Dose Intensity Anchors JAK Inhibitor Selection as Combinations and Targeted Agents Expand Options in Myelofibrosis

Blood counts and the ability to maintain dose intensity should guide selection among the 4 approved JAK inhibitors in myelofibrosis: ruxolitinib (Jakafi), fedratinib (Inrebic), momelotinib (Ojjaara), and pacritinib (Vonjo), according to Raajit K. Rampal, MD, PhD.

"What I would emphasize is the need to maintain dose intensity, and that should color how and which JAK inhibitor people use, rather than using suboptimal doses of drugs," Rampal said in an exclusive interview with OncLive®.

In the interview, Rampal discussed how cytopenia status can help inform JAK inhibitor selection and dosing, and he also expended on the potential roles of combination strategies and targeted therapies that could alter myelofibrosis management.

Rampal is director of the Center for Hematologic Malignancies and director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: How do cytopenias inform JAK inhibitor selection and dosing among the 4 approved agents in myelofibrosis?

Rampal: It's an important question because in the real world, we have a lot of patients with anemia or thrombocytopenia, and there are a number of considerations[for treatment selection]. There's a consideration about which JAK [inhibitor] you choose, but also how you use that JAK [inhibitor]. Starting with ruxolitinib, which is likely the most widely used drug, the dosing is based on platelet count, and that represents a challenge because we know that dose intensity matters. It is important to get [to] a dose of 10 mg twice daily or higher. Per the label, if the platelet[counts] are 50 x 10⁹/L to 100 x 10⁹/L, you're supposed to cut the dose to 5 mg twice daily, but there aredata to support the idea that you can step up the dose and get to 10 mg [twice daily] as long as the patient remains safe. When choosing a JAK inhibitor, we have to keep this concept of dose intensity as part of the center of the discussion.

Now, taking the same idea of patients with a platelet count of 50 x 10⁹/L to 100 x 10⁹/L, what if they're on the other end of things? What if they're at [a platelet count of] 55 x 10⁹/L or 60 x 10⁹/L? There, it's much more challenging to intensify ruxolitinib dosing, and that's the area where we have other JAK inhibitors available that can be used at full dose. One example is momelotinib, which… primarily has an indication for patients with anemia. As it turns out, anemia and thrombocytopenia often tend to go hand in hand in patients with myelofibrosis.

We also have pacritinib, which is labeled in [the] frontline for patients [with] platelet [counts] under 50 x 10⁹/L and does not require any dose reductions regardless of the platelet count, meaning that you can get to single-digit platelet counts and keep the dose. That's a big advantage of a drug like [pacritinib] in that particular patient population. Those are some of the major considerations [with approved JAK inhibitors] with [regard] to cytopenia.

How important is managing anemia and transfusion dependence for quality of life in patients with myelofibrosis?

As it pertains to blood counts, anemia is interesting because anemia is both a number and not a number, meaning that 2 patients may have a hemoglobin [level] of 9 g/dL, for example. One of them is going to the gym every day and working in the garden, while the other can't get off the couch. It depends on the patient.

Part of the concept of how we treat and what we treat is to not treat necessarily the number, but [we also need to] put this in the context of the patient. In some patients, tolerating anemia is a reasonable thing and doesn't require intervention because it's not affecting the patient's quality of life. In other patients, [improving anemia] becomes the most pressing concern for that patient in terms of helping them have a good quality of life.

How could you see combination approaches featuring JAK inhibitors integrated into myelofibrosis treatment?

[It's an] interesting question. None of these [investigational combinations] are FDA approved for the treatment of patients with myelofibrosis yet, but they offer an intriguing future because they all have some promising data, including some phase 3 data that look quite interesting.^1,2 It becomes a question of which approach is right for which patient.

Should everybody necessarily get a combination up front? I don't know that we have data to support that idea. However, based on what we know about spleen reduction and the rate of success of spleen reduction, the combinations that have been studied, principally pelabresib [CPI-0610] and selinexor [(Xpovio), both added to ruxolitinib], have shown better spleen volume response data. The question is: Does that matter?

There's the practical and there is the data-driven part of this, and the data suggests that patients who achieve [a spleen volume reduction of at least 35%] may have a better outcome overall.It's a complicated thing because [there are] probably multiple things that drive such a response. If that data holds up in multiple studies, then it's hard to say that this is not important. In a patient with a larger spleen, maybe doing a combination up front makes sense.

The second[factor] is the practical aspect [of combinations]. If we think about reducing the size of the spleen as we get data that it may make a difference for long-term outcomes, in the setting of patients who are going to transplant, we already have established data that going into transplant with a smaller spleen leads to quicker engraftment. This is clinically important. If you have a patient with a moderately enlarged spleen who needs to go to stem cell transplant, it probably makes more sense to start with a combination regimen to get them there quicker and with more depth of spleen response. It's not as if we have data that [say] that directly, but by inference of multiple datasets, that is not an unreasonable conclusion. We're going to have to define that future if and when that future hopefully comes.

How might CALR mutation–targeted therapies fit alongside JAK inhibitors in the myelofibrosis treatment paradigm?

[The development of CALR mutation–targeting therapies] is both an exciting time and a time raising a lot of new questions, because we don’t [fully] know how to think about this. [It's the] same thing with the combinations; we have to build the paradigm of the future as we get more data. With the data that we've seen from the [Incyte] drug [INCA033989] so far, there's clearly efficacy here in terms of spleen, symptoms, and anemia.

Is that [agent] going to be a combination partner with a JAK inhibitor? I don't know; there's not that much data that we have seen so far. Is it going to be an agent for second-line treatment, or is it going to be an agent for first-line treatment in patients [with CALR mutations]? All of these are possibilities, and none of them are mutually exclusive whatsoever.

We're going to need to see more data. We're going to need to see what the regulatory pathways are that tell us how we can use the drugs, but we can start to envision a future where we use them in many cases, or maybe all cases, with patients who have [CALR mutations], as an example.

How do you view anemia-directed agents such as luspatercept-aamt (Reblozyl) and elritercept (KER-050; TAK-226) for patients with myelofibrosis?

Anemia remains a big problem, and historically, most of our agents seem to revert to the mean of a 30% response rate, which means that many patients aren't getting what they need. With luspatercept, the phase 2 [ACE-536-MF-001 trial (NCT03194542)] data were striking, and with the phase 3 data [from the INDEPENDENCE trial (NCT04717414)] that were] presented at the 2026 EHA Congress, [statistical significance for the primary end point of red blood cell transfusion independence] was close, and [there was] probably some geographic impact on the outcome of the study.³

In the real world, we use luspatercept off-label all the time. It's in the National Comprehensive Cancer Network guidelines, so there is a justification, but it can absolutely be added on to ruxolitinib. It is being studied currently in combination with momelotinib, as well. We'll only see the future expand for luspatercept; clinically, to us, it's been a useful drug.

Elritercept has some provocative data. What's quite interesting with that drug is that there [are] some spleen data, as well as anemia data, in terms of response. That's quite interesting, we'll have to see how that data pan out ultimately, and [these data will] give us a better sense of how to use that drug by itself or in combination. We are in a better place than we've been for the treatment of anemia.

Where do you see the myelofibrosis treatment landscape heading as phase 3 data mature over the next few years?

If these drugs show efficacy, the next question will be: Does treating earlier make a difference? There's no cancer I can think of [where] treating later makes things better. We've been limited historically in our thinking because we had just ruxolitinib, and we didn't want to use it until we needed to use it.That thinking needs to change with multiple agents, but also now with new agents coming, hopefully, forward to the market.

That’s the next horizon. If you treat earlier, can you improve outcomes? Can you prevent progression? Can you improve overall survival? That's where I see things going.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial. Nat Med. 2025;31(5):1531-1538. doi:10.1038/s41591-025-03572-3
2. Bose P, Ali H, Al-Ali HK, et al. Selinexor plus ruxolitinib in Janus kinase inhibitor-naïve myelofibrosis: phase III SENTRY trial. J Clin Oncol. 2026;44(22):2098-2109. doi:10.1200/JCO-26-01080
3. Passamonti F, Kiladjian JJ, Mascarenhas J, et al. Efficacy and safety of luspatercept in patients with myelofibrosis on Janus kinase inhibitors who require red blood cell transfusions: primary analysis of the phase 3 INDEPENDENCE trial. Abstract presented at: European Hematology Association 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S215.