Blinatumomab: ECOG-ACRIN E1910 National Clinical Trials Network Clinical trial

By Mark Litzow, MD

ECOG-ACRIN E1910 National Clinical Trials Network Clinical trial. This is a phase three randomized trial. Blinatumomab for newly diagnosed bcr A negative. We also refer to the bcr. Gene Rearrangement is a Philadelphia chromosome. So these patients were negative for this finding, but they had acute lymphoblastic leukemia. Acute lymphoblastic leukemias is the acute leukemia counterpart of what Dr.Brown just told you about chronic lymphocytic leukemia. And these are the detectable cancer cells that we worry about. These are the blast cells that don’t function. And cause these patients to develop infections and bleeding and can be fatal if not treated. So the molecule we were testing is Blinatumomab, which is a bispecific T-cells.

Blinatumomab CD 19 and CD 3

You can see on the left that it combines the variable region of two antibodies, one directed against the CD 19, which is on the leukemia cancer cells. And the other is CD three, which is on T-cells. There’s a linker that combines these two variable regions. And so this molecule brings T-cells, normal T-cells, part of the immune cell immune system in proximity with a leukemia blast cancer cells, and kills it.

And this is a mode of action of this immunotherapy. Blinatumomab is already approved in multiple countries for the treatment of relapse and refractory acute lymphoblastic leukemia, and also in patients that have measurable residual disease, positive acute lymphoblastic leukemia. Here we aim to test it in patients who are MRD negative because we know that even though we can’t find leukemia in these patients’ bone marrow, it’s still hiding there and they can often relapse during their treatment.

Complication in trial design with Blinatumomab

These trials are complicated in their design, and I’ve tried to simplify that. Patients underwent standard induction chemotherapy to induce a remission. This lasted for about two months. They then had a one month course of intensification treatment to give chemotherapy to get into their central nervous system to prevent the leukemia from getting in there and causing disease.

At that point, they were randomized, and as you can see from the asterisk at the bottom, we did testing for measurable residual disease. So this. Standard definition of a remission in acute lymphoblastic leukemia is to have less than 5% blasts in their bone marrow. When these patients present, they often have 80 to 90% blasts. However, within that small amount of leukemia, there can be a small amount of blast cancer cells, there can be leukemia hiding there, and so we now have sensitive techniques to look for these low levels of leukemia. But, Some of these patients, we can’t find it. So this is when they’re, we say they’re measurable residual disease negative.

Consolidation Chemotherapy

So the patients were randomized on the right to get the standard treatment, which is consolidation chemotherapy. We’re consolidating the remission that we’ve achieved, and they get that for four monthly cycles. They then can go on and get maintenance chemotherapy, which can last up to a year or two.

And their total course of treatment, as I said, is two and a half years. The experimental group got Blinatumomab for two cycles and Blinatumomab is given intravenously and it’s infused over a month. So patients wear a pump and are able to be an outpatient and be mobile and up and about. But this is infused continuously for four weeks.

So they had two cycles of. Then they got the consolidation chemotherapy just like the patients in the control arm. And then they got two more cycles, Blinatumomab toward the end of that, and then they went to maintenance chemotherapy and patients could go off and have a bone marrow transplant if their doctor felt that was in their best interest.

So what we showed was the patients that got Blinatumomab plus chemotherapy had an improved survival. Over those that got the standard chemotherapy. So the black line is a patient who got Blinatumomab plus chemotherapy and their overall survival after three and a half months of follow up. This was a median follow up.

Was 83% versus in the red curve. You can see that that was at 65% for three and a half years, and you can see that the red curve is continuing to go down. Whereas we seem to have a plateau in the black curve. And we hope that means that these patients will continue to remain in remission and be cured.

And you can see the hazard ratio of 0.4. with the confidence intervals 2.24 to 0.75 so it did not cross one and this led to the statistically significant result of a P value of 0.003. So in conclusion, this trial E 1910 showed for the first time an overall survival advantage for adult patients who are M R D negative with BCR a negative B lineage, acute lymphoblastic leukemia.

Blinatumomab is combined with their chemotherapy and we feel that this represents a new standard of care for these patients and should be incorporated into their standard therapy. Thank you.