JAK Inhibitor Safety Is at the Heart of Treatment Selection in Myelofibrosis

Jamile M. Shammo, MD

Pre-existing cytopenias are one of many factors that will influence the selection between the 4 JAK inhibitors holding indications from the FDA for the treatment of patients with myelofibrosis, according to Jamile M. Shammo, MD, who added that in addition to disease symptomatology, the target of each agent should be considered, as it can dictate the toxicity profile patients will face.

“Ruxolitinib [Jakafi] was the first JAK inhibitor that was made available [in myelofibrosis], so a lot of practitioners are comfortable with using this drug, its dosing, and what to expect in terms of adverse effects [AEs],” Shammo said in an interview with OncLive®. That’s not to say that we shouldn’t make ourselves comfortable with the 3 other JAK inhibitors that are also approved; they certainly have clear indications.”

Beyond ruxolitinib, the JAK inhibitors fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara) are approved by the FDA for the treatment of patients with myelofibrosis.1 Momelotinib was the latest JAK inhibitor to earn FDA approval; the agent was approved in September 2023 for the treatment of adult patients with intermediate- or high-risk myelofibrosis, including primary or secondary myelofibrosis, and anemia.2

In the interview, Shammo, the Dr. Marjorie C. Barnett - Dr. Hau C. Kwaan Professor and professor of medicine (hematology and oncology) at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois, discussed general treatment considerations in myelofibrosis, the role of JAK inhibitors in the space as it relates to their unique AEs, and the potential development of combination approaches in the future.

OncLive: What disease- and patient-specific characteristics influence your general approach for treating patients with myelofibrosis?

Shammo: Treatment for [patients with] myelofibrosis should start with the correct diagnosis; you have to ensure that the diagnosis is accurately vetted. After that, you start to [consider] risk stratification. Any physician who’s [treating] a patient with myelofibrosis must utilize some form of [a] risk stratification tool. This is important because you must identify those [patients] who may be transplant eligible because transplantation remains the only curative option, [even though] a low percentage of patients may be eligible for it [initially]. Nevertheless, it’s important to identify those patients.

After this broad stratification by transplant and risk features, we also need to understand [a few] things. What are the disease characteristics? Is this patient symptomatic? Is there anemia? Is there a worsening trend over a short period of time?

It’s important to understand the pace of disease the patient is dealing with and then assess if they have splenomegaly or other symptoms because your choice of therapy may be modeled according to the symptoms [that are present]. Finally, you must consider certain comorbidities that your patient might have. [For example], some patients may have cardiac disease [and in that case] the degree of tolerability to anemia may be different [compared with] someone who may not have this condition or someone we has kidney dysfunction. The choice of therapeutic agent may be influenced, and the dosing could also be different.

What are some of the differences between the available JAK inhibitors in terms of their safety profiles?

The current JAK inhibitors vary in terms of their targets. Some are JAK1/2 inhibitors, including ruxolitinib, and others have other targets such as FLT3 for fedratinib. [Regarding] pacritinib and momelotinib, in addition to their JAK2 inhibition, they have properties related to ACVR1 inhibition, which to some extent may be correlated with mild anemia or perhaps improvement in anemia when patients are treated with those 2 agents.

[The agents differ] not only in terms of targets, but also in terms of consequences, because some of the targets are linked to toxicities. Any time you have FLT3 inhibition, then you’re [considering] gastrointestinal toxicities. [Additionally], any JAK2 inhibitor can cause cytopenias, because the molecule JAK2 is important in hematopoiesis. If you inhibit JAK2 activity, then it’s a given that the patient will deal with hematological toxicity, but the gradation of hematological toxicity may vary from one [agent] to another.

For example, with pacritinib the degree of thrombocytopenia is presumably less than other JAK inhibitors. Hence, the FDA approval is in the subset of patients with a platelet count below 50,000/µL at the time of diagnosis. Similarly, momelotinib had been shown to induce less anemia in this patient population. Therefore, for a patient who has significant anemia, I might consider momelotinib as a starting point.

What pivotal clinical trial data guide your treatment approach for patients with myelofibrosis?

I [first] consider where the patient is [in the treatment sequence]. In the frontline setting, if they have a decent hematopoietic reserve and they’re not necessarily a patient with cytopenic myelofibrosis, it’s reasonable to consider ruxolitinib or fedratinib. The choice between the 2 [agents] depends on the practitioner’s comfort as to which first-line drug they might use.

In the second line, you have to evaluate the patient characteristics, [including] tolerability, degree of cytopenia, degree of splenomegaly, and the symptomatology that comes with the diagnosis before determining the next phase [of therapy]. [It’s important to note] that none of the second-generation JAK inhibitors have been compared. We don’t have comparative trials between pacritinib, momelotinib, or fedratinib. All we have are clinical trials comparing them with best available therapy or ruxolitinib in the first line. Essentially, you’re looking at choices, and all those choices are laid out for practitioners to decide what would be best utilized depending on the [patient and disease] characteristics.

In 2022, you coauthored a case study which showed that transfusion independence was achieved with fedratinib plus luspatercept-aamt (Reblozyl) in an older patient with heavily pretreated intermediate-2–risk primary myelofibrosis. How has your opinion of that approach changed as drug development in the space has evolved over the years?

Once in a while, an idea produces good results that ultimately go beyond the case report and get confirmed in larger clinical trials, and that was the case [here]. My choice of adding luspatercept for this patient who received fedratinibin the second line after responding to ruxolitinib for 3 years and then became transfusion dependent was to some extent influenced by the approval of luspatercept in patients with MDS [myelodysplastic syndrome] and the degree of transfusion independence that those patients achieved.

[This approach] made sense because of the mechanism of action of luspatercept and the modulation of cytokine mediation with this drug to add it to an agent that I know can control spleen volume. In fact, the combination worked beautifully. There were certain instances where we had to hold luspatercept dosing because the patient exceeded the 11 g[/dL of hemoglobin] that are prerequisite for receiving the next dose. [This approach] is very interesting, but we have to wait for the results of the phase 3 INDEPENDENCE trial [NCT04717414] comparing the ruxolitinib/luspatercept combination with ruxolitinib alone.

What’s interesting about the combination case report I wrote is that this patient received luspatercept sequentially. After [the patient] received fedratinib for afew weeks, we noted that transfusion dependency continued, then luspatercept was added. That speaks to how we should be thinking about combination therapies in the future. If you [administer therapy] sequentially, then you are comfortable with the AE profile of one drug, and then [when] you add the second drug, [the AEs] become a bit easier [to manage].

In the phase 2 ACE-536-MF-001 study [NCT03194542], [which included] patients who received ruxolitinib and those who were transfusion dependent, [we saw that] patients who are on a stable dose of ruxolitinib who were transfusion dependent had the best benefit from luspatercept. This essentially tells us that sequential therapy may be what helped those investigators administer the drug as needed. [Additionally], the efficacy of the agent itself in rendering those patients transfusion independent cannot be overlooked.

What does the future of drug development in myelofibrosis hold and are there opportunities to expand beyond JAK inhibitors and into novel agent classes or combinations?

Combination therapies seem to be the trend moving forward. Can we improve response rates with combinations vs single agents? But to me, there’s another dimension to it, in that while we are trying to get better response rates, we want to make sure that patients are capable of living with this combination therapy, to the extent that they have a reasonable quality of life, and their symptoms are adequately controlled.

[Data from] 2 clinical trials with the combination of ruxolitinib and navitoclax or pelabresib both demonstrated doubling of the spleen volume reduction compared with the single agent. But when it comes to total symptom score assessment, that’s where it became clear that you may have to sacrifice symptomatology for spleen volume response. I would [consider] this [approach] if I knew that those patients had a better survival signal with the combination, but we don’t have those data yet. Long-term follow up relative to survival will be important in that regard.

There are many other novel [approaches] that are being investigated, [such as] selinexor [Xpovio] in combination with ruxolitinib and MDM2 inhibitors looking at modulating TP53 in combination with ruxolitinib. What about interferon [therapy] and ruxolitinib? That’s just to mention a few; luspatercept combinations are interesting. The future [of combinations] is rather interesting. All of us in the MPN [myeloproliferative neoplasm] community are waiting for the results of the vaccine trials, because I believe they could be of great value to patients who have CALR expression in their MPN.

References

1. Thaw K, Harrison CN, Sriskandarajah P. JAK inhibitors for myelofibrosis: strengths and limitations. Curr Hematol Malig Rep. 2024;19(6):264-275. doi:10.1007/s11899-024-00744-9
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 April 17, 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