A genetic fault has been identified in people with an aggressive type of leukaemia that can significantly affect how they respond to treatment.
The findings come from a clinical trial led by the University of Birmingham that 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.
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. The results may help doctors tailor treatment to improve the outlook for patients.
The trial, called RAvVA, was funded by the blood cancer research charity Bloodwise, and was delivered at 19 hospitals across the UK through the charity’s ‘Trials Acceleration Programme’ (TAP). The results of the trial have now been published in the journal Clinical Cancer Research.
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 out-patient, represents an important new treatment option.
Although the exact way azacitidine works is unknown, it is believed to interfere with DNA in cancer cells and restore the activity of genes that control the rate of cell growth. Not everyone will respond, however, and all people eventually relapse. Its effectiveness varies greatly from person to person, and it is hard to identify who will benefit most before treatment begins.
Previous smaller clinical trials had suggested that outcomes for people with AML or MDS could be improved by combining vorinostat, which blocks cancer growth, with 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 azacitidine alone.
It was found that adding vorinostat to azacitidine did not significantly improve treatment response or survival rates in people with AML or MDS. Those receiving the combination treatment survived for 11 months after diagnosis on average, compared to 9.6 months for people only treated with azacitidine. While this result was disappointing, 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 correlating the depth of response of patients treated with azacitidine on the trial with the genetic makeup of their cancer cells at diagnosis, 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. As people who had mutations in this gene had a poorer outcome, the Birmingham team believe that one of the ways that 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.
This is the first time that mutations in the CDKN2A gene mutation have been linked to poorer survival in people with AML treated with azacitidine and strikingly patients with the mutation survived on average for 4.5 months, compared to an average of 11 months for people without it.
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 who are less likely to do well.
The trial was led by Professor Charles Craddock, a Professor of Haemato-oncology at the University of Birmingham and Director of the Centre for Clinical Haematology run by University Hospitals Birmingham NHS Foundation Trust.
He said: “This important trial, delivered through the Bloodwise Trials Acceleration Programme, 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.”
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- Craddock et al (2017). ‘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. DOI: 10.1158/1078-0432.CCR-17-1423
- Read the paper.
- RAvVA is the Randomised Trial of 5-Azacitidine versus 5-Azacitidine in combination with Vorinostat in patients with Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndromes Ineligible for Intensive Chemotherapy.
- Acute myeloid leukaemia (AML) is a form of cancer that affects blood cells called myeloid cells, which include red blood cells, platelets and certain types of white blood cells. Patients experience uncontrolled growth of immature myeloid cells and do not produce enough healthy blood cells. Over 2,400 people are diagnosed with AML each year in the UK. It can affect anyone of any age, but the majority of patients are over 60. Chemotherapy and stem cell transplantation offer the best chance of a permanent cure. Many patients are too elderly to undergo intensive treatment, however, and overall fewer than one in five patients will survive for longer than five years after diagnosis.
- Myelodysplastic syndromes (MDS) is a type of blood cancer, in which the production of blood cells in the bone marrow is faulty. Just one type of blood cell can be affected or in some cases, MDS can cause a reduction in all types of blood cells. In addition to low blood counts, MDS share a common tendency to develop into acute myeloid leukaemia (AML) over time. The risk of this occurring depends on the type of MDS. Around 2,200 people are diagnosed with MDS each year in the UK.
- The University of Birmingham is a truly vibrant, global community and an internationally- renowned institution, in the top 100 globally. With approximately 28,000 students and 6,000 members of staff, its work brings people from more than 150 countries to Birmingham.
- The Trials Acceleration Programme (TAP) was launched in 2011 by Bloodwise to speed up blood cancer clinical trials. TAP is organised from a central hub at the University of Birmingham, which supports the efficient running of trials in hospitals, reducing the time it takes to open clinical trials in locations around the country. Bloodwise have a network of 13 TAP centres where they support a research nurse or other staff that help with clinical trials. Seven further hospitals are affiliated to TAP. These centres benefit from full access to the network, and can contribute to recruitment to individual TAP trials.
- Bloodwise is the UK’s specialist blood cancer research charity dedicated to improving the lives of people living with and beyond blood cancer. The charity, which was formed in 1960, changed its name from Leukaemia & Lymphoma Research in September 2015. Around 39,000 people of all ages, from children to adults, are diagnosed with blood cancers and related disorders every year in the UK. It is a complex disease area made up of over 100 individual diseases. Some affect thousands of people, such as common forms of leukaemia, lymphoma and myeloma. Others affect only a handful. But together, blood cancers are the fifth most common form of cancer, and the third largest cause of cancer death in the UK. The charity’s research is targeted at understanding more about blood cancer, finding causes, improving diagnosis and treatments, and running ground breaking clinical trials for patients. The charity champions patients’ needs by influencing relevant decision makers and influencers, and seeking to raise awareness of the issues faced by patients. Their patient services provide information, support and assistance to patients at every stage of their journey. For more information visit www.bloodwise.org.uk
- University Hospitals Birmingham (UHB) NHS Foundation Trust runs the Queen Elizabeth Hospital Birmingham (QEHB) and the original Queen Elizabeth Hospital (Heritage Building) and hosts the Institute of Translational Medicine (ITM). The Trust has approximately 1,400 beds, 32 theatres and a 100-bedded critical care until - the largest in Europe. QEHB is a Major Trauma Centre treating the most severely injured casualties from across the region. The hospitals are a regional centre for trauma, burns, plastics, neurosciences and cancer and in 2014 became a lead genomics centre as part of the NHS 100,000 Genomes Project. UHB has the largest solid organ transplantation programme in Europe. In 2016/17, UHB cared for over 1 million patients and currently employs over 9,500 members of staff. UHB is proud to host the Royal Centre for Defence Medicine (RCDM). The RCDM provides dedicated training for defence personnel and is a focus for medical research. UHB also holds the contract for providing medical services to military personnel evacuated from overseas via the aero medical service. UHB is one of only a small number of hospitals that can provide the full range of medical specialties – trauma, burns, plastics, orthopaedics, neurosurgery, critical care - needed to treat the complex nature of conflict injuries, all under one roof.