Despite huge advances in understanding the biology of leukaemia, driven mainly by genomic sequencing, change in clinical practice has lagged behind. In this context, the use of light microscopy and manual cell counting to assess response to treatment seemed particularly anachronistic to us. After more than 15 years of sustained effort from Professor David Grimwade and others, the techniques we have developed are becoming accepted as the new standard of care around the world, dramatically improving our ability to deliver personalised care for these patients.Dr Richard Dillon
09 June 2021
Over the last decade researchers at King’s have been working on ground-breaking ways to tailor Acute Myeloid Leukaemia treatment to individual patients
Every year around 3000 people in the UK are diagnosed with Acute Myeloid Leukaemia (AML) – an aggressive and frequently fatal form of blood cancer. Treatment for AML exists, but it is often risky, invasive and particularly taxing on patients, and fewer than half of AML sufferers survive longer than 2 years past their initial diagnosis.
Over the last decade researchers at King’s have been working on ground-breaking ways to tailor AML treatment to individual patients, identifying those who would respond well to Bone Marrow Transplantation (BMT) and detecting those at risk of relapse.
This work, undertaken by Professor David Grimwade, Professor Ellen Solomon and Dr Richard Dillon, has focussed on developing and implementing highly sensitive molecular tests which allow health workers to precisely measure an individual’s response to treatment. The results of this test inform the subsequent treatment approach.
By allowing for what the researchers term “molecularly guided therapy”, treatment for patients at high risk of relapse can be intensified, while those who are likely to be cured can be spared the risks of undergoing unnecessary treatment. At the same time, it has helped to determine which patients should undergo BMT.
Leading the field in research
Between 2009 and 2014 King’s led a clinical trial assessing 2569 samples obtained from 346 patients who had undergone intensive treatment for AML. The team discovered that molecular testing could provide vital prognostic information, revealing that molecular measurable residual disease (MRD) status made a significant difference to survival rates.
MRD status effectively split patients into two groups – those with MRD had a 24% chance of survival at three years, while those without MRD had a 75% chance of survival at the same end point.
These findings have had a tremendous impact on decision-making by providing an indicator of who is at risk of relapse and who would be a viable candidate for transplantation. BMT is a risky procedure, with a 10-20% chance of treatment-related death, so identifying whether a patient will respond well to transplant before surgery makes a significant difference to quality of life.
King’s researchers then investigated the impact that repeated MRD testing could have on predicting relapse in patients who had previously undergone treatment. This would allow for pre-emptive interventions to be deployed in an effort to prevent relapse.
They found that regular MRD testing was reliable in detecting relapse in a subset of AML patients with Acute Promyelocytic Leukaemia (APL), which accounts for 10% of AML. Regular molecular monitoring, together with pre-emptive molecularly guided salvage treatment, reduced the rate of disease relapse in APL AML patients from 12% to 5%.
Furthermore, in a follow-up study King’s researchers discovered that sequential monitoring can also reliably predict relapse in patients with non-APL AML, broadening the impact of their findings. In subsequent tests they found that by exploiting the window for pre-emptive intervention and offering a novel, non-intensive treatment (venetoclax + cytarabine), AML disease was cleared at the molecular level in 92% of the sample, and 83% of these patients had prolonged disease-free survival.
The results of this work give me a deep appreciation and gratitude that we were actually successful in an instance of translational research which resulted in amelioration of this terrible disease.Professor Ellen Solomon
Informing national clinical guidelines and cutting costs
This work by King’s researchers has prompted changes to clinical practice, resulted in improvements to quality of life and survival of AML patients, and has brought about NHS cost-saving.
During the height of the COVID-19 pandemic it was considered unsafe for AML patients to undergo intensive chemotherapy which would put them at greater risk of infection. With their knowledge of how different patient subgroups were likely to respond to novel therapies, King’s researchers were able to lead the development and continuous updating of national treatment guidelines based on the use of new drugs, preventing unnecessary infections and fatalities and freeing up NHS beds.
By identifying viable candidates for transplantation through molecular testing the UK could reduce its annual BMT procedures by approximately 100. At a cost of £100 000 per patient, this would mean an NHS saving of up to £10 000 000 a year. Similarly, treating patients at the time of molecular relapse as opposed to frank haematological relapse will substantially reduce the demand for healthcare resources.
At the moment, treatment for patients with AML remains fairly brutal. The development of molecular monitoring techniques in the APL subtype underpinned a complete therapeutic revolution and most patients with this disease are now are treated without chemotherapy. Our focus now is to harness the techniques we have developed to replicate this across other subtypes of AML, where effective molecularly targeted agents are finally starting to become available.Dr Richard Dillon
There are now 30 patients enrolled in this ongoing study, which has opened additional sites in Denmark and New Zealand.