Ruben Mesa, MD: Now, Stephen, we heard more at this year’s ASH [American Society of Hematology] meeting regarding pacritinib. It’s been a long story. I know we’ve all been involved to different degrees over the years. Interesting drug has an impact on IRAK1, safety in patients with thrombocytopenia. Why don’t you walk folks through a little bit about pacritinib? My sense is that it may be an option that they may be able to prescribe soon. What do they need to know about pacritinib?

Stephen Oh, MD, PhD: Sure. Pacritinib is another JAK2 [Janus kinase 2] inhibitor that also hits IRAK1 as you mentioned. It does have also activity against FLT3 [FMS-like tyrosine kinase 3] and is at least partially responsible for GI [gastrointestinal], some degree of GI toxicity that is seen with that drug is somewhat similar to fedratinib [Inrebic]. The drug has been, as we’re all aware, under investigation for quite some time with various hiccups along the road. But I think the clear theme that has emerged across several studies is that pacritinib is somewhat unique compared to the other JAK inhibitors in that it does not really cause thrombocytopenia. And as a result, can be used even in patients with very low platelet counts, even below 50, perhaps even in single digits. So that is very much a distinguishing factor with regard to pacritinib compared to the other JAK inhibitors. In particular, compared to ruxolitinib [Jakafi], where currently we would commonly use ruxolitinib for patients with platelet counts less than 100. But the dose may be limiting to the extent that a dose that would be able to provide adequate symptom and spleen benefit cannot be achieved in patients with very low platelet counts as far as ruxolitinib is concerned.

In that setting, in particular, I think that pacritinib could be a very useful option and fill that niche. It’s also begun to emerge that there appears to be this so-called cytopenic MF [myelofibrosis] phenotype, or that’s also been referred to as the myelodepletive phenotype. Patients who tend to be along a different spectrum versus those with a more proliferative phenotype, so, as the name cytopenic implies, their platelet counts tend to be lower. This often comes in conjunction with anemia. This may be a subset or a phenotype of MF that would be particularly suitable for treatments or responsive to pacritinib.

It's not a 100% black or white kind of classification, but these patients tend to be ones who, if they’re JAK2-positive, it tends to be lower JAK2 allele burden, or they may be triple-negative for the 3 common driver mutations, JAK2, CALR, and MPL, and often other mutations that are likely contributing to the phenotype. And this may also dovetail with IRAK as being a target of pacritinib in the sense that IRAK signaling is involved in inflammatory cytokine production, and that may be an additional mechanism that is not entirely related or driven by JAK2 that could explain responses seen with pacritinib.

Ruben Mesa, MD: That’s very helpful. It’s certainly an important unmet need. Thinking of those treatment guidelines. Platelets less than 50,000, we really don’t have any options and none that are approved, and it’s typically been pretty frustrating. This concept of the cytopenic MF really, really resonates with me in caring for these patients. Jamile had used earlier, the concept of proliferative MF, and this is somewhat the other end of the spectrum. And I think it’s accurate.

Think about your standard MF patient—big spleen, lots of symptoms, leukocytosis, maybe somewhat anemic—but particularly not markedly thrombocytopenic. Versus this other end of the spectrum, we now see significant anemia and thrombocytopenia sometimes traveling together. Another JAK inhibitor just a little bit further behind pacritinib but might be an option in the near future is momelotinib. Here is an agent that is inhibiting hepcidin, may help to improve anemia.

Earlier data suggesting improvements in spleen symptoms and anemia, and working its way through the last stages, possibly, of approval with a study that Srdan Verstovsek [MD, PHD, MD Anderson Cancer Center] and I are leading in the second-line setting called the MOMENTUM study. I think there is more to come, but I’m hopeful, that again, we’re going to evolve to this state of up to 4 JAK inhibitors, hopefully, 3 in the near term, but with some areas of differences, differentiation, and importance between them.

Before we talk about how these things fit in together, there’s a range of drugs with some other mechanisms of action that are being evaluated. Some a little further along in development and others a little bit earlier on in the pipeline. But 1 of the ones furthest along is the BET [bromodomain and extra-terminal motif] inhibitor called pelabresib. Jamile, this drug is I know being tested in a range of different settings. What do folks need to know about the experimental drug pelabresib?

Jamile Shammo, MD, FACP, FASCP: I sat through a presentation discussing some of the phase 2 data of the monotherapy in this agent, which is a BET inhibitor, in patients who have relapsed/refractory myelofibrosis. And by that, I mean patients who had been exposed to ruxolitinib and either progressed through it or were intolerant to the agent. And so, the study is interesting because it has 3 different arms. This particular arm is looking at this subset with the monotherapy subset, and then they have 2 others with combination with ruxolitinib, etc. And so, it was interesting to see that patients who were treated as such did have clinical responses in terms of—and how they separate them is by transfusion dependency or transfusion—independent populations, so they had different ways to assess the responses in both patient populations. Yes, the numbers are small. They have about 27 patients altogether.

But still, there was a signal for efficacy in this patient population. They had some lab measures that supported the fact that the effect as a BET inhibitor, which presumably inhibits NF [nuclear factor]-kappaB signaling.

So they measured also the cytokines along that pathway, and they demonstrated that, not only you have a spleen volume reduction, reduction in total symptom score, and reduction in transfusion dependency in those who were transfusion-dependent, but also you have a reduction in the cytokine signature that may be along the pathway of NF-kappaB. So goes along the proof of concept that the agent isn’t only effective, but also works through that mechanism of action that it presumably is why it’s effective. So more on that to come. And they’re planning actually a phase 3 randomized trial looking at the drug versus the combination with ruxolitinib, so that would be really interesting to see.

Ruben Mesa, MD: Very interesting indeed. The first time really looking at an alternative path to monotherapy with a JAK inhibitor as upfront therapy.

This transcript has been edited for clarity.