JAK2 Inhibition’s Role in Newly Diagnosed Myelofibrosis

Jeanne Palmer, MD

Vice Chair and Section Chief

for Hematology

Program Director for the Blood and Marrow Transplant Program

Mayo Clinic

Phoenix, AZ

At a live virtual event, Jeanne Palmer, MD, provided commentary on the development of myeloproliferative neoplasms in patients, particularly those with newly diagnosed aggressive myelofibrosis. She highlighted the importance of the Janus kinase (JAK)-STAT pathways and how mutations in genes such as JAK2 can change a prognosis and a physician’s approach to treatment. Furthermore, she discussed the data behind the use of JAK inhibitors in this patient population and how they benefit patients in multiple ways but present a challenge in certain subsets of patients.

DEVELOPMENT AND INHIBITION TARGETS OF MYELOPROLIFERATIVE NEOPLASMS

The pathogenesis of the myeloproliferative neoplasms [MPNs], particularly the ones that are BCR-ABL1 negative, [occurs] primarily through the JAK-STAT pathway.¹ This is where we find what we call the driver mutations, which are the mutations that are critical in making the disease progress. There are 3 different mutations that we more commonly see, with the first being JAK2 V617F.² So JAK1 and JAK2…are right below the cell membrane, [and with this mutation], JAK2 is the one that is mutated, and when it is mutated, it keeps the 2 receptors it’s attached to on, which keeps it constitutively activated. Therefore, it goes on and continues to signal throughout the cell to make the cell grow disproportionally to what it should be.

In polycythemia vera [PV], most mutations are JAK2 V617F; however, there is a small percentage [of mutations in patients with PV] that are JAK2 exon 12, which is a mutation in another part of the JAK2 gene.² The [other 2] driver mutations, which are less common, are MPL and calreticulin.¹

The MPL mutation is in the thrombo-poietin receptor...and the CALR mutation is in calreticulin, and what happens is the calreticulin sits outside of the cell membrane.¹ The CALR mutation is interesting because it is extracellular. There are currently different therapeutics that target that because it is outside of the cell. The calreticulin is divided into type 1 or type 2. The type 1 is associated with a good prognosis, [whereas] type 2 isn’t necessarily [tied to a good prognosis].²

There are many factors that influence the production of MPNs, and this is an area of a lot of research, but there are a couple of [factors] that are prominent. First, the JAK2 mutant clone provides a survival advantage, and any of the mutations that are present in these myeloproliferative cells make them grow a lot.³ They’re extremely tough, they’re difficult to kill, and they try to predominate. There’s also evidence that some of the inflammation can drive these so that you have the cells that create inflammation because of the mutations and then that further drives for the replication and reproduction of the cells.³

There are also higher incidences of prior autoimmune conditions in patients with MPNs, and there’s a genetic predisposition to some of the MPNs as well as to the JAK2 mutation. Disruption of the JAK-STAT pathway can also affect NF-κB signaling, and there’s defective negative feedback regulation, hence what I talked about before about the signal being constitutively on.³

PATHWAYS INVOLVED IN MYELOFIBROSIS

One of the things that we’re learning with myelofibrosis is that there are a number of different pathways involved. We all know about the JAK-STAT pathway, but there are a couple of other pathways that we think are probably important and help us differentiate the [use] of different JAK inhibitors. One of them is IRAK1 and the other one is ACVR1.⁴ IRAK1 primarily involves a lot of the inflammatory cytokines…whereas ACVR1 [affects] the hepcidin pathway. We all remember hepcidin...from medical school when we learned about that iron metabolism pathway that you thought you’d never have to learn again. Well, hepcidin has made a resurgence not only in anemia of chronic disease but also in myelofibrosis and PV. However, one of the problems in myelofibrosis is that patients’ hepcidin [levels] can be too high, so if you can suppress it, they may benefit [from that kind of treatment]. The ACVR1 pathway reduces hepcidin transcription, which is thought to help anemia...and [researchers] found that this also appears to be a target of pacritinib [Vonjo].⁴

PERSIST-2 FINDINGS DEMONSTRATE PACRITINIB’S ROLE IN TREATMENT

[The baseline characteristics of the PERSIST-2 (NCT02055781) study] showed that there were fairly equivalent patient populations [between the study arms].⁵ One thing to note about the baseline demographics...is that in the control arm, almost half the patients had ruxolitinib [Jakafi] as their best available therapy and were allowed to continue it at the dosing level appropriate [for them]... depending on their platelet level. Again, [for those with] 50 × 10⁹/L to less than 100 × 10⁹/L platelet count, the dose recommended was 5 mg twice a day, which is what most patients were on [in the control arm].⁵

When we look at the spleen volume reduction rate in PERSIST-2 [findings]...it is a 35% decrease, and this spleen volume reduction is not as impressive in this [study]. The [spleen volume reduction] percentage is less [with] pacritinib as we would see [with] ruxolitinib.⁵ I also want to point out that these patients [in this study] have lower platelet [count], have a lower JAK2 allele burden, and maybe are less likely to respond well to JAK inhibitors. However, it is important to note that in PERSIST-2 [findings], the spleen volume reduction was greater in the patients who received treatment compared with those who did not.⁵

People have looked at JAK2 burden and response to JAK inhibitors, but they were more compiled data rather than split. You need a lot more patients to be able to note that difference. I would not use JAK2 allele burden as a decision point of whether to give somebody a JAK inhibitor or not. But there are some circumstantial data that [suggest] if somebody has a higher JAK2 allele burden then they’re more likely to respond to treatment.⁶

But that’s more likely because [the patient] probably has a proliferative variant, they have the hyperproliferative disease rather than cytopenic disease, and those patients tend to be more likely to respond to therapy because you can dose them adequately because their counts are high enough.

When using pacritinib, it’s important to remember that we don’t expect to see platelet [count] improvement, but sometimes we [see it] because the spleen shrinks, and when the spleen shrinks, you have less sequestration. But in general, I’ve seen platelet [count] go down a lot, so it’s very important not to give this drug [while] thinking, “Oh, my patients’ platelet [levels] are going to go up.” And then [you see the platelet levels go down and think] the drugs [are] not working, because what you hope for is that this will flatline.

When we look at the hematologic response [to pacritinib in the PERSIST-2 study findings], you do see that change in platelet count.⁵ Although 400 mg daily is not the prescribing dose, [their platelet counts went up]. Although those 400-mg data are not included in a lot of analyses because the dosing that’s found to be the best is 200 mg twice a day, you’ll see that the platelet [count] for those who were on 200 mg of pacritinib twice a day is flat. I don’t have a good explanation why the platelet [count] went up in the 400-mg once-a-day [group], because the responses weren’t that great, so [it] wasn’t the dose that was chosen to move forward. In terms of the red blood cell transfusions over time, they went down in patients, so the lower the red blood cell transfusion, the better it is in patients who are on 200 mg of pacritinib twice a day.⁵

When you look at patients with low platelet [count], the impressive thing about pacritinib is that you can maximize the dose and maximize the spleen volume reduction. If you took patients [with low platelet count] who got ruxolitinib at 5 mg twice a day, about 10% of them will have a spleen volume reduction of greater than 35%, so this is an extremely low rate of spleen volume reduction.⁵ One of the things that’s important to remember about this is pacritinib allows maximal JAK inhibition for patients with low platelet [count]. If you have somebody with normal platelet [count] and give them pacritinib, you’re not going to see the same benefit as you would with ruxolitinib, but a big part of that is [due to] the limitations with the cytopenias. For patients who have thrombocytopenia, pacritinib provides a significant advantage because you can maximize the dose.

TOXICITIES TO CONSIDER WITH JAK INHIBITION

[In the PERSIST-2 trial findings], all the adverse events [AEs] were expected, but I want to point out diarrhea is a major AE with pacritinib [Figure⁵]. Whenever using pacritinib, it’s extremely important to give [the patient] antidiarrhea and antinausea [medicine] when you start this medication. The majority of patients will have diarrhea, and it can be a significant AE.⁵

[Researchers in this study also looked at]...viral infections [and saw that] zoster can be activated in these patients through fungal infection.⁷ That’s something of interest to me, especially because I live in Arizona, where we have a lot of valley fever, which is a fungal infection.

What they had found…was that [in] these infections, especially if you look at pacritinib vs best available therapy or when best available therapy is ruxolitinib, we don’t see as [many cases], and in...[other] secondary [malignant tumors], it was even [fewer with] pacritinib compared with best available therapy with ruxolitinib.⁷

Frankly, there’s a lot of focus on these numbers that...when you look at the absolute numbers of these events, [they] are extremely low, but this is one area that they are trying to highlight where there is less of an infection risk [with pacritinib].⁷

_References

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_{2. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405. doi:10.1056/NEJMoa1312542}

_{3. Mendez Luque LF, Blackmon AL, Ramanathan G, Fleischman AG. Key role of inflammation in myeloproliferative neoplasms: instigator of disease initiation, progression. and symptoms. Curr Hematol Malig Rep. 2019;14(3):145-153. doi:10.1007/s11899-019-00508-w}

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_{5. 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}

_{6. Vannucchi A, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: effects on phenotype, prognosis and change with treatment. Ther Adv Hematol. 2011;2(1):21-32. doi:10.1177/2040620710394474}

_{7. Pemmaraju N, Harrison C, Gupta V, et al. Risk-adjusted safety analysis of the oral JAK2/IRAK1 inhibitor pacritinib in patients with myelofibrosis. EJHaem. 2022;3(4):1346-1351. doi:10.1002/jha2.591}