MRD+ ALL: Evolving Role of BiTE Therapy

Transcript:

Mark R. Litzow, MD: Rachel, switching back to blinatumomab, there are some exciting data coming out from the COG [Children’s Oncology Group] study with blinatumomab presented as a late-breaking abstract at this ASH [American Society of Hematology] 2019 meeting. Can you tell us a little bit about that and the results and how that might impact treatment?

Rachel E. Rau, MD: I think we’re all very excited about the results of this trial, AALL1331, because it was a first relapse trial in which we took patients who were in their first relapse and defined them as high, intermediate, or low-risk on the basis of timing of relapse, site of relapse, and then response to 4-drug reinduction regimen. Patients who were high-risk were defined as those who had an early relapse or didn’t achieve MRD [minimal residual disease] less than 0.1%. And those patients were randomized post-induction to either 2 blocks of blinatumomab or standard chemotherapy.

And what we found is that the blinatumomab arm was superior in essentially every aspect. Patients achieved much higher rates of MRD negativity, I think in the 70% range after even one course of blinatumomab, compared to 40% in the standard chemotherapy arm. Additionally, the tolerability was striking. Very few patients on the blinatumomab arm had any substantial toxicity, whereas those on the standard chemotherapy arm, as you would predict, had higher rates of sepsis, febrile neutropenia, and some mortality due to therapy. Of course, we were looking at targeted toxicities with blinatumomab and saw that there were relatively low rates of CRS [cytokine release syndrome], as you would predict, because most patients had at least achieved a relatively low disease burden by the time we introduced it. And, additionally, we saw the expected amount of neurotoxicity, which is one of the known common adverse effects of blinatumomab. All the patients who experienced it, it resolved completely in those patients, so I think that’s also reassuring.

There was an additional arm of the trial that we don’t that we don’t know the results of yet. That was what we deemed our low-risk patients, those with a late relapse who did clear their MRD to less than 0.1% by the end of reinduction. For those patients, we replaced some of the intensive chemotherapy with blocks of blinatumomab versus just standard chemotherapy alone. The results of that arm of the study will be released at some point later down the road.

Mark R. Litzow, MD: Do you think the results of this study may affect transplant decisions on some of these patients?

Rachel E. Rau, MD: Well, the high- and intermediate-risk relapsed patients we still feel warrant transplant in in second CR [complete remission]. And so really it was a good bridge to transplant. A much higher percentage of patients on the blinatumomab arms actually were able to get to transplant, which is really the goal of therapy for that subset of patients. And I think in the low-risk patients, that is a population we think we can cure without stem cell transplant so it will be really interesting to see if we were able to do that to a higher degree in patients treated with blinatumomab instead of just chemotherapy alone.

Mark R. Litzow, MD: It surprised me when blinatumomab was initially studied, it was in MRD-positive patients in the adult world. There was a small study of 20 patients, but 16 of them, 80%, converted to MRD negativity. And the other interesting thing was that the BLAST trial, which was published last year that was run in Europe, mostly in Germany, actually duplicated those results in a much larger group of patients and led to the FDA [Food and Drug Administration] approval of blinatumomab.

I was involved in a study, and many of you know that we were moving blinatumomab to the upfront setting. We had a randomized trial of multiagent chemotherapy for patients between the ages of 30 and 70. And then we randomized them to either get several cycles of blinatumomab or not. And we’re going to see if using blinatumomab in the upfront setting can go after that minimal residual disease. Because certainly in our adult world, many patients become MRD-negative, but they still can relapse. We’re hoping that study may offer some additional benefit.

Ryan D. Cassaday, MD: I’d really hoped you were going to tell us the results of that study there, Mark. I thought you were leading up to that.

Mark R. Litzow, MD: Well, it just finished accrual in October, so I think you’ve got to give me a little more time.

Rachel E. Rau, MD: We’re also studying blinatumomab in our upfront population as well. A trial just opened this year in which patients who are MRD positive by flow cytometry and then a population of patients who are MRD positive by next-generation sequencing are randomized to chemotherapy alone or chemotherapy plus courses of blinatumomab. The other population of patients where I’m very excited that we’re introducing blinatumomab is our patients with Down Syndrome. So, as you know, patients with Down Syndrome have substantially higher rates of the development of B-cell ALL in particular. Those patients pose many of the challenges that you face with adult patients. They aren’t biologically the same. They don’t respond well to our chemotherapy, so their outcomes are poor, and they don’t tolerate the therapies we give them either. They tend to really fall apart with our standard chemotherapy regimens. So, for our high-risk patients with Down Syndrome we’re going to non-randomly assign them to chemotherapy arms in which we replace some of the intensive and toxic elements of therapy with courses of blinatumomab instead. We’re really excited and very happy to include this population of patients who are normally excluded from such clinical trials.

Mark R. Litzow, MD: Thank you. That’s very important.

Transcript Edited for Clarity