Acute myeloid leukemia, FLT3-positive

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Section editor
AK.JPG
 Ashwin Kishtagari, MD
Vanderbilt University
Nashville, TN, USA
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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.
For placebo or observational studies in this condition, please visit this page.

22 regimens on this page
26 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

NCCN

Upfront induction therapy, standard patients

7+3d (intermediate-dose)

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

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Erba et al. 2023 (QuANTUM-First) 2016-09-27 to 2019-08-14 Phase 3 (C) 1a. 7+3d & Quizartinib
1b. 7+3i & Quizartinib 		Seems to have inferior OS

Note: this was the lower bound of cytarabine dosing in QuANTUM-First.

Chemotherapy

7-day course


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stone et al. 2017 (RATIFY) 2008-2011 Phase 3 (C) 7+3d & Midostaurin Inferior OS
Erba et al. 2023 (QuANTUM-First) 2016-09-27 to 2019-08-14 Phase 3 (C) 1a. 7+3d & Quizartinib
1b. 7+3i & Quizartinib 		Seems to have inferior OS

Note: this was the upper bound of cytarabine dosing in QuANTUM-First.

Chemotherapy

Supportive therapy

  • "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 dosing details in manuscript PubMed NCT00651261
  2. QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in abstract PubMed NCT02668653
  3. Q-SOC: NCT04676243

7+3d & Midostaurin

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

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stone et al. 2017 (RATIFY) 2008-2011 Phase 3 (E-RT-esc) 7+3d (intermediate-dose) Superior OS (primary endpoint)
Median OS: 74.7 vs 25.6 mo
(HR 0.78, 95% CI 0.63-0.96)

Chemotherapy

Targeted therapy

Supportive therapy

  • 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

  • RATIFY, 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 dosing details in manuscript PubMed NCT00651261

7+3d & Quizartinib

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Erba et al. 2023 (QuANTUM-First) 2016-09-27 to 2019-08-14 Phase 3 (E-RT-esc) 1a. 7+3d; intermediate-dose
1b. 7+3i 		Seems to have superior OS (primary endpoint)
Median OS: 31.9 vs 15.1 mo
(HR 0.78, 95% CI 0.62-0.98)

Chemotherapy

Targeted therapy

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

Subsequent treatment

  • QuANTUM-First, patients who achieved complete remission (CR): HiDAC & Quizartinib consolidation. Stem cell transplantation was allowed.

References

  1. QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in abstract PubMed NCT02668653

7+3i

7+3i: 7 days of cytarabine + 3 days of idarubicin

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Erba et al. 2023 (QuANTUM-First) 2016-09-27 to 2019-08-14 Phase 3 (C) 1a. 7+3d & Quizartinib
1b. 7+3i & Quizartinib 		Seems to have inferior OS

Note: this was the lower bound of cytarabine dosing in QuANTUM-First.

Chemotherapy

  • Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m2)
  • Idarubicin 12 mg/m2 IV once per day on days 1 to 3

7-day course


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Erba et al. 2023 (QuANTUM-First) 2016-09-27 to 2019-08-14 Phase 3 (C) 1a. 7+3d & Quizartinib
1b. 7+3i & Quizartinib 		Seems to have inferior OS

Note: this was the upper bound of cytarabine dosing in QuANTUM-First.

Chemotherapy

  • Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m2)
  • Idarubicin 12 mg/m2 IV once per day on days 1 to 3

7-day course

References

  1. QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in abstract PubMed NCT02668653

7+3i & Quizartinib

7+3i & Quizartinib: 7 days of cytarabine, 3 days of idarubicin, Quizartinib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Erba et al. 2023 (QuANTUM-First) 2016-09-27 to 2019-08-14 Phase 3 (E-RT-esc) 1a. 7+3d; intermediate-dose
1b. 7+3i 		Seems to have superior OS (primary endpoint)
Median OS: 31.9 vs 15.1 mo
(HR 0.78, 95% CI 0.62-0.98)

Chemotherapy

  • Cytarabine (Ara-C) 100 mg/m2/day or 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 to 1400 mg/m2)
  • Idarubicin 12 mg/m2 IV once per day on days 1 to 3

Targeted therapy

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

Subsequent treatment

  • QuANTUM-First, patients who achieved complete remission (CR): HiDAC & Quizartinib consolidation. Stem cell transplantation was allowed.

References

  1. QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in abstract PubMed NCT02668653

DA 3 + 10

DA 3 + 10: Daunorubicin & Ara-C (Cytarabine), 3 days of daunorubicin + 10 days of cytarabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2015 (UK NCRI AML17) 2009-2014 Phase 3 (C) DA 3 + 10; high-dose Did not meet primary endpoint of OS

Note: this regimen is very similar to 7+3d (intermediate-dose); however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3.

Chemotherapy

10-day course

Subsequent treatment

References

  1. UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. link to original article contains dosing details in manuscript link to PMC article PubMed ISRCTN55675535
    1. Update: Burnett AK, Das Gupta E, Knapper S, Khwaja A, Sweeney M, Kjeldsen L, Hawkins T, Betteridge SE, Cahalin P, Clark RE, Hills RK, Russell NH; UK NCRI AML Study Group. Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. Haematologica. 2018 Oct;103(10):1654-1661. Epub 2018 Jul 5. link to original article link to PMC article PubMed

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

Azacitidine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2022 (LACEWING) 2016-NR Phase 3 (C) Azacitidine & Gilteritinib Did not meet primary endpoint of OS

Chemotherapy

28-day cycles

References

  1. LACEWING: Wang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, Chou WC, Laribi K, Esteve J, Altman JK, Havelange V, Watson AM, Gambacorti-Passerini C, Patkowska E, Liu S, Wu R, Philipose N, Hill JE, Gill SC, Rich ES, Tiu RV. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022 Oct 27;140(17):1845-1857. Epub 2022 Aug 2. link to original article PubMed NCT02752035

7+3d & Sorafenib

Regimen

Study Dates of enrollment Evidence
Uy et al. 2017 (CALGB 11001) 2011-NR Phase 2

Chemotherapy

Targeted therapy

7-day course

Subsequent treatment

  • CALGB 11001, patients not achieving a hypoplastic marrow on day 14: 5+2d & sorafenib re-induction
  • CALGB 11001, 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 dosing details in manuscript link to PMC article PubMed NCT01253070

Consolidation after upfront therapy

HiDAC & Midostaurin

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

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Stone et al. 2017 (RATIFY) 2008-2011 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle)

Targeted therapy

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 dosing details in manuscript PubMed NCT00651261

HiDAC & Quizartinib

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

Regimen

Study Dates of enrollment Evidence
Erba et al. 2023 (QuANTUM-First) 2016-09-27 to 2019-08-14 Non-randomized part of phase 3 RCT

Note: Patients undergoing allogeneic HSCT after consolidation proceeded to maintenance anytime between day +30 and day +180.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) by the following age-based criteria:
    • Younger than 60 years old: 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle)
    • 60 years old or older: 1500 mg/m2 IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle)

Targeted therapy

Up to 4 cycles

Subsequent treatment

References

  1. QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in manuscript PubMed NCT02668653

IDAC & Sorafenib

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

Regimen

Study Dates of enrollment Evidence
Uy et al. 2017 (CALGB 11001) 2011-NR Phase 2

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 dosing details in manuscript link to PMC article PubMed NCT01253070

Maintenance after upfront therapy, including allogeneic HSCT

Midostaurin monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Stone et al. 2017 (RATIFY) 2008-2011 Non-randomized part of phase 3 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 dosing details in manuscript PubMed NCT00651261
  2. ARO-021: NCT03258931
  3. HOVON 156 AML: NCT04027309

Quizartinib monotherapy

Regimen

Study Dates of enrollment Evidence
Erba et al. 2023 (QuANTUM-First) 2016-09-27 to 2019-08-14 Non-randomized part of phase 3 RCT

Note: Patients undergoing allogeneic HSCT after consolidation began maintenance anytime between day +30 and day +180. The dose of quizartinib was increased only if the mean QT interval corrected with Fridericia's formula [QTcF] was less than or equal to 450 ms on C1D15.

Preceding treatment

Targeted therapy

  • Quizartinib (Vanflyta) as follows:
    • Cycle 1: 30 mg PO once per day on days 1 to 14, then 60 mg PO once per day on days 15 to 28
    • Cycles 2 to 36: 60 mg PO once per day on days 1 to 28

28-day cycle for up to 36 cycles (3 years)

References

  1. QuANTUM-First: Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JEC, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF; QuANTUM-First Study Group. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 May 13;401(10388):1571-1583. Epub 2023 Apr 25. link to original article contains dosing details in manuscript PubMed NCT02668653

Sorafenib monotherapy

Regimen variant #1, 6 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xuan et al. 2020 (Sorafenib-Flt3 AML-2015) 2015-06-20 to 2018-07-21 Phase 3 (E-esc) Observation Superior 1-year cumulative incidence of relapse (primary endpoint)

Superior OS1 (secondary endpoint)
OS60: 72% vs 55.9%
(HR 0.55, 95% CI 0.34-0.88)

1Reported efficacy is based on the 2023 update.

Preceding treatment

Targeted therapy

6-month course


Regimen variant #2, 12 mos

Study Dates of enrollment Evidence
Uy et al. 2017 (CALGB 11001) 2011-NR Phase 2

Preceding treatment

Targeted therapy

28-day cycle for up to 12 cycles


Regimen variant #3, 2 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burchert et al. 2020 (SORMAIN) 2010-2016 Phase 3 (E-esc) Placebo Superior RFS (primary endpoint)
RFS24: 85% vs 53.3%
(HR 0.39, 95% CI 0.18-0.85)

Note: dose was escalated only if tolerated.

Preceding treatment

Targeted therapy

  • Sorafenib (Nexavar) as follows:
    • Cycle 1: 200 mg PO twice per day on days 1 to 14, then 400 mg PO twice per day on days 15 to 28
    • Cycles 2 to 26: 400 mg PO twice per day on days 1 to 28

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 dosing details in manuscript 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 dosing details in manuscript 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
    1. Update: Xuan L, Wang Y, Yang K, Shao R, Huang F, Fan Z, Chi P, Xu Y, Xu N, Deng L, Li X, Liang X, Luo X, Shi P, Liu H, Wang Z, Jiang L, Lin R, Chen Y, Tu S, Zhang Y, Sun J, Huang X, Liu Q. Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2023 Aug;10(8):e600-e611. Epub 2023 Jul 3. link to original article PubMed

Relapsed or refractory, salvage therapy

Midostaurin monotherapy

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fischer et al. 2010 (CPKC412A2104) 2002-NR Randomized phase 2b (E-de-esc) Midostaurin; 100 mg twice per day Not reported

Targeted therapy

28-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fischer et al. 2010 (CPKC412A2104) 2002-NR Randomized phase 2b (E-esc) Midostaurin; 50 mg twice per day Not reported

Targeted therapy

28-day cycles


Regimen variant #3

Study Dates of enrollment Evidence
Stone et al. 2004 NR Phase 2

Biomarker eligibility criteria

  • 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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00045942

Relapsed or refractory, further lines of therapy

Azacitidine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perl et al. 2019 (ADMIRAL) 2015-2018 Phase 3 (C) Gilteritinib Inferior OS

Note: Perl et al. 2019 does not contain dosing information for the control arm regimens; the dosing here is from other AML regimens.

Chemotherapy

28-day cycle for at least 4 cycles

References

  1. 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 WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, 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 Oct 31;381(18):1728-40. link to original article does not contain dosing details PubMed NCT02421939
    1. Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed

Azacitidine & Sorafenib

Regimen

Study Dates of enrollment Evidence
Ravandi et al. 2013 (MDACC 2010-0511) 2011-2012 Phase 2

Chemotherapy

Targeted therapy

Supportive therapy

  • "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 dosing details in manuscript link to PMC article PubMed NCT01254890

FLAG-Ida

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R) 2014-2017 Phase 3 (C) Quizartinib Seems to have inferior OS
Perl et al. 2019 (ADMIRAL) 2015-2018 Phase 3 (C) Gilteritinib Inferior OS

Chemotherapy

Growth factor therapy

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 dosing details in abstract PubMed NCT02039726
  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 WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, 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 Oct 31;381(18):1728-40. link to original article does not contain dosing details PubMed NCT02421939
    1. Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed
  3. ARO-013: NCT03250338

Gilteritinib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perl et al. 2017 (2215-CL-0101) 2013-2015 Phase 1/2
Perl et al. 2019 (ADMIRAL) 2015-2018 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. MEC
1b. FLAG-Ida
1c. LoDAC
1d. Azacitidine 		Superior OS1 (co-primary endpoint)
Median OS: 9.3 vs 5.6 mo
(HR 0.665, 95% CI 0.52-0.85)

1Reported efficacy is based on the 2022 update.

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 link to PMC article PubMed NCT02014558
  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 WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, 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 Oct 31;381(18):1728-40. link to original article contains dosing details in manuscript PubMed NCT02421939
    1. Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed
  3. 2215-CL-0303: NCT03182244

Low-dose Cytarabine monotherapy (LoDAC)

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R) 2014-2017 Phase 3 (C) Quizartinib Seems to have inferior OS
Perl et al. 2019 (ADMIRAL) 2015-2018 Phase 3 (C) Gilteritinib 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 dosing details in abstract PubMed NCT02039726
  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 WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, 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 Oct 31;381(18):1728-40. link to original article does not contain dosing details PubMed NCT02421939
    1. Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed

MEC

MEC: Mitoxantrone, Etoposide, Cytarabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R) 2014-2017 Phase 3 (C) Quizartinib Seems to have inferior OS
Perl et al. 2019 (ADMIRAL) 2015-2018 Phase 3 (C) Gilteritinib Inferior OS

Chemotherapy

28-day cycle for 1 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 dosing details in abstract PubMed NCT02039726
  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 WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, 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 Oct 31;381(18):1728-40. link to original article does not contain dosing details PubMed NCT02421939
    1. Update: Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. link to original article link to PMC article PubMed

Quizartinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R) 2014-2017 Phase 3 (E-switch-ooc) Investigator's choice of:
1a. LoDAC
1b. MEC
1c. FLAG-Ida 		Seems to have superior OS (primary endpoint)
Median OS: 6.2 vs 4.7 mo
(HR 0.76, 95% CI 0.58-0.98)

Note: Quizartinib was studied at a variety of doses; references are provided below for historic context; the dose here is from QuANTUM-R, and was only increased if certain QTc parameters were met; see the paper for details.

Targeted therapy

  • Quizartinib (Vanflyta) as follows:
    • Cycle 1: 30 mg PO once per day on days 1 to 15, then 60 mg PO once per day on days 16 to 28
    • Cycle 2 onwards: 60 mg PO once per day on days 1 to 28

28-day cycles

References

  1. CP0001: Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013 Oct 10;31(29):3681-7. Epub 2013 Sep 3. link to original article link to PMC article PubMed NCT00462761
  2. ACEAML: Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Krämer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, Levis M. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):889-903. Epub 2018 May 31. link to original article link to PMC article PubMed NCT00989261
  3. 2689-CL-2004: Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, Perl AE, Marie JP, Martinelli G, Kantarjian HM, Levis MJ. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018 Aug 9;132(6):598-607. Epub 2018 Jun 6. link to original article link to PMC article PubMed NCT01565668
  4. 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 dosing details in manuscript 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
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