Blinatumomab has been explored in ALL for many years and it’s very obvious that there is a learning curve that we have went through. When we started out with blinatumomab we didn’t really know if this would lead to a higher rate of cytokine release syndrome, for example, what would be the rate of neurotoxicity. The first clinical trials, yes indeed there was a safety signal for both those toxicities which are novel to this kind of therapy and very different from normal chemotherapy and the rate was roughly somewhere between 15-20% of being severe, so grade 3 and grade 4, but none of the patients were lost.
By getting more experience, identifying who would be at risk for getting a cytokine release syndrome now we have now developed a scheme that patients with high tumour burden, defined by LDH for example beyond 500 at relapsing with ALL or with a high bone marrow involvement, that those patients would definitely benefit from tumour reduction by giving them steroids or cyclophosphamide. And with those measures the rate of cytokine release syndrome has been brought down to 5% now in the TOWER trial which is a phase III trial comparing it to SOC chemotherapy. That’s just grade 3 cytokine release syndromes which were all manageable so no patient was lost. The advantage of blinatumomab is even if you discover that you will have a patient like that you just can turn off the infusion and the short half-life of blinatumomab of two hours helps here to curb the syndrome very quickly. So hence no patient was lost in the clinical trial due to cytokine release syndrome in all the blinatumomab trials so far.
The second toxicity that has been attributed to blinatumomab is neurotoxicity. It has been seen with lymphoma patients in the ballpark of about 25% grade 3, grade 4, leading to stopping the infusion. In ALL in the first trials we were talking something between 15-20% but now in the phase III trial it was brought down to single digit numbers of 9% which is due to perhaps educating the physicians, what is neurotoxicity, also in how to manage it. Also it was a surprising result that also in the chemotherapy arm 8% of the patients had also grade 3, grade 4 neurotoxicity which was surprising to us to see that. So overall the safety concern of neurotoxicity in my mind has been actually now quite well contained. Again no patient was lost due to neurotoxicity which is very important just looking at the recent data that has been coming out with other kinds of T-cell engaging immunotherapies targeting CD19 with CAR T-cells where you do loose patients due to neurotoxicity. So that’s quite a benefit in this context for blinatumomab. Also if it becomes difficult to handle we always can stop the infusion and it is clinically reversible also in the phase III trial within 48 hours. Patients can be re-infused again depending on what kind of neurotoxicity it is and it was seen you can also perhaps, if it’s seizure for example, apply then neuroleptic medication that would prevent the second onset of neurotoxicity.
So that is very good to see that, these two toxicities that have been attributed to blinatumomab have been now put into the right context and are also quite manageable in the hands of the investigator.
The second thing which I think is very important, an outcome of the TOWER trial in terms of the safety profile, is when you compare that to the patients receiving chemotherapy is that the rate of neutropenia infections was lower by quite a margin. It’s probably due to the fact that blinatumomab itself had a higher response rate so the neutrophils could recover and contribute to protecting the patient from infections, that is one hallmark. Secondly, the mode of action of blinatumomab, it doesn’t directly destroy healthy neutrophils as chemotherapy does so those two things are contributing to this advance of providing a safer therapy to our patients in that context.
Well if it can reduce toxicity compared to standard chemotherapy and if the toxicities that come with it can be managed to, like you say, equivalent to chemotherapy when should one not use blinatumomab? And if it is being used with these toxicities being so very well managed is that still retaining the clinical benefit? By turning off the infusion does that then reduce outcomes? Because it sounds like it’s almost too good to be true.
The question when to use blinatumomab really is driven by the efficacy of the drug and there is a poster here, or a talk actually, today at EHA which looks at patients treated in the first salvage versus second and third salvage. It’s quite obvious that patients in first salvage do very well, have also quite an extension of their life, when compared to chemotherapy treated with blinatumomab. So I don’t see any reason for patients not getting blinatumomab in first salvage as the efficacy is really quite remarkable with more than doubling the overall survival for those patients, creating close to a year which is quite an advantage in that situation. And with the reduction of severe safety issues it speaks a clear language when to use it.
In my mind the hierarchy of how to treat a patient with relapsed refractory ALL is first line would be blinatumomab and then second line would be then chemotherapy not the other way round. It’s just driven by efficacy, by safety profile and also by quality of life which is also apparently higher for patients receiving blinatumomab.
