Acute myeloid leukemia, FLT3-positive

Page editor
	Martin Schoen, MD, MPH St. Louis, MO

Note: these are biomarker-specific regimens 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 & Midostaurin

Cytarabine, Daunorubicin, and Midostaurin induction therapy for acute myeloid leukemia (AML)

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

7+3d & Sorafenib

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Regimen

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

Chemotherapy

• Cytarabine (Ara-C) 100 mg/m²/day IV continuous infusion on days 1 to 7 (total dose: 700 mg/m²)
• Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1 to 3
• 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 received re-induction with 5+2 & sorafenib
• Patients achieving a CR or CRi: IDAC & sorafenib consolidation

References

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

Consolidation after upfront therapy

HiDAC & Midostaurin

Cytarabine & Midostaurin consolidation therapy for acute myeloid leukemia (AML)

IDAC & Sorafenib

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

Regimen

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

Preceding treatment

• 7+3d & sorafenib induction

Chemotherapy

• Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours once per day on days 1 to 5
• Sorafenib (Nexavar) 400 mg PO twice per day for 28 days

Two 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

Maintenance after upfront therapy

Midostaurin monotherapy

Midostaurin (Rydapt) maintenance therapy for acute myeloid leukemia (AML)

Sorafenib monotherapy

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Regimen

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

Preceding treatment

• IDAC & Sorafenib consolidation

Chemotherapy

• Sorafenib (Nexavar) 400 mg PO twice per day

28-day cycle for up to 12 cycles

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

Sorafenib monotherapy after allogeneic stem cell transplant

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Regimen

Study	Evidence	Comparator	Efficacy
Buchert et al. 2018 (SORMAIN)	Phase III (E)	Placebo	Superior

Preceding treatment

• Allogeneic stem cell transplant

Chemotherapy

• Sorafenib (Nexavar) 200 mg PO twice per day, increasing to 400 mg PO twice per day

Up to 2 years

References

1. SORMAIN: Burchert A, Bug G, Finke J, Stelljes M, Rollig C, Wäsch R, Bornhäuser M, Berg T, Lang F, Ehninger G, Serve H, Zeiser R, Wagner E, Kroeger N, Wolschke C, Schleuning M, Elmaagacli A, Götze KS, Schmid C, Jost E, Wolf D, Böhm A, Thiede C, Haferlach T, Bethge W, Harnisch S, Wittenberg M, Rospleszcz S, Neubauer A, Brugger M, Strauch K, Schade-Brittinger C, Metzelder SK. Sorafenib As Maintenance Therapy Post Allogeneic Stem Cell Transplantation for FLT3-ITD Positive AML: Results from the Randomized, Double-Blind, Placebo-Controlled Multicentre Sormain Trial. Blood 2018, 132(Suppl 1), 661. Accessed February 13, 2019. link to abstract contains verified protocol Link to clinical trial registration

Relapsed or refractory, salvage therapy

Midostaurin monotherapy

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Variant #1

Study	Evidence	Comparator
Fischer et al. 2010	Randomized Phase IIB (E)	Midostaurin 100 mg twice per day

Chemotherapy

• Midostaurin (Rydapt) 50 mg PO twice per day

Continued indefinitely

Variant #2

Study	Evidence	Comparator
Fischer et al. 2010	Randomized Phase IIB (E)	Midostaurin 50 mg twice per day

Chemotherapy

• Midostaurin (Rydapt) 100 mg PO twice per day

Continued indefinitely

Variant #3

Study	Evidence
Stone et al. 2004	Phase II

Patients were required to have a FLT3 ITD or FLT3 p.D835Y mutation.

Chemotherapy

• Midostaurin (Rydapt) 75 mg PO TID

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. Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010 Oct 1;28(28):4339-45. Epub 2010 Aug 23. link to original article link to PMC article contains verified protocolPubMed

Relapsed or refractory, further lines of therapy

Gilteritinib monotherapy

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Regimen

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Perl et al. 2017	Phase I/II
ADMIRAL	Phase III (E)	Salvage Chemotherapy	Not reported

Chemotherapy

• Gilteritinib (Xospata) 120 mg PO once per day

28-day cycles

References

1. Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 Aug;18(8):1061-1075. Epub 2017 Jun 20. link to original article PubMed
2. ADMIRAL Clinical Trial

Azacitidine & Sorafenib

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Regimen

Study	Evidence
Ravandi et al. 2013	Phase II

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² SC or IV once per day on days 1 to 7
• 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 at treating physician's discretion

References

1. 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

Investigational agents

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

• Quizartinib (AC220)