Challenges Remain, But Research Abounds in Polycythemia Vera and Myelofibrosis

David S. Snyder, MD

Treatment options for patients with polycythemia vera (PV) and myelofibrosis have remained stagnant within the past few years, but there have been novel agents moving through the pipeline, explained David S. Snyder, MD, adding that there is uncertainty whether any of them will replace the role of transplant.

For example, in August 2019, the FDA approved fedratinib (Inrebic) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-PV or post-essential thrombocythemia) myelofibrosis.

“This disease has a lot of unmet needs; there have been a number of drugs that were promising and trials were started. For different reasons, several of them had to be put on hold by the FDA—many for toxicity issues. Then, most of them have been recently resurrected and the trials have continued. It looks like some of them are coming to fruition,” said Snyder, an associate chair and professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope.

Moreover, Snyder added, transplantation continues to be the only chance at cure. However, physicians need to be careful when performing transplantation to ensure it is not being performed too soon or late in the disease course.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Snyder highlights agents currently undergoing clinical trials for PV and myelofibrosis as well as how to most effectively treat patients using transplantation.

OncLive: What is the current research surrounding PV?

Snyder: There haven't been a lot of innovations in PV treatment; low-dose aspirin and phlebotomy have been the mainstay of treatment for a long time. There are good data from studies demonstrating the value of low-dose aspirin and the value of being strict with phlebotomies to maintain a hematocrit level below 45% for men and 42% for women.

For people who are considered high risk and require additional cytoreductive therapy, hydroxyurea has been the gold standard. For some patients, interferon becomes a good option. Now, there is a pegylated interferon, which is better tolerated.

In Europe, there is ropeginterferon alfa-2b (PEG-Intron), which is longer-acting formulation; it is not yet approved in the United States. A trial was done and has been updated comparing ropeginterferon alfa-2b versus hydroxyurea [to see what] the right patient population that can tolerate it is. There is an advantage to the ropeginterferon arm; it definitely keeps control of the counts of hematocrit, and that helps protects people from risk of thrombosis. Additionally, more than hydroxyurea, [ropeginterferon] can have an impact on the molecular burden of the disease. That is expected to have more of an impact on the course of the disease, not just controlling symptoms and manifestations, but actually changing the biology of the disease.

There are studies that are combining some of these agents, such as ruxolitinib (Jakafi), which is approved as second-line therapy for PV after failure or intolerance to hydroxyurea. There are studies that are combining interferon plus ruxolitinib to see how beneficial that combination might be.

What research in myelofibrosis is being conducted?

With momelotinib, the main feature is it seems to preserve hemoglobin, [unlike] ruxolitinib. Trials were a little bit mixed in that regard, but that's going forward as well.

Pacritinib is an agent that seems to be platelet-sparing. That's one of the main limiting factors using ruxolitinib. You're not supposed to use it for people with platelets below 50,000, whereas pacritinib seems to be safe and effective for people with platelet counts at those levels. A phase II trial just completed and a phase III trial is [underway], which focuses on the patients who have very low platelet counts since that is an unmet need.

There have been other drugs. Imetelstat is a totally different type of agent; it's a telomerase inhibitor. There was initial excitement about it in the early studies. However, it's not the easiest drug to manage, mainly because of myelosuppression, but it is still being tested in clinical trials.

What are the clinical implications of the fedratinib approval?

It’s good to have more than one choice. Right now, ruxolitinib is the only JAK2 inhibitor that has the ability to impact some of the key clinical features, such as splenomegaly and constitutional symptoms. Those are its main benefits, but not all patients can tolerate it because of [the risk for] thrombocytopenia or the toxicities. Fedratinib has some novel features to it; it attacks the JAK2 protein in two different locations rather than one. It might, therefore, be more effective. It's good to have [another] choice.

My concern, as [someone who performs transplants], is we're all waiting to find the drug or combination of drugs that's going to be a game changer and take the place of transplantation. [We want] something analogous to the chronic myeloid leukemia (CML) arena where imatinib (Gleevec) and the other TKIs that came along revolutionized how we manage those diseases. We rarely do stem cell transplants for those diseases now, because the drugs they have are so effective. Everyone is hoping that there will be a similar approach for myelofibrosis, but it's going to be a more difficult task to accomplish.

Myelofibrosis is a more complicated disease than CML. The JAK2 inhibitors by themselves are not changing the biology of the disease, but there are a number of combinations that are being tested, including a JAK2 inhibitor plus a second partner. Perhaps one of those will pan out to synergize and make a difference.

Until then, we have transplantation, which is the only curative option in 2019 and will likely remain so for the coming years. It's important for more patients and physicians to be aware of what can be accomplished with a transplant, who should be considered as a candidate, and when patients should be offered this approach. We don't like to go too soon or too late when making a decision about transplantation.

Who is eligible for transplant and what is the ideal timing of this procedure?

Because we now use reduced-intensity conditioning regimens, [it is] safer to offer this approach to patients who are older and/or have other comorbidities. Now instead of going up to age 55 or 60, there's no absolute upper age. It's more of a physiologic age rather than a chronologic age. The majority of our patients with myelofibrosis are in their 60s or 70s.

We're improving prognostic scoring systems. We have Dynamic International Prognostic Scoring System (DIPSS) and DIPSS-plus. Now, there's Mutation-Enhanced International Prognostic Scoring System (MIPSS) and MIPSS-plus. They're trying to fine-tune the precision of prognostication using molecular markers, genetics, and clinical parameters to better stratify patients. We're still learning how to use these prognostic scoring systems, but that is going to aid in selecting who is at higher risk and if they should move toward a transplant sooner.

[Going to transplant] too soon for me is a patient who is functioning at a very high level. Their quality of life is very good; they're doing the things they need and want to do. We don't want to jeopardize those good years. Short of these prognostic scoring systems, the type of clinical parameters that are being used are increasing red cell transfusion requirements or increasing myeloblasts in the blood. It remains to be shown how useful the new prognostic scoring systems are.

[Going to transplant] too late, in my mind, is a patient who has transformed to acute leukemia. It's not that you cannot do a transplant, but it becomes more complex because you have to go through induction chemotherapy first, you have to get them into some type of remission back to the chronic stage, and the outcomes are not as good as the patients who have not progressed to acute leukemia.

Where should future research efforts in PV and myelofibrosis focus?

[We should] continue the work being done in understanding the biology of the disease, including figuring out what additional molecular mutations are important in the pathogenesis in the progression of the disease and perhaps finding other targetable markers besides JAK2. [Examples include] such as IDH1/2, but there are other markers as well. [Research should] find drugs that can target those types of markers directly and then perhaps use them synergistically with the JAK2 inhibitors; that is the direction [research] should go in. [We need to] find a combination of agents that target different pathways within the cell that are likely to synergize and have more of an impact on the biology of the disease—more than the JAK2 inhibitor by itself.

The other direction [of research] is in the field of transplantation, which is to continue to develop these prognostic scoring systems and allow us to be more precise in predicting who is likely to benefit—perhaps [this means] going to transplant earlier than you otherwise might think. Additionally, [we’re evaluating] who has high-risk features based on molecular markers to help predict their outcomes.

Lastly, [we need to] continue to improve the safety and efficacy of transplant. Graft-versus-host disease (GVHD) remains one of the major obstacles so the work that's being done to improve to prevent or treat that. Ironically, ruxolitinib has become one of our most effective agents in treating GVHD and was recently approved for that indication. We're doing studies at City of Hope to see if it can be effective prophylactically in the early post-transplant setting to prevent GVHD.