Contributions
Abstract: EP390
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Acute myeloid leukemia (AML) is known to be associated with high lethality despite intensive treatment. Recently published study demonstrated that expression of IRAK4-L is mediated by mutant splicing factor U2AF1 and is associated with oncogenic signaling in human AML and myelodysplastic syndromes (MDS). Preliminary data from our ongoing Phase 1 dose escalation study demonstrated that treatment with IRAK4 inhibitor CA-4948 has shown early signs of clinical activity in patients with relapsed/refractory AML and high-risk MDS.
Aims
Our goal was to identify an effective combination of CA-4948 with standard-of-care (SOC) drugs for the treatment of FLT3-WT AML.
Methods
We used CellTiter Glo cell viability assay to evaluate the antitumor effects of CA-4948 in combination with AML SOC drugs daunorubicin, Ara-C, decitabine, azacitidine and venetoclax in FLT3-WT AML cell lines THP-1, F-36P, OCl-AML2 and GDM-1. GI50 (the concentration for 50% of maximal inhibition of cell proliferation) was determined for each drug in AML cell lines. Either GI50 (below peak plasma concentration) or peak plasma concentration (if GI50 was higher than peak plasma concentration) of each drug was used as clinically relevant concentration for combination experiments.
Results
We identified THP-1 and F-36P cell lines as resistant to clinically relevant concentrations of venetoclax, whereas OCl-AML2 cell line was resistant to the treatment with azacitidine. Synergistic effect of combining CA-4948 with Ara-C was observed in THP-1 cell line. We found that CA-4948 potentiated antitumor effects of azacitidine in 3 of 4 FLT3-WT AML cell lines whereas we did not observe any additive or synergistic effect of combining CA-4948 with decitabine. The combination of venetoclax and CA-4948 inhibited the cell growth in 2 of 4 AML FLT3-WT cell lines more effectively than either of the two agents alone. Moreover, we found that CA-4948 significantly potentiated antitumor effects of azacitidine+venetoclax in all AML FLT3-WT cell lines.
Conclusion
Our results demonstrate that combination of CA-4948, azacitidine and venetoclax exhibits synergistic activity in FLT3-WT leukemia cells providing a rationale for clinical testing of this combination in FLT3-WT AML patients.
Keyword(s): Acute myeloid leukemia, MDS/AML, Therapy
Abstract: EP390
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Acute myeloid leukemia (AML) is known to be associated with high lethality despite intensive treatment. Recently published study demonstrated that expression of IRAK4-L is mediated by mutant splicing factor U2AF1 and is associated with oncogenic signaling in human AML and myelodysplastic syndromes (MDS). Preliminary data from our ongoing Phase 1 dose escalation study demonstrated that treatment with IRAK4 inhibitor CA-4948 has shown early signs of clinical activity in patients with relapsed/refractory AML and high-risk MDS.
Aims
Our goal was to identify an effective combination of CA-4948 with standard-of-care (SOC) drugs for the treatment of FLT3-WT AML.
Methods
We used CellTiter Glo cell viability assay to evaluate the antitumor effects of CA-4948 in combination with AML SOC drugs daunorubicin, Ara-C, decitabine, azacitidine and venetoclax in FLT3-WT AML cell lines THP-1, F-36P, OCl-AML2 and GDM-1. GI50 (the concentration for 50% of maximal inhibition of cell proliferation) was determined for each drug in AML cell lines. Either GI50 (below peak plasma concentration) or peak plasma concentration (if GI50 was higher than peak plasma concentration) of each drug was used as clinically relevant concentration for combination experiments.
Results
We identified THP-1 and F-36P cell lines as resistant to clinically relevant concentrations of venetoclax, whereas OCl-AML2 cell line was resistant to the treatment with azacitidine. Synergistic effect of combining CA-4948 with Ara-C was observed in THP-1 cell line. We found that CA-4948 potentiated antitumor effects of azacitidine in 3 of 4 FLT3-WT AML cell lines whereas we did not observe any additive or synergistic effect of combining CA-4948 with decitabine. The combination of venetoclax and CA-4948 inhibited the cell growth in 2 of 4 AML FLT3-WT cell lines more effectively than either of the two agents alone. Moreover, we found that CA-4948 significantly potentiated antitumor effects of azacitidine+venetoclax in all AML FLT3-WT cell lines.
Conclusion
Our results demonstrate that combination of CA-4948, azacitidine and venetoclax exhibits synergistic activity in FLT3-WT leukemia cells providing a rationale for clinical testing of this combination in FLT3-WT AML patients.
Keyword(s): Acute myeloid leukemia, MDS/AML, Therapy