Results of a clinical trial may be able to help doctors tailor treatment for leukaemia patients.

Professor Charles Craddock, from the University of Birmingham (UoB) and Queen Elizabeth Hospital Birmingham (QEHB), led the trial, which was funded by the blood cancer research charity Bloodwise.

Throughout the UK, 19 hospitals delivered the clinical trial, through its Trials Acceleration Programme (TAP).

The trial, run by the UoB, examined whether survival times for people with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) could be improved by adding a biological drug called vorinostat to the current standard treatment, a drug called azacitidine.

The RavVA trial treated 259 people with AML or MDS, with half the participants receiving a combination of azacitidine and vorinostat, and half receiving the current standard treatment of azacitidine alone.

Although no additional benefit was seen by the new combination, people had a significantly worse outcome if their cancer cells carried a mutation to the CDKN2A gene.

For those who are fit enough to tolerate it, the best chance of a long-term cure for AML involves intensive chemotherapy followed by a stem cell transplant.

However high dose chemotherapy is poorly tolerated by older patients for whom the recently developed drug azacitidine, which can be delivered as an outpatient, represents an important new treatment option.

Azacitidine is believed to interfere with DNA in cancer cells and restore the activity of genes that control the rate of cell growth, though its effectiveness currently varies greatly.  

Previous smaller clinical trials had suggested that outcomes for people with AML or MDS could be improved by combining a biological drug called vorinostat – which blocks cancer growth – with azacitidine.

The trial found that adding vorinostat to azacitidine did not significantly improve treatment response or survival rates in people with AML or MDS.

Nevertheless, the study provides important new information that can be used to identify which patients are most likely to derive a clinical benefit from azacitidine therapy.

By comparing the genetic makeup of patients cancer cells with their response to azacitidine, they identified that people who had faults in CDKN2A, IDH1 and TP53 genes had significantly reduced overall survival times.

Importantly, CDKN2A is a gene that regulates the cell cycle by making several proteins that control cell growth, suggesting one of the ways azacitidine works is by causing cell cycle arrest.

This information will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.

The team believe that testing people newly diagnosed with AML and MDS for CDKN2A, IDH1 and TP53 genetic mutations could help doctors tailor treatment for people with these cells.

Professor Charles Craddock, Director of the Centre for Clinical Haematology which is run by University Hospitals Birmingham NHS Foundation Trust (UHB), said: “This important trial, delivered through the Bloodwise TAP, 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, said: “This study demonstrates how important clinical trials are to help us understand not just whether a possible new treatment approach works or not, but why it succeeds or fails.”

“By using samples from people with MDS and AML on this clinical trial, we have been able to understand the biology of blood cancer better.”

“As a result, 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.”