Abstract
Acute myeloid leukemia (AML) is the second most common type of leukemia in adults. Incidence of AML increases with age with a peak incidence at 67 years. Patients older than 60 years have an unfavorable prognosis due to resistance to conventional chemotherapy. Volasertib (BI 6727) is a cell-cycle regulator targeting polo-like kinase which has been evaluated in clinical trials in AML. We evaluated effects of volasertib in primary patient samples and NK cells. At equivalent doses, volasertib is cytotoxic to AML blasts but largely spares healthy NK cells. We then evaluated the effect of volasertib treatment in combination with BI 836858 on primary AML blast samples using antibody-dependent cellular cytotoxicity (ADCC) assays. Volasertib treatment of NK cells did not impair NK function as evidenced by comparable levels of BI 836858 mediated ADCC in both volasertib-treated and control-treated NK cells. In summary, volasertib is cytotoxic to AML blasts while sparing NK cell viability and function. Higher BI 836858 mediated ADCC was observed in patient samples pretreated with volasertib. These findings provide a strong rationale to test combination of BI 836858 and volasertib in AML.
Highlights
Acute myeloid leukemia (AML) is the second most common type of leukemia in adults; it is a disease associated with aging with a peak incidence at 67 years [1]
We show that at similar concentrations of volasertib, NK cells were relatively spared compared to AML blasts
Despite lower viability of NK cells at high concentrations of volasertib (1000 nM), we observed that antibody-dependent cellular cytotoxicity (ADCC) of BI 836858 mediated by NK cells was not lower with volasertib-treated NK cells
Summary
Acute myeloid leukemia (AML) is the second most common type of leukemia in adults; it is a disease associated with aging with a peak incidence at 67 years [1]. Polo like kinase 1 (PLK1) is a mitotic serine, threonine kinase and plays a crucial role in G2/M transition and mitosis [9,10,11]. It is over expressed in neuroblastoma [12], and leukemias [8, 13, 14] with lower expression in untransformed cells. Volasertib was shown to have higher event-free survival in a randomized phase 2 trial where volasertib was given in combination with lowdose cytarabine in AML patients [18]
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