Ruben Mesa, MD: Why don’t we pivot a little in terms of some of the combinations that are being looked at and how we might even weave it in? Jamile, we have pelabresib and rux [ruxolitinib], and we have some other things we certainly have done historically with adding things to ruxolitinib to try to help improve anemia–EPO [erythropoietin] or androgens. And there are even clinical trials going on now with updates at this year’s [2021] ASH [American Society of Hematology] with the addition of lucpatercept, which can help to improve anemia. Where do you think with what we know now with the pelabresib/ruxolitinib combination, where that might fit in? Might we start with that? Might we add one of these other things first, then use this as a backup? What do you think?

Jamile Shammo, MD, FACP, FASCP: I think it’s going to be dependent on what the clinical trials show. The idea of the combination therapy is very intriguing, it’s interesting. I prefer to have a second-line option that doesn’t necessarily involve combinations, but that’s my personal view, only because you’re probably, unless you’re using a nonmyelosuppressive agent, you probably aren’t giving a full dose, and you may be sacrificing some of the efficacy that had been reported initially. That’s why I think waiting for the phase 3 studies comparing single versus double agent [is important].

Yes, we’re all excited about having efficacy in the relapsed/refractory patient population, but I tend to be more careful about waiting to see. I’ll be honest with you, when I saw the design of this ADORE trial, where they took the backbone of this, being ruxolitinib, and then adding 5 different drugs to ruxolitinib, it just goes to show you that the perfect combination isn’t known yet. Is it going to be a PI3-kinase delta? Is it going to be a TGF-beta inhibitor? Is it going to be a TIM-3 inhibitor? I’m not exactly sure. I think it is very reasonable to do the study, and we can see; it may take quite a while. But we need to probably move in that direction because we do know that responses to ruxolitinib aren’t going to be a definite.

Ruben Mesa, MD: I think it’s a very valid point. People sometimes have me try to speculate what it will be. I do tell them that the data from the phase 3 studies are going to be incredibly important. Not only in terms of validating what was seen in the phase 2, but are there specific subsets? It’s a heterogeneous disease; I think it’s less likely that we as a field are going to say, everybody’s got to be on combination therapy to start with. I think one, it will likely be very expensive to be on 2 novel therapies; second, it may not be necessary in everyone. There may be natural subsets where it will make more sense or make less sense. Stephen, another combination that is fairly mature in its development is Navitoclax along with ruxolitinib, working on the apoptosis pathway, BCL-XL. What do you think about that combination? That’s being tested, where do you think that might fit?

Stephen Oh, MD, PhD: I think that certainly is a very interesting combination approach that’sunder investigation and perhaps getting close to approval. Based on the data that we’ve seen thus far, the combination may be able to provide deeper responses in terms of the metrics that we typically have been looking at, such as pain and symptom response. Perhaps even more so—again, we’re still waiting for phase 3 data to mature—the possibility of metrics that we don’t typically expect to see or have seen, such as molecular response, and the so-called holy grail of disease modification. That may be something that combination could provide, but that’s probably a little premature to be speculating about that. Again, we need to see the data. But let’s just say there may be some indication of that, and that would certainly factor in when you look at individual patients in terms of what are the goals of therapy.

If you imagine for instance, a patient for whom their primary issue is symptoms, and we’re not necessarily so much focused on long-term trajectory, but immediate/shorter-term relief of symptoms, then maybe monotherapy with ruxolitinib initially might be perfectly reasonable. When you are considering a different type of patient, for whom for instance, there may be a higher threshold in terms of acceptable toxicity that could come with a combination therapy such as Navitoclax, then maybe that would be an attractive option in that setting.

This transcript has been edited for clarity.