FLT3-ITD-positive acute myeloid leukemia: risk of relapse and refractory


American Journal of BioMedicine  Volume 2, Issue 8, pages 992-1009, September 2014


Bill A. Lynch; Suzan M. Lyman; Jan H. Kasper


The FMS-like tyrosine kinase 3 (FLT3-ITD) acute myeloid leukemia (AML) often present with more aggressive disease and have a significantly higher marrow blast percentage, higher likelihood of relapse, and shorter survival. Activating mutations of the kinase occur in about one third of patients with AML. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). A number of small-molecule kinase inhibitors such as lestaurtinib (CEP-701), midostaurin (PKC412), and tandutinib (MLN518) block the autophosphorylation of FLT3 and lead to inhibition of cell proliferation and induction of apoptosis; they have demonstrated clinical activity in patients with AML, in particular those with mutations. This review summarizes what is known regarding the FLT3-ITD targeting therapy.

Keywords: Acute myeloid leukemia; FLT3-ITD; Chemotherapy; Targeting therapy

Limited Access               HTML                 Full Text-PDF                Feedback   


1. Fröhling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: A study of the AML Study Group Ulm. Blood 2002; 100:4372–4380. [Abstract/FREE Full Text]

2. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002;100:1532–1542. [PubMed]

3. Knapper S, Mills KI, Gilkes AF, Austin SJ, Walsh V, Burnett AK. The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases. Blood 2006;108:3494–3503. [PubMed]

4. Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: Correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood  2002; 100:59–66.

5. Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, et. al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. Journal of Clinical Oncology 2010; 28:1856–1862. [PubMed]

6. Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111:2776–2784. [Abstract/FREE Full Text]

7. Rosnet O, Schiff C, Pebusque MJ, Marchetto S, Tonnelle C, Toiron Y, Birg F, Birnbaum D. Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Blood 1993;82:1110–1119. [PubMed]

8. Dezern AE, Sung A, Kim S, Smith BD, Karp JE, Gore SD, et al. Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: Outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant 2011;17(9):1404-9. [PubMed]

9. Gale RE, Hills R, Kottaridis PD, Srirangan S, Wheatley K, Burnett AK, Linch DC. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood 2005;106:3658–3665. [PubMed]

10. Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: A phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 2006; 24:460–466. [Abstract/FREE Full Text]

11. Gupta V, Tallman MS, Weisdorf DJ. Alloge-neic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood 2007; 117:2307–2318. [PubMed]

12. Pratz KW, Cortes J, Roboz GJ, Rao N, Arowojolu O, Stine A, et. al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood 2009;113:3938–3946. [PubMed]

13. Giles FJ, Stopeck AT, Silverman LR, Lancet JE, Cooper MA, Hannah AL, Cherrington JM, O'Farrell AM, et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 2003;102:795–801. [PubMed]

14. Bagrintseva K, Geisenhof S, Kern R, et al. FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L). Blood 2005;105:3679–3685. [Abstract/FREE Full Text]

15. Heidel F, Solem FK, Breitenbuecher F, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood 2006;107:293–300. [Abstract/FREE Full Text]

16. Wadleigh M, DeAngelo DJ, Griffin JD, et al. After chronic myelogenous leukemia: Tyrosine kinase inhibitors in other hematologic malignancies. Blood 2005;105:22–30. [Abstract/FREE Full Text]

17. Knapper S, Burnett AK, Littlewood T, et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 2006;108:3262–3270. [Abstract/FREE Full Text]

18. Fabbro D, Ruetz S, Bodis S, Pruschy M, Csermak K, Man A, Campochiaro P, Wood J, O'Reilly T, Meyer T. PKC412–a protein kinase inhibitor with a broad therapeutic potential. Anti-Cancer Drug Design 2000;15:17–28. [PubMed]

19. Safaian NN, Czibere A, Bruns I, Fenk R, Reinecke P, Dienst A, Haas R, Kobbe G. Sorafenib (Nexavar) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD+ acute myeloid leukemia. Leukemia Research 2009;33:348–350. [PubMed]

20. Smith BD, Levis M, Beran M, Giles F, Kantarjian H, Berg K, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 2004;103:3669–3676. [PubMed]

21. Reindl C, Bagrintseva K, Vempati S, et al. Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML. Blood 2006;107:3700–3707. [Abstract/FREE Full Text]

22. Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T, et. al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia 1997;11:1605–1609. [PubMed]

23. Armstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML, et.al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 2003;3:173–183. [PubMed]

24. McKenna HJ, Stocking KL, Miller RE, Brasel K, De Smedt T, Maraskovsky E, et. al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000;95:3489–3497. [PubMed]

Print Friendly, PDF & Email