Next-Generation JAK Inhibition for Patients With Myelofibrosis
During a Targeted Oncology case-based roundtable event, Jeanne M. Palmer, MD, discussed with participants how the approval of pacritinib for patients with myelofibrosis affects their treatment approach.
JEANNE M. PALMER, MD: What is your reaction to the data? Do you think they are good, bad, [or are you] indifferent?
JAIDEEP SHENOI, MD: The data about the IRAK1 [interleukin-1 receptor-associated kinase] and its activity [in pacritinib versus other JAK inhibitors] changed my understanding a little, as to why the platelets are not as low with pacritinib.1,2 Tangible low platelet [count] is one of the toughest things, at least in my practice, so a drug that we can use in that group of patients is reassuring.
PALMER: When you see something like this, especially in [patients with] low platelet counts, is that surprising to you?
RONALD GOLDBERG, MD: It's not surprising, because you're allowed to use it [in patients] with platelet count less than 50,000/μL. You have a fairly good percentage of shrinking the spleen; by shrinking the spleen, a lot of times, you're going to get a kick up of the platelets, and so it might be just the fact that you can use it with a platelet count less than 50,000/μL [that causes improvement].
PALMER: Yes. It's pretty amazing. So, how does pacritinib fit into your treatment plan?
SHENOI: My main concern is the loose stools. For example, in HER2-positive breast cancer, there's a drug called neratinib [Nerlynx], which causes a lot of diarrhea, and so they had the CONTROL study [NCT02400476], in which they preemptively gave colestipol [Colestid] to stop the diarrhea. Is this something that we should do for this drug which can cause diarrhea?
PALMER: I generally give patients a prescription for loperamide [Imodium] with very careful instruction to use it, and found that that usually works for them. It's a good thought of whether to do something more prophylactic for them, but I'm not sure that the adverse events (AEs) of diarrhea—they definitely exist, but they're not to the degree that I would say everybody gets them. I certainly see more gastrointestinal AEs in the patients I give pacritinib to.
CHUNHUI FANG, MD: I used [pacritinib] in 1 patient who cannot tolerate ruxolitinib [Jakafi], and then she used pacritinib…we used [loperamide], but she seemed to be doing OK. I was surprised the diarrhea was not an issue; she tolerated 100 mg twice [daily] and she's 85 years old. So we leave her be, and she's responding nicely in terms of cell count, and splenomegaly seemed to be getting better as well. We have 3 JAK2 inhibitors; [should we] still use ruxolitinib first, then the other 2? Or [is there] a chance to maybe move the other 2 to the first-line setting?
PALMER: That is a great question, because I think we're getting more JAK inhibitors. There's probably going to be another one that's going to be approved in June of next year [called momelotinib], so how are we going to use all of these?
ANDY JANG, MD: Isn't there a retrospective study…[where] they did a comparison between ruxolitinib and pacritinib, and it suggests that patients on pacritinib are able to maintain at the regular dose level? There's also a retrospective study that also suggests that there may be potentially a survival benefit. I think there's some suggestion that this drug may be better than ruxolitinib.
PALMER: I think the study you're thinking of, they did a subgroup analysis of the best available therapy patients who got ruxolitinib, and what they found was that the patients who got ruxolitinib, like you said, were much more likely to maintain their dose of pacritinib than ruxolitinib.3 Now, whether that will translate to a survival advantage, quite possibly so, because we know that if we reduce inflammation, reduce spleen size, these patients seem to live longer. I think it's more related to the fact that we're reducing all that bombardment of cytokines on the person's body. That helps them live longer. With ruxolitinib, you have to keep decreasing the dose, so you aren't able to fully JAK inhibit them, whereas with pacritinib, you are, because of the fact that it's much more tolerable on platelets. So you're right, patients who got the pacritinib were far more likely to maintain their dose.
I can't stress enough to counsel these patients to take prochlorperazine [Compazine] when they need to, and then to make sure that they have [loperamide] on hand; they will often need that.
PALMER: What factors do you think will be most influential in your decision for which JAK inhibitor to use?
JANG: I think now, platelet count is definitely the No. 1 [factor] to pick…no question about it.
PALMER: Absolutely, platelet count will be important. I think that's one of the biggest discriminators there. Do you think…the symptom burden is going to be different between the 2 of them?
JANG: Yes. When they did that study, they also suggested maybe the rate of SVR [spleen volume reduction] of 35% is maybe a little bit better with the pacritinib as well in terms of percentage of a [patient’s spleen size reduction].2,4
JANG: If I have a choice, I certainly will favor [pacritinib], especially the [in patients with a lower] platelet count.
PALMER: How about if they have a platelet count of 66,000/μL or 70,000/μL? Are these patients you'd feel more comfortable using pacritinib or ruxolitinib in?
JANG: In that situation, based on what I know…I would still favor pacritinib, not just on the platelet count issue, [but in terms of] the overall benefit. I think if you had prospective randomized data comparing them head-to-head, then that would be the final verdict, but based on what we have retrospectively, it does suggest pacritinib may be a better agent, [seeing as] the patient can stay on the optimum dose much longer.
GOLDBERG: Does anybody know what the copays are, which are always important to the patients, and if some insurance companies will OK payment, if the platelet count is above 50,000/μL and you're using pacritinib?
PALMER: They are being very particular on that. I had a patient who, when I gave him ruxolitinib, his platelets dropped to 48,000/μL, and then we stopped ruxolitinib and they popped right back up to 148,000/μL. So when I went to go get him pacritinib, they [said], “You can't use this, because his platelets are 148,000/μL,” and I had to write them a letter saying, “The last time I gave this [patient] ruxolitinib, his platelets dropped to 48,000/μL; he's on a blood thinner, so he needs to be on something like pacritinib.” They ended up giving it, but it takes a few hoops, so they are paying attention to that type of thing.
GOLDBERG: That's why reimbursement is always [a problem] lurking around the corner.
PALMER: Do any of these other things, like age, frailty, or comorbidities, factor into your decision?
GOLDBERG: Yes, they do, but I think the 2 main ones are [blood cell counts and symptom burden], especially the blood count for the pacritinib.
1. Singer JW, Al-Fayoumi S, Ma H, Komrokji RS, Mesa R, Verstovsek S. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor. J Exp Pharmacol. 2016;8:11-19. Published 2016 Aug 16. doi:10.2147/JEP.S110702
2. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818
3. Mascarenhas J, Bose P, Kiladijan JJ, et al. A retrospective head-to-head comparison between pacritinib and ruxolitinib in patients with myelofibrosis and moderate to severe thrombocytopenia. Blood. 2021;138(suppl_1):3639. doi:10.1182/blood-2021-146675
4. Verstovsek S, Mesa R, Talpaz M, et al. Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia. Haematologica. 2022;107(7):1599-1607. doi:10.3324/haematol.2021.279415