Oh Explores Current JAK Inhibitor Options for Primary Myelofibrosis

Stephen Oh, MD

Cochief, Division of Hematology

Associate Professor

Washington University School of Medicine in St Louis

St. Louis, MO

Targeted Oncology™: What are the treatment recommendations for patients with high-risk primary myelofibrosis?

OH: The NCCN [National Comprehensive Cancer Network] guidelines for high-risk myelofibrosis were updated in early 2022.¹ Notable for this discussion is the FDA approval of pacritinib [Vonjo] at the end of February 2022.² It’s now part of the NCCN guidelines. For patients with high-risk myelofibrosis, the first bifurcation is based on platelet count being greater than or less than 50 × 10⁹/L followed by whether they are a transplant candidate. If platelet count is greater than 50 × 10⁹/L and they are not a transplant candidate, the first-line treatment is ruxolitinib [Jakafi] or fedratinib [Inrebic].¹

For most of us, the first choice is generally ruxolitinib. But if the platelet count is less than 50 × 10⁹/L and they are not a transplant candidate, then that is where the label indication for pacritinib is. If the platelet count is greater than 50 × 10⁹/L and they have been treated with ruxolitinib and may or may not have had a good response or they lose the response or have an issue with ruxolitinib or fedratinib, what are the other available options?

Essentially one could consider any of the JAK inhibitors, including pacritinib, regardless of whether the platelet count is greater than or less than 50 × 10⁹/L. When you get to the second-line setting, you can use whichever agent might provide benefit. [That] is where it can get a little more liberal, but strictly speaking, the label indication for pacritinib is for patients with myelofibrosis with a platelet count of less than 50 × 10⁹/L.

What are the differences among the JAK inhibitors currently available for the management of myelofibrosis?

There are 3 currently approved JAK inhibitors for myelofibrosis. Ruxolitinib has been available now for over a decade, and for many years that was the only available JAK inhibitor, whereas fedratinib was approved in 2019 and pacritinib in early 2022.

They are approved for patients with intermediate- or high-risk myelofibrosis, but pacritinib is for patients with a platelet count less than 50 × 10⁹/L. The dosing for each is a little different. For ruxolitinib, the initial dosing is based on platelet count. For fedratinib, it’s a single 400-mg daily dose if the platelet count is at least 50 × 10⁹/L, whereas pacritinib is 200 mg twice daily.

They are all JAK inhibitors, so they obviously share that as a property, but there are distinctions among them. They all hit JAK2 with relatively comparable degrees of potency. One distinction with pacritinib is it doesn’t hit JAK1. Some literature suggests that the absence of significant JAK1 activity may be a partial explanation for why it can be safely used in patients with a low platelet count or in other ways doesn’t lower the platelet count [as] much as ruxolitinib does.³

There are additional targets of these drugs, including IRAK1 for pacritinib. IRAK1 is involved in inflammatory signaling, so it may contribute to the anti-inflammatory effect of pacritinib. Both pacritinib and fedratinib hit FLT3, which does cause some GI [gastrointestinal] toxicity.

What data support the use of ruxolitinib in myelofibrosis?

The data that support the use of ruxolitinib were initially from the COMFORT studies, which led to the approval of ruxolitinib for myelofibrosis. In the COMFORT-I trial [NCT00952289], patients were [randomly assigned] to treatment with ruxolitinib vs placebo. In COMFORT-II [NCT00934544] they were [randomly assigned] to treatment with ruxolitinib vs best available therapy [BAT].⁴

In both COMFORT-I and COMFORT-II, there were patients with at least 35% reduction in spleen volume, which is the typical metric for these JAK inhibitors and other agents in development. There was quite a stark distinction [among] ruxolitinib, placebo, and BAT. Virtually every patient treated with ruxolitinib had at least some degree of spleen response, and [approximately] 30% to 40% of patients met that primary end point of 35% reduction in spleen volume.⁴

This is something that matches up with my experience. It’s not generally a question of whether they are going to respond to ruxolitinib but a question of how much. Some may not have a robust spleen response, but most patients have at least some degree of improvement. Symptom response is also very similar. Most patients had at least some degree of symptom improvement. [Approximately] 40% to 50% of patients achieved a 50% reduction in the total symptom score. Across the board, each of these symptoms improved with ruxolitinib.⁴

The data indicate at least a modest improvement in overall survival [OS] in patients treated with ruxolitinib from the COMFORT-I and COMFORT-II studies. Keeping in mind that crossover was allowed with these studies, there are some confounding data here.⁵

[They make] any difference in survival more meaningful and suggest there are benefits [to] extended treatment with ruxolitinib. Is that a compelling argument to say that if you’ve been starting earlier, it will result in an additional benefit?

There is some correlation between spleen response and OS. In other words, those patients who achieved a robust spleen response were more likely to benefit in terms of OS. This was from 1 of those post hoc analyses where it’s not 100% clear.⁶ It’s more correlation than causation. From these data, one could argue we need to shoot for the maximal spleen response by maximiz[ing] dosing of ruxolitinib to achieve that degree of survival benefit. It’s not necessarily true, but it fits with the data that those who have deep spleen responses are more likely to have prolonged survival.

In terms of adverse effects [AEs], ruxolitinib is well tolerated, and most AEs were grade 1 and 2. Patients feel better on ruxolitinib. It doesn’t cause severe nausea, vomiting, and things like that. They tend to feel much better upon initiating treatment with ruxolitinib. It causes cytopenia. Obviously, many of these patients already [have cytopenia] at baseline, and in many cases, that will get worse with ruxolitinib. In the COMFORT-I study, there was a higher incidence of anemia and thrombocytopenia [than with placebo], and that is borne out by my experience in practice.⁴

I always counsel the patient when I start [them on] ruxolitinib that their hemoglobin and platelet counts are probably going to go down. That’s something we must accept as a trade-off. If they feel better despite that, it’s a net positive. But it is important to set expectations for patients when we start treatment with ruxolitinib.

There is some association with the dose and the degree of response. The spleen volume response going from less than 10 mg twice daily to 10 mg twice daily has a significant demarcation, [and] it does increase a little more as you go to higher doses. With symptom response, there’s a steep drop-off between 10 mg twice daily and less than 10 mg twice daily. In other words, we need to achieve a dose of at least 10 mg twice daily to get a meaningful symptom and spleen response. Below that, it’s difficult or less likely to achieve something meaningful.⁷

What data support the use of fedratinib in myelofibrosis?

The fedratinib data were from the JAKARTA study [NCT01437787]. Patients were [randomly assigned] to treatment with fedratinib at either 400 mg or 500 mg daily vs placebo.⁸

The results were analogous to ruxolitinib with a 35% reduction in spleen volume in 37% [of patients]. We do see with fedratinib some degree of GI toxicity: nausea, vomiting, and diarrhea. It is not common to have grade 3 or 4 AEs, but they had a high incidence of grade 1 and 2 AEs.

This is something I see in patients who were treated with fedratinib. They can be proactive in terms of [using] antidiarrheals and antinausea agents, but it is something that is unique to fedratinib compared with ruxolitinib. Like ruxolitinib, fedratinib causes anemia and thrombocytopenia.

There was an FDA hold for a relatively short time with fedratinib before it was approved due to reported cases of Wernicke encephalopathy. After further analysis, several of these cases were not bona fide Wernicke encephalopathy.⁹ It was thought that it was more about malnutrition in patients who had solid tumors who were being treated with fedratinib, but nonetheless, it raised concern in terms of safety.

The Wernicke encephalopathy is a black box warning on the FDA approval,¹⁰ but the bottom line is that if you’re going to use fedratinib, the recommendation is to check the thiamine level before starting treatment. I would recommend giving thiamine to every patient who is treated with fedratinib, regardless of their thiamine levels, because it’s cheap, easy, and nontoxic. With that in mind, I don’t see it as a huge issue in terms of safety.

What data support the use of pacritinib to manage myelofibrosis in patients with a platelet count below 50 × 10⁹/L?

The trials for pacritinib were PERSIST-1 [NCT01773187] and [PERSIST]-2 [NCT02055781]. The PERSIST-2 trial included a population of patients with myelofibrosis and a platelet count less than 100 × 10⁹/L. The approval is for a platelet count less than 50 × 10⁹/L, but in the study, patients had a platelet count of less than 100 × 10⁹/L.¹¹

For the baseline demographics, the BAT arm had [approximately] 50% of patients receiving ruxolitinib. There’s been some analysis that compares patients treated with ruxolitinib within the BAT arm, but again, about half of those patients in that arm did receive ruxolitinib.¹¹

Pacritinib [at] 200 mg twice daily, which is the FDA-approved dose, had a greater than 35% spleen volume reduction in 29% of patients with a platelet count less than 50 × 10⁹/L vs only 3% for the BAT arm, where only 1 patient out of 32 achieved that response. So it was a clear difference.¹² The symptom response was 32% for pacritinib vs 14% for BAT. Clearly, more patients treated with pacritinib achieved a 50% reduction in the total symptom score.

For the individual symptoms, across the board there was an improvement with pacritinib compared with BAT [Table¹¹]. For anemia, there’s some indication that pacritinib did improve hemoglobin [level], at least in some patients.

By week 24, the number of red blood cell transfusions twice daily in the pacritinib [arm] was a little lowercompared with BAT.

The change in platelet count was stable if not improved in patients treated with pacritinib.¹¹ This reinforces that in patients with very low platelet counts, pacritinib can be used without worrying about detrimental effects on the platelet count.

With FLT3 being a target of pacritinib, we expect some degree of GI toxicity, mostly grade 1 and 2, which can be an issue. We recommend that patients have antidiarrheal agents on hand. Consider up-front use of antiemetics at least initially. In many cases, the nausea will abate after a few weeks or months. So they may need it initially but then no longer need it.

_REFERENCES

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_{7. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13-21. doi:10.2147/ OTT.S53348}

_{8. Pardanani A, Tefferi A, Masszi T, et al. Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol. 2021;195(2):244-248. doi:10.1111/ bjh.17727}

_{9. Harrison CN, Mesa RA, Jamieson C, et al. Case series of potential Wernicke’s encephalopathy in patients treated with fedratinib. Blood. 2017;130(suppl 1):4197. doi:10.1182/blood.V130.Suppl_1.4197.4197}

_{10. Inrebic. Prescribing information. Impact Biomedicines Inc; 2022. Accessed February 6, 2023. https://bit.ly/3YvGL37}

_{11. 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}

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