Abstract 2641: Examining the potential therapeutic efficacy of the CDK inhibitor alvocidib in a pre-clinical model of myelodysplastic syndrome
Authors: Bertoli Ryan M. , Chung Yang Jo , Foulks Jason M. , Wokasch Anthony S. , Aplan Peter D. 
Published: June 2022

Myelodysplastic Syndrome (MDS) represents a group of hematologic malignancies characterized by pancytopenia and dysplastic morphology. High risk MDS is invariably fatal due to either severe cytopenia, or transformation to acute myeloid leukemia (AML). Inhibitors of transcription offer promising potential for new therapies. Modulation of CDK9 activity, which plays a critical role in controlling gene transcription through phosphorylation of RNA polymerase II, has been proposed as a novel therapeutic approach. In this study, we examined the efficacy of alvocidib, a broad spectrum CDK inhibitor with highest potency against CDK9, which is hypothesized to slow transcription via inhibition of CDK9, leading to stalled RNA Polymerase II and cell death. We employed a previously characterized pre-clinical model of MDS based on the NUP98-HOXD13 (NHD13) fusion gene, which induces MDS that progresses to AML in mice. In addition to alvocidib, we evaluated the in vitro efficacy of 5-Azacytidine (5-Aza) and Decitabine (DAC), which are hypomethylating agents used in treatment of MDS. The in vitro assays demonstrated a potent effect of alvocidib on cell lines that expressed the NHD13 fusion gene. Alvocidib induced a clear cytostatic effect and showed increasing cytotoxic effects with time, peaking at 70% cell death after 72 hours. Annexin-V staining further supported these results, revealing that most cells were apoptotic by 72 hours. Neither 5-Aza nor DAC treatment matched these effects in vitro. The in vivo assays were based on treatment of chimeric mice with both wild type (WT) and MDS hematopoiesis, generated by allogeneic hematopoietic stem cell transplant with bone marrow from WT and NHD13 mice. Four treatment groups (saline, 5-Aza, Alvocidib, and 5-Aza+Alvocidib) were assessed by serial flow cytometry and complete blood counts. In contrast to in vitro studies, in vivo results did not show a clear survival benefit from either group receiving alvocidib, whereas 5-Aza treatment demonstrated statistically significant survival. However, this study revealed several “exceptional responder” mice, defined as mice that demonstrated a ≥75% reduction in WBC count and a ≥50% reduction in NHD13 engraftment levels following transformation to AML; these exceptional responses were observed only in mice receiving alvocidib. This type of dramatic response has not previously been observed in over 20 prior chimeric transplant experiments employing the NHD13 mouse model. Ongoing efforts include follow-up studies to evaluate the frequency of exceptional responders, as well as identification of acquired mutations which collaborate with the initiating mutation (NHD13) to generate AML.

Citation Format: Ryan M. Bertoli, Yang Jo Chung, Jason M. Foulks, Anthony S. Wokasch, Peter D. Aplan. Examining the potential therapeutic efficacy of the CDK inhibitor alvocidib in a pre-clinical model of myelodysplastic syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2641.