Anemia-Focused Treatment Approaches Represent Future Directions in Myelofibrosis

JAK inhibitor add-on agents may address an unmet need for patients with myelofibrosis with disease- or treatment-related myelofibrosis, according to Anna B. Halpern, MD, who noted that standard myelofibrosis treatments can cause adverse effects that interfere with patient quality of life (QOL).

“Myelofibrosis is generally a [relatively] rare disease,” Halpern said in an interview with OncLive^®. “Having a second opinion at a center that treats a lot of myelofibrosis and has much clinical trial availability is a great option for any patient, particularly if they have higher-risk disease features.”

In the interview, Halpern discussed strides in the treatment of myelofibrosis with anemia, the shifting role of ruxolitinib (Jakafi) in this disease, and the importance of providing patients with access to clinical trials, as they may benefit from investigational treatment approaches.

Halpern also highlighted the potential benefits of moving JAK inhibitors to the upfront setting, as evidenced in cohort 3 of the phase 2 REFINE trial (NCT03222609), in which navitoclax plus ruxolitinib generated a spleen volume reduction of at least 35% (SVR35) at week 24 in subgroups of patients with JAK inhibitor–naïve myelofibrosis with historically poor prognoses, including patients at least 75 years of age (SVR35, 50%), those with a high Dynamic International Prognostic Scoring System score (SVR35, 33%), and those with HMR mutations (SVR35, 47%).¹ Furthermore, she explained clinical outcomes with ruxolitinib plus pelabresib (CPI-0610) in the phase 1/2 MANIFEST trial (NCT02158858), which showed that the combination elicited an SVR35 at 24 weeks in 68% of patients with JAK inhibitor–naïve disease.²

Halpern is a physician and an assistant professor in the Clinical Research Division at Fred Hutchinson Cancer Center, as well as an assistant professor of hematology at the University of Washington School of Medicine, both in Seattle.

OncLive: How does the mechanism of action of JAK-STAT inhibitors like momelotinib contribute to their potential to ameliorate disease-related anemia?

Halpern: Disease-related anemia is partially mediated through the hepcidin pathway. JAK-STAT signaling drives overproduction of inflammatory cytokines, leading to elevated hepcidin dysregulated iron metabolism. Through the inhibition of JAK-STAT signaling, JAK inhibitors have the potential to intervene in this pathway and improve anemia.

How does the clinical benefit seen with momelotinib compare with that seen with standard agents like ruxolitinib and danazol in the anemic myelofibrosis setting?

In a study that compared momelotinib with ruxolitinib in the upfront or JAK inhibitor–naïve setting, momelotinib was better than ruxolitinib at improving anemia-related outcomes, [such as] improving or decreasing transfusion dependence, increasing transfusion independence at week 24, and decreasing the need for red blood cells. Ruxolitinib was probably better for controlling symptoms, and [the agents] were generally similarly [effective] at controlling spleen [size].

Regarding the comparison [of momelotinib] with danazol, the phase 3 MOMENTUM trial [NCT04173494] was a randomized trial of momelotinib vs danazol. This was for patients who had previously been treated with a JAK inhibitor. [In this trial], momelotinib was superior to danazol in multiple outcomes, including symptom response score, at 25% vs 9% respectively, spleen response, at 23% vs 3% respectively, and transfusion independence, at 40% vs 13%, respectively. Overall, momelotinib probably has several advantages compared with danazol.

What unmet needs exist for patients with myelofibrosis, and what should be done to address these?

One of the biggest unmet needs I see often in clinic is anemia. [Anemia occurs] both because of disease and because it’s a treatment-emergent effect with some JAK inhibitors. Ruxolitinib primarily interferes with erythropoietin signaling in the JAK-STAT pathway, which is essential for erythropoiesis. We see anemia, both because of disease and ruxolitinib, that is challenging to treat. This is a big unmet need, particularly as anemia is correlated with QOL. It’s not the only aspect correlated with QOL in patients with myelofibrosis. Their inflammatory and cytokine profile, which JAK inhibitors can control, is also important. [Anemia is] just 1 component.

Another big unmet need is treating high-risk disease and preventing progression of disease and leukemic progression. That’s a big issue because we’re not yet sure whether our therapies are disease modifying.

What efforts are being made to move ruxolitinib and navitoclax to the frontline setting?

At the 2022 ASH Annual Meeting and Exposition, many exciting therapies in myelofibrosis, both standalone and JAK inhibitor add-ons, were presented. The data we saw at ASH with navitoclax were encouraging. An arm in the REFINE trial [investigated] ruxolitinib and navitoclax in a JAK inhibitor–naïve cohort. This study was interesting because we saw changes in bone marrow fibrosis as well as reduction in the variant allele frequency [VAF] of the driver gene mutation in many patients. Those outcomes are particularly of interest because they have the potential to be biomarkers for disease modification or the disease-modifying ability of this drug combination.

It’s hard to study whether the longer-term outcomes are correlates for leukemia, progression, and survival, so we need [outcomes] in the shorter term to study. The 2 candidates of bone marrow fibrosis and VAF are strong. We’ll look forward to larger trials with these [agents] in the upfront setting.

What did the MANIFEST trial reveal about the efficacy and clinical significance of pelabresib plus ruxolitinib?

The MANIFEST trial [investigated] the BET inhibitor pelabresib plus ruxolitinib. There were multiple arms, [including a] JAK inhibitor–naïve cohort, an upfront treatment arm. We saw a good reduction in spleen volume, as well as symptom score. Considering the outcomes that may correlate with disease modification, improvement in bone marrow fibrosis and reduction in VAF, we saw that 28% of patients had 1 or greater grade 1 improvement in fibrosis, and 29.5% had an over 25% reduction in the JAK2 V617F VAF. This is promising for this combination. Now, the randomized, double-blind, phase 3 MANIFEST-2 trial [NCT04603495] is evaluating this combination in the upfront setting in a larger cohort.

What new JAK inhibitor add-ons coming down the pike in myelofibrosis are you excited to see?

It’s hard to know. We have a lot of data in phase 2 trials investigating different cohorts of different patients. In oncology, sometimes we can have many promising data in phase 1 and 2 trials, but those do not always bear fruit or come out as clearly in randomized phase 3 trials. It’s hard to compare the results of these trials, even though they have similar eligibility criteria and outcomes. I will need to wait for the phase 3 trials to know how these drugs will go.

What is your main message for colleagues regarding emerging therapies in myelofibrosis?

We have had several new drugs approved for myelofibrosis in the past few years, which is wonderful. We always like to have many treatment options for patients. However, we have much room to go. If possible, referring patients early on to our center or other centers that have many clinical trials for myelofibrosis is wonderful. That way, they have access both to standards of care and treatments coming down the pipeline. We can help study whether these treatments will improve unmet needs and help modify the natural history of this disease, which is our goal. Referral to us, even just for a second opinion, [is important], so we can help guide treatment and think about [whether patients are] eligible for any of these clinical trials.

What ongoing myelofibrosis clinical trials at Fred Hutchinson Cancer Center are you excited about?

DISC-0974 is in an early-phase trial [NCT05320198]. We don’t have any data yet. However, this trial is open at our center, and it’s interesting. DISC-0974 is a first-in-class anti-HJV monoclonal antibody that is a key regulator of hepcidin production in humans. This is a monthly subcutaneous injection for only 6 injections, and it prevents signaling in the HJV pathway, which results in suppressed hepcidin and improved erythropoiesis. This is [a particular focus in the] issue of anemia in myelofibrosis. This is an add-on agent to a patient’s ruxolitinib, JAK inhibitor, or hydroxyurea. They stay on their baseline treatment, and we add this on for anemia.

These drugs that are [being investigated] and targeting the hepcidin pathway, both in this disease as well as in other myeloid neoplasms, like myelodysplastic syndrome, are exciting. I’m hopeful that this different mechanism of action with non-overlapping toxicities with traditional JAK inhibitors could be an interesting treatment approach for anemia. This trial is currently open, so we are happy to see any patients with anemia on their current therapies.

References

1. Passamonti F, Foran JM, Tandra A, et al. The combination of navitoclax and ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis mediates responses suggestive of disease modification. Blood. 2022;140(suppl 1):583-585. doi:10.1182/blood-2022-157949
2. Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MANIFEST: pelabresib in combination with ruxolitinib for janus kinase inhibitor treatment-naïve myelofibrosis. J Clin Oncol. Published online March 7, 2023. doi:10.1200/JCO.22.01972