FLAG (chemotherapy) explained

FLAG
Specialty:oncology

FLAG is a chemotherapy regimen used for relapsed and refractory acute myeloid leukemia (AML).[1] The acronym incorporates the three primary ingredients of the regimen:

  1. Fludarabine: an antimetabolite that, while not active toward AML, increases formation of an active cytarabine metabolite, ara-CTP, in AML cells;
  2. Arabinofuranosyl cytidine (or ara-C): an antimetabolite that has been proven to be the most active toward AML among various cytotoxic drugs in single-drug trials; and
  3. Granulocyte colony-stimulating factor (G-CSF): a glycoprotein that shortens the duration and severity of neutropenia.

FLAG and FLAG-based regimens can also be used in cases of concomitant AML and either acute lymphoblastic leukemia (ALL) or lymphoma. Because fludarabine is highly active in lymphoid malignancies, these regimens can further be used when patients have biphenotypic AML, in which cells display properties of both myeloid and lymphoid cells.

Intensified FLAG regimens

There are several intensified versions of the FLAG regimen in which a third chemotherapeutic agent is added.

FLAG-IDA

In the FLAG-IDA regimen (also called FLAG-Ida, IDA-FLAG, or Ida-FLAG), idarubicin—an anthracycline antibiotic that is able to intercalate DNA and prevent cell division (mitosis)[2] [3] [4] —is added to the standard FLAG regimen.

MITO-FLAG

MITO-FLAG (also called Mito-FLAG, FLAG-MITO, or FLAG-Mito) adds mitoxantrone to the standard regimen. Mitoxantrone is a synthetic anthracycline analogue (an anthracenedione) that, like idarubicin, can intercalate DNA and prevent cell division.[5] [6]

FLAMSA

FLAMSA adds amsacrine ("AMSA") to the standard FLAG regimen. (G-CSF is still included, even though the "G" is taken out of the acronym.) Amsacrine is an alkylating antineoplastic agent that is highly active toward AML, unlike more conventional alkylators like cyclophosphamide.[7] [8] [9] [10] [11] [12] [13]

The FLAMSA protocol is most often used as an induction part of a reduced-intensity conditioning regimen for patients eligible to undergo an allogeneic stem cell transplant. In this setting, it is often combined with other agents, such as:

Dosing

Standard FLAG

Drug Dose Mode Days
30 mg/m2 a day IV infusion over 30 min, every 12 hours in 2 divided doses Days 1–5
2000 mg/m2 IV infusion over 4 hours, every 12 hours in 2 divided doses, starting 4 hours after the end of fludarabine infusion Days 1–5
5 μg/kg From day 6 until neutrophil recovery

FLAG-IDA

Drug Dose Mode Days
30 mg/m2 a day IV infusion over 30 min, every 12 hours in 2 divided doses Days 1–5
2000 mg/m2 a day IV infusion over 4 hours, every 12 hours in 2 divided doses, starting 4 hours after the end of fludarabine infusion Days 1–5
10 mg/m2 Days 1–3
5 μg/kg SC From day 6 until neutrophil recovery

Mito-FLAG

Drug Dose Mode Days
30 mg/m2 IV infusion over 30 min, every 12 hours in 2 divided doses Days 1–5
2000 mg/m2 IV infusion over 3 hours, every 12 hours in 2 divided doses, starting 4 hours after the end of fludarabine infusion Days 1–5
7 mg/m2 IV infusion Days 1, 3 and 5
5 μg/kg SC From day 6 until neutrophil recovery

FLAMSA

Drug Dose Mode Days
30 mg/m2 IV infusion over 30 min, every 12 hours in 2 divided doses Days 1–4
2000 mg/m2 IV infusion over 4 hours, every 12 hours in 2 divided doses, starting 4 hours after the end of fludarabine infusion Days 1–4
100 mg/m2 IV infusion Days 1–4
5 μg/kg SC From transplant day (or Day 5 if FLAMSA is not a part of conditioning) until neutrophil recovery

Notes and References

  1. Visani G, Tosi P, Zinzani PL, et al . FLAG (fludarabine + high-dose cytarabine + G-CSF): an effective and tolerable protocol for the treatment of 'poor risk' acute myeloid leukemias . Leukemia . 8 . 11 . 1842–6 . November 1994 . 7526088.
  2. April 2003. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Annals of Hematology. 82. 4. 231–5. 10.1007/s00277-003-0624-2. 12707726. Pastore D, Specchia G, Carluccio P, etal. 7010268 .
  3. 2004. Use of fludarabine in the treatment of acute myeloid leukemia. The Hematology Journal. 5 Suppl 1. S62–7. 10.1038/sj.thj.6200392. 15079154. Jackson GH.
  4. November 2005. FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia. Annals of Hematology. 84. 12. 792–5. 10.1007/s00277-005-1090-9. 16047203. Specchia G, Pastore D, Carluccio P, etal. 34573900 .
  5. Luo S, Cai F, Jiang L, etal . Clinical study of Mito-FLAG regimen in treatment of relapsed acute myeloid leukemia . Experimental and Therapeutic Medicine . 5 . 3 . 982–986 . March 2013 . 23407597 . 3570250 . 10.3892/etm.2013.917.
  6. Hänel M, Friedrichsen K, Hänel A, etal . Mito-flag as salvage therapy for relapsed and refractory acute myeloid leukemia . Onkologie . 24 . 4 . 356–60 . August 2001 . 11574763 . 10.1159/000055107. 1423738 .
  7. Saure C, Schroeder T, Zohren F, et al. . Upfront allogeneic blood stem cell transplantation for patients with high-risk myelodysplastic syndrome or secondary acute myeloid leukemia using a FLAMSA-based high-dose sequential conditioning regimen . Biology of Blood and Marrow Transplantation . 18 . 3 . 466–72 . March 2012 . 21963618 . 10.1016/j.bbmt.2011.09.006. free .
  8. Chemnitz JM, von Lilienfeld-Toal M, Holtick U, etal . Intermediate intensity conditioning regimen containing FLAMSA, treosulfan, cyclophosphamide, and ATG for allogeneic stem cell transplantation in elderly patients with relapsed or high-risk acute myeloid leukemia . Annals of Hematology . 91 . 1 . 47–55 . January 2012 . 21584670 . 10.1007/s00277-011-1253-9. 25492905 .
  9. Krejci M, Doubek M, Dusek J, etal . Combination of fludarabine, amsacrine, and cytarabine followed by reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia . Annals of Hematology . 92 . 10 . 1397–403 . October 2013 . 23728608 . 10.1007/s00277-013-1790-5. 624910 .
  10. Boehm A, Rabitsch W, Locker GJ, etal . Successful allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia during respiratory failure and invasive mechanical ventilation . Wiener Klinische Wochenschrift . 123 . 11–12 . 354–8 . June 2011 . 21633813 . 10.1007/s00508-011-1590-7. 25079480 .
  11. Schmid C, Schleuning M, Tischer J, etal . Early allo-SCT for AML with a complex aberrant karyotype—results from a prospective pilot study . Bone Marrow Transplantation . 47 . 1 . 46–53 . January 2012 . 21358688 . 10.1038/bmt.2011.15. free .
  12. Zohren F, Czibere A, Bruns I, etal . Fludarabine, amsacrine, high-dose cytarabine and 12 Gy total body irradiation followed by allogeneic hematopoietic stem cell transplantation is effective in patients with relapsed or high-risk acute lymphoblastic leukemia . Bone Marrow Transplantation . 44 . 12 . 785–92 . December 2009 . 19430496 . 10.1038/bmt.2009.83. free .
  13. Schmid C, Weisser M, Ledderose G, Stötzer O, Schleuning M, Kolb HJ . [Dose-reduced conditioning before allogeneic stem cell transplantation: principles, clinical protocols and preliminary results] . de . Deutsche Medizinische Wochenschrift . 127 . 42 . 2186–92 . October 2002 . 12397547 . 10.1055/s-2002-34946.

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