Now, we’ve just been at an extremely interesting session but your study was on acute lymphoblastic leukaemia using an agent, blinatumomab. Could you tell me about this agent and what you were trying to do and why you were using it in a study of acute lymphoblastic leukaemia?
Blinatumomab is a new treatment principle which is a B-specific antibody. B-specific means that on one part it is directed to CD19 which is expressed on the surface of the B precursor ALL cell and the other part is CD3 which attaches to T-cells. This very small molecule brings the T-cells in very close proximity to the target B precursor cells. Due to this close proximity the T-cells get activated and they start to proliferate, expand and they start to kill the target cells. They can kill several target cells so they attach and detach and kill; they serial kill for a very effective treatment.
So basically it looks for the cancer cell but it also looks for the T-cell that can kill it?
Yes, it brings them together, put like this, and it helps the T-cells find the target cells.
And having done its dirty work against the cancer it can go off and do more?
Yes. That’s actually the truth, yes.
It sounds marvellous, what did you do in the study?
In the study we selected a patient group, patients with MRD positive ALL. This means they had a relatively low level disease, so at least below 5%. This sounds, at first sight, whether it is not very bad but these patients have chemotherapy resistant disease. It means that despite continued chemotherapy normally they would all relapse and therefore these patients have a very poor prognosis. We thought that this is a group of patients where we need new experimental drugs because chemotherapy doesn’t work. Therefore we selected blinatumomab as a potential drug for these patients.
What was the protocol for the study?
The protocol was the patients should receive at least one cycle of blinatumomab, one cycle means 28 days continuous infusion of this drug with a portable infusion pump, and after one cycle the primary endpoint was analysed. The primary endpoint was MRD complete response after one cycle, this actually means no MRD detectable any more.
Which presumably you tested by PCR?
Yes.
And were there any secondary endpoints that you were looking for?
Yes. The secondary endpoint was, of course, the tolerability, so adverse events. There were a number of other secondary endpoints like long-term survival, remission duration and so on which cannot be analysed at this point because the follow-up is not enough. So at this moment we focus on the anti-leukemic efficacy, the primary endpoint, and the adverse events.
What were the results?
The result was in 113 evaluable patients there was a 78% rate of complete MRD response and 85% rate of MRD response. This means that some of the patients had MRD below 10-4. And the efficacy results, efficacy was seen in all sub-groups of patients. We saw no prognostic factor that was seen in patients with high MRD levels, also with MRD after prior relapse. So it was effective in all subgroups.
Now, it’s a powerful agent, what about side effects?
The compound was mainly developed in relapsed refractory ALL so we know something about the side effects. In this trial nothing new came up so there are two types of toxicity, basically. One is related to the cytokine release, like fever with chills and these things, and the other type of toxicity is neurologic toxicity: one is tremor and another is encephalopathy t-type toxicity, for example, which starts with aphasia.
Clinically how significant, though, were these side effects?
Most of the side effects were really grade 1-2 so it can be handled, particularly neurologic toxicity can be handled by dexamethasone use. But in some of the patients the treatment had to be interrupted. I will show this data also on Monday. This is, of course, something which we would like to avoid and in this trial we also tried to continue the treatment of these patients at a lower dose level. I think this is a good approach.
What then could be the clinical implications coming out of this?
The compound is very effective in ALL and, based on the efficacy in relapsed refractory ALL, has just been registered by the FDA. So it will be available in the United States commercially. For me, the future of the clinical use is more in earlier phases of treatment, so not after relapse but before the relapse in the MRD setting, but even in the first line therapy.
What are your hopes about translating the benefits that you saw into the long term?
I have hopes which are based on our pilot trial where we used the compound in the MRD setting. In this pilot trial we have a number of long term survivors which did not receive any further chemotherapy, so just blinatumomab, and remained in long-term remission. In this trial we also observed very good results after the subsequent stem cell transplantation. So this creates my hopes that we will find similar results in this trial.
If you get removal of the molecule, so molecularly zero, the disease doesn’t seem to be there, could you stop taking the bi-specific antibody? Do you have possibly a cure?
No, I think we have always to speak about a certain detection level. Even if the patient is MRD negative it doesn’t mean that there are no blast cells anymore, unfortunately. Again, a detection level which is very sensitive, 0.01%, but blast cells are still present. They can also be present outside of the bone marrow, for example. So it is still open how many cycles we need of blinatumomab, how long it has to be continued, whether we also need further chemotherapy, for example. So these are things which remain to be evaluated.
What, then, should doctors take home from this?
They should take home that we have a very potent drug here which is active against acute lymphoblastic leukaemia and if the results are confirmed it can really change the standard treatment of ALL.
