It is a clinical trial that deals with an elderly population with essentially the highest risk type of acute lymphoblastic leukaemia which in the pre-kinase inhibitor era was uniformly fatal unless patients underwent stem cell transplant. So things changed somewhat and it has become standard to use chemotherapy plus a kinase inhibitor as the treatment for these patients and in younger patients go on to transplant but this is not an option in a patient population of this age range. So within the EWALL we developed a European backbone chemotherapy protocol on which we grafted experimental treatments. I will present the data on the combination with nilotinib which has been approved for quite a number of years for chronic myeloid leukaemia but we have little experience in acute lymphoblastic leukaemia.
The minimal cut-off was 55 years of age; it was only Ph positive ALL so no CML patients were allowed. We only allowed a minimal prior treatment as a pre-phase so these were de novo, newly diagnosed patients. CNS, cranial nervous system, involvement is a problem in this disease and it was not excluded.
Now this is the treatment schedule, it is, as usual, relatively complicated for acute lymphoblastic leukaemia and I would just like to emphasise different principles of treatment in that we rely heavily during the induction phase on the kinase inhibitor and we’ve minimised the chemotherapy in that we only use corticosteroids and essentially one drug called vincristine. During the later consolidation phases we use the somewhat more intensive regimen using essentially three drug combinations. So for this elderly patient group it is actually a significant intensity of chemotherapy during the later stages of treatment.
We looked at minimal residual disease, specifically at two time points – an early one after induction and a later time point – to assess the impact of induction and consolidation cycles in conjunction with nilotinib which was given throughout treatment and without interruption.
So this is a planned interim analysis that I am presenting, the study is still ongoing. Of the 56 patients I can report on 47 which were enrolled in time to provide at least minimum duration of follow-up. You can see that the median age was 65 but we did include patients up to the age of 85 in this clinical trial. None had CNS involvement. The enrolment started in 2012, it has picked up considerably and we are going now at a quite good clip of new enrolment. So 47 patients, 87% of them achieved a complete haematological remission. There was a low incidence of treatment failure and induction deaths of 4% and 2% respectively and in 3 patients there was early discontinuation so that we were not able to evaluate the response within the trial. So these are excluded although some of them actually achieved a CR later on but we are not counting them. The median time to achieve this response was 6 weeks.
This is the remission duration. I have to emphasise that the median follow-up is still short but it seems to be a highly effective treatment in that we’ve only a few relapses at this time. If we look at the overall survival we have in the range of 70% at 30 months. There were a number of patients who actually underwent allotransplant, this was something that was specifically allowed and even encouraged in the protocol, at the present time there is no survival benefit among the 9 patients who underwent transplant. It will be of interest to see how this will proceed, if the transplant free patients will do as well as the others.
Minimum residual disease is shown here and it emphasises that you have a significant further increase with the consolidation cycles plus the kinase inhibitor. So continuing the treatment in this form increases the depth of response and if we then look at the rate of MRD negativity using high quality assays then a quarter of the patients have undetectable PCR during the consolidation cycles and approximately 80% achieve something that we call a major molecular response.
So, in conclusion, the data I have presented show that the combination of nilotinib with this age adapted chemotherapy is highly effective. We do have quite a reasonable overall survival estimate at two years of just more than 70%. It does show you that at least in Europe allogeneic transplant is still considered an option even in this elderly population and we will see if it is needed or provides benefit or not. We do have an encouragingly high rate of molecular responses. We will await the completion of the study which is anticipated to occur in a few months’ time.
With that I would like to end by acknowledging the EWALL Group. We’re quite proud, actually, to have put together several European countries to act in conjunction with each other using the same therapeutic regimen going from clinical trial to clinical trial.