Evaluating in Vivo AZA Incorporation in Mononuclear Cells Following Vidaza or CC486

Summary

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MDS is an insidious and largely incurable haematological malignancy that increasingly impacts on the well-being of our ageing population, and one for which there has been no significant therapeutic advance since the introduction of injectable AZA (Vidaza®) over a decade ago. Furthermore, the basis f...

MDS is an insidious and largely incurable haematological malignancy that increasingly impacts on the well-being of our ageing population, and one for which there has been no significant therapeutic advance since the introduction of injectable AZA (Vidaza®) over a decade ago. Furthermore, the basis for the effectiveness of Vidaza® or lack thereof is not known and attempts at identifying genes that are reactivated and induce HSC differentiation have generally been unrewarding. It is also unclear whether these drugs work by inducing cellular differentiation or triggering apoptosis of the abnormal clone by activating permissive gene transcription. Recently developed assays permit genome-wide mutation analysis and assessment of gene expression and methylation at gene regulatory regions. Combined with functional studies, these assays are powerful tools that could help identify why some patients respond and others don't and why patients relapse after initial response. They can also help provide molecular insights into specific genes or pathways that could be manipulated to overcome primary or secondary drug resistance to AZA. Following the evaluation CC-486 safety in Phase 1 studies, a Phase 2, international, multicentre, randomized, open-label, parallel group study was launched and is currently recruiting to evaluate the efficacy and safety of CC-486 alone and in combination with durvalumab in participants with MDS who fail to achieve objective response to treatment with Vidaza®. However, at present there is no objective method of correlating clinical or molecular response with actual drug incorporation due to the lack of a robust assay to measure AZA incorporation in vivo. This gap has now been filled by the recent development of a liquid chromatography-mass spectrometry (LC-MS) based assay that is effective in measuring AZA pharmacokinetics in vivo; "AZA-MS: a novel mass spectrometry method to determine the intracellular pharmacokinetics of AZA therapy in vivo" (Unnikrishnan et al Leukemia 2017) and we will for the first time be able to directly compare Vidaza® incorporation with CC486 incorporation in the same patient and measuring clinical and molecular response after six cycles of the former followed by six cycles of the latter. The primary objective of the trial is to determine whether there is greater AZA incorporation in DNA in blood progenitors following 21 days of CC486 than there is with 7 days of Vidaza® in a 28- day treatment cycle and whether incorporation is associated with greater clinical and/or molecular response. The secondary objectives of the trial are based on outcomes from a compassionate access program conducted in NSW, Australia from 2008-09. MDS, MDS/AML and CMML patients who respond to Vidaza® were found to have a greater fraction of hematopoietic progenitor cells (HPCs) progressing through the cell cycle than patients who fail to respond to AZA (Unnikrishnan et al 2017). What is not known is whether increased replication is associated with increased AZA incorporation. The availability of an assay (AZA-MS) to measure AZA incorporation, and the ability to measure the fraction of replicative HPCs, forms the basis of the secondary objectives of this study. When applying the AZA-MS assay to samples collected from the compassionate access program, we also noted that AZA non-responders either do not incorporate AZA derivatives in DNA following Vidaza® or do incorporate AZA to levels comparable to that of responders yet still fail to respond (Unnikrishnan et al Leukemia 2017). Mechanisms of pharmacologically overcoming resistance would be quite different in the two instances. Longitudinal measurements of derivative AZA incorporation in DNA can now be combined with assays to evaluate whether patients who do not respond despite adequate drug uptake fail to activate downstream processes such as interferon/immune pathway activation or display check-point inhibition. This study will provide data to support individualised alternatives to optimise future AZA therapy.

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