Difference between revisions of "Acute myeloid leukemia, FLT3-positive"
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| style="background-color:#1a9851" |Phase III (E) | | style="background-color:#1a9851" |Phase III (E) | ||
|Salvage Chemotherapy | |Salvage Chemotherapy | ||
| − | |Superior OS | + | | style="background-color:#1a9851" |Superior OS |
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====Chemotherapy==== | ====Chemotherapy==== | ||
Revision as of 18:12, 11 August 2019
| Section editor | |
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Martin W. Schoen, MD, MPH Saint Louis University St. Louis, MO  mwschoen
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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
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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
- 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
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 on days 1 to 28
4- to 6-week cycle for 2 cycles
Subsequent treatment
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
Maintenance after upfront therapy, including allogeneic HSCT
Midostaurin monotherapy
Midostaurin (Rydapt) maintenance therapy for acute myeloid leukemia (AML)
Sorafenib monotherapy
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Variant #1, 12 mos
| Study | Evidence |
|---|---|
| Uy et al. 2017 (CALGB 11001) | Phase II |
Preceding treatment
Chemotherapy
- Sorafenib (Nexavar) 400 mg PO twice per day
28-day cycle for up to 12 cycles
Variant #2, 2 years
| Study | Evidence | Comparator | Efficacy |
|---|---|---|---|
| Burchert et al. 2018 (SORMAIN) | Phase III (E) | Placebo | Seems to have superior RFS |
Preceding treatment
- Allogeneic stem cell transplant
Chemotherapy
- Sorafenib (Nexavar) as follows:
- Cycle 1: 200 mg PO twice per day on days 1 to 14, then increasing to 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
- Abstract: 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 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
- 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 | ||
| Perl et al. 2019 ADMIRAL | Phase III (E) | Salvage Chemotherapy | Superior OS |
Chemotherapy
- Gilteritinib (Xospata) 120 mg PO once per day
28-day cycles
References
- 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
- Abstract: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Stasi AD, Stuart R, Olin R, Kasner M, Ciceri F, Chou W-C, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon S-S, Lee J-H, Pardee T, Fathi AT, Liu C, Liu X, Bahceci E, Levis MJ. Abstract CT184: Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial Cancer Res July 1 2019 (79) (13 Supplement) CT184; link to abstract Clinical Trial
Quizartinib monotherapy
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Regimen
| Study | Evidence | Comparator | Efficacy |
|---|---|---|---|
| Cortes et al 2019 (QuANTUM-R) | Phase III (E) | Salvage Chemotherapy | Superior OS |
Chemotherapy
- Quizartinib 60 mg PO once per day
References
- 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 Clinical Trial
Azacitidine & Sorafenib
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Regimen
| Study | Evidence |
|---|---|
| Ravandi et al. 2013 | Phase II |
Chemotherapy
- Azacitidine (Vidaza) 75 mg/m2 IV or SC 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
References
- 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.