Novel Agents May Enhance JAK Inhibitor Efficacy and Augment the Myelofibrosis Treatment Paradigm

Naseema Gangat, MBBS

The use of JAK inhibitors in patients with myelofibrosis requires careful consideration of patient characteristics and disease factors, and combination regimens comprising these agents and other targeted therapies have generated new questions about the optimal risk-benefit profile of myelofibrosis treatments, according to Naseema Gangat, MBBS.

“There are several clinical trials combining the JAK inhibitor ruxolitinib [Jakafi] with other agents that are undergoing phase 3 testing, which have not been conclusive, and we don’t know what the future of those drugs is,” Gangat said in an interview with OncLive^®.

In the interview, Gangat elaborated on the potential clinical significance of a phase 1 trial (NCT05936359) that is evaluating the CALR-directed monoclonal antibody INCA033989 as monotherapy and in combination with ruxolitinib in patients with myeloproliferative neoplasms, including myelofibrosis and essential thrombocythemia (ET).¹ This trial aims to identify the maximum tolerated dose and/or recommended dose for expansion of INCA033989, as well as determine the safety profile of the agent.

Gangat also discussed clinical factors that she uses to choose the optimal JAK inhibitors for individual patients with myelofibrosis, how JAK inhibitor–based combination regimens may affect the future of disease management, and tips for determining patient prognosis. In particular, she highlighted the ways that momelotinib (Ojjaara) has improved clinical practice since its 2023 FDA approval for the treatment of adult patients with intermediate- or high-risk myelofibrosis and anemia.² At the 2024 ASH Annual Meeting, a real-world, retrospective trial showed that among 45 evaluable patients with myelofibrosis who received the agent, 62.2% had an improvement in spleen size with a median reduction of 5 cm.³

Gangat is a professor of medicine and a consultant in hematology at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

OncLive: What does the overall myelofibrosis treatment paradigm look like?

Gangat: For myelofibrosis, several JAK inhibitors are approved. There are 4 [of these] drugs on the market. [Each of those agents has] advantages and disadvantages. Momelotinib affects anemia, spleen, and symptom management.

For the high-risk patients, [we still recommend considering] transplant. However, if a patient is not transplant eligible and in need of treatment, enrolling in clinical trials should be a priority. Otherwise, on the market, the treatment options are the 4 JAK inhibitors. Sequencing treatment with those JAK inhibitors and seeing which is better suited for the patient’s situation [is important].

What factors influence your decisions between the 4 FDA-approved JAK inhibitors for individual patients with myelofibrosis?

The whole patient situation has to be factored in because the toxicities associated with each of these agents are unique. Ruxolitinib has been on the market the longest—[it was initially approved in 2011]—and has the safest tolerability profile. It is not associated with much gastrointestinal [GI] toxicity. It’s an easy drug to tolerate, but it causes anemia. Anemia can [be a] hallmark feature of myelofibrosis in approximately one-third of patients, and as the [myelofibrosis] progresses, anemia becomes an even more prominent feature to the point [where patients] become transfusion [dependent]. That’s the downside of ruxolitinib, and that’s where the newer JAK inhibitors, pacritinib [Vonjo] and momelotinib, have a role.

Momelotinib can alleviate anemia in approximately 40% of patients, and it helps shrink the spleen and [alleviate] constitutional symptoms. It is associated with GI toxicity, and there can be peripheral neuropathy, so the patient’s medical history has to be put in perspective.

Fedratinib [Inrebic] is a JAK inhibitor that has been on the market for approximately 5 years but is used sparingly in my practice. It is similar to ruxolitinib in terms of spleen response and symptom response [rates]. It causes anemia, so it doesn’t have an advantage [over momelotinib], and it is associated with GI toxicity.

Pacritinib, on the other hand, is [FDA] approved for [patients with] myelofibrosis with platelet counts below 50 x 10⁹/L, so it has a bit of a niche [indication]. For example, if you have a patient whose platelet count is low and who is anemic, pacritinib may be considered, but it is also associated with diarrhea and [other] GI toxicities.

Ruxolitinib is usually the JAK inhibitor I go to in the first-line setting, unless the patient has anemia, [in which case you may choose] momelotinib. The other 2 [JAK inhibitors] fit [into the paradigm] depending on whether a patient has progressed on one and you want to pick another to see if they respond to that better. However, usually, if a patient’s splenomegaly is progressing on an optimized dose of ruxolitinib, it is difficult to get a spleen response by just switching the JAK inhibitor. Those situations require more of a drastic change in therapy than just switching from 1 agent to another within the same class of drugs.

How has the FDA approval of momelotinib for the treatment of patients with myelofibrosis and anemia affected how you use JAK inhibitors in myelofibrosis management?

With the approval of momelotinib, if there is an anemic patient or a patient with borderline hemoglobin [levels], for example 10 g/dL, who presents with myelofibrosis and requires treatment, momelotinib would be the better JAK inhibitor to go with, especially if they don’t have any other [symptoms] associated with [their disease] because [this agent is] more likely to preserve the hemoglobin [level] in these situations. If you [choose] ruxolitinib, sometimes it’s easier to [access] and maybe more financially feasible for the patient. [However, ruxolitinib] is likely to drop the hemoglobin [level], and the patient could be pushed to the transfusion range if they are starting with a borderline hemoglobin [level]. The approval of momelotinib gave us an agent that can target the 3 main problems that patients with myelofibrosis face, which are anemia, enlarged spleen, and constitutional symptoms.

What findings have been reported with JAK inhibitor–based combinations in myelofibrosis?

The new combinations have been exciting. Phase 3 studies have been completed with pelabresib [CPI-1610] plus ruxolitinib and navitoclax [ABT-263] plus ruxolitinib [in patients with JAK inhibitor–naive myelofibrosis]. Those studies showed much higher spleen responses [with the combinations compared with what has historically been seen with single-agent JAK inhibitors], but [those responses] came at the expense of toxicities. The toxicities were much higher with combinations, and the discontinuation rates were also high.

I don’t know if there will be further development of navitoclax [in myelofibrosis]. With pelabresib, we don’t know the latest update, [such as] whether it’s going to go further [toward] FDA approval. It generates a robust spleen response, but we don’t know at what cost, especially if it’s making the patients sicker.

In [the phase 2 MANIFEST trial (NCT02158858)], in terms of symptoms, [many] patients did not feel better, even though their spleens were shrunken. That tells you that [myelofibrosis is] not just about the spleen; it’s a multi-system disease with numerous manifestations. To make the patients feel better overall, there has to be more of a disease-modifying agent [in the treatment paradigm], and I don’t think the [JAK inhibitor–based] combination regimens [currently under investigation] have fulfilled that role.

What does the future look like for the myelofibrosis treatment armamentarium?

The future is exciting in the sense that there are several agents that patients have as treatment options. The combination therapies may have a role, for example, if a patient needs to be bridged to transplant and we need to shrink the spleen. Often, when patients’ [spleens do not shrink] with the available JAK inhibitors, we have to resort to splenectomy, which is a big surgery to get the big spleens removed, or spleen radiation. [JAK inhibitor–based combination regimens] may fill a void; if you can shrink the spleen in the pre-transplant setting, it may allow patients to [more easily] bridge to transplant.

New agents need to be explored. An exciting [phase 1] trial is going on with a CALR-directed antibody. Those [combinations] may have the potential for more disease modification than just BET inhibitors or BCL-XL inhibitors. The early data for the CALR [inhibitor] study are not reported yet. The trial is specifically for CALR-mutated myelofibrosis and patients with ET. It’s to be learned whether that [combination will] have more of an effect on the disease biology rather than just lower the [platelet] counts and help patients feel better.

How do you apply contemporary prognostic models for myelofibrosis in your practice?

Prognostic models can be complicated, specifically if they have many parameters and you have to use an online calculator when you’re busy. Usually, in my practice, I don’t look for the calculators.

It’s important to highlight some of the important genetic features of myelofibrosis. For example, if a patient has a type 1 CALR mutation, they are more likely to be in the low- or very low–risk category, particularly if they don’t have other high-risk mutations, such ASXL1, SRSF2, or U2AF1 Q157 mutations, and if they don’t have adverse clinical features. [Adverse] clinical features can be obvious, [and they include] severe anemia, constitutional symptoms, high white blood cell counts, and increasing circulating blast counts. [In the presence of those], you don’t have to go hunting for a calculator. If your patient does not have an adverse genetic profile and does not have any of those clinical features, their [disease is] going to be low- or very low–risk.

If they have adverse genetics, that pushes them into the intermediate- or high-risk category. Those are the patients you want to focus on for trial enrollment or early referral for allogeneic transplant. [Patients with] type 1 CALR mutations are in the genetically favorable group. The adverse [clinical features] category [includes patients with] ASXL1, SRSF2, and U2AF1 Q157 mutations.

Chromosomal status also needs to be looked into. Complex karyotype and chromosome 7 abnormalities [indicate a] very high–risk karyotype. That is the general schema of how to approach [determining a patient’s prognosis]. Clinical features are right there in front of you, and some salient genetic features can help you categorize [patients’ disease].

References

1. A Study to evaluate INCA033989 administered as a monotherapy or in combination with ruxolitinib in participants with myeloproliferative neoplasms. ClinicalTrials.gov. Updated December 10, 2024. Accessed January 7, 2025. https://clinicaltrials.gov/study/NCT05936359
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 January 7, 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. Perez-Lamas L, Diaz AS, Delgado RG, et al. Real-world outcomes of momelotinib as an alternative therapy to other JAK inhibitors in myelofibrosis patients with anemia. Blood. 2024;144(suppl 1):1790. 10.1182/blood-2024-200698