Revision as of 02:42, 15 August 2022

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

22 regimens on this page 26 variants on this page

Upfront induction therapy, standard patients

7+3d (intermediate-dose)

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

Regimen

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

Chemotherapy

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

Supportive medications

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

7-day course

References

RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains verified protocol PubMed NCT00651261
Q-SOC: NCT04676243
QuANTUM-First: NCT02668653

7+3d & Midostaurin

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

Regimen

FDA-recommended dose

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

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

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

Subsequent treatment

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

References

RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains verified protocol PubMed NCT00651261

7+3 & Quizartinib

7+3 & Quizartinib: 7 days of cytarabine, 3 days of daunorubicin or idarubicin, Quizartinib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Erba et al. 202 (QuANTUM-First)	2016-2021	Phase 3 (E-RT-esc)	7+3d (intermediate-dose)	Superior OS Median OS: 31.9 vs 15.1 mo (HR 0.78, 95% CI 0.62-0.98)

Chemotherapy

Cytarabine (Ara-C) 100 or 200 mg/m²/day IV continuous infusion over 7 days, started on day 1 (total dose: 700-1400 mg/m²)
Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1 to 3 or Idarubicin (Idamycin) 12mg/m2 IV once per day on days 1 to 3

Targeted therapy

Quizartinib (AC220) 40 mg PO twice per day on days 8 to 21

Supportive medications

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

Subsequent treatment

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

References

QuANTUM-First: Erba H, Montesinos P, Vrhovac R, et al: Quizartinib prolonged survival vs placebo plus intensive induction and consolidation therapy followed by single-agent continuation in patients aged 18-75 years with newly diagnosed FLT3-ITD+ AML. EHA 2022 Congress. Abstract S100. Presented June 11, 2022. NCT02668653

DA 3 + 10

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Burnett et al. 2015 (UK NCRI AML17)	2011-2013	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

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 verified protocol 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

7+3d & Sorafenib

Regimen

Study	Years 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

Patients not achieving a hypoplastic marrow on day 14: 5+2 & sorafenib re-induction
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 verified protocol 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	Years of enrollment	Evidence
Stone et al. 2017 (RATIFY)	2008-2011	Non-randomized portion of 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 (total dose per cycle: 18,000 mg/m²)

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 verified protocol PubMed NCT00651261

IDAC & Sorafenib

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

Regimen

Study	Years 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 verified protocol link to PMC article PubMed NCT01253070

Maintenance after upfront therapy, including allogeneic HSCT

Midostaurin monotherapy

Regimen

Study	Years of enrollment	Evidence	Efficacy
Stone et al. 2017 (RATIFY)	2008-2011	Non-randomized portion of RCT	CR rate: 59% after induction

Preceding treatment

HiDAC & Midostaurin consolidation

Targeted therapy

Midostaurin (Rydapt) 50 mg PO twice per day

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 verified protocol PubMed NCT00651261
ARO-021: NCT03258931
HOVON 156 AML: NCT04027309

Sorafenib monotherapy

Regimen variant #1, 6 months

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Xuan et al. 2020 (Sorafenib-Flt3 AML-2015)	2015-2018	Phase 3 (E-esc)	Observation	Superior 1-year cumulative incidence of relapse

Preceding treatment

Allogeneic stem cell transplant

Targeted therapy

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

6-month course

Regimen variant #2, 12 mos

Study	Years 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

28-day cycle for up to 12 cycles

Regimen variant #3, 2 years

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

Preceding treatment

Allogeneic stem cell transplant

Targeted therapy

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

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

References

CALGB 11001: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. link to original article contains verified protocol link to PMC article PubMed NCT01253070
SORMAIN: Burchert A, Bug G, Fritz LV, Finke J, Stelljes M, Röllig C, Wollmer E, Wäsch R, Bornhäuser M, Berg T, Lang F, Ehninger G, Serve H, Zeiser R, Wagner EM, Kröger N, Wolschke C, Schleuning M, Götze KS, Schmid C, Crysandt M, Eßeling E, Wolf D, Wang Y, Böhm A, Thiede C, Haferlach T, Michel C, Bethge W, Wündisch T, Brandts C, Harnisch S, Wittenberg M, Hoeffkes HG, Rospleszcz S, Burchardt A, Neubauer A, Brugger M, Strauch K, Schade-Brittinger C, Metzelder SK. Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN). J Clin Oncol. 2020 Sep 10;38(26):2993-3002. Epub 2020 Jul 16. link to original article contains verified protocol PubMed Link to clinical trial registration DRKS00000591
Sorafenib-Flt3 AML-2015: Xuan L, Wang Y, Huang F, Fan Z, Xu Y, Sun J, Xu N, Deng L, Li X, Liang X, Luo X, Shi P, Liu H, Wang Z, Jiang L, Yu C, Zhou X, Lin R, Chen Y, Tu S, Huang X, Liu Q. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1201-1212. Epub 2020 Aug 10. link to original article PubMed NCT02474290

Relapsed or refractory, salvage therapy

Midostaurin monotherapy

Regimen variant #1

Study	Years 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

Continued indefinitely

Regimen variant #2

Study	Years 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

Continued indefinitely

Regimen variant #3

Study	Years 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

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 verified protocol 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 verified protocol PubMed NCT00045942

Relapsed or refractory, further lines of therapy

Azacitidine monotherapy

Regimen

Study	Years 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 protocol 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	Years 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 medications

"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 verified protocol link to PMC article PubMed NCT01254890

FLAG-Ida

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R)	2014-2017	Phase 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 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 protocol 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	Years 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: 1. MEC 2. FLAG-Ida 3. LoDAC 4. Azacitidine	Superior OS¹ Median OS: 9.3 mo vs 5.6 mo (HR 0.665, 95% CI 0.52-0.85)

¹Reported efficacy is based on the 2022 update.

Targeted therapy

Gilteritinib (Xospata) 120 mg PO once per day

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 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 verified protocol 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	Years 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 protocol 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 protocol 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	Years 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 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 protocol 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 protocol 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2019 (QuANTUM-R)	2014-2017	Phase 3 (E-switch-ooc)	Investigator's choice of: 1. LoDAC 2. MEC 3. FLAG-Ida	Seems to have superior OS Median OS: 6.2 vs 4.7 mo (HR 0.76, 95% CI 0.58-0.98)

Note: Quizartinib is not yet approved in any domain.

Targeted therapy

Quizartinib (AC220) 60 mg PO once per day

Continued indefinitely

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. link to original article 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

Investigational agents

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

Crenolanib (CP-868,596)

@@ Line 1: / Line 1: @@
 {{#lst:Section editor transclusions|aml}}
 <big>'''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 [[Acute myeloid leukemia|main AML page]] for other regimens.'''</big>
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 8: / Line 7: @@
 |}
 {{TOC limit|limit=3}}
 =Upfront induction therapy, standard patients=
 ==7+3d (intermediate-dose) {{#subobject:e82156|Regimen=1}}==
 +3d: '''<u>7</u>''' days of cytarabine + '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin
 ===Regimen {{#subobject:cf53dd|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Years of enrollment
@@ Line 29: / Line 26: @@
 |}
 ====Chemotherapy====
 *[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 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
 ====Supportive medications====
 *"According to commonly accepted guidelines with no prophylactic IV antibiotics"
 *[[:Category:Granulocyte_colony-stimulating_factors|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===
-<!-- # '''Abstract:''' R. M. Stone, H. Dohner, G. Ehninger, M. Villeneuve, T. Teasdale, J. D. Virkus, L. R. Bressler, M. M. Seiler, G. Marcucci, R. A. Larson. CALGB 10603 (RATIFY): A randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. 2011 ASCO Annual Meeting abstract TPS199. [http://meetinglibrary.asco.org/content/81555-102 link to abstract]
-# '''Abstract:''' Richard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze Dohner, Christian Thiede, Guido Marcucci, Francesco Lo-Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson, Hartmut Dohner. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). 2015 ASH Annual Meeting plenary abstract 6. [https://ash.confex.com/ash/2015/webprogramscheduler/Paper80269.html link to abstract] '''contains protocol''' [https://clinicaltrials.gov/ct2/show/NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia (NCT00651261) at ClinicalTrials.gov] -->
 #'''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://www.nejm.org/doi/full/10.1056/NEJMoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28644114 PubMed] NCT00651261
 #'''Q-SOC:''' NCT04676243
 #'''QuANTUM-First:''' NCT02668653
 ==7+3d & Midostaurin {{#subobject:b7ea7e|Regimen=1}}==
 +3d & Midostaurin: '''<u>7</u>''' days of cytarabine, '''<u>3</u>''' days of '''<u>d</u>'''aunorubicin, Midostaurin
 ===Regimen {{#subobject:fef011|Variant=1}}===
@@ Line 56: / Line 44: @@
 |-
 |}
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Years of enrollment
@@ Line 71: / Line 59: @@
 |}
 ====Chemotherapy====
 *[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 1400 mg/m<sup>2</sup>)
 *[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> 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 medications====
 *[[Hydroxyurea (Hydrea)]] (no dosage specified) was allowed to be used for up to 5 days before the start of therapy while waiting for results of FLT3 mutation testing
 '''21-day course; retreatment with a second course was allowed if day 21 bone marrow biopsy showed residual AML.'''
 ====Subsequent treatment====
 *Patients who achieved complete remission (CR): [[#HiDAC_.26_Midostaurin|HiDAC & Midostaurin consolidation]]. Stem cell transplantation was allowed.
 ===References===
-<!-- # '''Abstract:''' R. M. Stone, H. Dohner, G. Ehninger, M. Villeneuve, T. Teasdale, J. D. Virkus, L. R. Bressler, M. M. Seiler, G. Marcucci, R. A. Larson. CALGB 10603 (RATIFY): A randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. 2011 ASCO Annual Meeting abstract TPS199. [http://meetinglibrary.asco.org/content/81555-102 link to abstract]
-# '''Abstract:''' Richard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze Dohner, Christian Thiede, Guido Marcucci, Francesco Lo-Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson, Hartmut Dohner. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). 2015 ASH Annual Meeting plenary abstract 6. [https://ash.confex.com/ash/2015/webprogramscheduler/Paper80269.html link to abstract] '''contains protocol''' [https://clinicaltrials.gov/ct2/show/NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia (NCT00651261) at ClinicalTrials.gov] -->
 #'''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://www.nejm.org/doi/full/10.1056/NEJMoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28644114 PubMed] NCT00651261
+==7+3 & Quizartinib {{#subobject:6d491a|Regimen=1}}==
++3 & Quizartinib: '''<u>7</u>''' days of cytarabine, '''<u>3</u>''' days of <u>d</u>aunorubicin or idarubicin, Quizartinib
+===Regimen {{#subobject:490c89|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Years of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|Erba et al. 202 (QuANTUM-First)
+|2016-2021
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#7.2B3d_.28intermediate-dose.29|7+3d (intermediate-dose)]]
+| style="background-color:#1a9850" |Superior OS<br>Median OS: 31.9 vs 15.1 mo<br>(HR 0.78, 95% CI 0.62-0.98)
+|-
+|}
+====Chemotherapy====
+*[[Cytarabine (Ara-C)]] 100 or 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose: 700-1400 mg/m<sup>2</sup>)
+*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 3 or [[Idarubicin (Idamycin)|Idarubicin]] ([[Idarubicin (Idamycin)|Idamycin]]) 12mg/m2 IV once per day on days 1 to 3
+====Targeted therapy====
+*[[Quizartinib (AC220)|Quizartinib]] (AC220) 40 mg PO twice per day on days 8 to 21
+====Supportive medications====
+'''21-day course; retreatment with a second course was allowed if day 21 bone marrow biopsy showed residual AML.'''
+====Subsequent treatment====
+*Patients who achieved complete remission (CR): HiDAC & Quizartinib consolidation. Stem cell transplantation was allowed.
+===References===
+#'''QuANTUM-First:''' Erba H, Montesinos P, Vrhovac R, et al: Quizartinib prolonged survival vs placebo plus intensive induction and consolidation therapy followed by single-agent continuation in patients aged 18-75 years with newly diagnosed FLT3-ITD+ AML. EHA 2022 Congress. Abstract S100. Presented June 11, 2022. [https://clinicaltrials.gov/ct2/show/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
 ===Regimen {{#subobject:211741|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Years of enrollment
@@ Line 115: / Line 119: @@
 ''Note: this regimen is very similar to [[#7.2B3d_.28intermediate-dose.29|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/m<sup>2</sup> IV every 12 hours on days 1 to 10
 *[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 '''10-day course'''
 ====Subsequent treatment====
 *DA 3+8 versus DA 3+8 & Lestaurtinib
 ===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/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. [http://www.bloodjournal.org/content/125/25/3878.long link to original article] '''contains verified protocol''' [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. [http://www.haematologica.org/content/103/10/1654.long 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=
 ==7+3d & Sorafenib {{#subobject:6ad412|Regimen=1}}==
@@ Line 133: / Line 132: @@
 ===Regimen {{#subobject:c95c56|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
 !style="width: 33%"|Years of enrollment
@@ Line 144: / Line 143: @@
 |}
 ====Chemotherapy====
 *[[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 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====
 *Patients not achieving a hypoplastic marrow on day 14: 5+2 & sorafenib re-induction
 *Patients achieving a CR or CRi: [[#IDAC_.26_Sorafenib|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. [http://www.bloodadvances.org/content/1/5/331 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366 PubMed] NCT01253070
 =Consolidation after upfront therapy=
 ==HiDAC & Midostaurin {{#subobject:a12f1b|Regimen=1}}==
 HiDAC & Midostaurin: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) & Midostaurin
 ===Regimen {{#subobject:c3e162|Variant=1}}===
@@ Line 171: / Line 161: @@
 |-
 |}
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
 !style="width: 33%"|Years of enrollment
@@ Line 182: / Line 172: @@
 |}
 ====Preceding treatment====
 *[[#7.2B3d_.26_Midostaurin|7+3d & midostaurin induction]], with CR
 ====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>)
 ====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_monotherapy|midostaurin maintenance]]
 ===References===
-<!-- # '''Abstract:''' R. M. Stone, H. Dohner, G. Ehninger, M. Villeneuve, T. Teasdale, J. D. Virkus, L. R. Bressler, M. M. Seiler, G. Marcucci, R. A. Larson. CALGB 10603 (RATIFY): A randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. 2011 ASCO Annual Meeting abstract TPS199. [http://meetinglibrary.asco.org/content/81555-102 link to abstract]
-# '''Abstract:''' Richard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze Dohner, Christian Thiede, Guido Marcucci, Francesco Lo-Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson, Hartmut Dohner. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). 2015 ASH Annual Meeting plenary abstract 6. [https://ash.confex.com/ash/2015/webprogramscheduler/Paper80269.html link to abstract] '''contains protocol''' [https://clinicaltrials.gov/ct2/show/NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia (NCT00651261) at ClinicalTrials.gov] -->
 #'''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://www.nejm.org/doi/full/10.1056/NEJMoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28644114 PubMed] NCT00651261
 ==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
 ===Regimen {{#subobject:b52969|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
 !style="width: 33%"|Years of enrollment
@@ Line 220: / Line 197: @@
 |}
 ====Preceding treatment====
 *[[#7.2B3d_.26_Sorafenib|7+3d & sorafenib induction]]
 ====Chemotherapy====
 *[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> 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_monotherapy|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. [http://www.bloodadvances.org/content/1/5/331 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366 PubMed] NCT01253070
 =Maintenance after upfront therapy, including allogeneic HSCT=
 ==Midostaurin monotherapy {{#subobject:e0bb17|Regimen=1}}==
 ===Regimen {{#subobject:9fe269|Variant=1}}===
 {| class="wikitable sortable" style="width: 80%; text-align:center;"
 !style="width: 25%"|Study
 !style="width: 25%"|Years of enrollment
@@ Line 257: / Line 223: @@
 |}
 ====Preceding treatment====
 *[[#HiDAC_.26_Midostaurin|HiDAC & Midostaurin consolidation]]
 ====Targeted therapy====
 *[[Midostaurin (Rydapt)]] 50 mg PO twice per day
 '''28-day cycle for up to 13 cycles (1 year)'''
 ===References===
-<!-- # '''Abstract:''' R. M. Stone, H. Dohner, G. Ehninger, M. Villeneuve, T. Teasdale, J. D. Virkus, L. R. Bressler, M. M. Seiler, G. Marcucci, R. A. Larson. CALGB 10603 (RATIFY): A randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. 2011 ASCO Annual Meeting abstract TPS199. [http://meetinglibrary.asco.org/content/81555-102 link to abstract]
-# '''Abstract:''' Richard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze Dohner, Christian Thiede, Guido Marcucci, Francesco Lo-Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson, Hartmut Dohner. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). 2015 ASH Annual Meeting plenary abstract 6. [https://ash.confex.com/ash/2015/webprogramscheduler/Paper80269.html link to abstract] '''contains protocol''' [https://clinicaltrials.gov/ct2/show/NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia (NCT00651261) at ClinicalTrials.gov] -->
 #'''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://www.nejm.org/doi/full/10.1056/NEJMoa1614359 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754190/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28644114 PubMed] NCT00651261
 #'''ARO-021:''' NCT03258931
 #'''HOVON 156 AML:''' NCT04027309
 ==Sorafenib monotherapy {{#subobject:23822e|Regimen=1}}==
 ===Regimen variant #1, 6 months {{#subobject:fgj9dcVariant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Years of enrollment
@@ Line 292: / Line 249: @@
 |}
 ====Preceding treatment====
 *Allogeneic stem cell transplant
 ====Targeted therapy====
 *[[Sorafenib (Nexavar)]] 400 mg PO twice per day on days +30 to +180
 '''6-month course'''
 ===Regimen variant #2, 12 mos {{#subobject:b50325|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
 !style="width: 33%"|Years of enrollment
@@ Line 313: / Line 265: @@
 |}
 ====Preceding treatment====
 *[[#IDAC_.26_Sorafenib|IDAC & Sorafenib consolidation]]
 ====Targeted therapy====
 *[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 '''28-day cycle for up to 12 cycles'''
 ===Regimen variant #3, 2 years {{#subobject:fd24dcVariant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Years of enrollment
@@ Line 337: / Line 284: @@
 |}
 ====Preceding treatment====
 *Allogeneic stem cell transplant
 ====Targeted therapy====
 *[[Sorafenib (Nexavar)]] as follows:
 **Cycle 1: 200 mg PO twice per day on days 1 to 14, then 400 mg PO twice per day if tolerated
 **Cycles 2 to 26: 400 mg PO twice per day
 '''28-day cycle for up to 26 cycles (2 years)'''
 ===References===
 #'''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. [http://www.bloodadvances.org/content/1/5/331 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637402/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29034366 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. [https://doi.org/10.1200/jco.19.03345 link to original article] '''contains verified protocol''' [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] NCT02474290
 =Relapsed or refractory, salvage therapy=
 ==Midostaurin monotherapy {{#subobject:badb27|Regimen=1}}==
 ===Regimen variant #1 {{#subobject:170b53|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
 !style="width: 20%"|Years of enrollment
@@ Line 373: / Line 312: @@
 |}
 ====Targeted therapy====
 *[[Midostaurin (Rydapt)]] 50 mg PO twice per day
 '''Continued indefinitely'''
 ===Regimen variant #2 {{#subobject:2dfbf4|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
 !style="width: 20%"|Years of enrollment
@@ Line 394: / Line 330: @@
 |}
 ====Targeted therapy====
 *[[Midostaurin (Rydapt)]] 100 mg PO twice per day
 '''Continued indefinitely'''
 ===Regimen variant #3 {{#subobject:c52466|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
 !style="width: 33%"|Years of enrollment
@@ Line 413: / Line 346: @@
 *FLT3 ITD or FLT3 p.D835Y mutation
 ====Targeted therapy====
 *[[Midostaurin (Rydapt)]] 75 mg PO three times per day
 '''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. [http://www.bloodjournal.org/content/105/1/54.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15345597 PubMed]
-<!-- Presented in part at the 45th Annual Meeting of the American Society of Hematology, December 6-9, 2003, San Diego, CA. -->
 #'''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. [https://doi.org/10.1200/jco.2010.28.9678 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135183/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20733134 PubMed] NCT00045942
 =Relapsed or refractory, further lines of therapy=
 ==Azacitidine monotherapy {{#subobject:531b70|Regimen=1}}==
 ===Regimen {{#subobject:39f96a|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
 !style="width: 20%"|Years of enrollment
@@ Line 445: / Line 370: @@
 ''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/m<sup>2</sup> 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1902688 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] 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]
 ==Azacitidine & Sorafenib {{#subobject:e3a8ee|Regimen=1}}==
 ===Regimen {{#subobject:9c1ff|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
 !style="width: 33%"|Years of enrollment
@@ Line 469: / Line 390: @@
 |}
 ====Chemotherapy====
 *[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 7
 ====Targeted therapy====
 *[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 ====Supportive medications====
 *"All patients received antimicrobials, supportive care, and transfusions of blood products according to the institutional guidelines."
 '''4- to 8-week cycles'''
 ===References===
-<!-- no pre-pub disclosed -->
 #'''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. [http://www.bloodjournal.org/content/121/23/4655.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674666/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23613521 PubMed] NCT01254890
 ==FLAG-Ida {{#subobject:d8c75b|Regimen=1}}==
 FLAG-Ida: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF (Filgrastim), '''<u>Ida</u>'''rubicin
 ===Regimen {{#subobject:5fa2cc|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
 !style="width: 20%"|Years of enrollment
@@ Line 512: / Line 423: @@
 |}
 ====Chemotherapy====
 *[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 2 to 6
 *[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV once per day on days 2 to 6
 *[[Idarubicin (Idamycin)]] 10 mg/m<sup>2</sup> IV once per day on days 2 to 4
 ====Growth factor therapy====
 *[[Filgrastim (Neupogen)]] 5 mcg/kg or 300 mcg/m<sup>2</sup> 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30150-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31175001 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1902688 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] 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:''' NCT03250338
 ==Gilteritinib monotherapy {{#subobject:0384e2|Regimen=1}}==
 ===Regimen {{#subobject:10f04d|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 537: / Line 440: @@
 |-
 |}
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Years of enrollment
@@ Line 558: / Line 461: @@
 ''<sup>1</sup>Reported efficacy is based on the 2022 update.''
 ====Targeted therapy====
 *[[Gilteritinib (Xospata)]] 120 mg PO once per day
 '''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30416-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28645776 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1902688 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] 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]
 #'''2215-CL-0303:''' NCT03182244
 ==Low-dose Cytarabine monotherapy (LoDAC) {{#subobject:48ba18|Regimen=1}}==
 LoDAC: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (cytarabine)
 <br>LDAC: '''<u>L</u>'''ow '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (cytarabine)
 ===Regimen {{#subobject:c9nqa0|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
 !style="width: 20%"|Years of enrollment
@@ Line 597: / Line 493: @@
 |}
 ====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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30150-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31175001 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1902688 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] 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]
 ==MEC {{#subobject:48e49b|Regimen=1}}==
 MEC: '''<u>M</u>'''itoxantrone, '''<u>E</u>'''toposide, '''<u>C</u>'''ytarabine
 ===Regimen {{#subobject:bd7f87|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
 !style="width: 20%"|Years of enrollment
@@ Line 633: / Line 523: @@
 |}
 ====Chemotherapy====
 *[[Mitoxantrone (Novantrone)]] 8 mg/m<sup>2</sup> IV push once per day on days 1 to 5, '''given third'''
 *[[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'''
 ===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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30150-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31175001 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1902688 link to original article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/31665578/ PubMed] 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]
 ==Quizartinib monotherapy {{#subobject:1684ae|Regimen=1}}==
 ===Regimen {{#subobject:aea7bc|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
 !style="width: 20%"|Years of enrollment
@@ Line 663: / Line 548: @@
 ''Note: Quizartinib is not yet approved in any domain.''
 ====Targeted therapy====
 *[[Quizartinib (AC220)]] 60 mg PO once per day
 '''Continued indefinitely'''
 ===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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30150-0/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31175001 PubMed] [https://clinicaltrials.gov/ct2/show/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://www.nejm.org/doi/full/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 02:42, 15 August 2022

Upfront induction therapy, standard patients

7+3d (intermediate-dose)

Regimen

Chemotherapy

Supportive medications

References

7+3d & Midostaurin

Regimen

Chemotherapy

Targeted therapy

Supportive medications

Subsequent treatment

References

7+3 & Quizartinib

Regimen

Chemotherapy

Targeted therapy

Supportive medications

Subsequent treatment

References

DA 3 + 10

Regimen

Chemotherapy

Subsequent treatment

References

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

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

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

References

Sorafenib monotherapy

Regimen variant #1, 6 months

Preceding treatment

Targeted therapy

Regimen variant #2, 12 mos

Preceding treatment

Targeted therapy

Regimen variant #3, 2 years

Preceding treatment

Targeted therapy

References

Relapsed or refractory, salvage therapy

Midostaurin monotherapy

Regimen variant #1

Targeted therapy

Regimen variant #2

Targeted therapy

Regimen variant #3

Biomarker eligibility criteria

Targeted therapy

References

Relapsed or refractory, further lines of therapy

Azacitidine monotherapy

Regimen

Chemotherapy