Prognostic impact of chromosomal abnormalities and copy number alterations in B-cell precursor ALL treated on UKALL14

Prof Anthony Moorman - Newcastle University, Newcastle, UK

What we did in this presentation is build upon the work that we had previously done which had shown that acquired chromosomal abnormalities in patients with adult acute lymphoblastic leukaemia were prognostic. So many years ago, about twelve years ago now, we showed this and in the subsequent trial, which is called UKALL14 which is the one I was presenting today, we had treated patients with high risk genetic abnormalities on a slightly different protocol. We classified them as high risk and therefore they’d had high risk therapy.

So the purposes of this paper was to a) see how the patients that we had treated high risk had fared, had their outcome improved or had it stayed the same; also to evaluate the prognostic relevance of additional chromosomal abnormalities that had been identified in the intervening period; and, thirdly, to look at the effect of secondary copy number alterations in this particular cohort.

So in terms of the outcome of patients that we had previously identified as high risk some of them had stayed the same, unfortunately, their outcome had not improved indicating that they needed alternative therapeutic approaches. One group had improved slightly which indicated that giving these patients a stem cell transplant was probably improving their outcome. We then identified a new subgroup of high risk patients from this that had a new genetic abnormality known as JAK-STAT abnormalities, and we found that they had a very poor outcome when treated as standard risk. So that particular finding will be taken forward into our next clinical trial where these patients will be treated as high risk.

The third outcome was where we were looking at patients with secondary copy number alterations. There what we had done is we had lifted a lot of the work that had been done in paediatric ALL to see if it was also prognostic in adult ALL. In that particular instance we found that it didn’t predict outcome in adult ALL. This is not surprising for a number of reasons, largely because the genes that we were looking at were particularly prevalent and important in paediatric ALL but that didn’t translate in this instance to adult ALL. So although that was a negative result it was an important one because it means that we will not be therefore taking forward that as a biomarker into the next clinical trial.

There were a total of 800 patients or so treated on UKALL14 in total and we were reporting on 653 that had B-cell precursor acute lymphoblastic leukaemia.  So not massive numbers but adult ALL is quite rare and these are all patients aged between 25 and 65. So this is still one of the largest cohorts that’s ever been assembled of adult ALL with that particular age range.

They’re going to impact clinical practice in terms of how these patients will be risk stratified in the next trial. So we’re currently in the design phase of the next trial so I’m working with my clinical colleagues who are going to be running that trial. What we will do is we will use that body of information to say, right, these are the patients that will receive the kind of standard arm of therapy; these are the kind of randomisations that you might want to look at in this particular very high risk cohort of patients. It offers the opportunity for clinicians to think about targeted therapy for some of these rarer subgroups of patients. So it’s really about just providing information for my clinical colleagues to make more informed decisions when they’re designing the next clinical trial. So all of this information will be included in the design of the next clinical trial, yes.