MPN Armamentarium Continues to Evolve Amid Expanding Pipeline

As the treatment landscape of myeloproliferative neoplasms (MPNs) continues to evolve, so too will the ability to optimize available agents in polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis, explained Ruben A. Mesa, MD, FACP.

“It is a very exciting time [to treat MPNs] as we have evolved dramatically from how we used to manage these diseases,” said Mesa. “We are working toward optimizing phlebotomy, providing adequate aspirin therapy, and perhaps moving interferon earlier on in treatment. These are all very relevant [topics]. We clearly have the pipeline for the future but trying to get everyone up to speed on the drugs that we have access to today is a key focus.”

In an interview with OncLive^® during the Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Mesa, director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discussed the current state of treatment in ET and PV, the underutilization of fedratinib (Inrebic) in myelofibrosis, and emerging JAK inhibitors on the horizon.

OncLive: What is the current state of treatment for patients with MPNs?

Mesa: I would put patients with MPNs into 2 different groups. There is early disease with ET and PV, where our management is still focused on trying to decrease the risk of thrombosis and bleeding. The use of aspirin, selective use of phlebotomy in PV, and certainly, cytoreduction with an interplay of hydroxyurea, pegylated interferon, JAK inhibitors such as ruxolitinib (Jakafi), and other agents depending on the scenario [are all management strategies].

The second group of patients are those with myelofibrosis. These patients have a more life-threatening MPN and tend to have a higher burden of disease with splenomegaly, symptoms, and cytopenia. They also have a much [higher] risk of disease-related mortality. There is a balance between timing of stem cell transplantation and medical therapy. We now have 2 approved therapies, ruxolitinib and fedratinib, with several other JAK inhibitors in the pipeline such as momelotinib and pacritinib. Other exciting new therapies and combinations are forthcoming as well.

Could you discuss the status of momelotinib and pacritinib?

We currently have ruxolitinib and fedratinib, which are both approved in the frontline setting. Fedratinib has good data to support its use in the second-line setting. Both agents can improve splenomegaly and symptoms, and they are likely to have a positive impact on survival.

Yet we know that there are still unmet gaps. There are some important, potential differences [between ruxolitinib and fedratinib] and the JAK inhibitors that are still in development.

Momelotinib has been shown to potentially improve anemia in addition to splenomegaly and symptoms. We have done a variety of analyses on the studies that have been done thus far with momelotinib, and it appears that this agent may inhibit hepcidin, a potential driver of anemia. Inhibiting hepcidin may be part of the reason we have seen improvements in anemia with momelotinib.

Further studies are currently ongoing [evaluating] momelotinib as a second-line therapy compared with danazol (Danocrine) as control in terms of improving anemia, splenomegaly, and symptoms in patients with myelofibrosis.

Pacritinib is a JAK2/FLT3 inhibitor that has shown [efficacy] in patients with marked thrombocytopenia from the early days of its testing. That is important because thrombocytopenia is frequently a dose-limiting toxicity of ruxolitinib, fedratinib, and other JAK inhibitors.

The ongoing PACIFICA study is trying to complete the regulatory experience with pacritinib for an indication that would likely include patients who have marked thrombocytopenia with myelofibrosis.

What are your thoughts on potentially rechallenging patients with ruxolitinib?

Laboratory data suggest a pause in JAK inhibitor therapy followed by rechallenging therapy may yield some clinical benefits or re-response. Anecdotal data from Cleveland Clinic and others have also shown there can be some benefit.

When an individual does not have the ability to participate in a clinical trial or does not have access to fedratinib, such as patients who are overseas where fedratinib may not be available, [rechallenging with ruxolitinib] is not an unreasonable consideration.

However, one would need to be mindful of the circumstance. Has the patient truly progressed? If they have, rechallenging with ruxolitinib is probably less likely to be beneficial. What was the quality of their response? Were they refractory [to ruxolitinib]? It is probably more likely to see a response in a patient who originally derived a great response and then lost it versus a patient who did not have a great response to begin with. Are you trying to recapture a response? It’s likely to be [a more helpful strategy] for a patient who has relapsed as opposed to a patient who is refractory.

I would strongly recommend fedratinib as second-line therapy for individuals who have access to it. Fedratinib has been underutilized in our community setting, but, being a different agent, it may have a higher likelihood of response. We have previously published on the experience [with fedratinib] from the JAKARTA 2 study that further supports that rationale.

What are the differences between ruxolitinib and fedratinib? What factors do you consider when selecting between the JAK inhibitors in the frontline setting?

Fedratinib is approved in the frontline setting. The drugs were tested in parallel. Ruxolitinib has been on the market for a much longer period of time, so I think there is a much greater comfort level [with ruxolitinib] compared with fedratinib. Fedratinib is included in the National Comprehensive Cancer Network guidelines, however, particularly for patients with intermediate2- to high-risk disease.

The reason for that difference is that patients with symptomatic low- and intermediate1-risk myelofibrosis are considered [appropriate for] ruxolitinib. There are no data yet in those groups with fedratinib.

Both agents are JAK2 inhibitors. As with any kinase inhibitor, they each have their own unique profiles. Fedratinib was tested at full dose for patients with a platelet count between 50,000/mL and 100,000/mL. We’ve published data on that, and it may be a group to consider fedratinib for in the frontline setting.

Would you highlight any data that came out of the 2020 ASCO Virtual Scientific Program and the 2020 European Hematology Association (EHA) Congress in MPNs?

There was a very interesting late-breaking abstract on treating low-risk patients with PV with pegylated interferon alpha versus phlebotomy alone with less events and better disease control. That is an ongoing study that has the potential to change disease management.

In terms of myelofibrosis, important data regarding the BET inhibitor [CPI-0610] either with ruxolitinib in the frontline or second-line setting may further set up some phase 3 clinical trials. Exciting data with navitoclax, added to therapy in patients who had suboptimal responses to ruxolitinib, and bomedemstat (IMG-7289), an LSD1 inhibitor added to therapy in the second-line setting in myelofibrosis, were also presented at the 2020 EHA Congress.

What challenges remain in MPNs that future research efforts should aim to address?

Progression in MPNs is quite challenging. We have increasingly had more active primary therapies, yet we have not achieved a state of remission or cure with medical intervention. We have a way to go in terms of improving efficacy. We are getting better at controlling [disease], but not curing or fundamentally achieving a minimal residual disease state. So, we still have some biological lessons to learn in terms of understanding drivers of progression and how we can further help to avoid disease progression in MPNs. We will learn much by [understanding] the mechanisms of action and [evaluating] combination therapies moving forward.

What is your take-home message to your colleagues?

The field of MPNs is a rapidly evolving space. Even our management of ET and PV is evolving. We just saw a study published in Blood that showed that using aspirin twice a day for patients with ET is probably more effective than once a day. So, our most basic therapies [are evolving].

In myelofibrosis, I’d like to highlight the important role data regarding fedratinib as we are still becoming familiar with the drug. Given that fedratinib is an option for prescribing physicians to give to patients with myelofibrosis who have suboptimal responses to ruxolitinib, it is very important to get caught up on the data with fedratinib.