Expanding JAK Inhibitor Arsenal Provides Additional Options Beyond Ruxolitinib in Myelofibrosis

Aaron Gerds, MD

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.”

In an interview with OncLive^®, 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.

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

Gerds: 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 FLT3; 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 × 10⁹/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 CALR 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.