Acute myeloid leukemia, FLT3-positive

Section editor
	Martin W. Schoen, MD, MPH Saint Louis University St. Louis, MO mwschoen

Note: these are regimens tested in biomarker-specific populations for patients with FLT3 internal tandem duplicated (FLT3-ITD) or tyrosine kinase domain mutated (FLT3-TKD) AML, please see the main AML page for other regimens.

22 regimens on this page 26 variants on this page

Upfront induction therapy, standard patients

7+3d (intermediate-dose)

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7+3d: 7 days of cytarabine + 3 days of daunorubicin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Stone et al. 2017 (RATIFY)	2008-2011	Phase III (C)	7+3d & Midostaurin	Inferior OS

Chemotherapy

• Cytarabine (Ara-C) 200 mg/m²/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m²)
• Daunorubicin (Cerubidine) 60 mg/m² IV over 5 minutes once per day on days 1 to 3

Supportive medications

• "According to commonly accepted guidelines with no prophylactic IV antibiotics"
• Granulocyte colony-stimulating factor recommended only for patients older than 50 years old whose leukemic blasts were negative for CD114 expression

7-day course

References

1. RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains verified protocol PubMed

7+3d & Midostaurin

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7+3d & Midostaurin: 7 days of cytarabine, 3 days of daunorubicin, Midostaurin

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Stone et al. 2017 (RATIFY)	2008-2011	Phase III (E-RT-esc)	7+3d (intermediate-dose)	Superior OS

Chemotherapy

• Cytarabine (Ara-C) 200 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 1400 mg/m²)
• Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1 to 3
• Midostaurin (Rydapt) 50 mg PO twice per day on days 8 to 21

Supportive medications

• Hydroxyurea (Hydrea) (no dosage specified) was allowed to be used for up to 5 days before the start of therapy while waiting for results of FLT3 mutation testing

21-day course; retreatment with a second course was allowed if day 21 bone marrow biopsy showed residual AML.

Subsequent treatment

• Patients who achieved complete remission (CR): HiDAC & Midostaurin consolidation. Stem cell transplantation was allowed.

References

1. RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains verified protocol PubMed

First-line induction therapy, older patients or "unfit" patients

7+3d & Sorafenib

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Regimen

Study	Evidence
Uy et al. 2017 (CALGB 11001)	Phase II

Chemotherapy

• Cytarabine (Ara-C) 100 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 700 mg/m²)
• Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1 to 3
• Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 7

7-day course

Subsequent treatment

• Patients not achieving a hypoplastic marrow on day 14 received re-induction with 5+2 & sorafenib
• Patients achieving a CR or CRi: IDAC & sorafenib consolidation

References

1. CALGB 11001: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. link to original article contains verified protocol link to PMC article PubMed

Consolidation after upfront therapy

HiDAC & Midostaurin

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HiDAC & Midostaurin: High Dose Ara-C (Cytarabine) & Midostaurin

Regimen

FDA-recommended dose

Study	Evidence
Stone et al. 2017 (RATIFY)	Non-randomized portion of RCT

Preceding treatment

• 7+3d & midostaurin induction, with CR

Chemotherapy

• Cytarabine (Ara-C) 3000 mg/m² every 12 hours IV over 3 hours every 12 hours on days 1, 3, 5 (total dose per cycle: 18,000 mg/m²)
• Midostaurin (Rydapt) 50 mg PO twice per day on days 8 to 21

28-day cycle for 4 cycles

Subsequent treatment

• Stem cell transplantation "was allowed" for eligible patients; others proceeded to midostaurin maintenance

References

1. RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains verified protocol PubMed

IDAC & Sorafenib

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IDAC & Sorafenib: Intermediate Dose Ara-C (Cytarabine) & Sorafenib

Regimen

Study	Evidence
Uy et al. 2017 (CALGB 11001)	Phase II

Preceding treatment

• 7+3d & sorafenib induction

Chemotherapy

• Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours once per day on days 1 to 5
• Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 28

4- to 6-week cycle for 2 cycles

Subsequent treatment

• Sorafenib maintenance

References

1. CALGB 11001: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. link to original article contains verified protocol link to PMC article PubMed

Maintenance after upfront therapy, including allogeneic HSCT

Midostaurin monotherapy

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Regimen

Study	Evidence	Efficacy
Stone et al. 2017 (RATIFY)	Non-randomized portion of RCT	CR rate: 59% after induction

Preceding treatment

• HiDAC & Midostaurin consolidation

Chemotherapy

• Midostaurin (Rydapt) 50 mg PO twice per day

28-day cycle for up to 13 cycles (1 year)

References

1. RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains verified protocol PubMed

Sorafenib monotherapy

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Regimen variant #1, 12 mos

Study	Evidence
Uy et al. 2017 (CALGB 11001)	Phase II

Preceding treatment

• IDAC & Sorafenib consolidation

Chemotherapy

• Sorafenib (Nexavar) 400 mg PO twice per day

28-day cycle for up to 12 cycles

Regimen variant #2, 2 years

Study	Evidence	Comparator	Efficacy
Burchert et al. 2018 (SORMAIN)	Phase III (E-esc)	Placebo	Seems to have superior RFS

Preceding treatment

• Allogeneic stem cell transplant

Chemotherapy

• Sorafenib (Nexavar) as follows:
  • Cycle 1: 200 mg PO twice per day on days 1 to 14, then increasing to 400 mg PO twice per day if tolerated
  • Cycles 2 to 26: 400 mg PO twice per day

28-day cycle for up to 26 cycles (2 years)

References

1. CALGB 11001: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. link to original article contains verified protocol link to PMC article PubMed
2. Abstract: Burchert A, Bug G, Finke J, Stelljes M, Rollig C, Wäsch R, Bornhäuser M, Berg T, Lang F, Ehninger G, Serve H, Zeiser R, Wagner E, Kroeger N, Wolschke C, Schleuning M, Elmaagacli A, Götze KS, Schmid C, Jost E, Wolf D, Böhm A, Thiede C, Haferlach T, Bethge W, Harnisch S, Wittenberg M, Rospleszcz S, Neubauer A, Brugger M, Strauch K, Schade-Brittinger C, Metzelder SK. Sorafenib As Maintenance Therapy Post Allogeneic Stem Cell Transplantation for FLT3-ITD Positive AML: Results from the Randomized, Double-Blind, Placebo-Controlled Multicentre Sormain Trial. Blood 2018, 132(Suppl 1), 661. Accessed February 13, 2019. link to abstract contains verified protocol Link to clinical trial registration

Relapsed or refractory, salvage therapy

Midostaurin monotherapy

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Regimen variant #1

Study	Evidence	Comparator
Fischer et al. 2010	Randomized Phase IIB (E-de-esc)	Midostaurin; 100 mg twice per day

Chemotherapy

• Midostaurin (Rydapt) 50 mg PO twice per day

Continued indefinitely

Regimen variant #2

Study	Evidence	Comparator
Fischer et al. 2010	Randomized Phase IIB (E-esc)	Midostaurin; 50 mg twice per day

Chemotherapy

• Midostaurin (Rydapt) 100 mg PO twice per day

Continued indefinitely

Regimen variant #3

Study	Evidence
Stone et al. 2004	Phase II

Patients were required to have a FLT3 ITD or FLT3 p.D835Y mutation.

Chemotherapy

• Midostaurin (Rydapt) 75 mg PO three times per day

28-day cycles

References

1. Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, Grandin W, Lebwohl D, Wang Y, Cohen P, Fox EA, Neuberg D, Clark J, Gilliland DG, Griffin JD. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005 Jan 1;105(1):54-60. Epub 2004 Sep 2. link to original article contains verified protocol PubMed
2. Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010 Oct 1;28(28):4339-45. Epub 2010 Aug 23. link to original article link to PMC article contains verified protocolPubMed

Relapsed or refractory, further lines of therapy

Azacitidine & Sorafenib

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Regimen

Study	Evidence
Ravandi et al. 2013 (MDACC 2010-0511)	Phase II

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² IV or SC once per day on days 1 to 7
• Sorafenib (Nexavar) 400 mg PO twice per day

Supportive medications

• "All patients received antimicrobials, supportive care, and transfusions of blood products according to the institutional guidelines."

4- to 8-week cycles

References

1. MDACC 2010-0511: Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, Pierce S, Daver N, Garcia-Manero G, Faderl S, Nazha A, Konopleva M, Borthakur G, Burger J, Kadia T, Dellasala S, Andreeff M, Cortes J, Kantarjian H, Levis M. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013 Jun 6;121(23):4655-62. Epub 2013 Apr 23. link to original article contains verified protocol link to PMC article PubMed

FLAG-Ida

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FLAG-Ida: FLudarabine, Ara-C (Cytarabine), G-CSF (Filgrastim), Idarubicin

Regimen

Study	Evidence	Comparator	Efficacy
Cortes et al. 2019 (QuANTUM-R)	Phase III (C)	Quizartinib	Seems to have inferior OS

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV over 30 minutes once per day on days 2 to 6
• Cytarabine (Ara-C) 2000 mg/m² IV once per day on days 2 to 6
• Idarubicin (Idamycin) 10 mg/m² IV once per day on days 2 to 4

Growth factor therapy

• Filgrastim (Neupogen) by one of the following:
  • 5 mcg/kg SC once per day on days 1 to 5
  • 300 mcg/m² SC once per day on days 1 to 5

28-day cycle for up to 2 cycles

References

1. QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article PubMed

Gilteritinib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Perl et al. 2017 (2215-CL-0101)	2013-2015	Phase I/II
Perl et al. 2019 (ADMIRAL)	2015-2018	Phase III (E-RT-switch-ooc)	Salvage Chemotherapy	Superior OS

Chemotherapy

• Gilteritinib (Xospata) 120 mg PO once per day

28-day cycles

References

1. 2215-CL-0101: Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 Aug;18(8):1061-1075. Epub 2017 Jun 20. link to original article PubMed
2. ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou W-C, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon S-S, Lee J-H, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019;381:1728-40. link to original article contains verified protocol Clinical Trial

LoDAC

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LoDAC: Low Dose Ara-C (cytarabine)
LDAC: Low Dose Ara-C (cytarabine)

Regimen

Study	Evidence	Comparator	Efficacy
Cortes et al. 2019 (QuANTUM-R)	Phase III (C)	Quizartinib	Seems to have inferior OS

Chemotherapy

• Cytarabine (Ara-C) 20 mg SC twice per day on days 1 to 10

28-day cycles

References

1. QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article contains protocol PubMed

MEC

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MEC: Mitoxantrone, Etoposide, Cytarabine

Regimen

Study	Evidence	Comparator	Efficacy
Cortes et al. 2019 (QuANTUM-R)	Phase III (C)	Quizartinib	Seems to have inferior OS

Chemotherapy

• Mitoxantrone (Novantrone) 8 mg/m² IV push once per day on days 1 to 5, given third
• Etoposide (Vepesid) 100 mg/m² IV over 2 hours once per day on days 1 to 5, given first
• Cytarabine (Ara-C) 1000 mg/m² IV once per day on days 1 to 5, given second

28-day cycle for up to 2 cycles

References

1. QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article contains protocol PubMed

Quizartinib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Cortes et al 2019 (QuANTUM-R)	Phase III (E-switch-ooc)	Investigator's choice of: 1. LoDAC 2. MEC 3. FLAG-Ida	Seems to have superior OS

Note: Quizartinib is not yet approved in any domain.

Chemotherapy

• Quizartinib 60 mg PO once per day

Continued indefinitely

References

1. QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. link to original article PubMed Clinical Trial

Prognosis

Prognosis in cytogenetically normal AML

1. Seminal paper comparing the mutational status of NPM1, FLT3, CEBPA, MLL, and NRAS with clinical outcome: Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008 May 1;358(18):1909-18. link to original article PubMed

Investigational agents

These are drugs under study with at least some promising results for this disease.

• Crenolanib (CP-868,596)