Department for Biomedical Research, University of Bern.
Department of Medical Oncology, Inselspital, Bern University Hospital, Switzerland.
Haematologica. 2018 Nov;103(11):1862-1872. doi: 10.3324/haematol.2018.191650. Epub 2018 Jul 5.
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.
FLT3 内部串联重复（ITD）阳性、高等位基因比（>0.5）的急性髓系白血病患者预后较差，尤其是在复发、对强化治疗耐药或不适合强化治疗的患者中，因此迫切需要新的治疗方法。联合使用针对突变型 FLT3 受体和细胞 p53 抑制剂的化合物可能是这种高危风险白血病亚组的一种有前途的治疗选择。因此，我们评估了 MDM2 和 FLT3 抑制剂以及用于常规诱导治疗的细胞毒性化合物作为单一药物以及联合使用时在诱导白血病细胞凋亡和细胞死亡方面的能力。急性髓系白血病细胞代表了所有主要的形态学和分子亚型，具有正常核型，包括 ITD（>0.5）和 FLT3 野生型、突变型和野生型，以及 TP53 突变型和野生型细胞系。突变或缺失的急性髓系白血病细胞对 MDM2 和 - 抑制剂具有耐药性。FLT3 抑制剂对 ITD 阳性野生型急性髓系白血病细胞的敏感性明显高于 ITD 阴性野生型细胞。存在 突变降低了野生型急性髓系白血病细胞对 MDM2 抑制剂 NVP-HDM201 的敏感性。此外，MDM2-和 - 抑制剂的联合使用优于单一药物治疗，米哚妥林和 NVP-HDM201 的联合使用对 ITD 阳性 TP53 野生型细胞与米哚妥林与常规诱导治疗的联合使用一样具有特异性和有效性。总之，MDM2 抑制剂 NVP-HDM201 和 抑制剂米哚妥林的联合使用是针对高等位基因 ITD 比的野生型急性髓系白血病细胞的最有效和最特异的治疗方法。这些数据表明，NVP-HDM201 和米哚妥林的联合使用可能是一种有前途的治疗选择，特别是在 ITD 阳性急性髓系白血病复发或对常规治疗耐药的情况下。
