Acute myeloid leukemia, FLT3-positive

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Martin W. Schoen, MD, MPH
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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.

14 regimens on this page
16 variants on this page

Contents


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

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

Targeted therapy

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

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

Targeted therapy

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 NCT01253070

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

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)

Targeted therapy

28-day cycle for 4 cycles

Subsequent treatment

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

Chemotherapy

Targeted therapy

4- to 6-week cycle for 2 cycles

Subsequent treatment

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 NCT01253070

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

Targeted therapy

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, 6 months

Study Years of enrollment Evidence Comparator Comparative Efficacy
Xuan et al. 2020 (Sorafenib-Flt3 AML-2015) 2015-2018 Phase III (E-esc) Observation Superior 1-year cumulative incidence of relapse

Preceding treatment

  • Allogeneic stem cell transplant

Targeted therapy

6-month course

Regimen variant #2, 12 mos

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

Preceding treatment

Targeted therapy

28-day cycle for up to 12 cycles

Regimen variant #3, 2 years

Study Years of enrollment Evidence Comparator Comparative Efficacy
Burchert et al. 2020 (SORMAIN) 2010-2016 Phase III (E-esc) Placebo Seems to have superior RFS

Preceding treatment

  • Allogeneic stem cell transplant

Targeted therapy

  • 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 NCT01253070
  2. SORMAIN: Burchert A, Bug G, Fritz LV, Finke J, Stelljes M, Röllig C, Wollmer E, Wäsch R, Bornhäuser M, Berg T, Lang F, Ehninger G, Serve H, Zeiser R, Wagner EM, Kröger N, Wolschke C, Schleuning M, Götze KS, Schmid C, Crysandt M, Eßeling E, Wolf D, Wang Y, Böhm A, Thiede C, Haferlach T, Michel C, Bethge W, Wündisch T, Brandts C, Harnisch S, Wittenberg M, Hoeffkes HG, Rospleszcz S, Burchardt A, Neubauer A, Brugger M, Strauch K, Schade-Brittinger C, Metzelder SK. Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN). J Clin Oncol. 2020 Sep 10;38(26):2993-3002. Epub 2020 Jul 16. link to original article contains verified protocol PubMed Link to clinical trial registration DRKS00000591
  3. Sorafenib-Flt3 AML-2015: Xuan L, Wang Y, Huang F, Fan Z, Xu Y, Sun J, Xu N, Deng L, Li X, Liang X, Luo X, Shi P, Liu H, Wang Z, Jiang L, Yu C, Zhou X, Lin R, Chen Y, Tu S, Huang X, Liu Q. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1201-1212. Epub 2020 Aug 10. link to original article PubMed NCT02474290

Relapsed or refractory, salvage therapy

Midostaurin monotherapy

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Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Fischer et al. 2010 (CPKC412A2104) 2002-NR Randomized Phase IIB (E-de-esc) Midostaurin; 100 mg twice per day Not reported

Targeted therapy

Continued indefinitely

Regimen variant #2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Fischer et al. 2010 (CPKC412A2104) 2002-NR Randomized Phase IIB (E-esc) Midostaurin; 50 mg twice per day Not reported

Targeted therapy

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.

Targeted therapy

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. CPKC412A2104: 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 NCT00045942

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

Targeted therapy

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 Years of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R) 2014-2017 Phase III (C) Quizartinib Seems to have inferior OS

Chemotherapy

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 NCT02039726

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

Targeted therapy

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 Years of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R) 2014-2017 Phase III (C) Quizartinib Seems to have inferior OS

Chemotherapy

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 NCT02039726

MEC

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MEC: Mitoxantrone, Etoposide, Cytarabine

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R) 2014-2017 Phase III (C) Quizartinib Seems to have inferior OS

Chemotherapy

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 NCT02039726

Quizartinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R) 2014-2017 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.

Targeted therapy

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 NCT02039726

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.