Ian Flinn, MD: There is another antibody that’s been developed, an antibody-drug conjugate for use in lymphoma. We’re talking about polatuzumab. It’s been approved with bendamustine and rituximab for refractory or relapsed large-cell lymphoma. But there are also data being presented at ASH [American Society of Hematology 2019 Annual Meeting & Exposition] this year about it being used in combination with lenalidomide and obinutuzumab. Lori, they were pretty good data too, right?

Lori A. Leslie, MD: Yes. This is a phase Ib study looking at patients very heavily pretreated with follicular lymphoma with 70% to 80% refractory to most recent line of therapy, all chemoimmunotherapy pretreated got a sequential additional of polatuzumab antibody-drug conjugate, lenalidomide, and obinutuzumab. High overall response rates—in the mid-70s, 75% is overall response rate with a high proportion, 65% achieving a complete response. Toxic in that most patients did have at least 1 adverse event. The majority of patients required a dose reduction of modification. Mostly of the lenalidomide component, but serious adverse events were low. I think that it will be an important potential option in the future, though patients would have to be carefully selected because there’s certainly toxicity.

Ian Flinn, MD: Yeah. And John, there were data that have previously been presented but builds on this backbone of looking at POLA [polatuzumab] with obinutuzumab, but actually it was not as good as the previous studies with rituximab. I don’t really understand why that would be. Maybe it’s just a fluke of the patients. Maybe it’s really not based on biology. But building on this study that we just discussed, how do you reconcile all this?

John Gribben, MD, DSc: From a purely pragmatic research point of view, it almost doesn’t make sense in terms of what we know about the mechanism of action and what’s been targeted with obinutuzumab and rituximab, but it should work differently with a POLA [polatuzumab] backbone. Of course, there are differences in the way those agents actually work inside the cell that may give us clues as to why there could be differences. Maybe those overcome as soon as you add in the lenalidomide, which then augments and changes the microenvironment.

We haven’t had much chance to talk about the microenvironment here, but we know how important that microenvironment is in lymphoma. A lot of that work tends to be done in the up-front setting. We know much less about the microenvironment in the previously heavily treated patient. So there’s all sorts of things that could be happening with not the tumor cell itself but how in vivo those agents work and interact with what the new milieu of cells are that are rendered that may impact on it.

So I think you’re right. The numbers of patients in those studies were really too small to comment. But whether if you’re using an antibody-based therapy here the way you are with POLA [polatuzumab], maybe you just need something else just to get you over that hurdle. Is it a first thing? And the second would be using a chemotherapy agent, which of course, is what in the end POLA [polatuzumab] is. If you’re talking to patients about a chemotherapy-free regimen and then you’re adding again a chemotherapeutic agent, at least you’re talking about adding a targeted chemotherapy agent. I think people find that more acceptable than going back to using chemotherapy with a chemotherapy-free regimen. At least you can feel that if you’re going to have to use chemotherapy, target it and try to decrease those toxicities.

Ian Flinn, MD: Excellent point.

Lori A. Leslie, MD: I was just going to say that I completely agree with focusing on the microenvironment. As we’re moving more toward immunomodulation and immunotherapy, chemotherapy-free options, and even looking at gut microbiome, that’s becoming very important. And in the field, can that predict toxicity to PI3 kinase inhibitors? I think that’s really an emerging field that’s going to be important in follicular lymphoma to help select which of these therapies we should be using.

Transcript Edited for Clarity