02 October 2017


Leukaemia patients who carry a specific genetic fault in their cancer cells could be affected by how they respond to treatment, a new UK study has found.

The results from the RAvVA clinical trial, led by researchers at the University of Birmingham, could help doctors to tailor treatment that will improve the outlook for people whose cancer cells carry a mutation in the CDKN2A gene, the researchers say.

The study looked to see if people with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) could survive for longer if their standard azacitidine treatment was supplemented by the biological drug vorinostat.

Researchers identified no additional benefit in people who had the combined treatment - but they found that the patients whose cancer cells had the mutation had a significantly worse outcome.

Azacitidine is believed to interfere with DNA in cancer cells and restore the activity of genes that control the rate of cell growth. However, everyone responds and all people eventually relapse.

Previous smaller clinical trials had suggested combining vorinostat, which blocks cancer growth, with azacitidine for an improved outcome.

In this trial, which is published in Clinical Cancer Research, 259 people with AML or MDS were recruited in 19 hospitals across the UK through Bloodwise’s ‘Trials Acceleration Programme’ (TAP).

Half received a combination of azacitidine and vorinostat, while the other half were prescribed azacitidine alone. Researchers found that those who had the combination treatment survived for 11 months after diagnosis on average, compared to 9.6 months for people only treated with azacitidine.

They correlated the depth of response of patients treated with azacitidine on the trial with the genetic makeup of their cancer cells at diagnosis, and discovered that people with faults in CDKN2A, IDH1 and TP53 genes had significantly reduced overall survival times.

Because people who had mutations in CDKN2A, which regulates the cell cycle by making several proteins that control cell growth, had a poorer outcome, the researchers believe that azacitidine works by causing cell cycle arrest.

They also believe that testing people newly diagnosed with AML and MDS for CDKN2A, IDH1 and TP53 genetic mutations could help doctors tailor treatment for people who are less likely to do well.

Charles Craddock, BSH President, professor of haemato-oncology at the University of Birmingham and director of the Centre for Clinical Haematology, said: 'This important trial has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasises the need for further studies with new drug partners for azacitidine.

'Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.'

Dr Alasdair Rankin, director of research at Bloodwise, added: 'This trial has taught us much more about how doctors might treat individual people living with MDS and AML differently, so we can improve their care.'

Source: Craddock et al. Outcome of Azacitidine Therapy in Acute Myeloid Leukemia is not Improved by Concurrent Vorinostat Therapy but is Predicted by a Diagnostic Molecular Signature. Clinical Cancer Research 27 September 2017; doi: 10.1158/1078-0432.CCR-17-1423


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