JAK Inhibitors Remain Central to Advancing Care in Myelofibrosis

Andrew Kuykendall, MD

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; P = .011).¹ 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% (P = .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 FDA approval of momelotinib for the treatment of adult patients with intermediate- or high-risk myelofibrosis and anemia.² 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%; P < .01).³

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

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.

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

Kuykendall: 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] JAK2-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 JAK, CALR, and MPL 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 FDA approved [in June 2024] 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.

References

1. 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. J Clin Oncol. 2017;35(34):3844-3850. doi:10.1200/JCO.2017.73.4418
2. 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
3. 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. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0