid leukemia and myelodysplasia. J Clin Oncol. 1995;13(11):2827–34. doi: 10.1200/JCO.1995.13.11.2827.

  19. Lee SR, Yang DH, Ahn JS, et al. The Clinical outcome of FLAG chemotherapy without idarubicin in patients with relapsed or refractory acute myeloid leukemia. J Korean Med Sci. 2009;24(3):498–503. doi: 10.3346/jkms.2009.24.3.498.

  20. Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373(12):1136–52. doi: 10.1056/NEJMra1406184.

  21. Patel JP, Gonen M, Figueroa ME. Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia. N Engl J Med. 2012;366(12):1079–89. doi: 10.1056/NEJMoa1112304.

  22. Wang LJ, Ding J, Zhu CY, et al. Clinic outcome of FLAG regimen treating patients with refractory and relapse acute myeloid leukemia. J Exper Hematol. 2016;24(1):19–24.

  23. Jun Xu, Ting-Ting Lv, Xiao-Fen Zhou, et al. Efficacy of common salvage chemotherapy regimens in patients with refractory or relapsed acute myeloid leukemia: A retrospective cohort study. Medicine. 2018;97(39): doi: 10.1097/MD.0000000000012102.

  24. Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005;23(9):1969–78. doi: 10.1200/jco.2005.06.027.

  25. Carella AM, Cascavilla N, Greco MM, et al. Treatment of poor risk acute myeloid leukemia with fludarabine, cytarabine and G-CSF (flag regimen): a single center study. Leuk Lymphoma. 2001;40(3–4):295–303. doi: 10.3109/10428190109057928.

  26. Ferrara F, Palmieri S, Pocali B, et al. De novo acute myeloid leukemia with multilineage dysplasia: treatment results and prognostic evaluation from a series of 44 patients treated with fludarabine, cytarabine and G-CSF (FLAG). Eur J Haematol. 2002;68(4):203–9. doi: 10.1034/j.1600-0609.2002.01651.x.

  27. Bao Y, Zhao J, Li Z-Z. Comparison of clinical remission and survival between CLAG and FLAG induction chemotherapy in patients with refractory or relapsed acute myeloid leukemia: a prospective cohort study. Clin Transl Oncol. 2018;20(7):870–80. doi: 10.1007/s12094-017-1798-8.

  28. 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(8):2908–13. doi: 10.1182/blood-2003-07-2195.

  29. Jackson G, Taylor P, Smith GM, et al. A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol. 2001;112(1):127–37. doi: 1046/j.1365-2141.2001.02551.x.

  30. Virchis A, Koh M, Rankin P, et al. Fludarabine, cytosine arabinoside, granulocyte-colony stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic syndromes. Br J Haematol. 2004;124(1):26–32. doi: 10.1046/j.1365-2141.2003.04728.x.

  31. Farooq MU, Mushtaq F, Farooq A, et al. FLAG vs FLAG-IDA: outcomes in relapsed/refractory acute leukemias. Cancer Chemother Pharmacol. 2019;83(2):1–2. doi: 10.1007/s00280-019-03792-8.

  32. Heinemann V, Murray D, Walters R, et al. Mitoxantrone-induced DNA damage in leukemia cells is enhanced by treatment with high-dose arabinosylcytosine. Cancer Chemother Pharmacol. 1988;22(3):205–10. doi: 10.1007/BF00273412.

  33. Loughlin S, Gandhi V, Plunkett W, et al. The effect of 9-beta-D-arabinofuranosyl-2-fluoroadenine and 1-beta-D-arabinofuranosylcytosine on the cell cycle phase distribution, topoisomerase II level, mitoxantrone cytotoxicity, and DNA strand break production in K562 human leukemia cells. Cancer Chemother Pharmacol. 1996;38(3):261–8. doi: 10.1007/s002800050480.

  34. Gabert J, Beillard E, Velden VH, et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer program. Leukemia. 2003;17(12):2318–57. doi: 10.1038/sj.leu.2403135.

  35. Willasch AM, Gruhn B, Coliva T, et al. Combined usage of Wilms’ tumor gene quantitative analysis and multiparameter flow cytometry for minimal residual disease monitoring of acute myeloid leukemia patients after allogeneic hematopoietic stem cells transplantation. Exp Ther Med. 2018;15(2):1403–9. doi: 10.3892/etm.2017.5547.

  36. Богданов К.В., Моторин Д.В., Никулина Т.С. и др. Мониторинг донорского химеризма и минимальной остаточной болезни у онкогематологических больных после аллогенной трансплантации гемопоэтических стволовых клеток. Биомедицинская химия. 2017;63(6):570–81. doi: 10.18097/PBMC

    [Bogdanov KV, Motorin DV, Nikulina TS, et al. Donor chimerism and minimal residual disease monitoring in leukemia patients after allo-HSCT. Biomeditsinskaya khimiya. 2017;63(6):570–81. doi: 10.18097/PBMC20176306570. (In Russ)]

  37. Pastore D, Specchia G, Carluccio P, et al. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol. 2003;82(4):231–5. doi: 10.1007/s00277-003-0624-2.

  38. Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 1998;58(2):105–9. doi: 1002/(sici)1096-8652(199806)58:2<105::aid-ajh3>;2-w.

  39. Nokes TJ, Johnson S, Harvey D, et al. FLAG is a useful regimen for poor prognosis adult myeloid leukaemias and myelodysplastic syndromes. Leuk Lymphoma. 1997;27(1–2):93–101. doi: 10.3109/10428199709068275.