Mesa Discusses Next Steps in Myelofibrosis

Ruben Mesa, MD

The August 2019 FDA approval of fedratinib (Inrebic) for adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis was a solid advance for the field, said Ruben Mesa, MD.

“The key takeaway is now we have fedratinib approved as second-line therapy and in the frontline setting. That is an incremental increase now that we have a second drug available. There are probably patients on ruxolitinib who are having suboptimal responses, so considering them for second-line therapy is important,” said Mesa.

Fedratinib was explored in patients with myelofibrosis previously treated with ruxolitinib in the multicenter, single-arm phase II JAKARTA-2 trial. In the ITT population (n=97), the proportion of patients who exhibited a 35% or greater reduction in spleen volume at the end of cycle 6 was 31% (95% CI, 22-41). In addition, the proportion of patients who exhibited a 50% or greater symptom response rate was 27% (95% CI, 18-37) in the ITT population.

In an interview with OncLive, Mesa, director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discussed the latest advancements in the treatment paradigm for patients with myelofibrosis.

OncLive: What are the current upfront options for myelofibrosis?

Mesa: The current upfront options for myelofibrosis include ruxolitinib, which has been approved for several years as a JAK 1/2 inhibitor, and fedratinib, which is also approved in frontline therapy for its ability to improve splenomegaly and burden symptoms in patients with intermediate- to high-risk myelofibrosis.

What are the data we see with first-generation JAK inhibitors?

These agents in the frontline setting have shown the ability to improve splenomegaly and burden symptoms in patients with both intermediate- and advanced-risk diseases. Additionally, there is a benefit that we believe will likely extend to improvements in survival with less debilitation and long-term patients having an impact. Some of these benefits are also in terms of bone marrow histologic features of the disease and other subtle evidence of disease modification.

What are the treatment options after these JAK inhibitors?

After patients have failed a frontline JAK inhibitor, fedratinib is an option in the second-line setting. My colleagues and I have previously conducted a second-line trial of fedratinib for patients who have failed ruxolitinib called the JAKARTA-2 study. In this study, we observed that patients who failed ruxolitinib would have a significant benefit in splenomegaly and burden symptoms.

Recently, we did an updated analysis looking at a stringent criterion for defining what constitutes ruxolitinib failure and found that there is about one-third of patients who have a clear response in terms of splenomegaly and burden symptoms with fedratinib if they failed ruxolitinib.

What are the challenges of using these agents?

The challenge with JAK inhibitors is that they can lead to the development of cytopenias. We need to manage that with dosage and, sometimes, in terms of patients as they become used to the agents. Additionally, with fedratinib, we need to be mindful of monitoring for thiamine levels and thiamine replacement. This is not a barrier in terms of use but something we need to be mindful of based on a very rare likelihood of Wernicke's that has developed in the past in a small percentage of patients. It is also managing around some gastrointestinal (GI) adverse events, but they are usually well managed, and some patients do not have it at all.

Are there other therapies under investigation in this space?

There are multiple therapies under investigation as second-line therapies either to be used alone or in combination. Some of interest include a BET inhibitor, which is working on the pathways at a variety of different levels and is particularly helpful for patients with the ASXL1 mutation. There were some favorable data from the MANIFEST study showing that BET inhibitors alone or in combination could be helpful. There is even some data looking at using it in combination with JAK inhibition in the frontline setting.

Additionally, there is data of adding navitoclax along with ruxolitinib in patients having a suboptimal response. There were some favorable data from a phase II study [showing that a] LSD1 inhibitor had a benefit in the second-line setting. In addition, there are data with luspatercept trying to improve anemia which we also saw a benefit.

There are other agents in the pipeline. I myself participated with the National Cancer Institute—funded MPN Research Consortium where we have a variety of studies in this setting. There is one on AVID200 looking at TGF-ß. That is a phase I study so we are hopeful that it will be active.

What are the remaining challenges in treating myelofibrosis?

Many challenges remain. We have therapies that are active, but they are not curative. We looked to see how we can better deepen and lengthen the responses. We have largely been looking at single agents so what combinations will make an incremental benefit and how we measure those. We still do not fully understand why patients progress, but once we do understand that, we will be in a better situation to monitor any surrogate endpoints.

What combinations look the most promising?

The current time both the BET inhibitors and navitoclax combinations with ruxolitinib are very interesting. Certainly, the data we have shown a strong path moving forward, as well as the combination of luspatercept with ruxolitinib. In addition, there is a benefit in patients with more advanced disease moving toward acute leukemia that has been shown with ruxolitinib and hypomethylating therapy, such as decitabine or azacitidine, that both can be given together and are safely tolerated and have activity.

How do fedratinib and ruxolitinib compare with regard to toxicities?

Their toxicities are slightly different, with ruxolitinib we know that there is an increased risk with secondary skin cancers. There can be some degree of immunosuppression and rare immunocompromised infections, as well. For fedratinib, GI toxicities are probably more prevalent than they are with ruxolitinib and there is the issue of thymine.

What is the key takeaway from your presentation?

There are clinical trials available, but these drugs are more accessible for patients to be able to have second-line therapy now. There is also a tremendous amount of investigation and focus for these patients in terms of new therapies being developed and more therapies coming in the future.

I would also say that there are 2 other JAK inhibitors that are completing their rounds of testing that may become available in the future. Momelotinib, which may have differentiation around cytopenias and anemia, and pacritinib, which may be safe in patients with macrothrombocytopenia. I would love to see a situation where we have multiple agents available and tailor our therapies more appropriately in the frontline and second-line settings as it relates to JAK inhibition.

Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib (FEDR) in myelofibrosis (MF) patients previously treated with ruxolitinib (RUX): A reanalysis of the JAKARTA-2 study. J Clin Oncol. 37, 2019 (suppl; abstr 7057). doi: 10.1200/JCO.2019.37.15_suppl.7057