Acute myeloid leukemia, FLT3-positive

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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.

9 regimens on this page
11 variants on this page


Upfront induction therapy, standard patients

7+3d & Midostaurin

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

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Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
Stone et al. 2017 (RATIFY) Phase III (E) 7+3d (intermediate-dose) Superior OS

Chemotherapy

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

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

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

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

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

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Regimen

FDA-recommended dose
Study Evidence
Stone et al. 2017 (RATIFY) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

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

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

Chemotherapy

Two cycles

Subsequent treatment

References

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

Maintenance after upfront therapy

Midostaurin monotherapy

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

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Regimen

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

Preceding treatment

Chemotherapy

Continuously for up to 12 months

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

Sorafenib monotherapy

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Regimen

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

Preceding treatment

Chemotherapy

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

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 BID

Chemotherapy

Continued indefinitely

Variant #2

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

Chemotherapy

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

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

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

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.