FLAG (chemotherapy)

FLAG is an acronym for a chemotherapy regimen used for relapsed or refractory acute myelogenous leukemia (AML).

The FLAG and FLAG-based regimens can also be used in cases where:

• There are concomitant AML and acute lymphoblastic leukemia;
• There are concomitant AML and lymphoma; or
• The patient has so-called "biphenotypic" AML (where the cells display properties of both myeloid and lymphoid cells), since fludarabine is highly active in lymphoid malignancies.

Standard FLAG Regimen

The FLAG regimen consists of:

1. (FL)udarabine: An antimetabolite that is not active itself in AML; however, it increases the formation of an active cytarabine metabolite, ara-CTP, in AML cells;
2. High-dose Cytarabine ((A)ra-C): An antimetabolite that has proven to be the most active in AML among various cytotoxic drugs in single-drug trials;
3. Granulocyte colony-stimulating factor ((G)-CSF): To shorten the duration and severity of neutropenia.^[1]

Intensified FLAG Regimens

There are also 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 ("IDA") 's added to the standard FLAG regimen.

Idarubicin is an anthracycline antibiotic that is able to intercalate DNA and prevent cell division (mitosis).^[2][3][4]

MITO-FLAG

MITO-FLAG (also called Mito-FLAG, FLAG-MITO, FLAG-Mito) adds mitoxantrone ("MITO") to the standard FLAG regimen.

Mitoxantrone is a synthetic anthracycline analogue (an anthracenedione) that is able to intercalate DNA and prevent cell division (mitosis).^[5][6]

FLAMSA

FLAMSA adds amsacrine ("AMSA") to the standard FLAG regimen. (G-CSF is still included in this regimen, even though the "G" is taken out of the acronym.)

Amsacrine is an alkylating antineoplastic agent that is highly active in 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 pre-transplant conditioning regimen for patients eligible to undergo an allogeneic stem cell transplant. In this setting, it is often combined with other agents, such as:

• Cyclophosphamide (FLAMSA-CYC), and/or
• Busulfan or treosulfan (FLAMSA-BU or FLAMSA-TREO), and/or
• Melphalan (FLAMSA-MEL), and/or
• Total body irradiation given shortly after the end of FLAMSA, to prepare the patient for transplant.

Dosing Regimen

Standard FLAG without additions

Drug	Dose	Mode	Days
(FL)udarabine	30 mg/m^2 a day	IV infusion over 30 min, every 12 hours in 2 divided doses	Days 1–5
(A)ra-C	2000 mg/m^2	IV infusion over 4 hours, every 12 hours in 2 divided doses, starting 4 hours after the end of fludarabine infusion	Days 1–5
(G)-CSF	5 µg/kg	SC	From day 6 till neutrophil recovery

FLAG-IDA

Drug	Dose	Mode	Days
(FL)udarabine	30 mg/m^2 a day	IV infusion over 30 min, every 12 hours in 2 divided doses	Days 1–5
(A)ra-C	2000 mg/m^2 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
(IDA)rubicin	10 mg/m^2	IV bolus	Days 1–3
(G)-CSF	5 µg/kg	SC	From day 6 till neutrophil recovery

Mito-FLAG

Drug	Dose	Mode	Days
(FL)udarabine	30 mg/m^2	IV infusion over 30 min, every 12 hours in 2 divided doses	Days 1–5
(A)ra-C	2000 mg/m^2	IV infusion over 3 hours, every 12 hours in 2 divided doses, starting 4 hours after the end of fludarabine infusion	Days 1–5
(Mito)xantrone	7 mg/m^2	IV infusion	Days 1, 3 and 5
(G)-CSF	5 µg/kg	SC	From day 6 till neutrophil recovery

FLAMSA

Drug	Dose	Mode	Days
(FL)udarabine	30 mg/m^2	IV infusion over 30 min, every 12 hours in 2 divided doses	Days 1–4
(A)ra-C	2000 mg/m^2	IV infusion over 4 hours, every 12 hours in 2 divided doses, starting 4 hours after the end of fludarabine infusion	Days 1–4
(AMSA)crine	100 mg/m^2	IV infusion	Days 1–4
Filgrastim	5 µg/kg	SC	From transplant day (or from day 5 if FLAMSA is not a part of conditioning) till neutrophil recovery

References

1. Visani G, Tosi P, Zinzani PL, et al. (November 1994). "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. PMID 7526088.
2. Pastore D, Specchia G, Carluccio P, et al. (April 2003). "FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience". Annals of Hematology 82 (4): 231–5. doi:10.1007/s00277-003-0624-2. PMID 12707726.
3. Jackson GH (2004). "Use of fludarabine in the treatment of acute myeloid leukemia". The Hematology Journal. 5 Suppl 1: S62–7. doi:10.1038/sj.thj.6200392. PMID 15079154.
4. Specchia G, Pastore D, Carluccio P, et al. (November 2005). "FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia". Annals of Hematology 84 (12): 792–5. doi:10.1007/s00277-005-1090-9. PMID 16047203.
5. Luo S, Cai F, Jiang L, et al. (March 2013). "Clinical study of Mito-FLAG regimen in treatment of relapsed acute myeloid leukemia". Experimental and Therapeutic Medicine 5 (3): 982–986. doi:10.3892/etm.2013.917. PMC 3570250. PMID 23407597.
6. Hänel M, Friedrichsen K, Hänel A, et al. (August 2001). "Mito-flag as salvage therapy for relapsed and refractory acute myeloid leukemia". Onkologie 24 (4): 356–60. doi:10.1159/000055107. PMID 11574763.
7. Saure C, Schroeder T, Zohren F, et al. (March 2012). "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. doi:10.1016/j.bbmt.2011.09.006. PMID 21963618.
8. Chemnitz JM, von Lilienfeld-Toal M, Holtick U, et al. (January 2012). "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. doi:10.1007/s00277-011-1253-9. PMID 21584670.
9. Krejci M, Doubek M, Dusek J, et al. (October 2013). "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. doi:10.1007/s00277-013-1790-5. PMID 23728608.
10. Boehm A, Rabitsch W, Locker GJ, et al. (June 2011). "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. doi:10.1007/s00508-011-1590-7. PMID 21633813.
11. Schmid C, Schleuning M, Tischer J, et al. (January 2012). "Early allo-SCT for AML with a complex aberrant karyotype—results from a prospective pilot study". Bone Marrow Transplantation 47 (1): 46–53. doi:10.1038/bmt.2011.15. PMID 21358688.
12. Zohren F, Czibere A, Bruns I, et al. (December 2009). "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. doi:10.1038/bmt.2009.83. PMID 19430496.
13. Schmid C, Weisser M, Ledderose G, Stötzer O, Schleuning M, Kolb HJ (October 2002). "[Dose-reduced conditioning before allogeneic stem cell transplantation: principles, clinical protocols and preliminary results]". Deutsche Medizinische Wochenschrift (in German) 127 (42): 2186–92. doi:10.1055/s-2002-34946. PMID 12397547.