Harmonisation of CLL diagnosis and detection of residual disease monitoring by flow cytometry
Dr Andrew Rawstron - St James Institute of Oncology, Leeds, UK
Can you tell me a bit about your research and what you presented today?
We’re a haematological oncology laboratory with a multidisciplinary lab in Leeds; we do a lot of work for clinical trials across the UK. So the work we were presenting is really about how to harmonise the diagnosis and the monitoring of chronic lymphocytic leukaemia. We’re quite a big lab in the UK and we collaborate with other laboratories across Europe and the US and also in Australia in getting the best ways to diagnose and monitor people.
Most of the work I’ve done for the past two decades now is on minimal residual disease analysis. We’re just getting to a stage now where the treatments are so good that the conventional response assessment isn’t working well enough anymore to differentiate between treatments and tell which ones are the best, the best option. More sensitive measures of detecting response have been around for a decade or so but they’re now coming into practice, needing to be applied in every trial. So we’ve done a lot of work in trying to make sure that everybody does it in the same way, or at least gets to the same sensitivity so that you can compare a trial in Australia, in America, in Europe.
Having completed that harmonisation effort we actually found that there was a lot of variation in how people diagnose CLL. So it seems like it should be something that’s absolutely standard and there have been diagnostic criteria for many decades. They allow a flexibility in the diagnosis so that as many people as possible can gain access to treatment. That flexibility means that different centres do things slightly differently and it may affect the type of patient that enrols into a clinical trial; it may affect which patients get access to clinical trials. So the presentation for this meeting was about how to harmonise the diagnosis without trying to be too restrictive, so maintaining the access for different patients but also making sure that different laboratories did it in the same way so that the same people were being given a diagnosis of CLL. Those people who have a borderline disease with other disorders, at least we know we can capture that information and maybe they will actually respond better to some of the treatments that are being offered to CLL patients. At the moment we don’t know so having a harmonised approach to diagnosis is quite important.
So, specifically, what results did you present today?
Initially we just did a survey of everybody’s practice and found what the experts around the world thought should be an absolute minimum requirement for diagnosis. Then, because it has to work across different resource settings, in some places in the world you’ll have a very low resource lab next to an extremely highly resourced lab, both trying to do similar diagnostic techniques. So in terms of a global harmonisation effort you need to have something that will work in both those settings but then also for the higher resource areas you want to ensure that the best markers are being looked at, that everybody is looking at least at the most relevant markers for diagnosis. So we had a core set of markers that everybody should be using to diagnose CLL and then another set of markers that people should be incorporating routinely if they have the resources. Hopefully over the next few years that will help really identify a uniform group of patients and where there are people who fall slightly outside of that uniform set we can look with the latest molecular techniques to find out whether they fit better in another disease category or whether they fit better with CLL.
So, for example, there are lots of molecular pathway abnormalities that have been identified over the last few years in different B-cell disorders, different cancers across the spectrum, and there may be more than one in an individual patient. So if a patient has one pathway plus a pathway that’s common in a different disease together they may look diagnostically borderline between the two and they may respond better to different treatments.
What are your future plans for research down the track?
Having got the set of criteria the next thing to do is to test that prospectively to then find out exactly what the molecular abnormalities are in the patients who have borderline diagnostic features. It’s one part of the things that we’re doing amongst the clinical trials. The other harmonisation effort that I was talking about before, the minimal residual disease assessment, the need to assess response is changing as the treatments get better. So at the moment the threshold we look for is 1 in 10,000 cells, one CLL cell in 10,000 normal leukocytes as a threshold for MRD. But actually it’s a gradation, so if you have less than one in a million cells at the end of treatment those patients have an improved survival. So the other strand to the research that we do in Leeds and in collaboration with other people is how to move that detection limit forward so we can assess response better.
