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 - Tập 108 - Trang 3262-3270 - 2006
Steven Knapper, Alan K. Burnett, Tim Littlewood, W. Jonathan Kell, Sam Agrawal, Raj Chopra, Richard Clark, Mark J. Levis, Donald Small

Tóm tắt

AbstractActivating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately one third of patients with acute myeloid leukemia (AML) and are associated with adverse prognosis. The important role played by FLT3 in the survival and proliferation of blasts, and its overexpression in most patients with AML, make FLT3 an attractive therapeutic target. We undertook a phase 2 trial of the FLT3-selective tyrosine kinase inhibitor lestaurtinib (CEP701) used as monotherapy in untreated older patients with AML not considered fit for intensive chemotherapy, irrespective of FLT3 mutation status. Lestaurtinib was administered orally for 8 weeks, initially at a dose of 60 mg twice daily, escalating to 80 mg twice daily, and was generally well tolerated. Clinical activity, manifest as transient reductions in bone marrow and peripheral-blood blasts or longer periods of transfusion independence, was seen in 3 (60%) of 5 patients with mutated FLT3 and 5 (23%) of 22 evaluable wild-type FLT3 patients. Laboratory data demonstrated that clinical responses occurred where the presence of sustained FLT3-inhibitory drug levels were combined with in vitro cytotoxic sensitivity of blasts to lestaurtinib. Further evaluation of this compound, in combination with cytotoxic chemotherapy or other targeted agents, is warranted in both FLT3 mutant and wild-type patients.

Tài liệu tham khảo

Sawyers CL. Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid leukemia. Cancer Cell. 2002;1: 413-415. McKenna HJ, Stocking KL, Miller RE, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood. 2000;95: 3489-3497. Mackarehtschian K, Hardin JD, Moore KA, et al. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity. 1995;3: 147-161. Birg F, Courcoul M, Rosnet O, et al. Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood. 1992;80: 2584-2593. Rosnet O, Buhring HJ, Marchetto S, et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia. 1996;10: 238-248. Carow CE, Levenstein M, Kaufmann SH, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87: 1089-1096. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10: 1911-1918. Abu-Duhier FM, Goodeve AC, Wilson GA, et al. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol. 2001;113: 983-988. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97: 2434-2439. Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia. 2003;17: 1738-1752. Zhang S, Fukuda S, Lee Y, et al. Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling. J Exp Med. 2000;192: 719-728. Lavagna-Sevenier C, Marchetto S, Birnbaum D, Rosnet O. FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates. Leukemia. 1998;12: 301-310. Marchetto S, Fournier E, Beslu N, et al. SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor. Leukemia. 1999;13: 1374-1382. Zheng R, Levis M, Piloto O, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood. 2004;103: 267-274. Drexler HG. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia. 1996;10: 588-599. Kelly LM, Liu Q, Kutok JL, et al. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood. 2002;99: 310-318. Kelly LM, Kutok JL, Williams IR, et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci U S A. 2002;99: 8283-8288. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98: 1752-1759. Meshinchi S, Woods WG, Stirewalt DL, et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 2001;97: 89-94. Frohling 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. Levis M, Allebach J, Tse KF, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002;99: 3885-3891. Weisberg E, Boulton C, Kelly LM, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1: 433-443. O'Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101: 3597-3605. O'Farrell AM, Yuen HA, Smolich B, et al. Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia. Leuk Res. 2004;28: 679-689. Kelly LM, Yu JC, Boulton CL, et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell. 2002;1: 421-432. Fiedler W, Mesters R, Tinnefeld H, et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood. 2003;102: 2763-2767. Fiedler W, Serve H, Dohner H, 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. Smith BD, Levis M, Beran M, 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. Stone RM, DeAngelo DJ, Klimek V, 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. de Angelo J, Stone R, Heaney ML, et al. Phase II evaluation of the tyrosine kinase inhibitor MLN518 in patients with acute myeloid leukemia bearing a FLT3 internal tandem duplication mutation [abstract]. Blood. 2004;104: 1792a. Marshall JL, Kindler H, Deeken J, et al. Phase I trial of orally administered CEP-701, a novel neurotrophin receptor-linked tyrosine kinase inhibitor. Invest New Drugs. 2005;23: 31-37. Knapper S, Burnett AK, Gilkes AF, et al. The in vitro sensitivity of primary AML blasts to two FLT3 inhibitors and cytarabine appears independent of FLT3 mutation status [abstract]. Blood. 2003;102: 24a. Knapper S, Burnett AK, Gilkes AF, Mills KI, Walsh V. CEP701 and PKC412 predictably and reliably inhibit FLT3 phosphorylation in primary AML blasts but their induction of a cytotoxic response appears to be much more variable [abstract]. Blood. 2004;104: 95a. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100: 2292-2302. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin.Trials. 1989;10: 1-10. Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol. 1990;8: 813-819. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21: 4642-4649. Mills KI, Walsh V, Gilkes AF, Agrawal SG, Knapper S. Novel observation of three FLT3 codons mutated in tandem in an elderly acute myeloid leukaemia patient. Br J Haematol. 2006;132: 116-117. Levis M, Murphy KM, Pham R, et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood. 2005;106: 673-680. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414: 105-111. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001; 344: 1038-1042. 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. Brown P, Levis M, McIntyre E, et al. Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner [abstract]. Blood. 2005;106: 2467a. Levis M, Smith BD, Beran M, 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 [abstract]. Blood. 2005;106: 403a.
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Blood

Tập 108

3262-3270

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