Value of JAK Inhibitors in Myelofibrosis Management
A broader overview of the role that JAK inhibitors play in patients with myelofibrosis and how that role has continued to evolve in the current treatment paradigm.
Transcript:
John O. Mascarenhas, MD: In that respect, let’s talk about the benefits of JAK inhibitors and some of the longer-term benefits of these outcome measures. We often talk about JAK inhibition with the goal of reducing the spleen and obviously improving the symptom burden. Gabby, why is reducing the spleen so important? Are there data that suggest that beyond the fact that the patient may look slimmer, fit into their clothes better, be able to eat a fuller meal, does it have any other impact beyond that?
Gabriela S. Hobbs, MD: That’s a great question. There are emerging data correlating spleen improvement with survival. It also depends on what your goal is for the patient, like we were talking about before. If this is a patient for whom your goal is to get them to transplant, we know that having massive splenomegaly before transplant probably doesn’t correlate with good outcomes post-transplant. There are some large retrospective series that have demonstrated that patients who are treated with ruxolitinib pretransplant and have good responses have better treatment outcomes. That’s a good reason to not just start a person on a JAK inhibitor, but to try to fully maximize the dose that they can get on and to shrink that spleen before transplant. Then there have been other recent analyses, not just with ruxolitinib, but also with pacritinib, showing patients in certain groups, if they’re treated with pacritinib and they have a spleen volume reduction of greater than 10%, for example, maybe they have an improvement in survival. We don’t have a ton of clarity yet on all the benefits of the JAK inhibitors, but certainly for the patients and their quality of life, improving their splenomegaly is important.
One more thing I wanted to add is, if you have a patient who has a lot of symptoms, has large splenomegaly, it’s not just about getting their spleen smaller to get them to transplant, but you’re also, by lowering that systemic inflammation, by getting that patient out of that hyperinflammatory state, that patient has a better performance status. That patient can do more and be more prepared for transplant. I think the JAK inhibitors, by lowering that inflammation, [help get patients] better prepared for their transplant or whatever other treatments are ahead.
John O. Mascarenhas, MD: Perfectly said. It’s fascinating that splenomegaly is a hallmark of myelofibrosis, it’s driven by extramedullary hematopoiesis. It obviously contributes to symptom burden and frailty. We know JAK inhibitors across the board are effective in reducing the spleen. That gives you that immediate satisfaction, gratification as a physician that you’ve improved that aspect of the disease and patients feel and look better. It’s intriguing that there are data, both initially from ruxolitinib and now from pacritinib, that it might matter more than just the here and now. That even the 10% reduction that was seen in the low platelet patient population with pacritinib afforded a survival benefit that wasn’t realized with BAT [best available therapy], including ruxolitinib at low doses. Enforcing the idea that dose matters, that maximizing spleen reduction to optimize the use of JAK inhibitor probably does matter. To Kristen’s point, you have to go carefully and individualize the therapy, but you want to some extent maximize their JAK inhibitor therapy dose and schedule in order to optimize not just the reduction of their spleen, but probably as a surrogate, the higher likelihood of enjoying the fuller benefit of JAK inhibitors.
Unfortunately, JAK inhibitors don’t reliably induce histopathologic remission. I’m not sure we understand what we’re looking at from a biologic standpoint in terms of why patients live longer. I don’t think you guys think it’s because literally their spleen is smaller. It’s got to be a surrogate for something else dampening that inflammatory cue that somehow allows for a modest but real improvement in survival. That’s important to consider when dosing. You don’t want to dose lightly and underdose a JAK inhibitor either. Since we’ve been talking about pacritinib as it relates to low platelets and the survival data that have been presented more recently, Andrew, do you want to provide us with any kind of insight? Why is pacritinib different? It’s a JAK inhibitor. Are there distinctions about its kinome profile that would lead you to believe it would have maybe advantages over other inhibitors?
Andrew T. Kuykendall, MD: Yes, pacritinib is somewhat more of a JAK2-selective inhibitor as well, which maybe differentiates it from ruxolitinib. Fedratinib is also somewhat selective toward JAK2 as well. Pacritinib has this additional inhibition of IRAK1 and ACVR1 as well, and maybe ACVR1 is a story that’s just been emerging over the last 6 to 12 months. We understand that the differences, these additional tyrosine kinase inhibition profiles, may differentiate one JAK inhibitor from another. For a long time, I think more so you’re trying to explain what you’ve seen in practice, right? I think the early trials with pacritinib were interesting in the fact that it didn’t seem to cause the same degree of myelosuppression that was seen with ruxolitinib and fedratinib. Some of this has been attributed to potentially IRAK1. This is an NF-κB pathway target that may be involved in maybe some other symptoms, some cytopenias, different inflammatory pathway. Then more recently built off the knowledge that momelotinib is an ACVR1 inhibitor, it was seen that pacritinib may be a more robust ACVR1 inhibitor. This is something that is a relevant target in the treatment of anemia and cytopenias. Perhaps this is why we can leverage pacritinib in this more cytopenic myelofibrosis population, and certainly do so safely, and target splenomegaly and symptoms with full doses of this JAK inhibitor in a patient population that it would be difficult to provide fedratinib or ruxolitinib to.
John O. Mascarenhas, MD: Excellent.
Transcript edited for clarity.
Improving Disease Modification and Immune Responses in Myelofibrosis With Pelabresib
November 16th 2024David M. Swoboda, MD, and Andrew Kuykendall, MD, spoke about the current treatment strategies and potential advancements that may improve outcomes such as spleen volume reduction in the myelofibrosis field.
