Acute myeloid leukemia, FLT3-positive

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

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

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

1. 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

1. UK NCRI AML17: Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m² vs 60 mg/m² in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 Jun 18;125(25):3878-85. Epub 2015 Apr 1. link to original article contains 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

1. CALGB 11001: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. link to original article contains verified protocol link to PMC article PubMed NCT01253070

Consolidation after upfront therapy

HiDAC & Midostaurin

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

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

1. CALGB 11001: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. link to original article contains verified protocol link to PMC article PubMed NCT01253070

Maintenance after upfront therapy, including allogeneic HSCT

Midostaurin monotherapy

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

1. RATIFY: Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. Epub 2017 Jun 23. link to original article link to PMC article contains verified protocol PubMed NCT00651261
2. ARO-021: NCT03258931
3. 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

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

Relapsed or refractory, salvage therapy

Midostaurin monotherapy

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

1. Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, Grandin W, Lebwohl D, Wang Y, Cohen P, Fox EA, Neuberg D, Clark J, Gilliland DG, Griffin JD. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005 Jan 1;105(1):54-60. Epub 2004 Sep 2. link to original article contains verified protocol PubMed
2. CPKC412A2104: Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010 Oct 1;28(28):4339-45. Epub 2010 Aug 23. link to original article link to PMC article contains verified 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

1. ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article does not contain 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

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

1. QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article PubMed NCT02039726
2. ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article does not contain 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
3. 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

1. 2215-CL-0101: Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 Aug;18(8):1061-1075. Epub 2017 Jun 20. link to original article PubMed NCT02014558
2. ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article contains 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
3. 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

1. QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article contains protocol PubMed NCT02039726
2. ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article does not contain 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

1. QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. Epub 2019 Jun 4. Erratum in: Lancet Oncol. 2019 Jul;20(7):e346. link to original article contains protocol PubMed NCT02039726
2. ADMIRAL: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-40. link to original article does not contain 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

1. QuANTUM-R: Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. link to original article PubMed NCT02039726

Prognosis

Prognosis in cytogenetically normal AML

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

Investigational agents

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

• Crenolanib (CP-868,596)