Page 122 - 2018_11-Haematologica-web

Haematologica 2018 Volume 103(11):1862-1872
1Department for Biomedical Research, University of Bern and 2Department of Medical Oncology, Inselspital, Bern University Hospital, Switzerland
Ferrata Storti Foundation
Acute Myeloid Leukemia
MDM2- and FLT3-inhibitors in the treatment of FLT3-ITD acute myeloid leukemia, specificity and efficacy of NVP-HDM201 and midostaurin
Katja Seipel,1,2 Miguel A.T. Marques,1 Corinne Sidler,1 Beatrice U. Mueller2 and Thomas Pabst2
ABSTRACT
Prognosis for FLT3-ITD positive acute myeloid leukemia with high allelic ratio (>0.5) is poor, particularly in relapse, refractory to or unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds target- ing both the mutated FLT3 receptor and cellular p53 inhibitors might be a promising treatment option for this poor risk leukemia subset. We therefore assessed MDM2 and FLT3 inhibitors as well as cytotoxic com- pounds used for conventional induction treatment as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. Acute myeloid leukemia cells represented all major mor- phologic and molecular subtypes with normal karyotype, including FLT3-ITD (>0.5) and FLT3 wild type, NPM1 mutant and NPM1 wild type, as well as TP53 mutant and TP53 wild type cell lines. Acute myeloid leukemia cells with mutated or deleted TP53 were resistant to MDM2- and FLT3-inhibitors. FLT3-ITD positive TP53 wild type acute myeloid leukemia cells were significantly more susceptible to FLT3-inhibitors than FLT3-ITD negative TP53 wild type cells. The pres- ence of a NPM1 mutation reduced the susceptibility of TP53 wild type acute myeloid leukemia cells to the MDM2 inhibitor NVP-HDM201. Moreover, the combined use of MDM2- and FLT3-inhibitors was supe- rior to single agent treatment, and the combination of midostaurin and NVP-HDM201 was as specific and effective against FLT3-ITD positive TP53 wild type cells as the combination of midostaurin with conven- tional induction therapy. In summary, the combined use of the MDM2 inhibitor NVP-HDM201 and the FLT3 inhibitor midostaurin was a most effective and specific treatment to target TP53 and NPM1 wild type acute myeloid leukemia cells with high allelic FLT3-ITD ratio. These data suggest that the combined use of NVP-HDM201 and midostaurin might be a promising treatment option particularly in FLT3-ITD positive acute myeloid leukemia relapsed or refractory to conventional therapy.
Introduction
Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by blocked differentiation and deregulated proliferation of hematopoietic precur- sor cells. At the cellular level, specific genetic and epigenetic alterations lead to changes in cellular signaling pathways including the common inactivation of the p53 tumor suppressor axis, and thereby contribute to blocked differentiation and accumulation of leukemic blasts in the blood and the bone marrow. The past decade has witnessed major advances in our comprehension of the biologic hetero- geneity of AML.1 AML genetic variants are assigned into favorable, intermediate and poor risk categories, and a major molecular subgroup within the poor risk AML is characterized by genetic alterations of the FLT3 receptor gene. FLT3 internal tan-
Correspondence:
thomas.pabst@insel.ch
Received: February 20, 2018. Accepted: June 29, 2018. Pre-published: July 5, 2018.
doi:10.3324/haematol.2018.191650
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/11/1862
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