MDM2- and FLT3-inhibitors in the treatment of -ITD acute myeloid leukemia, specificity and efficacy of NVP-HDM201 and midostaurin.

Seipel, Katja; Marques, Miguel A T; Sidler, Corinne; Mueller, Beatrice U; Pabst Müller, Thomas Niklaus (2018). MDM2- and FLT3-inhibitors in the treatment of -ITD acute myeloid leukemia, specificity and efficacy of NVP-HDM201 and midostaurin. Haematologica - the hematology journal, 103(11), pp. 1862-1872. Ferrata-Storti Foundation 10.3324/haematol.2018.191650

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Prognosis for -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 targeting 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 compounds 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 morphologic and molecular subtypes with normal karyotype, including -ITD (>0.5) and FLT3 wild type, mutant and wild type, as well as TP53 mutant and wild type cell lines. Acute myeloid leukemia cells with mutated or deleted were resistant to MDM2- and -inhibitors. -ITD positive wild type acute myeloid leukemia cells were significantly more susceptible to FLT3-inhibitors than -ITD negative wild type cells. The presence of a mutation reduced the susceptibility of wild type acute myeloid leukemia cells to the MDM2 inhibitor NVP-HDM201. Moreover, the combined use of MDM2- and -inhibitors was superior to single agent treatment, and the combination of midostaurin and NVP-HDM201 was as specific and effective against -ITD positive TP53 wild type cells as the combination of midostaurin with conventional induction therapy. In summary, the combined use of the MDM2 inhibitor NVP-HDM201 and the inhibitor midostaurin was a most effective and specific treatment to target and wild type acute myeloid leukemia cells with high allelic -ITD ratio. These data suggest that the combined use of NVP-HDM201 and midostaurin might be a promising treatment option particularly in -ITD positive acute myeloid leukemia relapsed or refractory to conventional therapy.

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