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 Blood, 1 November 2004, Vol. 104, No. 9, pp. 2912-2918.
Prepublished online as a Blood First Edition Paper on July 8, 2004; DOI 10.1182/blood-2003-05-1669.

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NEOPLASIA

Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis

Ian J. Griswold, Lei J. Shen, Paul La Rosée, Shadmehr Demehri, Michael C. Heinrich, Rita M. Braziel, Laura McGreevey, Andrea D. Haley, Neill Giese, Brian J. Druker, and Michael W.N. Deininger

From the Howard Hughes Medical Institute, Oregon Health and Science University Cancer Institute, Portland; the Department of Pathology, Oregon Health and Science University, Portland; the Portland VA Medical Center, Portland; Millenium Pharmaceuticals, San Francisco, CA; and the III. Medizinische Universitätsklinik, Fakultät für klinische Medizin Mannheim der Universität Heidelberg, Germany.

Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL–positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.


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