FLAG (chemotherapy)

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
Specialty	oncology
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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:

• 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

Standard FLAG

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 until 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 until 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 until 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 Day 5 if FLAMSA is not a part of conditioning) until 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. S2CID 7010268.
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. S2CID 34573900.
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. S2CID 1423738.
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. S2CID 25492905.
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. S2CID 624910.
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. S2CID 25079480.
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.