Histone deacetylases targeted as new strategy against graft versus host disease
Professor Sung Choi – University of Michigan, Ann Arbor, USA
Bone marrow transplantation is a potentially curative therapy for many haematological malignancies as well as non-malignant conditions. Unfortunately, acute graft versus host disease remains a serious barrier to the successful application of bone marrow transplant and over the past two to three decades the prevention therapies for acute GVHD have remained largely unchanged. So in work that has been done in Dr Ruddy’s laboratory over the past decade we have had exciting results using a novel therapeutic drug known as a histone deacetylase inhibitor, vorinostat, in being able to reduce inflammatory proteins that are known to be involved in the cascade leading up to GVHD. What we saw when we gave mice the vorinostat drug is that it improved their mortality, overall survival, as well as reduced the cardinal features of acute GVHD. So after a decade of work that was done in the laboratory we were able to translate our findings in humans using this concept.
What are the current statistics for this procedure?
The incidence of acute GVHD by day 100 is typically in the range of 20-60%, depending on the donor you use or the regimen that is used. So we based, initially when we designed the trial, on controls that had an incidence at day 100 of about 48% and our study was able to reduce the incidence all the way down to 21%. Notably, what is more exciting is that this severe lethal form of GVHD, grade 3-4, was reduced all the way down to 4% from controls of about 20%. So we’re pretty excited about the findings.
What will the clinical impact be?
This would have a significant impact because we see not only that this drug is tolerable, patients aren’t developing worse infections, worse relapse rates. So the impact could be huge in terms of being able to minimise GVHD, not take it away all the way, like you heard that is a little bit is essential, in a sense, to help prevent against leukaemia, but it could have a significant impact if we could reduce it to where it is a tolerable and treatable degree.