JAK Inhibitor–Based Combos and Mutation-Specific Regimens Comprise the Future of Myelofibrosis Management

Treatment with JAK inhibitor monotherapy has lowered transfusion burdens, improved anemia, and reduced spleen size in patients with myelofibrosis, leading to an era of ongoing clinical trials that are evaluating this class of agents in combination with other myelofibrosis therapies, according to Claire Harrison, MD, FRCP, FRCPath.

“Increasingly, we’re thinking of earlier treatment for patients [so we can] intervene earlier, get a better outcome, and sustain [that outcome],” Harrison said in an interview with OncLive®.

In the interview, Harrison, a professor at Guy’s and St. Thomas’ Hospital in London, United Kingdom, discussed the importance of accurate myelofibrosis diagnosis and considering patient fitness for select treatments; ongoing research that may inform the evolving clinical utility of JAK inhibitors in this disease space; an outline for optimal treatment sequencing based on patient and disease characteristics; and the potential future implications of mutation-specific therapies.

She spotlighted the clinical implications of findings from a longitudinal study of transfusion intensity in patients with myelofibrosis who received momelotinib (Ojjaara), which showed that across 3 randomized clinical trials, the rates of patients with improved or stable transfusion intensities were higher among those who received momelotinib compared with those who received ruxolitinib (Jakafi), danazol, or best available therapy.1

She also highlighted the rationales for ongoing clinical trials she is involved in that are evaluating novel JAK inhibitor–based combinations in patients with myelofibrosis. The single-arm, phase 2 FEDORA trial (EudraCT 2021-004056-42) is investigating fedratinib (Inrebic) plus ropeginterferon alfa-2b-njft (Besremi) in patients with JAK2 V617F–positive primary or secondary myelofibrosis.2 This trial aims to provide data to support phase 3 evaluation of the combination in this population.

Furthermore, the phase 3 SENTRY trial (NCT04562389) is examining selinexor (Xpovio) plus ruxolitinib vs placebo plus ruxolitinib in patients with JAK inhibitor­–naive myelofibrosis.3 The primary end points include the proportion of patients with a spleen volume reduction of at least 35% (SVR35) and absolute mean change in total symptom score from baseline to week 24.

OncLive: What is your general algorithm for treating patients with myelofibrosis, and how do mutations such as SF3B1 affect patient prognosis and treatment decision-making?

Harrison: Myelofibrosis is a complicated disorder, and patients can vary a lot [regarding their disease] outlook and the way they present. In general, the first, most important [consideration] is to be sure you have the right diagnosis. Scrutinizing all the diagnostic information, even for a patient who has come from another hospital, for example, is important.

Mutations are an important part of that [information], as are symptoms, [such as] the presence of splenomegaly, etc. Then, I try to assess the general fitness of the patient—[including] other comorbidities that [may affect] our ability to treat them—and establish the main disease problems for them. [I also ensure they have a good understanding of their disease], referring them to patient advocacy where appropriate. I always use the words ‘blood cancer’ when I talk about this condition [with patients].

Then, to calculate prognosis, there are many different prognostic tools for myelofibrosis; however, the more modern ones incorporate mutations. As a broad principle, the presence of a mutation—such as CALR, JAK2, or MPL—helps us establish a likely diagnosis of a myeloproliferative neoplasm. However, there are additional mutations, and I always look for additional mutations if a patient has triple-negative disease.

[Other mutations can also] be useful for prognosis. There are some high molecular risk mutations. These generally include ASXL1, B7-H2, IDH1/2, SRSF2, U2AF1, p53, RUNX1, and NRAS. [The presence of any of those mutations would tell me] I need to think about prognosis.

Then, considering the prognosis of the patient makes me ask [whether we] need to proceed to transplant if I’m ever thinking about transplant. [If the patient is] young and low risk, I’m probably going to [consider transplant] at some point. Or maybe they’re over the age of 75 years or unfit [for transplant].

Then, I would consider the individual parameters. Interestingly, some mutations can influence different parameters of the disease without influencing prognosis. A good example is SF3B1 mutations, which are often associated with anemia. Sometimes, where there’s a tricky diagnosis, these patients can also have features of myelodysplastic syndromes [MDS], in particular MDS with ring sideroblasts. Although on their own, [SF3B1 mutations do not have] prognostic significance, they can cause anemia. We broadly [use] a problem-based approach and [consider] whether we’re going to go to transplant.

If systemic therapy is decided on as the first course of action, how likely are you to choose momelotinib in this setting? How has this agent been integrated into your clinical practice?

Momelotinib is the most recent JAK inhibitor to be approved. Pacritinib [Vonjo] is approved [by the FDA in the United States], but it’s not approved elsewhere in the world. Momelotinib is interesting and offers a lot of potential for patients. [It is a] JAK1 and JAK2 inhibitor, so it is similar to ruxolitinib. [Momelotinib also] has an intriguing effect on the ACVR1 pathway, therefore affecting hepcidin [levels] and ameliorating anemia.

What we want to see for patients treated with [momelotinib] is a benefit for spleen symptoms and improvement in anemia. Given that anemia is present in one-quarter to one-third of patients [with myelofibrosis] at diagnosis, it becomes more prevalent over time, and it is an [adverse effect (AE) associated with] many other treatments, including ruxolitinib and fedratinib, [momelotinib] holds great promise for patients. It is approved for the management of anemia symptoms and splenomegaly. It can be used in different countries for different indications, but broadly it can be used in both the first- and second-line [myelofibrosis] settings. Readers may have different approvals in their countries, and they would have to look at those.

There are some different [AEs associated with momelotinib] to bear in mind. First, you have to be careful about cardiac toxicity and liver toxicity. There’s [the potential for] first-dose hypotension and the potential for neuropathy. Those need to be watched, and [we need to] warn patients about gastrointestinal AEs. However, generally, it’s a well-tolerated drug. It is a good choice for patients as a monotherapy.

Dosing is flat. You don’t have to think about starting platelet counts. You can treat a patient with a platelet count down to 25 × 109/L. Given that anemia and thrombocytopenia often [develop] together, that’s extremely useful. [Momelotinib] offers the opportunity to [administer] full-intensity treatment, and therefore is probably a good partner as we consider combination approaches in the future.

A study you coauthored evaluated transfusion intensity in patients with JAK inhibitor–naive or –experienced myelofibrosis who received momelotinib. What were the key findings from this analysis?

There are many ways of [interpreting data] regarding anemia, anemia responses, and transfusion. We showed that with momelotinib, approximately 30% of patients attained transfusion independence over a rolling 8- to 12-week period. The attainment of transfusion independence was independently associated with a survival benefit for patients. Anemia and requiring transfusions have the opposite effect.

However, we saw in the first analysis [of this study] that transfusion frequency or intensity also dropped in many patients. A 50% reduction in transfusion intensity may seem like a softer end point, but if you’re a patient who has to come every 2 weeks for transfusion, and then you end up only having to come every 4 weeks, that’s a great result. We also saw that although there wasn’t a highly significant P value regarding survival association [with momelotinib], reducing transfusion intensity or requirement was associated with a trend [toward] survival benefit.

These are all important nuances. Statistical [outcomes are] one thing, but real-life terms are important to a patient. [Considering] use of blood, day ward capacity, risks of transfusion, etc., [is also] important. Additionally, with transfusion comes iron overload, and that brings another burden for patients.

What data do you use to support second- and later-line treatment sequencing decisions in patients with myelofibrosis?

Times have changed for patients with myelofibrosis. We now have 3 or 4 approved JAK inhibitors, depending on which part of the world you live in. We have to consider the sequencing of those therapies and other supportive therapies—such as erythropoiesis-stimulating agents like danazol, for example—and sequencing to transplantation. [The treatment paradigm] can become complicated. You have to think logically with an approach to a patient.

[When] starting [with] the most intensive treatment, most patients receive a JAK inhibitor prior to transplant. Interestingly, at the 2024 ASH Annual Meeting, there was a complex presentation from Nico Gagelmann, MD, [of University Medical Center Hamburg-Eppendorf, in Germany], evaluating mathematical modeling suggesting timing to go to transplant. Also, recently, a paper [was published] suggesting that patients [with myelofibrosis] who had molecular responses [with JAK inhibitors] did better with transplant [than those without responses].

[When you] take a patient to transplant, [you should] take them at the peak of their response to a JAK inhibitor, if they’re a good transplant candidate. Otherwise, you might want to wait if they have a poor donor or are high risk, and sequence through other JAK inhibitors. However, don’t take a patient through 3 different JAK inhibitors if you are ultimately going to transplant them and they’re likely to have a good outcome [with transplant].

[Other treatment options] depend on whether you have clinical trial availability. I always believe in offering my patients a clinical trial because those are usually associated with good outcomes for patients and spreading knowledge.

However, broadly speaking, [decisions between] available agents depend on the patient profile. [If a] patient is profoundly anemic, momelotinib is a good choice for first-line therapy. If they have a heavy symptom burden but are not particularly anemic or thrombocytopenic, ruxolitinib is a good option. Data [presented] at ASH showed that fedratinib was a good option for patients in the second-line setting when the platelet counts are between 50 × 109/L and 100 × 109/L.

[These decisions] depend on individual parameters for the patient, as well as their need [for treatment]. Why are you moving to a second-line therapy? If you’re moving to a second-line therapy because the patient has toxicity, you have to consider overlapping toxicities. [These decisions] become complicated.

You’re a co-investigator on the phase 1/3 SENTRY and phase 2 FEDORA trials. What are the objectives of these studies?

At a top level, the objective of all clinical studies is to identify a better treatment for patients. There are some other benefits, such as identifying different end points. That’s something we need for myelofibrosis. In our current clinical trial portfolio, we have some first-line studies where we’re looking to see whether we can do better than ruxolitinib as a first-line agent. How we measure ‘better’ is a bit controversial, but for now, it is [measured as the] proportion of patients who achieve SVR35 and a symptom response.

The FEDORA study is open in the United Kingdom [and is] combining fedratinib with pegylated interferon in the frontline setting. That’s not a randomized study—it’s a small study looking for biological activity [with the combination]. Animal model data [that have been] presented suggest that could be the case.

The SENTRY, or XPORT-MF-034 study, is investigating the combination of selinexor and ruxolitinib vs ruxolitinib alone upfront. Selinexor is an interesting [agent] because it affects several parameters, such as NF-κB [signaling], JAK-STAT signaling, the p53-mediated apoptosis pathway, and the cellular export of targets.

For balance, there is also the phase 3 POIESIS study [NCT06479135] using navtemadlin [KRT-232], which has an interesting design. [This study is] treating all patients upfront with ruxolitinib. If they don’t meet SVR35 and/or 50% symptom response, they are randomly assigned to receive navtemadlin or [placebo as a ruxolitinib add-on].

Then, there has been the phase 3 TRANSFORM-1 study [NCT04472598] with navitoclax and the ongoing phase 3 MANIFEST-2 trial [NCT04603495] evaluating pelabresib [CPI-0620]. All these [trials] are trying to find a better frontline therapy because many of us were taught that we should give the best treatment first for patients when the disease is less complicated and try to get the best outcome [early in the treatment course].

How might mutation-specific therapies alter the myelofibrosis treatment paradigm going forward?

There’s tons of fascinating [research] in the field of myelofibrosis. We’re still figuring out p53 mutations and what to do with them, [including] single-hit and double-hit [mutations], etc. That’s topical and important because we are targeting the MDM2 pathway and potentially need to better understand [how that affects] p53.

The mutation-targeted therapies are also exciting. There are at least 2 clinical trials ongoing with either the CALR [inhibitor] from Incyte or the bispecific antibody from Johnson & Johnson in patients with myelofibrosis and essential thrombocythemia. I’m hoping to see data from these soon. [Additionally], pseudokinase domain and mutation-specific inhibitors of JAK2 are being tested in the clinic.

References

1. Harrison CN, Mesa R, Talpaz M, et al. Longitudinal assessment of transfusion intensity in patients with JAK inhibitor-naive or -experienced myelofibrosis treated with momelotinib. Clin Lymphoma Myeloma Leuk. 2025;25(3):199-211. doi:10.1016/j.clml.2024.10.001
2. McIlroy G, Gaskell C, Jackson A, et al. Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial. BMC Cancer. 2025;25(1):56. doi:10.1186/s12885-024-13383-3
3. Study of selinexor in combination with ruxolitinib in myelofibrosis (SENTRY). ClinicalTrials.gov. Updated February 5, 2025. Accessed February 19, 2025. https://clinicaltrials.gov/study/NCT04562389