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Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412
Open accessAbstract
Leukemic cells from 30% of patients with acute myeloid leukemia (AML) have an activating mutation in the FLT3 (fms-like tyrosine kinase) gene, which represents a target for drug therapy. We treated 20 patients, each with mutant FLT3 relapsed/refractory AML or high-grade myelodysplastic syndrome and not believed to be candidates for chemotherapy, with an FLT3 tyrosine kinase inhibitor, PKC412 (N-benzoylstaurosporine), at a dose of 75 mg 3 times daily by mouth. The drug was generally well tolerated, although 2 patients developed fatal pulmonary events of unclear etiology. The peripheral blast count decreased by 50% in 14 patients (70%). Seven patients (35%) experienced a greater than 2-log reduction in peripheral blast count for at least 4 weeks (median response duration, 13 weeks; range, 9-47 weeks); PKC412 reduced bone marrow blast counts by 50% in 6 patients (2 of these to < 5%). FLT3 autophosphorylation was inhibited in most of the Corresponding patients, indicating in vivo target inhibition at the dose schedule used in this study. PKC412 is an oral tyrosine kinase inhibitor with clinical activity in patients with AML whose blasts have an activating mutation of FLT3, suggesting potential use in combination with active agents, such as chemotherapy.
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Cited by
Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation
Stone, R. M., Mandrekar, S. J., Sanford, B. L., Laumann, K., Geyer, S., Bloomfield, C. D., Thiede, C., Prior, T. W., Döhner, K., Marcucci, G., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1614359 · Cited by 2,250
Self-citation‘Acute myeloid leukemia: a comprehensive review and 2016 update’
De Kouchkovsky, I., & Abdul-Hay, M. (2016) · Blood Cancer Journal · doi:10.1038/bcj.2016.50 · Cited by 1,317
Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies
Abdel-Wahab, O., Mullally, A., Hedvat, C., Garcia-Manero, G., Patel, J., Wadleigh, M., Malinge, S., Yao, J., Kilpivaara, O., Bhat, R., et al. (2009) · Blood · doi:10.1182/blood-2009-03-210039 · Cited by 727
Self-citationFischer, T., Stone, R. M., DeAngelo, D. J., Galinsky, I., Estey, E., Lanza, C., Fox, E., Ehninger, G., Feldman, E. J., Schiller, G. J., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.9678 · Cited by 504
Self-citationDebiec-Rychter, M., Cools, J., Dumez, H., Sciot, R., Stul, M., Mentens, N., Vranckx, H., Wasag, B., Prenen, H., Roesel, J., et al. (2005) · Gastroenterology · doi:10.1053/j.gastro.2004.11.020 · Cited by 494
Metadata
- Authors
- Stone, R. M., DeAngelo, D. J., Klimek, V., Galinsky, I., Estey, E., Nimer, S. D., Grandin, W., Lebwohl, D., Wang, Y., Cohen, P., Fox, E. A., Neuberg, D., Clark, J., Gilliland, D. G., & Griffin, J. D.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2005-01-01
- Volume
- 105
- Issue
- 1
- Pages
- 54-60
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2153345005
- Cited by
- 657
- References
- 0
- FWCI
- 24.72
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Stone, R. M., DeAngelo, D. J., Klimek, V., Galinsky, I., Estey, E., Nimer, S. D., Grandin, W., Lebwohl, D., Wang, Y., Cohen, P., Fox, E. A., Neuberg, D., Clark, J., Gilliland, D. G., & Griffin, J. D. (2005). Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. https://doi.org/10.1182/blood-2004-03-0891
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