Insights From: Max S. Topp, MD, University Hospital of Wuerzburg
Max S. Topp, MD: With the BLAST trial, we now have a really long-term follow-up of more than 4 years. So the data are mature. We now can really clearly ask, with the high response rates, what does it mean for the patients long term? Our patient will be cured. It looks like there are going to be about half the patients being cured with this modality. So with the sequence of blinatumomab plus transplant or blinatumomab and no transplant in elderly patients, the majority of patients in that setting will be cured.
So what is the key adverse effect that we have seen? And this is not unique to blinatumomab. This has actually been seen in every therapy, immunological therapy, that engages with CD19 as a target on the leukemic cells and uses effector mechanism T cell. In CAR [chimeric antigen receptor] T-cell therapy and also blinatumomab, we see neurotoxicity. And the rate of that in the BLAST trial was 14% grade 3 or grade 4 neurotoxicity.
But because blinatumomab is a drug with a very short half-life of just 2 hours, by switching off blinatumomab we can change the infusion, and patients actually clinically resolve those problems within 48 hours back to baseline. So there are no long-term effects that we personally have seen clinically in these patients.
So that is very different to the CAR-T therapy, where you have some patients actually going all the way to the ICU [intensive care unit] and dying from it. So it is, in my mind, a very safe drug in that situation. And we know also exactly when this occurs. It occurs within the first 7 or 8 days after initiating therapy. So you just keep the patient, and you watch them to see what happens. And there will be only a few patients down the road when you continue therapy who will experience neurotoxicity as late onset.
It is maybe only just 2% overall of the whole population who will have neurotoxicity outside the hospital system. But guidance and teaching the patients really helps in reducing detrimental risks that occur in those patients. But apart from that, we have not seen any cytokine release syndrome. That’s very clear because you don’t have a huge target volume to battle with. So cytokine release syndrome is a very rare event, and if it occurs it’s just grade 1—it’s not grade 3—and the patient doesn’t have to enter the ICU in that situation.
And the other adverse event that occasionally has been seen are ID problems, infectious disease problems, but that’s related most likely to the previous medical history of being treated with chemotherapy plus blinatumomab depleting all B cells: not just in ALL [acute lymphoblastic leukemia] but also the B cells that may produce immunoglobulin. So yes, it puts the patients a little more at risk for infectious complications, but once you recognize that, that can be easily be treated by substituting for IgGs; or in a set of patients, maybe giving them antibiotic prophylaxis in that setting. So after getting over the initial start, in my mind, it is a very safe drug to be used in that context.
Leukemia is something that is treated in Europe in centers. It’s not a disease like acute leukemia that is treated by private practitioners. So the patients, after they have completed blinatumomab therapy, may then go later on to the primary practitioners or the specialists in their hometown. But then the therapy is over, so there are no long-term effects that I have seen in these patients. Obviously they’re still at risk of getting a relapse, but the patients are in so much of a better condition than the previous chemotherapy patients, who may enter that arena down the road too.
So the only thing is that physicians, as such, have to be aware that you are dealing with this neurotoxicity, this late onset of neurotoxicity, which is rare. I mean, 1% to 2% of the patients may experience this late toxicity. So then it could be quite severe. It could be a seizure in that situation. So I think that’s the only thing that we may have to educate about more broadly, but that can be done by giving guidance to the family in the paperwork. If this happens, just turn it off, and within 2 hours the drug is gone and you have resolved it. And then you just continue treating the neurological complication, which would be the seizure, adequately and according to the guidelines.
The blinatumomab was tested so far only in Philadelphia chromosome–positive disease in the relapsed and refractory situation. There’s no trial in the MRD [minimal residual disease] situation that has been published that showed that. So the data there basically mirror what we’ve seen in the Ph-negative relapsed and refractory situation. They have a response rate roughly around 40%, small numbers on that clinical trial, so it is within the range that you would see with the Ph-negative BCR-ABLs. So toxicity profile didn’t differ. There was no additional safety signal in those patients.
Nevertheless, the patient’s history to get there is different because in the Ph-positive ALL, even apart from chemotherapy, you have tyrosine kinase inhibitors that you can use, and they have to have at least 2 lines of those. Prior to that, you could maybe argue that the patients who were treated in the Ph-positive have more lines of therapies than the patients who were Ph-negative in that situation. But it is a drug that works equally well in those patients.