Pre-Conference Perspectives on Hematologic Malignancies - Episode 7
John Leonard, MD: OK, and then we’re going to now move to a category of drug that is similar to some that we see in other lymphoid or myeloid malignancies and some that are not. This is flotetuzumab. It’s a mab so I can say it better. And this is, however, not quite a mab or I guess it is a DART protein, which is a version of a bispecific molecule targeting on the one hand, CD23, and on the other hand, CD3, again to engage T cells and bring them in and presumably have an antileukemic effect there. So, what are your thoughts on this study?
Alexander Perl, MD: I think we’re all excited to use immunotherapy for AML, and given the experience with immunotherapy and ALL, everybody says this is hopefully something that we can just move from one disease to another because look at how it works there. And that’s the promise. The challenge is actually execution. It’s relatively easy to get a lymphoid-selective antigen you can go after with an antibody or a CAR-T cell. It’s much harder to do that in AML because so many of these antigens are expressed on normal cells in hematopoiesis. So, CD123, which is what’s targeted by flotetuzumab here, is expressed on hematopoietic stem cells and early progenitors. It’s expressed in other tissues including vascular endothelium. There is the potential for these drugs to create toxicity, and that has been an issue with drugs that were developed to target CD123 with FDA holds on a few of these agents. And some developments actually were canceled because of toxicity. What’s notable for that reason is that this seems to be more successful. They actually have been able to give this drug from a phase I study, flotetuzumab, which, again, is a bispecific CD123 and CD3, recognizing dual affinity retargeting molecule—that’s the DART—was able to be given by infusion to 45 patients in a dose escalation study, and they did see cytokine-released syndrome in the study. They did also see responses. So, they’ve basically looked like they’ve found a manageable way to give immunotherapy with a single agent here for relapse/refractory patients, and I think that’s very encouraging.
It’s a small study in terms of looking at what the optimal dose is, and I think the follow-up is still limited but this is encouraging. And, again, this is not the only drug in this realm. There are many other companies that are developing drugs to look at this. There are many other targets that could be looked at, whether it’s CD123, CD33, CLL1, CD47, the checkpoint inhibitors, there are many different ways we could look at this in terms of, how do we get immunotherapy to work for AML? I don’t think anybody knows the right answer, but it’s encouraging to see some early success in terms of a feasible regimen, and then we can figure out what works the best.
John Leonard, MD: Is your sense that these are ultimately going to be developed and obviously there will be patient subsets who are at least hypothesized to be more or less relevant? But is your sense that these will ultimately be built on the 7N3 or low-dose ara-C? Are they going to be things that are bridges of transplant, if you had to look in crystal ball for this kind of category of drugs?
Alexander Perl, MD: I think the hard thing here is you’ve got to do what works in the relapsed/refractory setting to at least show you have activity and safety, because that’s where you can develop drugs. But once you see something that works, you want to move it as early as possible. And I think knowing that allotransplant works in first remission better than after relapse, anything that’s immune-based, we’re going to want to move early on. Is this going to replace chemotherapy? I think that’s a bit of a stretch. But can we find ways that we can reduce the toxicities of chemotherapy? That’s what was very encouraging about many of these new drugs. Whether it’s adding venetoclax to low-intensity chemotherapy or oral outpatient agents, like ivosidenib, or perhaps a FLT3 inhibitor, just finding ways to make therapy easier is important, because it’s currently very toxic.
John Leonard, MD: So, you referenced allotransplant, and we have some data on older patients getting nonmyeloablative allotransplant. Where is that fitting in things? It’s amazing how the age range has gone up and how the options have come up for older patients at various points of the course of their disease, whether it’s MDS or AML. What do these latest data tell us? Is there something helpful there?
Alexander Perl, MD: I think what these data tell us first off is that standard therapy has actually gotten better over the years and allotransplant has gotten better, but who benefits has been a question, for those over the age of 60. We have a lot of data on how to use cytogenetics or even molecular prognostication under the age of 60. But a lot less to go on in terms of how do we use diagnostic tests, that we now all have, to guide our therapy for older patients, who are the majority of the patients we treat. And while we can give transplants, not without regard to age, to more and more and more patients, and fairly easily up to the age of 70 or so, how well does that work?
And I think what the study shows, from the ALFA group by Gardin and colleagues, is basically that the major benefit in older patients still is restricted to the most high-risk patients by either molecular or karyotype prognostication. Here, they use the ELN classification, which has been validated across the H-gamma, but in order to say how well it could have actually predict who benefited from transplant, really the most sizable benefit was seen in the ELN adverse group with not an obvious benefit for transplant in other patients, which I think is a little bit eye opening, but I don’t know that this is really a definitive answer. I think this is a start to likely more and more groups reporting their experience with this. We have those data for younger patients and we have less complete database in older patients.
John Leonard, MD: Well, again, we’ll come back to some of these issues in a few minutes.
Transcript Edited for Clarity