JAK Inhibitors Persist, While Novel Agents Aim for Disease Modification in Myelofibrosis

Despite the longstanding benefit afforded by JAK inhibitors, the next needed frontier in myelofibrosis research lies in developing therapies capable of extending survival and eradicating disease, according to Aaron Gerds, MD, MS.

“[The roles of the approved JAK inhibitors] do sort out in different ways, even though there are 4 of them, based on their mechanisms of action, the proposed targets they’re hitting, and the clinical trials that have been done,” Gerds said in an interview with OncLive® following a State of the Science Summit™ on hematologic malignancies, which he cochaired.

In the interview, Gerds discussed the distinct targets and clinical applications of each of the JAK inhibitors that are FDA approved for the treatment of patients with myelofibrosis, ongoing trials that aim to broaden metrics of treatment efficacy in this disease, and the need for disease-modifying drugs to improve upon previous successes in the treatment paradigm.

Gerds is an assistant professor in the Department of Medicine at the Case Western Reserve University School of Medicine in Cleveland, Ohio; the deputy associate director for clinical research and a member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center; and a physician in the Department of Hematology and Medical Oncology at Cleveland Clinic.

OncLive: How do each of the FDA-approved JAK inhibitors fit into the myelofibrosis treatment paradigm?

Gerds: We now have 4 FDA-approved JAK inhibitors available for the treatment of patients with myelofibrosis here in the United States.^1,2,3,4 You may ask yourself: Why do we have 4 JAK inhibitors? Why do we need multiple? But if you look at the mechanisms of action, it helps you understand why.

They all inhibit wild-type JAK2, and that anchors all of them. That’s what they do in similarity. But the other [targets] they inhibit separate them and help us begin to understand which populations of patients they may be most effective for.

For example, pacritinib [Vonjo] also inhibits ACVR1, which is important [for influencing] hepcidin [levels] and inflammatory anemia, and it also inhibits IRAK1, which is important in the pathobiology of myelodysplastic syndrome [MDS]. Pacritinib would be good for cytopenic myelofibrosis, particularly for patients with platelet counts less than 100,000 or less than 50,000 [platelets per µL].

Momelotinib [Ojjaara] is a JAK1/JAK2 inhibitor, just like ruxolitinib [Jakafi], but it also inhibits ACVR1, which is important in that hepcidin pathway. If we can lower hepcidin levels, we can alleviate anemia. Momelotinib makes sense in treating patients who need a JAK inhibitor who are also anemic and have hemoglobin levels less than 10 [g/dL].

Ruxolitinib is kind of [the JAK inhibitor] prototype. It inhibits JAK1, JAK2, and a few other molecules. It remains the standard of care for patients who have relatively preserved counts who need their spleens reduced, their symptoms improved, or who are maybe going on to transplant.

Both pacritinib and fedratinib [Inrebic] hit FLT3, which accounts for some of the adverse effects [associated with these agents]. We see gastrointestinal toxicity in particular, but they also may have some proliferative effects, as well antiproliferative effects. However, fedratinib has good second-line data from the phase 2 JAKARTA-2 trial [NCT01523171]. It can sit behind ruxolitinib [in the treatment sequence] and still regain spleen and symptom responses that were otherwise lost.

What ongoing research may further clarify where each of these JAK inhibitors fit best into the treatment sequence for patients with myelofibrosis?

There are several large studies ongoing in the myelofibrosis world that we’re eagerly awaiting initial or additional results from. At the top of the list right now is the randomized phase 3 [IMpactMF] trial [NCT04576156] of imetelstat [Rytelo] for the treatment of patients with myelofibrosis. The reason we’re all holding our breath for this trial is [that it] pits overall survival [OS] as the primary end point. That is a bold move, and a move that is needed in the field. The end points of spleen volume reduction and symptom burden response are important, but they’re not perfect end points. You can lower myelofibrosis-related symptoms, but you can’t make patients completely asymptomatic. It’s tricky to look at symptoms and symptom burden improvement, especially in the context where the comparator arm is a JAK inhibitor like ruxolitinib.

The imetelstat study is a randomized trial in the post-JAK inhibitor setting asking the question: Can imetelstat improve survival? You can’t get a cleaner question than that. The boldness of that study and that end point is why we’re all eagerly awaiting those results.

We are also looking forward to hearing the updates on the phase 3 INDEPENDENCE study [NCT04717414], primarily because the top-line results were released in a press release by the sponsor noting that the trial didn’t hit its primary end point, but that there may be some key secondary points it’s hitting on.⁵ Luspatercept-aamt [Reblozyl] is already FDA approved for the treatment of patients with anemia associated with MDS.⁶ The phase 2 [ACE-536-MF-001] trial [NCT03194542] in myelofibrosis [with anemia] showed responses [with luspatercept], and [the use of this agent in this population] is endorsed by the NCCN guidelines.^7,8

[INDEPENDENCE] was the phase 3 trial that was supposed to push that label and expand it to include myelofibrosis. But the question is: Without hitting its primary end point, can it still do that? Is there a path forward for that label expansion, and what key secondary end points were hit? Why didn’t we see that primary end point? We’re all ready to get into the details of the results.

There’s a randomized phase 3 trial with selinexor [Xpovio] that’s ongoing, as well as a randomized phase 3 trial with the MDM2 inhibitor navtemadlin [KRT-232]. Those results are going to be [reported] a little further out based on how the studies are accruing, but we’re eagerly awaiting them.

There’s also the ongoing analysis and follow-up of the phase 3 MANIFEST-2 trial [NCT04603495] of ruxolitinib vs ruxolitinib plus pelabresib [CPI-0610], a BET inhibitor. The initial results have been presented, and some follow-up results [have been shared] as well.^9,10 But given the fact that a large chunk of the patients had intermediate-1–risk disease on that study, important end points like event-free survival and OS may take more time to see. I credit the field. We’re being patient and riding this out to see whether those survival curves will eventually split, as we think they may based on the initial tangential results we saw with the early reports on that study.

What unmet needs persist within the MPN treatment field?

As it stands, in the field of MPNs, we have 4 JAK inhibitors that are FDA approved for the treatment of patients with myelofibrosis, but they fall short on disease modification. They do modify disease because they make patients’ lives better. Patients live longer when they receive JAK inhibitors vs when they do not. But these agents do not kill off myelofibrosis cells, reverse scar tissue, or bend survival curves to where they plateau. That’s what we’re looking for: therapies that take the survival curves and plateau them.

With JAK inhibitors, you see an improvement in the survival curves, but they continuously march toward 0. We want to see therapies that bend those curves significantly and root out disease. We have lots of therapies that improve symptoms, improve enlarged spleens, and improve anemia, but if we can root out disease, all those other [effects] will follow. That’s what we’re angling toward. That’s what all these new therapies that are in late-stage trials or early development are going for: How can we bend those survival curves more than we’ve done so far with JAK inhibitors?

References

1. FDA approves drug for adults with rare form of bone marrow disorder. FDA. Updated March 1, 2022. Accessed October 16, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-adults-rare-form-bone-marrow-disorder
2. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed October 16, 2025. 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. Jakafi. Prescribing information. Incyte; 2023. Accessed October 16, 2025. https://www.jakafi.com/jakafi-prescribing-information
4. FDA approves fedratinib for myelofibrosis. FDA. August 16, 2019. Accessed October 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis
5. Bristol Myers Squibb announces topline results from phase 3 INDEPENDENCE trial for Reblozyl (luspatercept-aamt) in adult patients with myelofibrosis-associated anemia. News release. Bristol Myers Squibb. July 18, 2025. Accessed October 16, 2025. https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Announces-Topline-Results-from-Phase-3-INDEPENDENCE-Trial-for-Reblozyl-luspatercept-aamt-in-Adult-Patients-with-Myelofibrosis-Associated-Anemia/default.aspx
6. US FDA approves Bristol Myers Squibb’s Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed October 16, 2025.
7. Gerds AT, Harrison C, Kiladjian JJ, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis. Blood Adv. 2024;8(17):4511-4522. doi:10.1182/bloodadvances.2024012939
8. NCCN. Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes, version 1.2026. Updated October 9, 2025. Accessed October 16, 2025. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf
9. Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus Kinase Inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Blood. 2023;142(suppl 1):628. doi:10.1182/blood-2023-179141
10. Mascarenhas JO, Grosicki S, Chraniuk D, et al. Updated results from the phase 3 Manifest-2 study of pelabresib in combination with ruxolitinib forJanus kinase inhibitor-naïve patients with myelofibrosis. Blood. 2024;144(suppl 1):3178. doi:10.1182/blood-2024-193193