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	Ashwin Kishtagari, MD Vanderbilt University Nashville, TN, USA LinkedIn

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

NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Acute Myeloid Leukemia.

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

Cytarabine (Ara-C) 100 mg/m²/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m²)
Daunorubicin (Cerubidine) 60 mg/m² IV over 5 minutes once per day on days 1 to 3

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

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 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

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
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
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

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 once per day on days 1 to 3

Targeted therapy

Midostaurin (Rydapt) 50 mg PO twice per day on days 8 to 21

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

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

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)
Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1 to 3

Targeted therapy

Quizartinib (Vanflyta) 40 mg PO once per day on days 8 to 21

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

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

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

Quizartinib (Vanflyta) 40 mg PO once per day on days 8 to 21

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

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

Cytarabine (Ara-C) 100 mg/m² IV every 12 hours on days 1 to 10
Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1, 3, 5

10-day course

Subsequent treatment

DA 3+8 versus DA 3+8 & Lestaurtinib re-induction

References

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

Azacitidine (Vidaza) 75 mg/m² SC once per day on days 1 to 7

28-day cycles

References

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

Cytarabine (Ara-C) 100 mg/m²/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m²)
Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1 to 3

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 7

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

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

7+3d & midostaurin induction, with CR

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

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

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

7+3d & Quizartinib or 7+3i & Quizartinib induction, with CR

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

Quizartinib (Vanflyta) 40 mg PO once per day on days 6 to 19

Up to 4 cycles

Subsequent treatment

Quizartinib maintenance (see note)

References

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

7+3d & sorafenib induction

Chemotherapy

Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours once per day on days 1 to 5

Targeted therapy

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

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

HiDAC & Midostaurin consolidation

Targeted therapy

Midostaurin (Rydapt) 50 mg PO twice per day on days 1 to 28

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

References

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
ARO-021: NCT03258931
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

HiDAC & Quizartinib consolidation, +/- allogeneic HSCT

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

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

Allogeneic stem cell transplant consolidation

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day on days +30 to +180

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

IDAC & Sorafenib consolidation

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 28

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

Allogeneic stem cell transplant consolidation

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

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
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
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

Midostaurin (Rydapt) 50 mg PO twice per day on days 1 to 28

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

Midostaurin (Rydapt) 100 mg PO twice per day on days 1 to 28

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

Midostaurin (Rydapt) 75 mg PO three times per day on days 1 to 28

28-day cycles

References

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
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

Azacitidine (Vidaza) 75 mg/m² SC once per day on days 1 to 7

28-day cycle for at least 4 cycles

References

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

Azacitidine (Vidaza) 75 mg/m² IV or SC once per day on days 1 to 7

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day

Supportive therapy

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

4- to 8-week cycles

References

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

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) 5 mcg/kg or 300 mcg/m² SC once per day on days 1 to 5

28-day cycle for up to 2 cycles

References

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
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
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)
Awaiting publication (2215-CL-0303)	2018-2023	Phase 3 (E-switch-ooc)	1a. MEC 1b. FLAG 1c. LoDAC	TBD if different primary endpoint of OS

¹Reported efficacy is based on the 2022 update.

Targeted therapy

Gilteritinib (Xospata) 120 mg PO once per day on days 1 to 28

28-day cycles

References

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
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
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

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

28-day cycles

References

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
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

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 1 to 2 cycles

References

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
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

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
ACE_AML: 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
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
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

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

@@ Line 13: / Line 13: @@
 {{TOC limit|limit=3}}
 =Guidelines=
-'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any article published 5+ years ago to be for historical purposes, only.'''
+'''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.'''
-==[https://www.nccn.org/ NCCN]==
+==NCCN==
-*''NCCN does not have guidelines at this granular level; please see [https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf NCCN Guidelines - Acute Myeloid Leukemia].''
+*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411 NCCN Guidelines - Acute Myeloid Leukemia].''
 =Upfront induction therapy, standard patients=
 ==7+3d (intermediate-dose) {{#subobject:e82156|Regimen=1}}==
@@ Line 40: / Line 40: @@
 *[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)
 *[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV over 5 minutes once per day on days 1 to 3
-'''One course'''
+'''7-day course'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2 {{#subobject:cf53dd|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
@@ Line 130: / Line 131: @@
 |2016-09-27 to 2019-08-14
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|1a. [[#7.2B3d_.28intermediate-dose.29|7+3d]]; intermediate-dose<br>1b. [[#7.2B3i_888|7+3i]]
+|1a. [[#7.2B3d_.28intermediate-dose.29|7+3d]]; intermediate-dose<br>1b. [[#7.2B3i|7+3i]]
 | style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 31.9 vs 15.1 mo<br>(HR 0.78, 95% CI 0.62-0.98)
 |-
@@ Line 144: / Line 145: @@
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*QuANTUM-First, patients who achieved complete remission (CR): [[#HiDAC_.26_Quizartinib_888|HiDAC & Quizartinib]] consolidation. Stem cell transplantation was allowed.
+*QuANTUM-First, patients who achieved complete remission (CR): [[#HiDAC_.26_Quizartinib|HiDAC & Quizartinib]] consolidation. Stem cell transplantation was allowed.
 </div></div>
 ===References===
@@ Line 171: / Line 172: @@
 *[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700 mg/m<sup>2</sup>)
 *[[Idarubicin (Idamycin)|Idarubicin]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3
-'''One course'''
+'''7-day course'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2 {{#subobject:oboxnd|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
@@ Line 212: / Line 214: @@
 |2016-09-27 to 2019-08-14
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|1a. [[#7.2B3d_.28intermediate-dose.29|7+3d]]; intermediate-dose<br>1b. [[#7.2B3i_888|7+3i]]
+|1a. [[#7.2B3d_.28intermediate-dose.29|7+3d]]; intermediate-dose<br>1b. [[#7.2B3i|7+3i]]
 | style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 31.9 vs 15.1 mo<br>(HR 0.78, 95% CI 0.62-0.98)
 |-
@@ Line 226: / Line 228: @@
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*QuANTUM-First, patients who achieved complete remission (CR): [[#HiDAC_.26_Quizartinib_888|HiDAC & Quizartinib]] consolidation. Stem cell transplantation was allowed.
+*QuANTUM-First, patients who achieved complete remission (CR): [[#HiDAC_.26_Quizartinib|HiDAC & Quizartinib]] consolidation. Stem cell transplantation was allowed.
 </div></div>
 ===References===
 #'''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. [https://doi.org/10.1016/S0140-6736(23)00464-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37116523/ PubMed] [https://clinicaltrials.gov/study/NCT02668653 NCT02668653]
 ==DA 3 + 10 {{#subobject:5c0062|Regimen=1}}==
-DA 3 + 10: '''<u>D</u>'''a unorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine
+DA 3 + 10: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine
 <div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:211741|Variant=1}}===
@@ Line 262: / Line 264: @@
 #'''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/m<sup>2</sup> vs 60 mg/m<sup>2</sup> 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. [https://doi.org/10.1182/blood-2015-01-623447 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505010/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25833957/ PubMed] ISRCTN55675535
 ##'''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. [https://doi.org/10.3324/haematol.2018.189514 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165825/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29976746/ PubMed]
 =First-line induction therapy, older patients or "unfit" patients=
 ==Azacitidine monotherapy {{#subobject:5ujvv0|Regimen=1}}==
@@ Line 341: / Line 344: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (total dose per cycle: 18,000 mg/m<sup>2</sup>)
+*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle)
 ====Targeted therapy====
 *[[Midostaurin (Rydapt)]] 50 mg PO twice per day on days 8 to 21
@@ Line 352: / Line 355: @@
 ===References===
 #'''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. [https://doi.org/10.1056/nejmoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28644114/ PubMed] [https://clinicaltrials.gov/study/NCT00651261 NCT00651261]
+==HiDAC & Quizartinib {{#subobject:aquf1b|Regimen=1}}==
+HiDAC & Quizartinib: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & Quizartinib
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:c3eqc2|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)]
+|2016-09-27 to 2019-08-14
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+|-
+|}
+''Note: Patients undergoing allogeneic HSCT after consolidation proceeded to maintenance anytime between day +30 and day +180.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#7.2B3d_.26_Quizartinib|7+3d & Quizartinib]] or [[#7.2B3i_.26_Quizartinib|7+3i & Quizartinib]] induction, with CR
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cytarabine (Ara-C)]] by the following age-based criteria:
+**Younger than 60 years old: 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle)
+**60 years old or older: 1500 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 3, 5 (6 doses per cycle)
+====Targeted therapy====
+*[[Quizartinib (Vanflyta)]] 40 mg PO once per day on days 6 to 19
+'''Up to 4 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#Quizartinib_monotherapy|Quizartinib]] maintenance (see note)
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1016/S0140-6736(23)00464-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37116523/ PubMed] [https://clinicaltrials.gov/study/NCT02668653 NCT02668653]
 ==IDAC & Sorafenib {{#subobject:c2cc06|Regimen=1}}==
 IDAC & Sorafenib: '''<u>I</u>'''ntermediate '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & Sorafenib
@@ Line 405: / Line 444: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Midostaurin (Rydapt)]] 50 mg PO twice per day
+*[[Midostaurin (Rydapt)]] 50 mg PO twice per day on days 1 to 28
 '''28-day cycle for up to 13 cycles (1 year)'''
 </div></div>
@@ Line 412: / Line 451: @@
 #'''ARO-021:''' [https://clinicaltrials.gov/study/NCT03258931 NCT03258931]
 #'''HOVON 156 AML:''' [https://clinicaltrials.gov/study/NCT04027309 NCT04027309]
+==Quizartinib monotherapy {{#subobject:anmo4b|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:q3fqc2|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1016/S0140-6736(23)00464-6 Erba et al. 2023 (QuANTUM-First)]
+|2016-09-27 to 2019-08-14
+| style="background-color:#91cf61" |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.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#HiDAC_.26_Quizartinib|HiDAC & Quizartinib]] consolidation, +/- allogeneic HSCT
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====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)'''
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1016/S0140-6736(23)00464-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37116523/ PubMed] [https://clinicaltrials.gov/study/NCT02668653 NCT02668653]
 ==Sorafenib monotherapy {{#subobject:23822e|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
@@ Line 457: / Line 524: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
+*[[Sorafenib (Nexavar)]] 400 mg PO twice per day on days 1 to 28
 '''28-day cycle for up to 12 cycles'''
 </div></div><br>
@@ Line 475: / Line 542: @@
 | style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>RFS24: 85% vs 53.3%<br>(HR 0.39, 95% CI 0.18-0.85)
 |}
+''Note: dose was escalated only if tolerated.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
@@ Line 482: / Line 550: @@
 ====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 if tolerated
+**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
+**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)'''
 </div></div>
 ===References===
 #'''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. [https://doi.org/10.1182/bloodadvances.2016003053 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366/ PubMed] [https://clinicaltrials.gov/study/NCT01253070 NCT01253070]
 #'''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. [https://doi.org/10.1200/jco.19.03345 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32673171/ PubMed] [https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-018539-16/AT Link to clinical trial registration] DRKS00000591
 #'''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. [https://doi.org/10.1016/s1470-2045(20)30455-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32791048/ PubMed] [https://clinicaltrials.gov/study/NCT02474290 NCT02474290]
-##'''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 Jul 3:S2352-3026(23)00117-5. Epub ahead of print. [https://doi.org/10.1016/s2352-3026(23)00117-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37414062/ PubMed]
+##'''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. [https://doi.org/10.1016/s2352-3026(23)00117-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37414062/ PubMed]
 =Relapsed or refractory, salvage therapy=
@@ Line 512: / Line 581: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Midostaurin (Rydapt)]] 50 mg PO twice per day
+*[[Midostaurin (Rydapt)]] 50 mg PO twice per day on days 1 to 28
-'''Continued indefinitely'''
+'''28-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
@@ Line 533: / Line 602: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Midostaurin (Rydapt)]] 100 mg PO twice per day
+*[[Midostaurin (Rydapt)]] 100 mg PO twice per day on days 1 to 28
-'''Continued indefinitely'''
+'''28-day cycles'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
@@ Line 554: / Line 623: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Midostaurin (Rydapt)]] 75 mg PO three times per day
+*[[Midostaurin (Rydapt)]] 75 mg PO three times per day on days 1 to 28
 '''28-day cycles'''
 </div></div>
@@ Line 625: / Line 694: @@
 |2014-2017
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Quizartinib_monotherapy|Quizartinib]]
+|[[#Quizartinib_monotherapy_2|Quizartinib]]
 | style="background-color:#fc8d59" |Seems to have inferior OS
 |-
@@ Line 645: / Line 714: @@
 </div></div>
 ===References===
-#'''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. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726]
+#'''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. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726]
 #'''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. [https://doi.org/10.1056/nejmoa1902688 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] [https://clinicaltrials.gov/study/NCT02421939 NCT02421939]
 ##'''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. [https://doi.org/10.1182/blood.2021011583 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9197557/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35081255/ PubMed]
 #'''ARO-013:''' [https://clinicaltrials.gov/study/NCT03250338 NCT03250338]
 ==Gilteritinib monotherapy {{#subobject:0384e2|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
@@ Line 674: / Line 744: @@
 |Investigator's choice of:<br>1a. [[#MEC|MEC]]<br>1b. [[#FLAG-Ida|FLAG-Ida]]<br>1c. [[#Low-dose_Cytarabine_monotherapy_.28LoDAC.29|LoDAC]]<br>1d. [[#Azacitidine_monotherapy_2|Azacitidine]]
 | style="background-color:#1a9851" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 9.3 vs 5.6 mo<br>(HR 0.665, 95% CI 0.52-0.85)
+|-
+|[https://clinicaltrials.gov/study/NCT03182244 Awaiting publication (2215-CL-0303)]
+|2018-2023
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+|1a. [[#MEC|MEC]]<br>1b. [[#FLAG|FLAG]]<br>1c. [[#Low-dose_Cytarabine_monotherapy_.28LoDAC.29|LoDAC]]
+| style="background-color:#d3d3d3" |TBD if different primary endpoint of OS
 |}
 ''<sup>1</sup>Reported efficacy is based on the 2022 update.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Gilteritinib (Xospata)]] 120 mg PO once per day
+*[[Gilteritinib (Xospata)]] 120 mg PO once per day on days 1 to 28
 '''28-day cycles'''
 </div></div>
@@ Line 702: / Line 779: @@
 |2014-2017
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Quizartinib_monotherapy|Quizartinib]]
+|[[#Quizartinib_monotherapy_2|Quizartinib]]
 | style="background-color:#fc8d59" |Seems to have inferior OS
 |-
@@ Line 717: / Line 794: @@
 '''28-day cycles'''
 </div></div>
 ===References===
 #'''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. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726]
@@ Line 735: / Line 813: @@
 |2014-2017
 | style="background-color:#1a9851" |Phase 3 (C)
-|[[#Quizartinib_monotherapy|Quizartinib]]
+|[[#Quizartinib_monotherapy_2|Quizartinib]]
 | style="background-color:#fc8d59" |Seems to have inferior OS
 |-
@@ Line 750: / Line 828: @@
 *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given first'''
 *[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''
-'''28-day cycle for up to 2 cycles'''
+'''28-day cycle for 1 to 2 cycles'''
 </div></div>
 ===References===
 #'''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. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726]
@@ Line 772: / Line 851: @@
 | style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 6.2 vs 4.7 mo<br>(HR 0.76, 95% CI 0.58-0.98)
 |}
-''Note: Quizartinib is only approved in Japan.''
+''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.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Quizartinib (Vanflyta)]] 60 mg PO once per day
+*[[Quizartinib (Vanflyta)]] as follows:
-'''Continued indefinitely'''
+**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'''
 </div></div>
 ===References===
@@ Line 782: / Line 863: @@
 <!--
 # '''Abstract:''' Jorge E. Cortes, Alexander E Perl, Hervé Dombret, Sabine Kayser, Björn Steffen, Philippe Rousselot, Giovanni Martinelli, Elihu H. Estey, Alan K Burnett, Guy Gammon, Denise Trone, Eugen Leo, and Mark J. Levis Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients ≥ 60 Years of Age with FLT3 ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 48. [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/48 link to abstract] -->
-# '''ACE:''' 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. [https://doi.org/10.1016/s1470-2045(18)30240-7 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8152787/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29859851/ PubMed] [https://clinicaltrials.gov/study/NCT00989261 NCT00989261]
+# '''ACE<sub>AML</sub>:''' 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. [https://doi.org/10.1016/s1470-2045(18)30240-7 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8152787/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29859851/ PubMed] [https://clinicaltrials.gov/study/NCT00989261 NCT00989261]
 # '''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. [https://doi.org/10.1182/blood-2018-01-821629 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6085992/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29875101/ PubMed] [https://clinicaltrials.gov/study/NCT01565668 NCT01565668]
-#'''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. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726]
+#'''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. [https://doi.org/10.1016/s1470-2045(19)30150-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31175001/ PubMed] [https://clinicaltrials.gov/study/NCT02039726 NCT02039726]
 =Prognosis=
 ==Prognosis in cytogenetically normal AML==
 #''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. [https://doi.org/10.1056/NEJMoa074306 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18450602/ PubMed]
-=Investigational agents=
-''These are drugs under study with at least some promising results for this disease.''
-*[[Crenolanib (CP-868,596)]]
 [[Category:Acute myeloid leukemia regimens]]
 [[Category:Biomarker-specific pages]]
 [[Category:Acute leukemias]]

Difference between revisions of "Acute myeloid leukemia, FLT3-positive"

Revision as of 23:19, 10 June 2024

Guidelines

NCCN

Upfront induction therapy, standard patients

7+3d (intermediate-dose)

Regimen variant #1

Chemotherapy

Regimen variant #2

Chemotherapy

Supportive therapy

References

7+3d & Midostaurin

Regimen

Chemotherapy

Targeted therapy

Supportive therapy

Subsequent treatment

References

7+3d & Quizartinib

Regimen

Chemotherapy

Targeted therapy

Subsequent treatment

References

7+3i

Regimen variant #1

Chemotherapy

Regimen variant #2

Chemotherapy

References

7+3i & Quizartinib

Regimen

Chemotherapy

Targeted therapy

Subsequent treatment

References

DA 3 + 10

Regimen

Chemotherapy

Subsequent treatment

References

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

Azacitidine monotherapy

Regimen

Chemotherapy

References

7+3d & Sorafenib

Regimen

Chemotherapy

Targeted therapy

Subsequent treatment

References

Consolidation after upfront therapy

HiDAC & Midostaurin

Regimen

Preceding treatment

Chemotherapy

Targeted therapy

Subsequent treatment

References

HiDAC & Quizartinib

Regimen

Preceding treatment

Chemotherapy

Targeted therapy

Subsequent treatment

References

IDAC & Sorafenib

Regimen

Preceding treatment

Chemotherapy

Targeted therapy

Subsequent treatment

References

Maintenance after upfront therapy, including allogeneic HSCT

Midostaurin monotherapy

Regimen

Preceding treatment

Targeted therapy