Reactions to the Latest Data on JAK Inhibition for Myelofibrosis

John O. Mascarenhas, MD

Professor of Medicine, Icahn School of Medicine

Director, Center for Excellence for Blood Cancers and Myeloid Disorders

Director, Adult Leukemia Program

Tisch Cancer Institute, Mount Sinai

New York, NY

DISCUSSION QUESTION:

• What are your reactions to the data from the studies of ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo)?

JOHN O. MASCARENHAS, MD: What is your impression across these 3 drugs and the data you’ve seen?

LESLIE WORONA, MD: With the pacritinib, it’s very interesting that you don’t have to wait until the platelets are low.¹ I like the generalized neutral dosing. It’s much easier to give. It seems like there might be even more patient compliance.

MASCARENHAS: I would agree. You can dose the drug at 200 mg twice a day…particularly in a busy practice that can be burdensome to figure out what platelet count you’re dealing with at any given time and what the dose of ruxolitinib should be given that platelet count. This is pretty straightforward and, I agree, it might make compliance easier to give the same 200 mg dose twice a day.

WORONA: Right. It sounds almost like apixaban [Eliquis] taking over for warfarin.

MASCARENHAS: Where do you see pacritinib fitting into your treatment plans? [The data showed that in patients with] low platelets there was improvement in spleen size and symptoms.² Where do you see pacritinib going forward now as an approved drug?

DORIS PONCE, MD: I see it more in the space of patients for whom you can’t use ruxolitinib up front. I see this as a substitute for that. Whereas, if my patient is able to get ruxolitinib, I see this as a second-line option.

MASCARENHAS: Do you see the platelet count as the main determinant of when to use pacritinib or not?

ILYA BLOKH: As of today, yes. It sounds like [for those with] the low platelet count, that’s the go-to drug. [The data] made me think it sounds like a potentially good first-line drug for all patients with myelofibrosis in the future.

MASCARENHAS: If you’re going to use pacritinib, what would be your instructions or advice to the patient moving forward?

MARC J. BRAUNSTEIN, MD, PhD: You would have them report any fatigue and any symptoms of reduction of blood counts.¹ I guess that [is all I would advise]. Is there anything else that you advise patients?

MASCARENHAS: In the case of pacritinib, I probably overstress the potential for gastrointestinal [GI] toxicity. If they’ve been on ruxolitinib, they’ve not had that experience; then you put them on pacritinib, [if] they start developing diarrhea it can throw them off. I think if they’re not anticipating it, it’s almost worse, so I oversell the GI toxicity. I basically guarantee them they’re going to have nausea and diarrhea, and then if they do, they’re prepared. They have their medications at home. If they don’t, then they’re really thrilled that they didn’t have that toxicity.

Other than that, it’s a JAK inhibitor so we’re going to have to watch blood counts as we normally would, and hopefully the idea is we’re going to improve both spleen and symptom burden. That can sometimes happen rapidly, within a week you could start to see those benefits. But I aim for at least 3 months, at a minimum, before I start to look at any JAK inhibitor, including pacritinib, as a drug that may not afford them that benefit.

PONCE: [Thrombotic events were a] part of the package insert [for pacritinib].¹ I was wondering if this had relevance.

MASCARENHAS: In the package insert there is concern about thromboembolic events that come from other JAK inhibitors in rheumatologic diseases that have now created this added language in these package inserts. It’s very misleading. Unfortunately, the way it reads out, it would almost suggest that pacritinib is associated with thrombotic events in the studies, but that’s not the case. This is a warning that’s popping up now because of concerns that have been seen in controlled studies in the rheumatologic space with JAK inhibitors they used in that space, not these drugs. There hasn’t been a signal of concern.

Just to be clear, there was a brief clinical hold on [pacritinib] due to concerns of cardiovascular events, and that was, upon further review, removed and the drug moved on. Subsequent studies have shown that there isn’t an increase in cardiovascular risk with pacritinib. But, in some of the other drugs in rheumatologic diseases, there is this concern that has prompted the FDA to put this label across all their JAK inhibitors. It’s unfortunate because I think it’s a little bit misleading the way it reads, but that’s a good [observation].

AILEEN L. CHEN, MD: Pacritinib can cause [as much as a 34% rate] of thrombocytopenia in the first few weeks.² How do you judge this as a AE from pacritinib or the work [of the disease]? Because [myelofibrosis] causes thrombocytopenia, right?

MASCARENHAS: The trial is sometimes confusing because these patients went on with low platelets and then any dip in their platelet count would get picked up immediately as new treatment-emergent AE. Patients could have fluctuations or even worsening of the platelet count as the natural history of the disease. I tend to treat through those cytopenias, particularly in the first month or 2, and support them with platelet transfusions before I start dose modifying the pacritinib. But one has to look at the kinetics of how that platelet count dropped, when it dropped, the extent of the drop of the platelet count, and whether the patient is having any manifestations of epistaxis to make decisions about reducing the dose or even holding the drug for a period of time to wait for the counts to come back.

Typically, you can get the patients through the first month or 2 and treat them through the cytopenias, and then my experience has been that it evens out and you don’t get those fluctuations in platelet count. I bring them in weekly for blood counts, in the case that you find someone who drops their platelet count on the drug. It’s unlikely there’s going to be disease progression in the first week or 2 on the drug, but it can be the natural course of the patient with myelofibrosis.

_References:

_{1. Vonjo. Prescribing information. CTI BioPharma Corp, 2022. Accessed September 19, 2022. https://bit.ly/3BrtGho}

_{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}