Seminars in Hematology
Volume 45 , Pages S17-S21 , July 2008

Targeting FLT3 for the Treatment of Leukemia

  • Donald Small

      Affiliations

    • Corresponding Author InformationAddress correspondence to Donald Small, MD, PhD, Kyle Haydock Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center, CRB1-251, 1650 Orleans St, The Johns Hopkins University, Baltimore, MD 21231

References 

  1. Small D, Levenstein M, Kim E, Carrow C, Amin S, Rockwell P, et al. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci U S A. 1994;91:459–463
  2. Carrow C, Levenstein M, Kaufmann S, Chen J, Amin S, Rockwell P, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87:1089–1096
  3. Brown P, Small D. FLT3 inhibitors: A paradigm for the development of targeted therapeutics for paediatric cancer. Eur J Cancer. 2004;40:707–721
  4. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–1918
  5. Gilliland DG, Griffin JD. Role of FLT3 in leukemia. Curr Opin Hematol. 2002;9:274–281
  6. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97:2434–2439
  7. Bao L, Wang X, Ryder J, Ji M, Chen Y, Chen H, et al. Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: Subtypes, cytogenetic features and FLT3 mutations. Eur J Haematol. 2006;77:35–45
  8. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–4335
  9. Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, Tjoa TK, et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 2001;97:89–94
  10. Rombouts WJ, Blokland I, Lowenberg B, Ploemacher RE. Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia. 2000;14:675–683
  11. Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia. 2003;17:1738–1752
  12. Meshinchi S, Alonzo TA, Stirewalt DL, Zwaan M, Zimmerman M, Reinhardt D, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108:3654–3661
  13. Bornhauser M, Illmer T, Schaich M, Soucek S, Ehninger G, Thiede C. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. 2007;109:2264–2265
  14. Gale RE, Hills R, Kottaridis PD, Srirangan S, Wheatley K, Burnett AK, et al. 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
  15. Levis M, Tse KF, Smith BD, Garrett E, Small D. A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood. 2001;98:885–887
  16. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70
  17. Levis M, Allebach J, Tse KF, Zheng R, Baldwin BR, Smith BD, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002;99:3885–3891
  18. Brown P, Meshinchi S, Levis M, Alonzo TA, Gerbing R, Lange B, et al. Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition. Blood. 2004;104:1841–1849
  19. 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
  20. Knapper S, Burnett AK, Littlewood T, Kell WJ, Agrawal S, Chopra R, 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
  21. Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54–60
  22. O'Farrell AM, Foran JM, Fiedler W, Serve H, Paquette RL, Cooper MA, et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res. 2003;9:5465–5476
  23. Fiedler W, Serve H, Döhner H, Schwittay M, Ottmann OG, O'Farrell AM, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood. 2005;105:986–993
  24. DeAngelo DJ, Amrein P, Kovacsovics TJ, Klisovic R, Powell BL, Cooper M, et al. Phase 1/2 study of tandutinib (MLN518) plus standard induction chemotherapy in newly diagnosed acute myelogenous leukemia (AML). Blood. 2006;108:51a;(abstr 158)
  25. DeAngelo DJ, Stone RM, Heaney ML, Nimer SD, Paquette RL, Klisovic RB, et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood. 2006;108:3674–3681
  26. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood. 2004;104:1145–1150
  27. Brown P, Levis M, McIntyre E, Griesemer M, Small D. Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner. Leukemia. 2006;20:1368–1376
  28. Levis M, Smith D, Beran M, Baer M, Erba HP, Cripe L, et al. A randomized, open-label study of lestaurtinib (CEP-701), an oral FLT3 inhibitor, administered in sequence with chemotherapy in patients with relapsed AML harboring FLT3 activating mutations: clinical response correlates with successful FLT3 inhibition. Blood. 2005;106:121a;(abstr 403)
  29. Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G, et al. Phase IB study of PKC412, an oral FLT3 kinase inhibitor, in sequential and simultaneous combinations with daunorubicin and cytarabine (DA) induction and high-dose cytarabine consolidation in newly diagnosed adult patients (pts) with acute myeloid leukemia (AML) under age 61. Blood. 2006;108:50a;(abstr 157)
  30. Burnett A. AML17: A programme of treatment development in younger patients with acute myeloid leukaemia and high risk myelodysplastic syndrome. http://www.controlled-trials.com/cctspringview2/mrct/showTrial.html?mrid=274435&srch=Accessed February 25, 2008
  31. Brown P, Levis M, McIntyre E, Griesemer M, Small D. Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner. Leukemia. 2006;20:1368–1376
  32. Brown P, Levis M, Shurtleff S, Campana D, Downing J, Small D. FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood. 2005;105:812–820
  33. Piloto O, Levis M, Huso D, Li Y, Li H, Wang MN, et al. Inhibitory anti-FLT3 antibodies are capable of mediating antibody-dependent cell-mediated cytotoxicity and reducing engraftment of acute myelogenous leukemia blasts in nonobese diabetic/severe combined immunodeficient mice. Cancer Res. 2005;65:1514–1522
  34. Piloto O, Nguyen B, Huso D, Kim KT, Li Y, Witte L, et al. IMC-EB10, an anti-FLT3 monoclonal antibody, prolongs survival and reduces nonobese diabetic/severe combined immunodeficient engraftment of some acute lymphoblastic leukemia cell lines and primary leukemic samples. Cancer Res. 2006;66:4843–4851

 STATEMENT OF CONFLICT OF INTEREST: Research support/Principal Investigator: Imclone Systems, Ambit Biosciences, Xanthus Pharmaceuticals.

PII: S0037-1963(08)00123-6

doi: 10.1053/j.seminhematol.2008.07.007

Seminars in Hematology
Volume 45 , Pages S17-S21 , July 2008

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