Dr Harrison on Investigational JAK Inhibitor–Based Combinations in Myelofibrosis

“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. [In doing so, we can] try to achieve the best outcomes [early in the treatment course].”

Claire Harrison, MD, FRCP, FRCPath, professor, Guy’s and St. Thomas’ Hospital, discusses ongoing research with JAK inhibitor–based combination regimens in the frontline setting for patients with myelofibrosis.

Ongoing clinical trials in myelofibrosis aim to identify more effective first-line treatments beyond ruxolitinib (Jakafi), Harrison begins. Notably, clinical efficacy in myelofibrosis trials is primarily measured by the proportion of patients achieving spleen volume reduction of at least 35% (SVR35) and symptomatic improvement, she explains.

The nonrandomized, United Kingdom–based, phase 2 FEDORA trial (EudraCT 2021-004056-42) is evaluating the JAK inhibitor fedratinib (Inrebic) in combination with ropeginterferon alfa-2b-njft (Besremi) in the frontline setting in patients with 

 V617F–positive primary or secondary myelofibrosis. Preclinical data from animal models have shown the potential biological activity of this combination, although further validation is required, Harrison says.

Furthermore, the phase 3 SENTRY/XPORT-MF-034 trial (NCT04562389) is assessing selinexor (Xpovio) plus ruxolitinib vs ruxolitinib alone in treatment-naive patients. Selinexor is of interest in myelofibrosis due to its effects on NF-κB, JAK-STAT signaling, p53-mediated apoptosis, and nuclear export mechanisms, Harrison reports. Selinexor is also being investigated for patients with thrombocytopenic myelofibrosis, she notes.

The POIESIS trial (NCT06479135) is investigating navtemadlin (KRT-232) as an add-on to ruxolitinib in patients with JAK inhibitor–naive myelofibrosis. This trial has a unique design in that all patients initially receive ruxolitinib and are then randomly assigned to receive navtemadlin or placebo if they do not achieve SVR35 or at least a 50% symptom response, according to Harrison.

Additionally, the phase 3 TRANSFORM-1 (NCT04472598) and MANIFEST-2 (NCT04603495) trials investigated navitoclax and pelabresib (CPI-0620), respectively, as potential frontline agents. These studies uphold the clinical practice of initiating the most optimal therapy early in the disease course to maximize long-term outcomes, Harrison concludes.

Videos

Claire Harrison, MD, FRCP, FRCPath, discusses ongoing research with first-line JAK inhibitors for patients with myelofibrosis.

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 

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.

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 

 V617F–positive primary or secondary myelofibrosis.

 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.

 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.

: What is your general algorithm for treating patients with myelofibrosis, and how do mutations such as 

 affect patient prognosis and treatment decision-making?

: 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 

—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 

. [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 

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, [

 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 × 10

/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 

 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 

, 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 × 10

[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 

 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.

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. 

. 2025;25(3):199-211. doi:10.1016/j.clml.2024.10.001

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. 

. 2025;25(1):56. doi:10.1186/s12885-024-13383-3

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

Articles

Claire Harrison, MD, FRCP, FRCPath, discusses research that may evolve the clinical use of JAK inhibitors and mutation-specific therapies in myelofibrosis.

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

Dr Gerds on Efficacy Data Supporting the Use of Momelotinib in Myelofibrosis With Anemia

“These [data] reinforce the concept that momelotinib is a drug that can do both. It can shrink spleens and improve symptoms, as well as treat anemia in patients with myelofibrosis.”

Aaron Gerds, MD, assistant professor of medicine, Department of Hematology and Medical Oncology, deputy director, Clinical Research, Cleveland Clinic Taussig Cancer Institute, discusses data from the phase 3 SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials, which supported the 

 for patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.

SIMPLIFY-1 was a prospective, randomized trial comparing momelotinib vs ruxolitinib (Jakafi) as frontline therapy forpatients with myelofibrosis who had not previously been treated with a JAK inhibitor, Gerds begins. In the study,treatment with momelotinib led to a noninferior reduction in spleen volume compared with ruxolitinib, he reports. However, momelotinib was somewhat less effective than ruxolitinib in alleviating symptom burden. Although this method for measuring symptom burden has limitations, the finding raised questions about momelotinib’s role in symptom management, Gerds explains.

Additionally, data from SIMPLIFY-1 suggested that momelotinib may provide benefit in terms of anemia management, Gerds continues. Patients treated with momelotinib experienced less anemia compared with those on ruxolitinib. This was an early indication that momelotinib might serve as a dual-purpose therapy, addressing anemia and targeting spleen size and symptoms, he emphasizes.

Building on these findings, the MOMENTUM trial was conducted to evaluate momelotinib in patients with anemia who had prior exposure to a JAK inhibitor and continued to experience splenomegaly and symptom burden, Gerds expands. In this trial, momelotinib was compared with danazol, an established agent for managing anemia in myelofibrosis, he adds. Momelotinib outperformed danazol regarding spleen volume reduction and symptom burden improvement. Additionally, momelotinib demonstrated a noninferior improvement in anemia, reinforcing its unique ability to target all 3 critical aspects of myelofibrosis management. This positions momelotinib as a versatile treatment option for patients with complex needs, Gerds concludes.

Aaron Gerds, MD, discusses data from the SIMPLIFY-1 and MOMENTUM trials which support the use of momelotinib in myelofibrosis with anemia.

Although ruxolitinib (Jakafi) remains a cornerstone in myelofibrosis treatment, the increased availability of alternative JAK inhibitors such as momelotinib (Ojjaara) has helped lower the threshold for switching therapies among patients who are not responding optimally to standard therapy, according to Aaron Gerds, MD, who added that there is growing excitement ongoing research with new combination strategies and therapies outside the JAK inhibitor family.

“We have 4 JAK inhibitors that are FDA approved to treat myelofibrosis. This is a fantastic thing and a recent development over the last couple of years… but there’s more to come,” Gerds stated. “We are a stone’s throw away from new agents coming along, [including] agents that aren't JAK inhibitors, which will be a welcome addition to our armamentarium. It's an exciting time, and I expect a lot of rapid change in the way we treat patients with myelofibrosis over the next 2 to 5 years.”

, Gerds discussed how momelotinib has fit into the expanding arsenal of JAK inhibitors in myelofibrosis; detailed the differences in molecular targets, efficacy, and toxicity profiles between available JAK inhibitors, alongside strategies to proactively manage such toxicities; and expanded on ongoing research into JAK inhibitor–based combinations and new end points to more accurately measure outcomes in patients with myelofibrosis.

Gerd is an assistant professor of medicine, Hematology and Medical Oncology, at Cleveland Clinic Taussig Cancer Institute in Ohio.

: How do risk stratification models and symptom burden guide your approach to managing myelofibrosis?

 My general approach is in line with the guidelines. In short, we use risk stratification models that predict overall survival [OS] in different populations of patients to [better] understand what to expect over time. Those risk models also help us identify patients who we might want to consider [for] transplant earlier rather than later.

Secondly, treatment today is driven by symptoms and symptom burden. If a patient has spleen-related or cytokine-related symptoms, we would consider a JAK inhibitor. If a patient has significant cytopenia, such as anemia, we would want to use an anemia-directed agent. If patients are otherwise feeling well, [where] there are no major deficits in terms of anemia and their disease is not high risk, we would continue with careful observation. Thus far, there are no data that strongly support preemptive treatment in myelofibrosis.

What differentiates momelotinib from other JAK inhibitors?

All the JAK inhibitors that are commercially available today block JAK2 wild-type specifically, and then everything else they do distinguishes them from each other. Ruxolitinib and momelotinib both also inhibit JAK1; fedratinib [Inrebic] and pacritinib [Vonjo] inhibit 

; and momelotinib and pacritinib both inhibit ACVR1, which is the [protein] we think that improves anemia in patients with myelofibrosis. Inhibiting ACVR1 lowers hepcidin levels, thus making iron available for erythropoiesis. It basically reverses the anemia of inflammatory block in these patients, so that is an important mechanism [to target].

What data from the phase 3 SIMPLFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials supported 

the 2023 FDA approval of momelotinib in myelofibrosis

SIMPLIFY-1 was a prospective, randomized trial of patients [with myelofibrosis] previously untreated with a JAK inhibitor, comparing momelotinib vs ruxolitinib in the frontline setting. Key take-home points from that study were that momelotinib was not any worse than ruxolitinib at shrinking spleens, but it was a bit inferior to ruxolitinib in terms of decreasing symptom burden as measured by a greater than 50% reduction in tumor symptom score [TSS 50] at week 24. Of course, this is a flawed methodology to measure symptom burden, [so we need to] take that with a grain of salt. What was also clear in SIMPLIFY-1 was that patients had less anemia on momelotinib relative to ruxolitinib. That's one of the first clues we saw [indicating that momelotinib] might be a helpful agent for anemia, as well as a JAK inhibitor [capable of reducing spleen size] and [improving] symptoms.

[Following] various studies and other trials, MOMENTUM was developed. [The] trial [enrolled] patients who had anemia and prior JAK inhibitor [exposure] with significant splenomegaly and symptom burden, and it compared momelotinib with danazol. Danazol was selected as a comparator arm because it is an active [treatment] for anemia in patients with myelofibrosis. What we saw in that study was no surprise. Momelotinib was better than danazol at treating spleens and symptoms; again, we wouldn't expect that with the mechanism of danazol. It was also not inferior to danazol at treating anemia. This reinforces the concept that momelotinib is a drug that can do both: it can shrink spleens and improve symptoms, as well as treat anemia, in patients with myelofibrosis.

Since its FDA approval, how have you integrated momelotinib into your clinical practice? Have you encountered any challenges with this?

That niche of patients with myelofibrosis who also have anemia is the group that you think about with momelotinib. [This could be] someone with a relatively decent platelet count north of 75 × 10

/L and a hemoglobin [level of] less than 10 g/dL who requires spleen or symptom control. That's the group of patients you would consider for this agent. It's been straightforward to incorporate into my everyday practice as another tool on the shelf that we can reach for quite easily with these patients.

For these patients, some of the things to watch out for were clearly outlined in a lot of the clinical trials that have been done. There is some mild gastrointestinal [GI] toxicity with this medication; patients do experience some nausea or diarrhea. We want to warn patients about that and, if they are experiencing those adverse effects [AEs], try to mitigate those with anti-diarrheals or antiemetics. The other thing that can happen [with] momelotinib is a reduction in platelet count. Certainly, we want to closely monitor platelet counts for patients with thrombocytopenia. Typically, thrombocytopenia occurs within the first month or 2 of treatment. However, we still want to monitor beyond that for the emergence of thrombocytopenia because we would want to [reduce] the dose of momelotinib to account for that.

What strategies do you recommend to proactively manage toxicities associated with JAK inhibitors, and how do these differ based on the specific agent being used?

Other JAK inhibitors do have AEs that we want to be proactive about; in particular, pacritinib and fedratinib have GI toxicities owing to their inhibition of FLT3. That's namely nausea and some diarrhea. For all my patients starting on pacritinib and fedratinib, I give them an antiemetic before they start [treatment]. Generally, those toxicities are worse in the first month and dissipate by the second and third months of treatment. [However,] we want to be proactive.

The more proactive we are with [prophylaxis], the less of an issue [AEs] are with ruxolitinib. We often talk about the development of cytopenias upon treatment, so you want to closely monitor for anemia and thrombocytopenia. Also, with ruxolitinib, there is weight gain. For many patients with myelofibrosis who have lost weight due to their disease, this is a welcomed AE. However, for others who have not lost weight, it is something worth noting, as are the same mechanisms of leptin elevation. We often talk about checking cholesterol regularly when on ruxolitinib. The weight gain and cholesterol increases are something that we don't normally see with the other JAK inhibitors.

With ruxolitinib, we also observe, over time, an increased risk of non-melanoma skin cancers and precancerous skin lesions. I often recommend that my patients have yearly skin exams with a dermatologist to identify and remove any brewing lesions. With all JAK inhibitors, it is recommended to do a remote hepatitis panel and make sure there's no hepatitis lurking that we don't know about. [We should also] ask patients if they have any history that might increase their risk for tuberculosis before starting them on a JAK inhibitor.

What are some of the limitations of using spleen volume reduction at week 24 (SVR24) as an end point in myelofibrosis, and how might future trials address or account for them?

Ruxolitinib was approved on the basis that it made people feel better. It also shrinks spleens, but its [approval] was [primarily due to] the symptom burden improvement. The somewhat arbitrary metric—the reduction in MPN-SAF [TSS] at week 24—was set as a gold standard for response and symptom burden improvement. The problem is that this is not a very dynamic measure. That is coupled with the fact that patients who don't have even myelofibrosis [could] have symptoms [associated with the disease]. Lots of people can have fatigue for lots of different reasons, and it's not necessarily because they have myelofibrosis. Although a new therapy can certainly improve symptoms from myelofibrosis, [they’re still] human. [Therefore,] significant and large reductions in symptom burden may not be a realistic end point.

We must become more creative on how we measure improvement in quality of life as well as symptom burden. There are proposals to take a more dynamic look over time at symptom burden improvement. Another effort is looking at area under the curve of symptom burden improvement, which [may] capture symptom burden improvement in a better, more dynamic way. It's not so much that drugs are not effective at [improving symptom burden]; [it’s that] we have to come up with a better tool to measure it.

Secondly, we need to start using other key end points in our trials as primary end points. OS is at the top of the list. Event-free survival and duration of response are also important end points. Now that we have [multiple] JAK inhibitors and we're developing new therapies, we also have to develop these more advanced end points for our patients.

What are some potential combination strategies with JAK inhibitors coming down the pike in myelofibrosis?

The combination era is upon us. We have multiple trials that are either in phase 3 or are completed. [This includes] pelabresib [(CPI-0610) plus ruxolitinib] in the [phase 3] MANIFEST-2 trial [NCT04603495], which everyone has their eye on right now. It is in the follow-up phase, where patients have been enrolled onto the trial and the primary end points have passed. It was a positive trial for the primary end point of SVR24. We're looking closely at the long-term data because we want to see more patients [experience the] immediate benefit of SVR and symptom burden improvement, and we want to see a more durable responses and better outcomes with a combination. That will be a key end point as we follow this trial over the next year or 2.

[Single-agent] imetelstat [Rytelo] is in testing in a randomized phase 3 trial [NCT04576156]. Combinations with [imetelstat and] JAK inhibitors might be difficult due to their overlapping toxicities, but that [trial] is something else we have our eyes on. The MDM2 inhibitor navtemadlin has also entered the phase 3 [POIESIS] trial [NCT06479135], where [it is being evaluated as an add-on to ruxolitinib]. Selinexor [Xpovio], the XPORT-blocking molecule that's already FDA-approved for multiple myeloma, [is being evaluated in combination with ruxolitinib in the phase 3 SENTRY trial (NCT04562389)].

We're looking forward to even more innovative therapies, such as monoclonal antibodies that target 

 mutations, bispecific antibodies that do the same, and type II JAK inhibitors entering development.

What is your main message for colleagues regarding the future of myelofibrosis management?

First and foremost, we don't have to hang on to ruxolitinib to the bitter end. We can [continue treatment with ruxolitinib if] a patient is doing great, but if they're not optimized on ruxolitinib—meaning that their spleen is not shrinking, they're not feeling better, they're getting transfusions, and they're on a maximal dose of ruxolitinib—we need to think about an alternative JAK inhibitor because they are available and they're effective. The threshold to switch [therapies] is a lot lower than when we didn't have alternative agents. It's an exciting time, and I expect a lot of rapid change in the way we treat patients with myelofibrosis over the next 2 to 5 years.

Aaron Gerds, MD, discusses differences in molecular targets, efficacy, and toxicity profiles between available JAK inhibitors in myelofibrosis. 

Expanding JAK Inhibitor Arsenal Provides Additional Options Beyond Ruxolitinib in Myelofibrosis 

Dr Kuykendall on the Advantages of Treatment With Momelotinib in Myelofibrosis

“Momelotinib can do what other JAK inhibitors can do, which is improve splenomegaly and disease-related symptoms. Overall, it is well tolerated, too. However, momelotinib tends to—likely through its ability to inhibit ACVR1—lead to more available iron use, which can get rid of the anemia that goes along with myelofibrosis. That’s the advantage.”

Andrew Kuykendall, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, 

discusses the advantages of treatment with momelotinib

 (Ojjaara) over older-generation JAK inhibitors in myelofibrosis.

Momelotinib offers a unique advantage among JAK inhibitors by addressing both splenomegaly and disease-related symptoms while also improving anemia in patients with myelofibrosis, Kuykendall begins. Like other JAK inhibitors, it effectively reduces spleen volume and alleviates symptoms, but it stands out due to its favorable tolerability profile, with fewer gastrointestinal adverse effects compared with agents like pacritinib (Vonjo) and fedratinib (Inrebic).

The distinguishing feature of momelotinib is its ability to inhibit ACVR1, a key modulator of hepcidin, which is involved in iron metabolism. By suppressing hepcidin, momelotinib increases the availability of iron for erythropoiesis, thereby alleviating anemia, Kuykendall explains. Anemia affects nearly all patients with myelofibrosis during their disease course, and managing this condition without exacerbating it is a critical goal in treatment, he emphasizes. Decreasing anemia also reduces the need for blood transfusions, which can significantly enhance a patient’s quality of life by minimizing the burden of frequent blood work and transfusion-related health care visits, Kuykendall notes.

Although highly effective, standard ruxolitinib (Jakafi) is often associated with a decline in hemoglobin levels, particularly early in treatment, Kuykendall says, explaining that this can be problematic for patients presenting with baseline hemoglobin levels near the threshold for transfusion dependence. Starting these patients on ruxolitinib may increase the risk of requiring transfusions, which can negatively affect quality of life despite the drug’s efficacy in controlling splenomegaly and symptoms, he states.

Overall, momelotinib provides an effective alternative to other available agents in myelofibrosis, especially for patients at risk of or experiencing significant anemia, Kuykendall concludes.

Andrew Kuykendall, MD, discusses the advantages of treatment with momelotinib vs older-generation JAK inhibitors in myelofibrosis.

The clinical successes seen with JAK inhibitor monotherapy in patients with myelofibrosis have helped fuel the rationale for the development of JAK inhibitor–based combination regimens that may increase spleen volume reduction (SVR) and decrease symptom burden in this population, according to Andrew Kuykendall, MD.

Kuykendall highlighted how the evolution of data with momelotinib (Ojjaara) has informed the use of this agent. In the phase 3 SIMPLIFY-1 trial (NCT01969838), momelotinib was noninferior to ruxolitinib (Jakafi) regarding SVR of at least 35% at week 24 in patients with intermediate-to-high–risk myelofibrosis (n = 432; 

 In total, 26.5% of patients who received momelotinib achieved this outcome vs 29.0% of those who received ruxolitinib (noninferiority difference, 0.09; 95% CI, 0.02-0.16). However, noninferiority was not met for momelotinib vs ruxolitinib regarding a total symptom score (TSS) reduction of at least 50% (

= .98); these respective rates were 28.4% and 42.2% (noninferiority difference, 0.00; 95% CI, –0.08 to 0.08).

However, data from a subset of patients from SIMPLIFY-1, as well as from the phase 3 MOMENTUM trial (NCT04173494), supported the 2023 

 for the treatment of adult patients with intermediate- or high-risk myelofibrosis and anemia.

 In MOMENTUM, 25% of patients in the momelotinib arm achieved a Myelofibrosis Symptom Assessment Form v4.0 TSS reduction of at least 50% vs 9% of those in the danazol (Danocrine) arm (treatment difference, 16%; 95% CI, 6%-26%; 

“Taking all those data into account, you can understand where exactly [momelotinib] fits into the algorithm,” Kuykendall explained in an interview with 

In the interview, Kuykendall, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida, discussed the current role of JAK inhibitors in the treatment of patients with myelofibrosis, his clinical experience using momelotinib in his practice, and how the use of this class of agents may evolve in the future.

: What is your general algorithm for treating patients with myelofibrosis?

: Patients with myelofibrosis present in a variety of ways, and you have to try to individualize therapy for each patient. Patients with myelofibrosis [can] present with an incidental finding with relatively few symptoms, [such as] a spleen that is not enlarged and blood counts that look okay. You can observe those patients for some time. You might have to consider thrombotic risk reduction, especially in [patients with] 

-mutated disease. You might treat those patients like you would a patient with polycythemia vera or essential thrombocythemia with cytoreductive therapies, such as interferon or hydroxyurea. However, the minority of patients present like that.

Most patients present with some degree of symptoms. We can largely put those groups in 2 buckets, although there is considerable overlap between the 2 buckets. [One group is] patients who present with constitutional symptoms, [such as] fevers, chills, night sweats, bone pain, and weight loss, as well as splenomegaly, which could be causing its own symptoms in terms of abdominal discomfort and pain. In those patients, we have standard treatment with JAK inhibitors. We now have 4 approved JAK inhibitors: ruxolitinib, fedratinib [Inrebic], momelotinib, and pacritinib [Vonjo]. Those agents are good at improving disease-related symptoms, as well as symptomatic splenomegaly.

On the other hand, [other] patients have more anemia [as] their main issue, [which may require] transfusions or cause considerable fatigue or shortness of breath. For those patients, historically, we’ve used agents like erythropoiesis-stimulating agents [ESAs]. If the erythropoietin level is lower than 125 mU/mL, we can also use drugs like danazol; in the past, we’ve also used thalidomide or lenalidomide [Revlimid] as immunomodulatory drugs to help with that anemia. Interestingly, now we have 2 approved JAK inhibitors that may be able to help with anemia: momelotinib and pacritinib. Those are beginning to be used more in patients dealing with more anemia and thrombocytopenia. Luspatercept-aamt [Reblozyl] is also an interesting agent that is approved for myelodysplastic syndromes [MDS], but it has data in myelofibrosis as well.

However, in reality, when we’re thinking of anemia agents, oftentimes we’re looking at where the buckets [of patients] overlap. We’re looking at patients who have some degree of constitutional symptoms, splenomegaly, and anemia or thrombocytopenia. That group is where momelotinib and pacritinib make a ton of sense because they can reduce spleen size, improve disease-related symptoms, and not harm platelet counts or hemoglobin counts; [they may] even help those [counts stabilize or increase] to some degree.

How has momelotinib, the most recent JAK inhibitor to receive FDA approval for patients with myelofibrosis, been integrated into your practice?

[Momelotinib] is an agent we were anticipating having access to for a long time. It had a long development process that included multiple phase 3 trials. Ultimately, it got approved [for patients with myelofibrosis] in September 2023. We had already identified patients who were going to be appropriate for this therapy and were excited to start this therapy. When it finally got approved, it was easily incorporated into the practice.

Over the past year, we’ve better understood where exactly to fit this [agent into the myelofibrosis treatment paradigm]. Oftentimes, once we have access to agents, we get a feel for where they’re going to be useful in our practice. The label is broad for patients with myelofibrosis and anemia. It can be used regardless of the line of therapy. I’ve used it in the frontline setting in patients presenting with the need for transfusions and symptomatic splenomegaly or [other] symptoms. The second-line setting is where we’ve used it the most in patients who are currently receiving ruxolitinib but are dealing more with issues of anemia and maybe even needing to decrease their doses of ruxolitinib.

What advantages does momelotinib have over older-generation agents?

Momelotinib can do what other JAK inhibitors can do, which is improve splenomegaly and disease-related symptoms. Overall, it is well tolerated, too. It is not associated with a lot of the gastrointestinal [GI] adverse effects [AEs] that have been associated with pacritinib and fedratinib.

However, momelotinib tends to—likely through its ability to inhibit ACVR1—lead to more available iron use, which can get rid of the anemia that goes along with myelofibrosis. ACVR1 modulates hepcidin, and [if] we can do that, we can free up iron to be used to make more red blood cells. That’s the advantage [of momelotinib].

Anemia is a pervasive issue with myelofibrosis. Virtually every patient with myelofibrosis will have to deal with anemia at some point. Momelotinib will likely be a treatment option for most patients during the course of their disease, and you can leverage this agent hoping to get the same benefits in terms of SVR and symptoms without [worrying that you] might push a patient into needing a blood transfusion.

For all the successes with ruxolitinib, it is associated with anemia. We know that when we put patients on ruxolitinib, we’re likely going to see a decline in their hemoglobin levels, especially early on. In patients who present with hemoglobin levels of 7.5, 8.0, or 8.5 g/dL, there is concern that starting them on [ruxolitinib] might push them into a need to give them transfusions. That may negatively affect their quality of life [QOL] when you factor in the need to get blood work and transfusions done. Momelotinib [presents] a real opportunity to do something beneficial for these patients.

What data from the SIMPLIFY-1 and MOMENTUM trials support how you use momelotinib in clinical practice?

The SIMPLIFY-1 trial was ultimately a negative study, but it had positive results. This study was designed to enroll patients with myelofibrosis who had splenomegaly symptoms and had never [received] a JAK inhibitor. They were randomly assigned 1:1 to receive either ruxolitinib or momelotinib. [This trial compared] the 2 JAK inhibitors head-to-head and was designed as a noninferiority study.

Momelotinib was noninferior to ruxolitinib in terms of SVR. However, ruxolitinib outperformed momelotinib in its ability to improve symptoms. Momelotinib was also good at improving symptoms, just not to the same degree. Ruxolitinib seemed to have a bit of an edge over momelotinib in terms of symptom [improvement].

The caveat was that momelotinib had a favorable effect on patients with myelofibrosis in terms of anemia and need for transfusion. More patients who received ruxolitinib started requiring transfusions when they were receiving [treatment] than the number of patients who were receiving momelotinib. That caveat didn’t necessarily get factored into the evaluation of that study.

Although that [trial] did not lead to an approval, down the road, it led to the development of the MOMENTUM study, [which] was designed to take into account what was learned from SIMPLIFY-1. [MOMENTUM enrolled] patients who [had already received] ruxolitinib [and were] anemic. [This trial needed] to have patients with anemia because that is where momelotinib seems to be the most beneficial. [Patients needed] to have splenomegaly and symptoms, and then [investigators were] going to see how they did [with momelotinib].

[Did momelotinib improve] overall disease-related symptoms and QOL? The primary end point was TSS after 24 weeks. To evaluate that subjective end point, you need a blinded comparator arm, which was [patients who received] danazol. Momelotinib was superior to danazol in its ability to improve symptoms, [reduce] spleen [size], and [improve] transfusion status.

Overall, when you take into account [the available] agents [for patients with myelofibrosis, you may say that momelotinib] is a reasonable option as a frontline agent if you’re picking the right patient, [meaning] someone who’s anemic and likely to benefit from this agent. However, at the same time, [momelotinib is] an option for patients who have previously received ruxolitinib but are now dealing with anemia and still have [an enlarged] spleen and symptoms.

How do the AEs associated with JAK inhibitors tend to compound, and how can these AEs be mitigated?

You can break down the AEs associated with JAK inhibitors into hematologic AEs or nonhematologic AEs. From a nonhematologic AE profile, ruxolitinib is well tolerated with few nonhematologic AEs, especially in the short term. In the long term, [AEs include] weight gain, herpes zoster/shingles reactivation, and nonmelanoma skin cancers. We see those with more frequency, but those are more long-term AEs.

Fedratinib and pacritinib are often associated with more GI AEs, such as nausea, vomiting, and diarrhea. Some of those can be well mitigated with antiemetic therapy and antidiarrheals. Fedratinib [has a] black box warning for encephalopathy, including Wernicke encephalopathy, that happened in a small number of patients during development; therefore, you have to check thiamine levels. Pacritinib is associated with an increased risk of grade 3 or higher bleeding that was seen during its development as well, so that needs to be taken into account with its use.

Momelotinib, from a nonhematologic AE profile, [is associated with] mild GI AEs, [including] maybe a bit more nausea than we see with ruxolitinib. Otherwise, the GI AEs are comparable [with those seen with ruxolitinib]. During the development [of momelotinib], there were concerns with peripheral neuropathy, which we did not see as much of in MOMENTUM, but [this is an AE] to keep an eye on.

However, beyond those [nonhematologic AEs], the main [toxicities associated with] JAK inhibitors, especially the early-generation ones, are hematologic AEs. These tend to compound because [myelofibrosis is] a disease that [is associated with the same AEs]. In later stages of the disease, [patients are] likely to become anemic, require transfusions, and become thrombocytopenic. It’s challenging when you start a patient on an agent that’s there to help with spleen [size] and symptoms but tends to exacerbate some of the complications that come from the disease itself down the road.

One way to combat that with ruxolitinib is with alternative dosing strategies. There are studies investigating starting at lower doses and gradually increasing upward as tolerated. We can also consider adding agents with ruxolitinib. Lots of studies have evaluated adding ESAs, danazol, or luspatercept, which are agents that can support the anemia that may develop during treatment with ruxolitinib. Some of those combination studies haven’t been done with other agents, though you could argue that maybe [certain combinations] would still make sense if you’re using a different JAK inhibitor.

When we’re using JAK inhibitors and considering long-term therapy, we have to think about what we can do to assess and get rid of many treatment-related AEs because some of the AEs will come from the disease. [As we decrease doses] of ruxolitinib, its efficacy tends to wane. That’s where some of these newer JAK inhibitors may positively [decrease] anemia and thrombocytopenia. There may be a cut point where you say even though there is a benefit to some degree [with ruxolitinib], we’re losing that as we decrease the dose, and maybe we should switch to an alternative JAK inhibitor that we can fully dose that’s not going to cause as much anemia and thrombocytopenia.

You coauthored a paper in September 2024 outlining other plausible therapeutic targets and combination strategies with JAK inhibitors. Within that umbrella, what targets and combinations are most promising and why?

It’s hard to see a future that doesn’t include JAK inhibitors. They’re so effective at targeting the driver mutations—the 

 mutations—that give patients the disease. JAK inhibitors block that pathway. It’s hard to say that we’re going to come up with [an effective class of agents] that’s completely different from a JAK inhibitor. That’s why combination therapies make sense.

Our goal in managing this disease is to firstly provide more comprehensive control of the disease, either by delaying progression of the disease or getting the disease to go away altogether. There are [a few] ways we’re going to accomplish that. One, we’re going to come up with better targeted therapies, including better JAK inhibitors and maybe CALR- or MPL-directed therapies, that are directly targeting the driver mutations, which are the core of the disease, and doing so in a more potent fashion than we currently do.

Or we can understand that this is a complex disease. We can use the current JAK inhibitors, maybe improve upon them if we can, but also add a combination partner that’s going to [target] the other aspects of the disease that otherwise go somewhat ignored, or at least pushed off to the side. Often, patients don’t just have 1 mutation. They have mutations in 2 or 3 different genes. They’re having too much proliferation, and they’re also having dysfunctional blood cell production. Just treating those patients with a single agent isn’t going to be enough to meaningfully affect that disease; therefore we need to bring in something else.

I was excited about [findings with] pelabresib [CPI-0610], a BET inhibitor, and navitoclax [ABT-263], a BCL-XL inhibitor, that were presented at the 2023 ASH Annual Meeting. Both those agents showed that what we find preclinically can play out in clinical trials. Phase 3 trials showed that the addition of these agents [to ruxolitinib] doubled the spleen response. Spleen response is what dictates whether a drug gets approved. Single-agent ruxolitinib [has historically elicited] a spleen response [rate] of approximately 34% to 35%. When adding in pelabresib or navitoclax, those rates increased closer to approximately 65% to 66%.

Unfortunately, both of those agents were required by the FDA to also improve symptoms compared with single-agent [JAK inhibitors], and they didn’t do that as much as they needed to. Navitoclax came up a bit short in improving symptoms. Pelabresib improved symptoms when it was added to ruxolitinib but not to a statistically significant degree, so [the phase 3 MANIFEST-2 trial (NCT04603495)] missed that key secondary end point.

However, I’m still excited about those agents, and if not those specific agents, those pathways. There’s benefit to be had there. It’s on us now, as investigators in the field, to better define what it means to show benefit and measure success. Just showing SVR isn’t enough. It’s difficult to, on the fly, create and validate new end points.

In addition, as far as combination partners, one I’m excited about now is selinexor [Xpovio]. This XPO1 inhibitor showed exciting data in the frontline setting in earlier-phase studies. The phase 3 trials [with selinexor will] still run into the same problems, as far as end points go. Although this agent has been exciting early on, it has a bit of a murky future. Is it going to be judged to the same degree that pelabresib and navitoclax were judged?

I am also excited about imetelstat [Rytelo], which was 

 for patients with MDS who are anemic, low-to-intermediate risk, and require transfusions. However, in myelofibrosis, [imetelstat] might be disease modifying. I’m excited to see how [imetelstat] can be used in combination with ruxolitinib as we move forward.

There is a smattering of other agents that are there to help with anemia and maybe support the hemoglobin and transfusion requirements. Elritercept [KER-050] is being developed, and luspatercept is in ongoing development.

What is your main message for colleagues about JAK inhibitors in myelofibrosis that they should apply to their practice or research?

We have a long way to go. We have had some successes with JAK inhibitors, and we’ve now expanded the use of JAK inhibitors to most patients, including those who are cytopenic. However, we need to continue to move further. We need to figure out ways to modify the disease. The only way we’re going to do that is to enroll patients on clinical trials. That’s how we develop agents. That’s how we get these successes.

Work with your local academic centers and ask patients if they’re interested in being on clinical trials. We have clinical trials in the first-, second-, and third-line settings for patients who are anemic and thrombocytopenic. We have a lot of options.

Typically [in these trials], we’re adding another agent to a standard-of-care backbone. There’s little downside to patients going on some of these clinical trials because at worst, they get to meet with an expert in the field who’s going to give them education and talk to them a lot about the disease and go through it in depth with them. If patients go on one of these trials, usually they are receiving a backbone of ruxolitinib, which is a standard therapy, or another JAK inhibitor. Then what we’re trying to do is build upon that by adding an agent on top.

Consider clinical trials. Talk about them with patients. Create a working relationship with your local myeloproliferative neoplasm expert where you can talk to them about developments that are going on and share care of these patients. [Academic oncologists are] happy to help; we have a passion for this.

Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naïve patients with myelofibrosis. 

. 2017;35(34):3844-3850. doi:10.1200/JCO.2017.73.4418

Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed December 6, 2024. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia

Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. 

. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0

Andrew Kuykendall, MD, discusses the current role of JAK inhibitors in myelofibrosis and how the use of this class of agents may evolve.

Moving the Needle With JAK Inhibition in Myelofibrosis | Supplements and Featured Publications

Dr Harrison on Investigational JAK Inhibitor–Based Combinations in Myelofibrosis

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

Dr Gerds on Efficacy Data Supporting the Use of Momelotinib in Myelofibrosis With Anemia

Expanding JAK Inhibitor Arsenal Provides Additional Options Beyond Ruxolitinib in Myelofibrosis

Dr Kuykendall on the Advantages of Treatment With Momelotinib in Myelofibrosis

JAK Inhibitors Remain Central to Advancing Care in Myelofibrosis