EHA 2016

Blinatumomab improves survival of relapsed B-cell leukaemia

Prof Max Topp - University of Würzburg, Würzburg, Germany

We at this conference presented for the first time a randomised phase III trial where blinatumomab was compared to standard chemotherapy in patients with relapsed or refractory B-precursor ALL.

Can you tell us more about that trial and the comparisons that you were making?

The trial was performed to confirm our first phase II trial in ALL where we saw 43% of these patients can respond to immunotherapy reaching a complete remission. So the aim of the trial was to compare if blinatumomab can result in an overall survival benefit for patients when compared to standard chemotherapy. The chemotherapy that was chosen reflects the standard therapies that are used for these patients and are usually quite intense chemotherapy for those patients.

And what kind of results did you find from the trial?

The primary endpoint of the trial was to demonstrate overall survival benefit for those patients. So standard chemotherapy therapy leads to an overall survival of about 4.0 months in this clinical trial whereas in patients treated with blinatumomab the survival was almost doubled to 7.7 months. This also was clearly shown that the complete remission rate in the patient cohort was almost double for the patients who were treated with blinatumomab when you compare that to standard chemotherapy and also the depth of the response, the MRD response, was clearly much more enhanced in patients being treated with blinatumomab.

How can these results be brought forward to people working in the clinic?

Obviously this will first help to set the stage that blinatumomab is actually available for patients. Blinatumomab has just very recently been approved by the European Medical Agency and now the drug is now being rolled out to be approved in every other country. The UK, for example, Germany, France, Italy, with now a phase III randomised trial demonstrating overall survival benefit for the first time for an immunotherapy agent in this patient cohort really will obviously convince regulators but also doctors to use this drug more broadly.

Do you think it has any wider applications for different patient cohorts?

It definitely does. Obviously this is the worst of the worst, we are talking about relapsed refractory ALL patients also selected for negative prognostic factors. To show that patient population that blinatumomab is leading to overall survival benefit will lead to more investigations if blinatumomab can be incorporated into front line therapy. Actually that is happening because we already have performed a phase II trial in patients with minimal residual disease. Minimal residual disease means that after you do standard chemotherapy you still find a clone that is still detectable by PCR technology. We know that those patients, normally speaking, will be relapsing in about 95% of the cases. So we already have done blinatumomab in those patients too, leading to a result of converting MRD positivity into MRD negativity in those patients and also have shown that those patients actually do much better than patients who actually weren’t treated with blinatumomab. So in summary we have now a lot of evidence that actually integrating blinatumomab in front line therapies is advantageous and these clinical trials will be being performed in different study groups throughout Europe and in the world.

That’s all I have to ask, is there anything that you would like to add?

You always have to look at the efficacy of the drug but you also have to balance it to the side effects. So chemotherapy usually leads to infectious complications, to death, to neutropenia in those patients. Blinatumomab in this clinical trial demonstrated that the rate of severe infections as well as severe neutropenias was clearly reduced in those patients. Blinatumomab, as many immunotherapy agents, has some novel toxicities. So in the phase II trials blinatumomab led to neuro events and neurotoxicity in about 14% of the cases which meant the patients had to interrupt treatment. In this clinical trial there were two observations that we made: a) the rate of neurotoxicity was reduced to 8% so this may be due to better managing the patients, and b) chemotherapy itself also had the same rate so that was very surprising to us to actually see that toxicity that we felt was dose limiting for blinatumomab is actually not any way different to what we know from chemotherapy. The second key thing is that as it is immunotherapy cytokine release syndrome has been shown to be a part of the toxicity profile of immunotherapy. So with blinatumomab it’s only about 4% of the patients who actually have severe cytokine release syndrome. When you compare that to other immunotherapy agents which are now being discussed heavily, also at this conference, the ‘CAR’ technology, where you have toxicity with cytokine release syndrome in the range of about 30%, grade 3, grade 4 cytokine release syndrome, patients go into ICU, blinatumomab doesn’t have anything like that. So that’s the second key message, apart from also demonstrating overall survival benefit it’s also that the toxicity profile is in favour of this new agent.