I would like to start by giving you some background information on this trial which is kind of unique. I want to emphasise three points: first is the role of MRD assessment in ALL, the second is how to treat MRD positive patients in the best way and the third is blinatumomab which is a really new treatment principle for the management of ALL.
So ALL is basically a disease of the bone marrow and traditionally the disease is measured by simply counting the blasts on a bone marrow smear under the microscope. The sensitivity of this method is 5%- if the blast count is below 5% we speak of the complete hematologic remission but we know that still blast cells are present in the body and this is called minimal residual disease. Several methods are available in ALL to measure minimal residual disease; in our study we focussed on a PCR based method, a quantitative PCR of individual gene rearrangement. The reason why we chose this method is that it is available or applicable in more than 90% of ALL patients and it is a very well standardised method for evaluation of MRD.
Now, the second thing which is important here is what is the biological meaning of MRD persistence. We know from a number of clinical trials that persistent MRD leads to a very poor prognosis in ALL patients. You can see on the bottom of the slide on the right side data from the German ALL trial showing that patients with persistent MRD, which is here named molecular failure, nearly all relapse despite continued chemotherapy. So this is a group of patients which is basically resistant to conventional chemotherapy drugs. On the left side you can see that this high relapse rate also translates into a poor overall survival and nowadays this is the poorest subgroup of adult ALL which is identified by molecular failure.
Now how can we optimally treat these patients? In ALL we usually offer patients a stem cell transplantation if they have a poor prognosis because this is the most intense treatment which is available nowadays. Most of the study groups have this indication now for patients with molecular failure of ALL but unfortunately these patients also have a higher relapse rate after the subsequent stem cell transplantation. So this is a good treatment but still not optimal and we need urgently new treatment approaches to treat these chemotherapy resistant patients and these new treatment approaches should be non-chemotherapy. The goal is here to achieve a molecular remission, to avoid the full relapse and also to perform then a stem cell transplantation in complete molecular remission. We should not forget about the patients who cannot get a transplant, for example older patients, and in these patients of course it’s a goal to achieve a continuous complete remission with these new compounds.
Here comes blinatumomab it is a new treatment principle, a B-specific antibody which is on one side directed to CD19, CD19 is expressed on the surface of B precursor ALL blast cells, and on the other side is directed to CD3 and thereby attracts CD3 positive T cells, brings them in very close proximity to the target cells and with this activation of the T cells the T cells proliferate and they perform a serial kill of the target cells which is very effective. There are some data from a small pilot study from Germany where we treated 20 patients with MRD positive ALL and the response rate with this trial was 80%. There are much more data with blinatumomab in relapsed refractory ALL, this also led to the FDA approval just a few days ago. But the difference in this trial is that we treat the patient before the full relapse.
So we included patients with MRD positive ALL above the age of 18. The detection level in the image had to be above 10-3, so quite high MRD levels, close to the full relapse. The primary endpoint of the study was complete MRD response and of course a secondary endpoint of adverse events. There are also a number of long-term outcome parameters as secondary endpoints but they cannot be analysed at this time point, a longer follow-up is needed. 116 patients were included in the trial, an international trial in several European countries.
This is the treatment overview. All patients had to receive at least one cycle. One cycle means 28 days of continuous infusion of blinatumomab then the primary endpoint assessment. After this first cycle patients could receive three more cycles or a stem cell transplantation at any other time point if a donor was available. Afterwards the patients entered the long-term efficacy and survival follow-up.
This slide shows you the major results of this trial and I would like to explain first of all the endpoints because we have to get a little bit used to the new MRD based remission assessment in ALL. So the primary endpoint was complete MRD response after cycle 1, this means no MRD detectable with a minimum sensitivity of 10-4. There was an exploratory endpoint which is MRD response; the difference is that also patients were calculated here who were still MRD positive but below 10-4.  There are two patient populations which we analysed, the first is the total population of all patients and here the complete MRD response rate was 78% and the MRD response 85%. The second patient group where we analysed these results is an efficacy analysis set, this is of course a more relevant group of patients because these are the patients who really fulfil the entry criteria with [?? 6:38] MRD level above 10-3 and also no full relapse. Here the results are slightly different: 80% complete MRD response and 85% MRD response.
Interestingly we didn’t find any prognostic factor for the achievement of MRD response although the responses were achieved in patients at any age, in patients with prior relapse and also in patients with different MRD levels at the start of the treatment. The adverse events profile showing here the events with the frequency of more than 10% has two types of adverse events. The first type are events which are somehow correlated to the cytokine release like fever, chills and fatigue. This was observed in most of the patients but in most cases the adverse events were only grade 1 and 2. The other type of adverse events are neurologic events, most frequent symptoms were tremor and aphasia in 29% and 30% of the patients. Also here most of the events were grade 1 or 2 but still these events are clinically relevant because they can lead to treatment interruption in some of the patients. This is, of course, something which we do not like to do in these patients.
To conclude, this is the first international multi-centre trial in adult ALL with an MRD based patient inclusion and MRD endpoint established by central MRD assessment in a central lab. Most patients achieved a complete MRD response within one cycle, so a very rapid response. Responses occurred in all subgroups of the patients. Adverse events were mostly related to the T cell activation but there were also clinically relevant neurologic events, most of them had grade 1 or 2. The follow-up data of this trial will show whether the good MRD response rate will translate in a long-term outcome benefit.
For me personally this trial is very important because an up-to-date trial where we use new methods, PCR based methods, to identify patients with a high risk of relapse and treat them before the relapse occurs. The second point is that we use a new endpoint which is, of course, also MRD based, and the third is that we use new non-chemotherapy treatment to eradicate this highly resistant persistent ALL subgroup.